TRAILBLAZINGSYNTHETICTHE
FUTURE WITH
CHEMISTRYEMERGINGRESEARCH
BIOMATERIALSTRENDS REPORT

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Project Team
Project Planning

Publicity and Promotion:

Westlake University: Yigong Shi, Jiaxing Huang

CAS: Caroline Ma, Jinying Zhang, Peter Carlton,
Peter Jap, Tina Tomeo, Erica Brown, Chris Cotton

CAS, a division of the American Chemical Society:
Manuel Guzman, Gilles Georges, Michael Dennis,
Craig Stephens, Dennis McCullough, Dawn Riedel,Dawn George, Caroline Ma
Research & Analysis
Westlake University: Yutao Zhan, Xinning Wang,
Wen Xiao
CAS: Angela Zhou, Kevin Hughes, Chia-Wei Hsu,
Rumiana Tenchov, Julian Ivanov, Yi Deng, Eva
Nesbit, Robert Bird, Janet Sasso, Leilani Lotti Diaz

Project Management:
Westlake University: Yutao Zhan, Xinning Wang
CAS: Sunny Yu, Li Zheng, Jennifer Sexton,
Christopher Barbosky, Dharmini Patel,
Sabrina Lewis
Consultants
Westlake University: Jianjun Cheng, Bowen Zhu,
Chengchen Guo, Huaimin Wang, Lei Wang,
Yue Zhang

ACS International India Pvt. Ltd: Kavita Iyer,
Krittika Ralhan, Magesh Ganesan, Saswata
Banerjee, Ankush Maind

Acknowledgements
This report has also received contribution from Menghua Gao, Yuan Yao, Ran Jin and Zijie Yang of Westlake
University and others. We would like to express our heartfelt thanks to all the help!

Table of Contents
Synopsis··········································································································································································2I.

Introduction·························································································································································3II.

Antibacterial Materials··································································································································6III. Lipid-Based Materials·································································································································29
IV. Bioinks·······························································································································································52
V.

Programmable materials····························································································································75

VI. Protein-Based Materials···························································································································100VII. Self-Healing materials·······························································································································120
VIII. Bioelectronic Materials······························································································································143
IX. Sustainable Materials for Biomedical Applications ···········································································169
X. Conclusions····················································································································································194
XI. Methods·························································································································································197

Trailblazing
thethefuturewithemerging
biomaterials| 1| 1
Trailblazing
futurewithemerging
biomaterials

Synopsis
Health stands as the bedrock of human existence and the linchpin for a high-quality life, therefore
research in this area represents a vital global aspiration for a healthier future. Yet, the evolving societal
landscape and environmental shifts have ushered in diverse health challenges. Issues such as the rapidtransmission of infectious diseases like COVID-19 and environmental pollution pose significant threats
to human well-being. Modern lifestyles further elevate the risks of chronic diseases and mental healthconcerns. Confronting these shared health challenges has become an urgent global imperative.
Materials silently influence our quality of life, continually enhancing human health, from commonplaceconsumer goods to intricate medical devices and surgical materials. Materials science, through its
involvement in cutting-edge medical equipment, improved drug delivery systems, innovative diagnostic
tools, and the development of intelligent monitoring and sustainable materials, emerges as a key element
in improving human health. Strides in material science have become pivotal in propelling advancements inhealthcare, and the future augmentation of human health will increasingly hinge on progress in materials
science. Ongoing fundamental research and the application of novel materials are not only steering
the future trajectory of the health industry but also shaping the industries of the future, catalyzing theformation of transformative productive forces.
This report is a collaborative effort between Westlake University and CAS, a division of the American
Chemical Society. Together, teams from these two organizations delved into the dynamic landscape ofthe future development of materials used in biomedical applications. Westlake University focuses on
cutting-edge scientific research, dedicates itself to breakthroughs in advanced technology, emphasizes
interdisciplinary collaboration, and consistently places the promotion of human health and well-being as
one of its core missions. CAS, with its diverse reservoir of expert scientific knowledge, extensive collectionof indexed content, and state-of-the-art data analytics capabilities, stands as a singular hub uniquely
positioned to generate panoramic insights into scientific trends. These two organizations have collaborated
to explore the role of materials to address the challenges confronting human health, with the goals of
unraveling future trends in materials development to provide foresight for pertinent scientific research andindustrial advancement, and to spark profound discussions and facilitate extensive exchanges within thescientific, industrial, and investment community, contributing to build a healthy future together.

I. Introduction
Over the past two decades, the realm of
biomaterials has undergone a surge in researchand development. These materials, which aredesigned to interact with the human body to
perform therapeutic and diagnostic functions,hold the promise of revolutionizing the landscapeof healthcare. In this report, you will find materials
that allow antitumor drugs to target tumor cells,
then release drug payloads; materials that canheal themselves autonomously after being cut
or sheared; implantable devices that are safely
absorbed by the body over time; and conductive,
soft, stretchable composite materials that are used
to make two-way electrical interfaces bridging
dynamic human tissue and precision electronics.
This report’s unprecedented level of detail andexpansive scope is made possible through adynamic fusion of interdisciplinary expertise atWestlake University and CAS, coupled with the
CAS Content CollectionTM, the largest humancurated collection of scientific data in the word.
This database, housing nearly 60 million journaland patent records across chemistry, biomedicine,materials science, and more, has been analyzed
by specialists to unveil the substances, chemical
reactions, and scientific concepts discussed ineach.
The eight emerging research areas in this reportwere identified using the approach described in
the Methods section as a representation of themost active and fast-growing fields of biomaterials
research (where a field is often signified by its
most prominent feature, where the feature may
be a specific material type, application, or function).
The selection of these fields was the result of aseamlessly integrated research process among data
scientists and biomaterial scientists. This process
involved utilizing cutting-edge natural language
processing methods, with iterative adjustment andrefinement by biomaterial scientists, to identify
emerging research areas. The report has also
undergone multiple peer review cycles, ensuringthat each revelation within it stands as a pinnacle ofscientific rigor.
In this report, each research area has its own
chapter and begins by recent publication trends,
with information including:– Comparison of the growth of journaland patent publications as an indicatorof research, development, andcommercialization interest in the field.
– Leading research institutions for journal
publications.
– Leading patent assignees and theirgeographical distribution.
– Time trends in patent publications broken
down by geography.
– Chronological flow of filing initial patentapplications within patent families, leading
eventually to individual patent publicationsin national patent offices.
Next, the materials used in each of the topic areas
and their key applications are presented anddiscussed. Throughout this discussion, examples
from literature are provided to illustrate prominent
trends. Most chapters also include additional
data to address topics that were found to be
especially relevant for that chapter. (The chapter
on self-healing materials, for example, contains a
breakdown of the chemical mechanisms used toprovide self-healing properties.)
To highlight recent examples of innovative
biomaterials research, each chapter includes
tables of notable journal articles and patentpublications from 2018-2023. These examples
represent the range of materials identified
through data analysis, and were selected based onjournal impact factor, number of citations, and theassignee (for patents). Finally, the most difficult
challenges facing each topic are identified.
The report has yielded a series of fascinating
insights, exploring the ongoing innovation andevolution in the field of biomaterials. Some of the
topic areas, for example protein-based materials,
have been well known to science for more than 20
years, but have shown continued research interestin recent years. Others, like bioinks, are relatively
new fields of research that have undergone rapid
expansion, with the majority of research having
been published in the past 5 years. In at least
two areas, lipid-based materials and sustainablebiomaterials, research interest has increased
significantly due to the use of these materials in
the response to the COVID-19 pandemic.1, 2

Trailblazing the future with emerging biomaterials | 3

The diversification in biomaterial researchencompasses both applications and thesubstances used in them. A representative listof substances that appear in this report includes
naturally-derived polymers, such as silk, chitosan,
and DNA, chemically modified naturally-derived
polymers, stem cells, synthetic polymers including
PEDOT:PSS, metals, alloys, and nanoscalematerials such as carbon nanotubes. In addition,a strong trend in many of the topic areas is
combining individual substances to make highly
engineered composites or hybrid materials thatcan perform complex functions, while maintaining
biocompatibility.
Notable applications that appear throughout
the eight chapters include drug delivery, woundhealing, tissue engineering, implantable devices,and sensors, among others. A significant
fraction of the research efforts in biomaterials
today involves combining or modifying existingmaterials, or discovering new materials, to achieve
improved performance for these applications,with the goal of developing them to the point ofclinical use.

The materials used in these applications canhave several synergistic properties. For example,
drug delivery materials can possess both theability to self-heal, preserving their physical form
after placement inside the body, combined witha stimulus-response profile that triggers therelease of a drug payload at a specific location,such as tumor or infection sites. 3 Multi-functional
biomaterials can also cross between application
areas, such as self-healing antimicrobial materials
developed for wound healing.4, 5Overall, this report aims to provide a thoroughoverview of the rapidly advancing field ofbiomaterials research, including insightful
guidance on the expected future research
trajectories in this field. Additionally, we aspire forthe information contained herein to serve as avaluable resource for professionals involved in thedevelopment and commercialization of emerging
biomaterial technologies. By offering datasupported insights into anticipated growth areas,
challenges, and opportunities for new materials
and applications, we aim to facilitate informed
decision-making within this dynamic industry.

Biocompatibility

AMPs

Lipid-based
GelMA

Films

Tissue engineering

Carbon nanomaterials

Wound healing

Protein-based

Self-assemblyGelatinLigninStimuli-responsive

Bioinks

ChitosanDNA

Natural polymers

Piezoelectric sensors

Bioelectronics

Non-covalent interactions

MetalsAntibacterial materials

Biosensors

Drug delivery

Exosomes

Silicon

Liposomes

Bioprinting

Electronic skin

Stem cells

Porosity

Programmable

Gels

PVA

Sustainable

Implants

Hydrogels

PDMS

Biodegradable

Silk

Nanocomposites

Graphene Self-healing materials Multifunctional

Synthetic polymers

PEG

Figure 1. Word cloud representing key concepts in this report. (blue: 8 chapters in the report, light blue: applications, purple:
broad material categories, red: specific materials, dark purple: forms, black: properties). Terms were chosen to be representativeof the content of this report and are purely illustrative.

References(1) Patrício Silva, A. L.; Prata, J. C.; Walker, T. R.; Duarte, A. C.; Ouyang, W.; Barcelò, D.; Rocha-Santos, T.
Increased plastic pollution due to COVID-19 pandemic: Challenges and recommendations. Chemical
Engineering Journal 2021, 405, 126683. DOI: https://doi.org/10.1016/j.cej.2020.126683.
(2) Tenchov, R.; Bird, R.; Curtze, A. E.; Zhou, Q. Lipid Nanoparticles-From Liposomes to mRNA Vaccine
Delivery, a Landscape of Research Diversity and Advancement. ACS Nano 2021, 15 (11), 16982-17015. DOI:
10.1021/acsnano.1c04996.
(3) Wu, M.; Chen, J.; Huang, W.; Yan, B.; Peng, Q.; Liu, J.; Chen, L.; Zeng, H. Injectable and Self-Healing
Nanocomposite Hydrogels with Ultrasensitive pH-Responsiveness and Tunable Mechanical Properties:
Implications for Controlled Drug Delivery. Biomacromolecules 2020, 21 (6), 2409-2420. DOI: 10.1021/acs.
biomac.0c00347.
(4) Zhao, X.; Liang, Y.; Huang, Y.; He, J.; Han, Y.; Guo, B. Physical Double-Network Hydrogel Adhesives
with Rapid Shape Adaptability, Fast Self-Healing, Antioxidant and NIR/pH Stimulus-Responsivenessfor Multidrug-Resistant Bacterial Infection and Removable Wound Dressing. Advanced Functional
Materials 2020, 30 (17), 1910748. DOI: https://doi.org/10.1002/adfm.201910748.
(5) Hu, C.; Zhang, F.; Long, L.; Kong, Q.; Luo, R.; Wang, Y. Dual-responsive injectable hydrogels
encapsulating drug-loaded micelles for on-demand antimicrobial activity and accelerated
wound healing. Journal of Controlled Release 2020, 324, 204-217. DOI: https://doi.org/10.1016/j.
jconrel.2020.05.010.

Trailblazing
thethefuturewithemerging
biomaterials| 5| 5Trailblazing
futurewithemerging
biomaterials

II. Antibacterial Materials
Introduction

Antibacterials are a class of antimicrobials thattarget bacteria. Depending on their effect onbacterial cells, antibacterials can be classified
either as bactericidal, which kill the bacterium,or bacteriostatic, if they arrest the bacterial
growth.1 Since the discovery of Penicillin G in the
1940s, various classes of antibiotics have beendeveloped. Lack of regulation and overuse ofantibiotics in both humans as well as animals has
led to various bacteria becoming unresponsive tonumerous classes of existing antibiotics and thisphenomenon is referred as multidrug resistance(MDR).2-4 The development of resistance towards
existing drugs is an urgent problem crippling theworld with the World Health Organization (WHO)declaring antimicrobial resistance as one of the
top 10 global health threats. 5 According to data
presented by the Centers for Disease Control andPrevention (CDC), more than 2.8M antimicrobialresistant (AMR) bacterial infections occur eachyear leading to 35K+ deaths per year.6 Amongst
resistant bacteria, ESKAPEE pathogens (anacronym for a group of Gram-positive and Gramnegative bacteria such as Enterococcus faecium,
Staphylococcus aureus, Klebsiella pneumoniae,
Acinetobacter baumannii, Pseudomonas
aeruginosa, Enterobacter species, and E.coli ) areresponsible for the largest fraction of hospitalacquired infections (HAIs).7-9
To create awareness about the diverse andprevalent resistant bacterial species, the
CDC has published a list of microbes andclassified them as either urgent antimicrobial
resistance threats, serious AMR threats, or AMR
watchlist (microbes that could become serious
threats in the future due to their propensity
to become multidrug resistant) in 2019.10, 11
The serious AMR threat category comprisesof drug-resistant Acinetobacter, Neisseria
gonorrhoeae, Clostridioides difficile, andEnterobacterales. Resistant variants of bacteriasuch as Staphylococcus aureus, Pseudomonas
aeruginosa, Enterococcus, Mycobacterium
tuberculosis, Salmonella, Shigella, Campylobacter,and Streptococcus pneumoniae are featured in
the CDC’s serious AMR threat list. Drug-resistant
Mycoplasma genitalium and Bordetella pertussis
are included in the CDC's watch list as they havethe potential to become multidrug-resistant in thenear future. To counter the problem of increasing
drug resistance, traditional small molecule-based
antibiotics continue to be developed. However,development has been slow, and novel classes
remain elusive. A continued necessity for newer
antibiotics and a lack of newer classes of smallmolecule antibiotics have led researchers to
explore other avenues. In addition to traditional
antibiotics, biomaterials with antibiotic functions,such as antimicrobial polymers, antimicrobial
peptides (AMPs), antimicrobial enzymes,
nanomaterials, bacteriophages can reduce (notreplace) antibiotics usage and biomaterials which
are biocompatible as scaffolds for antibiotics,
such as glass, ceramics, polymers, can help more
effective drug delivery and act, in a way reducing
the load of drugs.12-17 This interest is exemplified
by the increase in journal publications in the fieldof antibacterial biomaterials over the last two
decades (Figure 1). Growth in patent publications
appears to be more modest indicating a gap
between research and commercialization of
antibacterial biomaterials (Figure 1).
In this chapter, we showcase our findings withregards to publication trends from extensive
analysis of more than 90,000 documents (journals
and patents) from the CAS Content Collection,
spanning two decades of research (2003-2023) inthe field of antibacterial biomaterials. In addition
to a publication trend overview, we also identified
emerging materials in the field, their forms, andapplications.

Number of publications

10,000

JournalPatent

8,000
6,000

*

4,000
2,000

20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
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20
12
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20
15
20
16
20
17
20
18
20
19
20
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20
21
20
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20
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0
Publication year
Figure 1. Number of journal and patent publications per year in the field of antibacterial materials (shown as blue and yellow
bars, respectively) for the last two decades (2003-2023). * The data for 2023 only include months from Jan to Aug.

Journal and patent publication trends

Ranking research institutions firstly by the volume
of journal publications followed by the average
number of citations per publication allowed
identification of the leading organizations in
antibiotic research. The top 15 organizations
show a diverse spread across different countries
or regions (Figure 2). The United States ofAmerica (USA) and China (CHN) led by a small
margin, each contributing 3 organizations to the
top 15, respectively. This was closely followedby the Republic of Korea (KOR) and Singapore(SGP), each contributing 2 organizations. While
the University of British Columbia ranked
relatively low in terms of the actual number ofjournal publications (little more than 60), theaverage number of citations per publication
was >90 indicating the scientific impact of thosepublications. An example of a journal publicationfrom the University of British Columbia with a highnumber of citations is “Anti-adhesive antimicrobial
peptide coating prevents catheter-associatedinfection in a mouse urinary infection model”.18
The geographical distribution of commercial
and non-commercial entities in terms of patentdocuments published shows overlapping members(Figure 3). China (CHN) leads by a wide margin
for both commercial and non-commercialorganizations accounting for >50% of patents
published. The United States of America(USA) accounts for a much smaller fraction
as compared to its contribution to patentpublications for other biomaterials discussed
in this report. This may indicate low interest in
antibiotic development because of the highcosts associated with antibiotic discovery anddevelopment and limitations on the use of new
antibiotics which reduce their market size andthus potential earnings. Additionally, bacterial
infections, especially of the multi-drug resistantvariety, are perceived to be more prevalent inand therefore a bigger problem in developing or
low- and middle-income countries as compared
to developed or high-income countries.19
However, this perception might be flawed as due
to extensive globalization the world has become
extremely interconnected and increasingly
diseases affecting human beings can no longer
be contained in any given geographical area,
perhaps best exemplified by the COVID-19
pandemic. Other key countries or regions in the
Trailblazing the future with emerging biomaterials | 7

Average number of citations per publication
University of British Columbia
Sharif University of Technology
Massachusetts Institute of Technology
Xi'an Jiaotong University
The University of Hong Kong
Seoul National University
Bar-Ilan University
Nanyang Technological University
Chonbuk National University
University of California
National University of Singapore
Hubei University
University College London
Harvard University
Nanjing University

Citations per publication
Number of journal publications (CAN)
Number of journal publications (CHN)
Number of journal publications (USA)
Number of journal publications (SGP)
Number of journal publications (IRN)
Number of journal publications (GBR)
Number of journal publications (KOR)
Number of journal publications (ISR)
Number of journal publications (HKG, CHN)

Number of journal publications

Figure 2. Leading research organizations in the field of antibacterial biomaterials over the last two decades (2003-2023) from the
CAS Content Collection. Bar graphs have been color coded by country/region with standard three letter codes used to represent
countries/regions.

commercial and non-commercial sectors include:
Japan (JPN), Republic of Korea (KOR), Germany(DEU), Russia (RUS), India (IND), Italy (ITA),
United Kingdom (GBR) and France (FRA). Japan
in particular appears to have a more favorable
contribution in patent publications by commercialorganizations as compared to non-commercialorganizations (Figure 3). Among the commercial
patent assignees, Chinese companies led theway accounting for 60% of the top 15. This wasfollowed by Japan with 25% and the United States
which made up the remainder. The Japanesecompanies Lion Corporation and Kao Corporation
appear to have been more active in the early partof the 2010s with patent publications related tothe use of antibiotics in oral hygiene including
incorporating antibacterial agents in dentifrices(JP2010150155A 20 and JP2011136956A 21). Similarly,
Colgate-Palmolive, a US-based company, also haspatents mostly focused on antibacterial agentsin oral care (US20190185490A122). The Chinesecompany Guangdong Taibao Medical Technology
Co., Ltd. applied for patents starting in 2013
for the use and incorporation of biomaterials
such as chitosan and alginate among others
in medical dressings aimed at wound healing(CN103356692A 23 and CN106267309A 24). Other
Chinese commercial organizations part of the
top 15 such as Suzhou BEC Biology Technology

Co., Ltd. as well as Guangzhou Rainhome
Pharm & Tech Co., Ltd. also appeared to have
similar commercial pursuits i.e. use of chitosan
and other biomaterials in wound healing(CN105617451A 25 and CN107970488A 26). In termsof non-commercial organizations, the leading
entities all originate from China with Sichuan
University, South China University of Technology,
and Zhejiang University leading of the rest by amodest margin (Figure 3). Sichuan University
appears to have been more prolific after 2010 withpatents revolving around diverse areas including
iron oxide nanoparticles for targeted delivery ofantibacterial agents (CN115040662A 27) and use ofa polymer, polyurethane, in antibacterial coatings(CN103214646A 28).
The overall growth of patent publications showsa distinct upward trend for the Republic of Korea
and Japan post-2020 and India post-2018 (Figure
4A). Germany and the United Kingdom also
show modest increases in the number of patents
published. While the US showed an increase inpatent publications in the early 2000s (between
2003 and 2008), this was followed by a decrease in
2009-2010 with a more or less flat trajectory until
the present year. Among the leading countries orregions, China is the only one that shows a sharp
and dramatic increase in patent publications,almost doubling between 2012 and 2016. This
growth appears to have continued beyond 2016
to the present year at a fast rate. In terms of
the sheer volume of patent publications, China
clearly dominates having 16 times as many patentpublications in 2021-2022 as USA. An analysis ofpatent family activity data in Figure 4B shows theflow from the patent assignee country (left) to thepatent office where the first application in a given
family is filed (center) and finally to the destination
patent office for individual patent publications
within the family. For China, the country leading

Others9%

CHN 53%

Top 10patent assignees

in terms of sheer volume of patent publications,an overwhelming majority of patent applications
appear to have been filed and granted at theirhome office. The US and UK had a greaternumber of patent filings at the World Intellectual
Patent Office (WIPO) than at their respective
home offices. On the other hand, Japan, Republicof Korea, and India showed a distinct preference
for their respective home offices both for the
initial and destination patent filings. Germany
and Italy appear to only show preference for theirrespective home offices for the initial patent filing

FRA (1%)
GBR (2%)
ITA (2%)
IND
3%
RUS
3%
3% DEU

2003-2023

5%
9%

Others11%

KOR

CHN 60%

Top 10patent assignees

BRZ (1%)
DEU (2%)ITA
2% JPN
2% FRA2%
3% IND

2003-2023

JPN

7%

11%

4%

KOR

6%

RUS

USA

USA

Commercial

Non-commercial
120

40

100

35

80

30
25

60

20
15

40

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Patent assignees

Figure 3. Leading patent assignees in the field of antibacterial biomaterials over the last two decades (2003-2023) as reflectedin the CAS Content Collection. Patent assignees have been separated in to two groups: commercial and non-commercial. Bargraphs have been color coded by country/region to match color scheme used in donut charts. Standard three letter codes used
to represent countries/regions.
Trailblazing the future with emerging biomaterials | 9

(A)

3,000

250
200

2,500

KOR
USA
JPN
IND

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Number of patent publications

100

2,000

CHN

RUS
DEU
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20
04
20
05
-2
00
20
6
07
-2
00
20
8
09
-2
01
20
0
11
-2
01
20
2
13
-2
01
20
4
15
-2
01
20
6
17
-2
01
20
8
19
-2
02
20
0
21
-2
02
2

0
20
03
-

1,500

1,000

500
KOR
2
21

-2

02

0
20

19

-2

02

8
20

20

17

-2

01

6
01

20

15

-2

01
-2

20

13

20
11
-

4

12

0
20

09

-2

01

8
20

20

07

-2

00

6
00
-2
05

20

20

03

-2

00

4

0

USA
JPN
IND
RUS
DEU
GBR

Publication year
(B)

CHN: 15,587

CHN: 15,624

CHN: 16,107

USA: 8,928

WIPO: 8,807

USA: 4,875

JPN: 2,644

USA: 3,184

DEU: 1,690

JPN: 1,881

KOR: 1,618

OTH: 495

GBR: 1,135
IND: 963
FRA: 919
ITA: 642
CAN: 557

DEU: 1,174
IND: 788
EPO: 667

JPN: 2,489
EUR: 2,106
KOR: 1,533
CAN: 1,050
IND: 906
BRZ: 415

FRA: 543

MEX: 313
DEU: 260

KOR: 1,423

Others: 1,567

ITA: 367

Figure 4. (A) Growth in patent publications in the field of antibacterial biomaterials for the leading countries or regions overthe last two decades (2003-2022) from the CAS Content Collection. (B) Sankey graph depicting flow of patent families in the
antibacterial biomaterials field between assignee countries or regions (left), office where the first application in a family is filed(center) and the office where individual patent publication activities take place (right).

Enterococcus, Acinetobacter, and Proteus (Figure
5A). Drug-resistant strains for several of these
species have been identified and classified as
threats by authorities such as the WHO and
CDC. Publications associated with the ESKAPEE
pathogens show steady and consistent growth
for the last two decades (Figure 5B). Similarly,
publications associated with bacterial speciesclassified as “Urgent” threats by the CDC also
show steady growth (Figure 5C). Overall, thesetrends are indicative of the interest in developing
antibacterial biomaterials to combat the very
real and growing threat of multidrug-resistantbacteria.

with a more or less even spread across various
patent offices worldwide in terms of the finaldestination.
We analyzed both journal and patent publications
in our dataset exhaustively in an effort toidentify the research interest distribution acrossdifferent bacterial species (Figure 5A). The
two genera, Staphylococcus and Escherichia
account for half of all publications associatedwith bacterial species. Other key bacterial species
that appear to be of interest in the field ofantibacterial biomaterials include Pseudomonas,
Bacillus, Klebsiella, Salmonella, Streptococcus,

2

0

02
-2

21

8

02

-2

19

20

6

01

-2

17

20

20

4

01

-2

01

-2

15

13

20

0

12

20

11
-

20

8

01

-2

09

20

6

4

00

-2

07

20

20

40
30
20

0
21

-2

02

2

8

02

-2

19

20

6

01

-2

17

Publication year

20

20

15

-2

01

4
01

0

-2

13

20

20

11
-

20

8
09

20

05

20

03
20

-2

01

0

12

10

6

Pseudomonas

50

00

12%

60

-2

3%

70

07

Bacilli

Carbapenem-resistant Enterobacterales
Drug-resistant Neisseria gonorrhoeae
Clostridioides difficile
Carbapenem-resistant Acinetobacter

80

20

Klebsiella

00

00

-2
05

20

Publication year

00

4%

0

-2

4%

5

20

9%

7%

10

4

6%

Escherichia

5%15

Salmonellae (C)

4%

19%

27%

3%

20

00

1%
2%
2%
3%
2%
2%

25

-2

21%

Staphylococcus aureus
Acinetobacter baumannii
Klebsiella pneumoniae
Pseudomonas aeruginosaEnterobacter spp.
Enterococcus faecium

30

-2

27%

35

03

Staphylococci

Listeria (1%)
Enterobacteria (1%)
Micrococci (1%)
Protei2% Acinetobacters
2% 1%Enterococci
2%
0.5%
2%
3%
1%
2%
Streptococci
2%
3%
2% 2%

Relative publication growth (%)

Citrobacteria (0.4%)
Saccharomyces (0.3%)
Burkholderia (0.2%)
Haemophili (0.1%)

Relative publication growth (%)(B)
Clostridia (0.4%)
Helicobacters (0.4%)
Aeromonas (0.5%)
Serratia (1%)
Mycobacteria (1%)
Lactobacilli (1%)
Shigellae (1%)
Vibrios (1%)

20

(A)

Figure 5. (A) Distribution of publications (journals and patents) in the field of antibacterial biomaterials across various bacterial
species. Growth in publications (journals and patents) associated with (B) ESKAPEE pathogens and bacteria classified as (C)“urgent” threats by the CDC in the field of antibacterial biomaterials. Data includes both journal and patent publications fromthe CAS Content Collection for the last two decades (2003-2022) in the field of antibacterial biomaterials.

Trailblazing the future with emerging biomaterials | 11

Key materials, properties/forms andapplications

Data mined from the CAS Content Collection
allowed the identification and classification of
biomaterials occurring/used frequently in the fieldof antibacterial biomaterials into the following
broad categories:– Polymers				– Organic molecules– Metals and metal oxides– Carbon-based materials– Protein-based materials– Others
The quantitative distribution of identified materials
and their breakdown across various categories
are shown in Figure 6. Three of the bigger
categories have been further sub-divided togive a more nuanced/granular view of emerging
materials – polymers into synthetic, natural, andconductive, organic molecules into antibiotics, andothers (consisting of substances such as steroids,
quaternary ammonium compounds, zinc chloride,silver chloride, etc.) and metal into noble andtransition metals.
Relative growth in publications of a few
shortlisted materials identified as emerging
across the last two decades are shown in Figure
7A. Graphene shows a sharp and continued
increase in publications post-2014. The use ofgraphene oxide29 and graphene-based hybrid
nanocomposites in the form of hydrogels for
antibacterial effect has been reported. 30, 31 Other
emerging materials include polycaprolactone(PCL) and chitosan – a synthetic and a naturalpolymer, respectively; metals such as zinc, copper,and silver known for their antibacterial properties;
antimicrobial peptides (AMP) and quaternaryammonium-containing compounds. Chitosan isamong the few biomaterials that possess inherent
antimicrobial activity. 32 This along with otherfavorable properties such as biocompatibility,
biodegradability, and abundance along with
reduced propensity of development of resistanceby bacterial species means that chitosan has
been explored in novel ways including as a carrierfor drug delivery,33 in combination with othermaterials34 and incorporated into hydrogels alongwith other polymers and loaded with antibiotics

for drug delivery and wound healing. 35 Recently,
a light-responsive chitosan nano-assembly36 anda synthetic analog of chitosan with improved
antimicrobial efficacy have been developed. 37
Chitosan and its derivatives continue to be of highinterest in the field of antibacterial biomaterials.
The synthetic biodegradable polymer,
polycaprolactone, is often used in conjunction
with other biomaterials such as gelatin, 38 silica,39
and others40 fashioned into nanostructures,41-43
hydrogels, etc. for applications such as targeted
drug delivery44 and wound healing.41 Despite theantimicrobial effect/activity of metals such as
silver,45, 46 copper,47, 48 and zinc49 being well-known,
interest in these materials has sustained over theyears with efforts being made to use these metals
in combination with other biomaterials in novel
ways. Silver in particular continues to be utilizedalong with other biomaterials in combating
multi-drug resistant strains50, 51 including for the
disruption of biofilms. 52 In addition, dead bacteriawith accumulated silver appear to retain the ability
to kill other living bacteria in its vicinity,53, 54 an
effect that can be exploited for increased/greater
antimicrobial effect.
AMPs are small peptides of variable lengthcomposed of natural amino acids55 which areclassified by their structures, sources, activities,
and other properties. 56 Interest in AMPs has
been consistent with several AMP candidates
currently in clinical trials.57 A large majority ofthe protein-based materials identified in ourdataset result from AMPs. In terms of growth inpublications, we see a steady growth over thelast two decades. This is in agreement with theoverall sustained interest in AMPs as alternatives
to traditional antibiotics. A few examples of AMPs
in the context of biomaterials include the use of
AMPs as anti-biofilm agents for medical implants
and devices58-60 as well as incorporation of AMPs
in hydrogels61 and AMP-polymer conjugates.62-64
Ceramics loaded with antibiotics have beenused for local/targeted delivery of antibiotics forprolonged periods of time (up to several days),especially in bone-related applications.65, 66
Biomaterials such as bamboo, which are naturally
antibacterial, are being explored in their natural orcomposite forms for biomedical applications suchas designing medical gauze and would dressing
for accelerated wound healing.67-69

Trailblazing the future with emerging biomaterials | 13

Transition
metals

Metal
OthersoxidesNoble
metalsPolymers

OthersOrganic
molecules

Carbonbased

OthersAntibiotics

Metals andmetal oxides

Proteinbased

*

*

*

NaturalConductive

Synthetic

Figure 6. Distribution of materials in the field of antibacterial biomaterials over the last two decades (2003-2022) from the CAS Content Collection. Size of the circle corresponds tonumber of publications (journals and patents). Growth of materials marked with an asterisk are shown in Figure 7.

*

*

*

Established classes of antibiotics such as
tetracyclines, macrolides, and others havereportedly been used in conjunction withbiomaterials often to aid in their delivery andto boost their antibacterial effectiveness inapplications such as tissue engineering andwound healing.70-73 Among the various classesof antibiotics, we identified a few that appear
to be most prolific and show a steady rate ofincrease in publications (Figure 7B). These
classes of antibiotics are most often formulated/
incorporated into either hydrogel, nano-based
systems such as nanoparticles, nanofibers,
nanosheets, etc., or liposomes. Among thevarious forms listed, nano-based systems appear
to dominate (Figure 8A). All the forms show
steady growth more so over the last decade.
Hydrogels and quantum dots in particular showa sharp growth in publications post-2016 (Figure
8B). Liposomes, a subtype of nanocarriers was
originally focused on packaging and deliveryof anticancer drugs, but is increasingly being
explored for effective delivery of antibiotics.74-76
For instance, a hydrogel comprising lignin andsilver nanoparticles has shown antibiotic activity
against S. aureus, a Gram-positive bacterium,
and E. coli, a Gram-negative bacterium indicating

To understand the preference for a particularform, we searched for various classes of antibiotics
and forms and generated a Sankey graph tovisually represent these co-occurrences (Figure9). Among the different classes of antibiotics, amajority had a higher number of co-occurrenceswith nano-based systems as compared to otherforms, the exceptions being oxazolidinones,
glycylcyclines, phosphonic acids, amphenicols,
and aminocyclitol which showed co-occurred
more or less evenly across hydrogels, nano-based
systems, and liposomes (Figure 9). We generated
a heat map to effectively showcase co-occurrences
between specific bacterial species and the classes

35
30
25
20

LigninGraphene
Polycaprolactone
Zinc
ChitosanAntimicrobial peptides
CopperSilverQuaternary compounds
Ceramic

15
10
5

20
15

Macrolides
Ansamycins
Anthracyclines
Aminoglycosides
Oxazolidinones
Aminocyclitols

10
5
0

20
0

320
04
520
06
20
07
-2
00
20
8
09
-2
01
20
0
11
-2
01
20
2
13
-2
01
20
4
15
-2
01
20
6
17
-2
01
20
8
19
-2
02
20
0
21
-2
02
2

0

20
0

25

Amphenicols
Penicillins & Beta lactams
Lincosamides
Tetracyclines
Sulfonamides
Phosphonic acids
Quinolones & fluoroquinolones
Carbapenem
Glycylcyclines
Nitroimidazoles

Publication year

20
03
-2
00
20
4
05
-2
00
20
6
07
-2
00
20
8
09
-2
01
20
0
11
-2
01
20
2
13
-2
01
20
4
15
-2
01
20
6
17
-2
01
20
8
19
-2
02
20
0
21
-2
02
2

45
40

Relative publication growth (%)(B)

Relative publication growth (%)(A)

its applicability and versatility.77 In another recent
example, a self-assembled peptide hydrogel
made from naphthyl anthranilamide capped,
short cationic peptides that showed promising
antibacterial activity against S. aureus and E.
coli.78 The high surface area to volume ratio of
nanoparticles allows them to deliver antibacterial
drugs effectively.79, 80 Nanoparticles made using
silver, gold, selenium, calcium oxide, copper,
titanium dioxide, iron oxide, poly (lactic-coglycolic acid) (PLGA), chitosan, etc. are widely usedin the field of antibacterials.81-86

Publication year

Figure 7. Growth in publications for (A) emerging materials and (B) major classes of antibiotic drugs in the field of antibacterial
biomaterials from the CAS Content Collection for 2003-2022. Data includes both journal and patent publications.

of antibiotics deployed against them (Figure 10).
The bacterial species we chose to focus on werebased on our findings described earlier i.e., themost prevalent bacterial species in the current
dataset of antibacterial materials (Figure 5A).
Discussed below are a few observations from theheat map:

3. Certain broad-spectrum antibiotics suchas tetracycline and their derivatives likeglycylcycline are effective against both
Gram-positive (Staphylococcus) and Gramnegative bacteria (Escherichia) which also
correlates well with literature.89, 90
The distribution of applications that antibacterial
biomaterials can be utilized for is shown in Figure
11A. One of the biggest applications is the useof biomaterials to effectively target and deliver
antibiotics accounting for nearly 12K publicationsin the last two decades (2003-2023). Biomaterials
such as antimicrobial peptides, enzymes, andbiopolymers are being used effectively in thefield of antibiotics.12 Another major application
involves the use of antibacterial biomaterials
in the design and fabrication of medical
apparatuses, devices, and implants to reduce therisk of infections. Various polycationic polymers(including quaternary ammonium salt-containing
polymers), zwitterions, polyethylene glycol (PEG),
and antibacterial peptides are used to design
antimicrobial coatings for preventing bacterial
infections.91-93 Besides these, other notable

1. The bacterial species that co-occurred mostfrequently across the different classes ofantibiotics are Staphylococcus, Escherichia,
Pseudomonas, and Klebsiella. This is
unsurprising since drug-resistant strainsof Staphylococcus, Pseudomonas, andKlebsiella have long been identified.
2. Certain classes of antibiotics are more
effective against Gram-negative bacteria
while some have a preferential effectagainst Gram-positive bacterial species.
For instance, carbapenems (including
imipenem, doripenem, and meropenem)
are mostly effective against Gram-negative
bacteria belonging to genera such as
Acinetobacter, Escherichia, Klebsiella,
Pseudomonas, Enterobacter etc.87, 88

5.6K
Number of publications(Journals and patents)
2003-2023

32K
Nano-based

Hydrogels45
40

Quantum dots
Hydrogels
Nano-based
Liposomes

35
30
25
20
15
10
5
0

-2
00
4
-2
00
20
6
07
-2
00
20
8
09
-2
01
20
0
11
-2
01
20
2
13
-2
01
20
4
15
-2
01
20
6
17
-2
01
20
8
19
-2
02
20
0
21
-2
02
2

3K

50

20
05

Liposomes

Relative growth in publications (%)

Quantum dots

(B)

522

20
03

(A)

Publication year

Figure 8. (A) Distribution of various forms in the field of antibacterial biomaterials and (B) relative growth in publications related
to chosen forms in the field of antibacterial biomaterials over the last two decades from the CAS Content Collection.

Trailblazing the future with emerging biomaterials | 15

applications of antibacterial biomaterials appear to
be in the food industry and as antifouling agents.
PEG-based materials, zwitterions, hydrogels,cationic, and fluoropolymers are some commonlyused antifouling agents94, 95 used to coat surfaces
in order to prevent bacterial infections. In thefood industry, antibacterial biomaterials areused to increase the shelf-life of perishable foodproducts by preventing bacterial infections.
Phenolic compounds, enzymes such as lysozyme,
and antimicrobial peptides are a few examples ofbiomaterials being actively utilized to design more
effective and safer food preservatives.95-97

Penicillin and beta lactams: 3,822

Fluoroquinolones: 1,671

Quinolones: 1,542

Nano-based: 9,979

Others: 1,338
Tetracyclines: 1,155
Aminoglycosides: 1,031

Hydrogels: 1,894

Macrolides: 711
Anthracyclines: 461

Liposomes: 1,843

Carbapenems: 373
Ansamycins: 417
Sulfonamides: 357
Lincosamides: 270
Nitroimidazoles: 236
Oxazolidinone: 122
Glycylcyclines: 75
Phosphonic acids: 62
Amphenicols: 31
Aminocyclitol: 42

Figure 9. Sankey graph showing co-occurrences between various classes of antibiotics and the forms such as nano-based,hydrogels and liposomes. Data is for publications (journals and patents) in the field of antibacterial biomaterials from the CAS
Content Collection for the period 2003-2023.

Trailblazing the future with emerging biomaterials | 17

14.0
Quinolones &fluoroquinolones
17.9
17.9
15.6
4.8
8.3
3.3
3.3
4.3
2.5
3.6
4.8
0.6
1.4
1.1
1.2
1.0
1.2
0.8
0.9
1.4
0.7
0.9
1.4
0.9
0.3

Carbapenem
6.5
15.1
17.2
1.6
14.8
1.9
2.0
3.1
2.8
9.5
10.4
0.3
1.2
0.5
0.8
0.8
0.9
1.0
1.1
2.7
0.5
0.9
3.4
0.9
0.2

Tetracyclines
15.3
16.6
10.9
5.8
7.0
4.2
4.6
5.5
2.2
3.3
4.1
0.8
1.7
2.2
2.5
1.7
1.8
1.7
1.2
1.3
1.4
1.5
1.4
1.0
0.5

Low

8.7

7.8
Macrolides
16.3
12.8
11.4
5.4
5.9
5.4
4.0
6.9
1.9
2.6
3.2
1.0
2.3
2.6
1.9
2.1
1.8
1.9
1.1
1.2
3.5
1.4
0.9
1.6
0.7

6.0
Aminoglycosides
13.0
15.7
17.4
4.7
9.1
2.6
3.7
4.4
2.5
4.5
6.3
0.7
1.9
1.2
1.5
1.3
1.3
1.1
1.2
1.5
0.6
0.9
1.8
0.8
0.4

10.2
Ansamycin
19.2
12.1
9.2
4.7
5.2
4.3
3.2
6.3
2.0
2.7
3.9
0.8
7.0
2.1
2.1
1.8
1.8
2.8
1.4
1.2
1.7
1.1
1.1
1.6
0.7

3.7
Lincosamide
18.3
10.3
9.2
4.6
5.5
6.0
3.7
7.4
2.0
3.4
3.7
0.6
2.4
3.7
2.3
2.4
1.7
3.6
1.2
1.3
1.4
1.5
1.0
1.9
0.8

2.8

1.6
Oxazolidinone
21.6
9.3
7.7
2.9
5.3
6.0
2.8
11.3
2.2
3.8
3.5
0.1
3.4
1.5
1.7
1.7
1.4
3.3
1.7
1.6
1.5
1.0
1.5
2.7
0.4

0.5
Anthracyclines
24.0
24.2
10.6
8.6
4.2
3.1
3.6
3.9
1.4
0.8
1.9
1.1
2.5
0.3
0.6
1.7
1.4
1.4
0.6
0.3
0.8
0.6
0.3
1.4
0.8

Glycylcycline
7.1
15.2
7.7
1.4
16.5
2.3
2.5
3.5
3.1
11.6
9.8
0.2
1.7
0.5
0.9
0.5
1.7
1.5
0.9
3.5
0.9
0.7
4.5
1.4
0.3

1.8
Sulfonamide
14.2
17.9
13.5
4.0
7.7
3.0
3.2
4.1
2.2
4.4
5.1
0.5
1.7
1.5
2.1
1.3
1.3
2.1
1.9
1.9
1.0
2.1
1.7
1.1
0.6

2.6

2.5
Phosphonic
acid
14.8
18.5
14.0
1.5
8.0
3.1
3.3
4.3
2.3
4.6
5.3
0.5
1.7
1.6
1.1
1.4
1.4
2.1
2.0
2.0
1.0
2.1
1.8
1.2
0.6
Nitroimidazole
12.2
11.9
6.8
5.0
4.0
7.7
3.1
6.5
1.4
2.3
2.3
0.4
2.8
5.3
2.1
1.8
1.7
8.2
1.1
1.0
7.1
0.4
1.0
2.4
1.7

1.5

High

Aminocyclitol
8.0
10.0
9.3
4.8
5.5
5.2
4.6
4.8
3.2
4.1
3.9
0.7
4.6
2.1
4.3
2.1
2.7
4.3
2.7
3.0
2.1
1.8
2.5
3.4
0.5

0.6
Amphenicols
8.5
16.9
6.9
5.8
3.2
9.0
6.3
5.3
1.6
1.6
1.6
0.5
2.6
1.6
7.9
2.1
0.5
4.2
1.6
1.1
1.1
5.3
2.6
2.1
0.0

0.3
Others
17.5
17.8
11.0
5.2
6.9
3.6
4.1
5.1
2.0
3.4
3.5
0.9
3.2
1.7
1.8
1.7
1.7
1.3
1.1
1.3
1.1
1.3
1.4
0.9
0.4

8.7

12K

1K 1K

11K

(B)

0
20

Publication year

12
10
14
16
18
20
22
20
20
20
20
20
20
20
11
09
13
15
17
19
21
20
20
20
20
20
20
20
8

00
2
70
20

6
00
2
5-

Drug delivery
Medical apparatus
Hydrogels
Wound healing
Tissue engineering
Food industry
Anti-fouling

0
20

4
00
2
3-

0

500

1000

1500

2000

2500

3000

Figure 11. (A) Distribution of applications in the field of antibacterial biomaterials and (B) and growth in publications related to chosen
applications in the field of antibacterial biomaterials over the last two decades from the CAS Content Collection.

5.6K Hydrogels

5.4K Wound healing

Tissue engineering
1.7K

Food industry

Number of publications(Journals and patents)
2003-2023

Antifouling

Medical apparatus

Drug delivery(A)

Figure 10. Heat map showing co-occurrences between major antibiotic classes and bacterial species. Data is for publications (journals and patents) in the field of antibacterial biomaterials
from the CAS Content Collection for the period 2003-2023. Values shown are in percentages.

Staphylococcus
Escherichia
Pseudomonas
Bacillus
Klebsiella
Streptococcus
Salmonella
Enterococcus
ProteusEnterobacter
Acinetobacter
Micrococcus
Mycobacterium
Lactobacillus
VibrioListeria
Shigella
Clostridium
Burkholderia
Serratia
Helicobacter
Aeromonas
Citrobacter
Haemophilus
Saccharomyces

26.7
Penicillin &β lactams
24.9
16.5
12.6
4.1
8.3
2.9
3.0
3.9
2.1
4.2
4.8
0.6
0.9
1.0
1.0
1.0
1.1
0.9
0.7
1.4
1.0
0.8
1.6
0.7
0.3

Number of publications

Notable journal articles and patents

Table 1 consists of a set of research articles
published from 2020-2023 that are representativeof emerging trends in this field. Articles wereselected on the basis of collective factors suchas journal impact factor, citations, and typeof study and describe the usage of different
antibacterial materials for various bacterial
species. Notable examples from Table 1 include
an article titled “Graphdiyne-modified TiO2
nanofibers with osteoinductive and enhanced
photocatalytic antibacterial activities to prevent
implant infection” published in 2020 in Nature
Communications. The article describes the useof a stable carbon allotrope-based nanomaterial(GDY), that forms a composite with titanium oxide(TiO2) nanofibers to improve the antibacterial
properties of titanium oxide. TiO2 /GDY nanofibers
have enhanced photocatalytic and ROS
production activity.98
Another example includes a recent publication
titled "Injectable wound dressing based oncarboxymethyl chitosan triple-network hydrogelfor effective wound antibacterial and hemostasis”
which describes the synthesis of a hydrogel
comprising carboxymethyl chitosan (CMCS),
oxidized dextran ((OD), and poly-γ-glutamic
acid (γ-PGA). Components of CMCS-OD-γPGA (COP) hydrogel such as CMCS and OD are
responsible for antibacterial action while γ-PGA
is responsible for wound healing and maintaining
homeostasis at the wound site.
Furthermore, researchers at Westlake University
have developed chitin and cellulose nanofibrilbased adhesive tape which can be incorporated
with antibiotics. In this article, nanofibril-stabilized
latex (poly-2-ethylhexyl acrylate-co-polymethyl

acrylate) was infused with the antifungal drug
miconazole nitrate. The resultant antibiotic-loaded
tape was used to effectively inhibit the growth ofStaphylococcus aureus.99
Table 2 shows notable patents in the field ofantibacterial biomaterials published from 2018 to2023. Patents were selected based on relevance,
novelty, applicability, and field of study. Mostof these involve different forms of biomaterials
and their diverse applications. For instance,
US10662203B2 by Hoffmann La Roche Inc.
describes the synthesis of heterocyclic compounds
that can be used as DNA gyrase/topoisomerase
inhibitors thereby eliminating bacterial
infections.100
In another example, US11234997B2 describes
the topical formulation that comprises varying
ratios of galactooligosaccharide and xylitol(ranging from 1:10 to 10:1). These formulations
selectively inhibited the formation of biofilmby Staphylococcus aureus and helped toreduce atopic dermatitis without causing skininflammation and irritation.101
In a recent example, CN113277563B describes acomposite powder made using molybdenumdoped cesium tungsten bronze/montmorillonite
where montmorillonite acts as a carrier formolybdenum doped cesium tungsten bronze
which is loaded on to the surface of the film.
These composites were used to inhibit the growthof E. coli.102

Table 1. Notable journal articles in the field of antibacterial biomaterials in recent years.

Year

Title

JournalResearch InstituteApplication

2020

Designing a 0D/2D S-scheme
heterojunction over polymeric carbon
nitride for visible-light photocatalytic
inactivation of bacteria103

Angewandte
ChemieWuhan University

Antibacterial coating effective against S.
aureus.

2020

Graphdiyne-modified TiO2 nanofibers
with osteoinductive and enhanced
photocatalytic antibacterial activities toprevent implant infection98

NatureCommunications

Guangzhou
Laboratory andWuhan University

Graphdiyne (GDY) composite TiO2
nanofiber with antibacterial properties.

2021

Dual-Dynamic-Bond Cross-Linked
Antibacterial Adhesive Hydrogel Sealants
with On-Demand Removability for PostWound-Closure and Infected Wound
Healing104

ACS Nano

Xi'an Jiaotong
University

Self-healing antibacterial containing
quaternized chitosan (QCS) for woundhealing after methicillin-resistant
Staphylococcus aureus (MRSA) infection.

2021

Anti-bacterial and wound healingpromoting effects of zinc ferrite
nanoparticles105

Journal of
Nanobiotechnology

University ofCalifornia

Synthesis and testing antibacterial
activity of zinc ferrite (ZnFe2O4)
nanoparticles against S. aureus and E.
coli.

2020

Near-Infrared Light-Triggered NitricOxide-Enhanced Photodynamic Therapy
and Low-Temperature Photothermal
Therapy for Biofilm Elimination106

ACS Nano

Chongqing
University

Anti-biofilm activity of AI-MPDA
Nanoparticles containing mesoporous
polydopamine (MPDA), L-arginine(l-Arg), and indocyanine green (ICG).

2021

Dy2BaCuO5/Ba4DyCu3O9.09 S-scheme
heterojunction nanocomposite withenhanced photocatalytic and antibacterial
activities107

Journal of theAmerican CeramicSociety

University of Kashan

Nanoparticles made from asemiconductor combination(Dy2BaCuO5/Ba4DyCu3O9.09) weresynthesized and tested for antibacterial
activity against E. faecalis, S. aureus, K.
pneumonia, and E. coli.

2022

Facile formation of injectable quaternizedchitosan/tannic acid hydrogels with
antibacterial and ROS scavenging
capabilities for diabetic wound healing108

International
Journal of Biological
Macromolecules

Wenzhou Medical
University

Antibacterial activity of hydrogel madeby introducing tannic acid (TA) intoquaternized chitosan (QCS) matrix
against S. aureus and E. coli.

2022

Promoting the healing of infected
diabetic wound by an anti-bacterial
and nano-enzyme-containing hydrogelwith inflammation-suppressing, ROSscavenging, oxygen, and nitric oxidegenerating properties109

Biomaterials

Zhejiang University

Antibacterial activity of Poly (PEGMA-coGMA-co-AAm) (PPGA) based hydrogels
crosslinked with hyperbranched polyL-lysine (HBPL)-modified manganesedioxide (MnO2) against methicillinresistant S.aureus (MRSA) infection.

2022

Cellulose or chitin nanofibril-stabilized
latex for medical adhesion via tailoring
colloidal interactions99

Carbohydrate
Polymers

Westlake University

Using cellulose and chitin nanofibrils
to form adhesive tapes which exhibit
antibacterial activity

2022

Multi-crosslinking hydrogels with robust
bio-adhesion and pro-coagulant activity
for first-aid hemostasis and infected
wound healing110

Bioactive Materials

Sichuan University

Hydrogels comprising carboxymethyl
chitosan (CMCS), sodium alginate(SA), and tannic acid were tested for
antibacterial activity against S. aureus
and E. coli.

2023

Injectable wound dressing based oncarboxymethyl chitosan triple-networkhydrogel for effective wound antibacterial
and hemostasis111

International
Journal of Biological
Macromolecules

Shanghai University

Antibacterial effect of a hydrogel
comprising carboxymethyl chitosan(CMCS)/oxidized dextran (OD)/poly-γglutamic acid (γ-PGA).

Trailblazing the future with emerging biomaterials | 19

Table 2. Notable patent publications in the field of antibacterial biomaterials in recent years.

Description of patented
technology

Patent number

Publication year

Patent assignee

Title

JP2018159860A112

2018

Tokai Optical Co Ltd

Optical product containing
metal ion-carrying zeolite

An optical multilayer product withan antireflective film coated withan organic antibacterial agent.

CN107536725A113

2018

Guangzhou Weimeizi
Industrial Co Ltd

A kind of multiple-effectoral cavity composition andits application containing
hyaluronic acid mixtures

Oral care composition comprisingdifferent combinations ofhyaluronic acid (in some cases withzinc citrate) used as antibacterials.

JP2019065375A114

2019

Harada Metal Industry Co.,
Ltd., National Institute ofAdvanced Industrial Science& Technology, Japan

Copper alloy powder having
antibacterial properties andantivirus properties andarticle using the same

Antibacterial coating formulation
containing copper alloy powder(comprising 0.10% tin, 0.01%
phosphorus and remaining
copper).

US10662203B2100

2020

Hoffmann La Roche Inc

Novel pyrido [2,3-b]indole compounds for thetreatment and prevention ofbacterial infections

Heterocyclic compound to inhibit
bacterial DNA gyrase and/or
topoisomerase IV, in turn inhibiting
bacterial growth.

US11065223B2115

2021

University of Texas System,
USA

Antibacterial composition
and its use

Antimicrobial compositionin the form of woundointment containing esterified
polygalacturonic acid and a C6-12
fatty acid.

CN110067042B116

2021

Donghua University

Konjac glucomannan-based
antibacterial hydrogel fiberand preparation method
thereof

Antibacterial hydrogel fiber
comprising Konjac glucomannan
polymerizable monomer, alginate,
guanidine salt polymerizable
monomer, deionized water, andpolymerization initiator.

US11459296B2117

2022

Infex Therapeutics Ltd
Medivir AB

Preparation of sulfamoyl
pyrrolecarboxylic acids as
antibacterial agents

Nitrogen-containing heterocyclic
compounds that act as Metallo-βlactamase inhibitors.

US11234997B2101

2022

Rottapharm SpA

Antibacterial activity ofgalactooligosaccharide andxylitol in dermatologicaltreatments

Anti-biofilm activity of topicalformulation comprisinggalactooligosaccharide and xylitol
in different ratios.

US11691967B2118

2023

The Board of Trustees of the
University of Illinois, USA

Antibiotics effective forgram-negative pathogens

Organic compounds with antibiotic
activity, selectively against gramnegative bacteria.

CN113277563B102

2023

Nanjing Zhouninglin
Advanced Materials
Technology Co Ltd, Nanjing
Normal University

Molybdenum doped
cesium tungsten bronze/
montmorillonite composite
powder and preparation
method and application
thereof

Synthesis and antibacterial activityof molybdenum doped cesium
tungsten bronze/montmorillonite
composites.

Challenges and perspectives

Development of novel antibiotics requires athorough understanding of the host immune
system and the interaction of host cells with
antibiotics. There are various traditional antibiotic
approaches/materials being used to treat bacterial
infections but the major challenges in this areaare:– One common challenge in this field is thedevelopment of antimicrobial resistancein bacterial species, which happens at amuch faster pace as compared to the ofdevelopment of any novel antibiotic.1, 119– The same levels of antibiotic treatment
produce varied results in different
individuals in any population, due to thedifferences in the host immune system.120– The development of antibiotics is morechallenging for highly infectious, Gramnegative bacteria as compared to Grampositive ones, due to the presence ofa lipopolysaccharide (LPS) rich, outermembrane. The outer membrane acts as
a barrier and prevents the entry of various
drug molecules inside the bacterial cell.121, 122– The limited market size, short treatment
duration, and reduced price of antibiotic
agents reduce the willingness ofpharmaceutical companies to invest in
antibiotic drug development.123– Another major challenge is the treatment ofbacterial infections if the bacteria is prone tobiofilm formation, which is a densely packed
community of bacteria embedded within
an extracellular matrix. Biofilms preventthe entry of antibiotics and the lowest
concentration of antibiotics entering thebiofilm can promote the rapid developmentof antimicrobial resistance.14, 124
Various emerging approaches such as the use of
antimicrobial peptides, enzymes, bacteriophages,
and CRISPR-Cas technology are being tried toenhance the efficacy of antibiotics and counterthe problem of rapid antimicrobial resistancedevelopment. Artificial intelligence (AI) has
slowly started entering the field of antibiotics
where machine-learning based algorithms arebeing leveraged to identify successful antibiotic
candidates. However, the widespread use of
AI is still in the nascent stages, and it requires
more research endeavors in the future.123 In
addition, continued advancements are needed intranslating more antibiotic-based materials into
various clinical applications.

Trailblazing
thethefuturewithemerging
biomaterials| 21
Trailblazing
futurewithemerging
biomaterials| 21

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III. Lipid-based materials
Introduction

The field of pharmaceuticals has witnessed
remarkable progress recently, driven by
innovations in drug delivery technologies.
Traditionally, drug delivery has been a complex
puzzle, often challenged by the limited solubility,
stability, and bioavailability of many therapeutic
agents. These constraints have led researchers
on a quest to find more effective ways to deliverdrugs to their intended targets within the body.
Therefore, drug delivery systems play a crucialrole in optimizing the therapeutic benefits ofmedications while minimizing side effects andimproving patient compliance. Among thetransformative advancements in drug delivery
technologies, lipid-based drug delivery systems
have emerged as a formidable force in the worldof pharmaceutical science and practice offering
a dynamic range of solutions that transcend
traditional pharmaceutical boundaries.

Iiposome

mRNA-carrying
lipid nanoparticle

drug-loaded
liposome

solid lipid
nanoparticle

Lipid-based drug delivery systems are ingeniously
designed carriers, benefitting from the inherent
biocompatibility and versatility of lipids andtailored to encapsulate, transport, and releasea wide array of therapeutic agents, including
small molecule drugs, genes, and biologics. Theirelegance lies in their ability to overcome someof the most pressing challenges in drug delivery.
These challenges include improving the solubilityof poorly water-soluble drugs, protecting labile
compounds from degradation, and precisely
targeting disease sites within the body.1-9
Lipid nanocarriers can be divided into various
categories, including solid lipid nanoparticles(SLNs), nanostructured lipid carriers (NLCs),
liposomes, lipid-based micelles, and lipid
prodrugs (Figure 1). SLNs consist of solid lipids,
while NLCs combine solid and liquid lipids,
offering enhanced drug-loading capacity andtargeted
liposome“stealth”
liposome

nanostructured
lipid carrier

cubosome

Figure 1. Schematic representation of various types of lipid nanoparticles. Adapted from Tenchov et al.1

Trailblazing the future with emerging biomaterials | 29

flexibility. Liposomes are spherical vesicles withlipid bilayers surrounding an aqueous core, while
lipid-based micelles have amphiphilic molecules
forming micellar structures. Lipid nanocarriers
offer several advantages, such as improved drug
solubility, enhanced bioavailability, controlled
drug release, targeted delivery, and protection oflabile drugs from degradation.1, 5, 8, 10, 11 Exosomes
are similar to liposomes but originating from
biological systems and secreted by mosteukaryotic cells. They possess unique properties
such as innate stability, low immunogenicity,
biocompatibility, and good bio-membrane
penetration capacity, making them superior
natural nanocarriers for efficient drug delivery anddiagnostics.12-15

a wide spectrum of diseases and conditions. Theirversatility, biocompatibility, and ability to address
specific drug delivery challenges make themvaluable tools in pharmaceutical research anddevelopment. Besides drug delivery, lipid-basedmaterials have also found applications in otherfields such as cosmetics16, 17 and agriculture18,19
among others. These diverse applications have
led to a sustained interest in lipid-based materials
as seen by the more or less steady increase injournal publications (Figure 2). Growth in patentpublications have been more modest indicating
unmet commercial potential (Figure 2).
In the present report we showcase our findings
with regards to publication trends from extensive
analysis of more than 46,000 documents (journals
and patents) spanning across two decades(2003-2023) in the field of lipid-based materials
from the CAS Content Collection. In addition toa publication trend overview, we also identified
emerging materials in the field and theirapplications.

Lipid nanocarriers have revolutionized drugdelivery by overcoming limitations related to drug
solubility, stability, bioavailability, and targeted
delivery. They continue to play a pivotal role in
improving drug delivery, expanding treatment
options, and enhancing patient outcomes across

3,500

JournalPatentNumber of publications

3,000
2,500

*

2,000
1,500
1,000
500

23

22

20

20

21

20

20

20

19

18

20

20

17

16

20

20

15

14

20

20

13

20

11
12
20

20

10

20

09

20

08

07

20

20

06

05

20

20

04

03

20

20

0
Publication year
Figure 2. Number of journal and patent publications per year in the field of lipid-based materials (shown as blue and yellow bars
respectively) over the period of the last two decades (2003-2023). * The data for 2023 only include months from Jan to Aug.

Journal and patent publication trends

From the top 150 organizations in terms of volume
of journal publications, we identified leadingorganizations involved in research related tolipid-based materials on the basis of average
number of citations per publications. Nearly halfof the top 15 organizations originate in the USA
which is followed closely by China contributing 4
institutions (Figure 3). The University of Alberta,
the only organization originating in Canada leads
the pack with an average number of citations per
publication of >160 (Figure 3). One such highly
cited article from the University of Alberta titled“Spray-freeze-dried liposomal ciprofloxacin
powder for inhaled aerosol drug delivery”
describes the formation and characterization ofliposomal-encapsulated ciprofloxacin, a broadspectrum antibiotic designed to be delivered via
inhalation to prevent bacterial infections.20
The trends in geographical distribution of patentassignees separated into commercial and noncommercial organizations show a high degreeof overlap, a trend echoed in other biomaterials
addressed in this report (Figure 4). Across bothcategories, the USA and China dominate with theformer contributing greater numbers of patentpublications in terms of commercial organizations.

On the other hand, non-commercial organizationsin the USA and China have published similar
numbers of patent documents. Other important/
key countries or regions in terms of volume ofpatent publications include: Germany (DEU),
Japan (JPN), the Republic of Korea (KOR), France(FRA), Italy (ITA), India (IND) and Switzerland(CHE). More than 65% of the leading commercialorganizations involved in research in lipidbased materials originate in the USA. Patentsfrom ModernaTX, a biotechnology company
from the USA, appear to be related to the useof lipid nanoparticles to deliver active payloads
including drug molecules, proteins and mRNAfor the treatment of cancer and other disorders(WO2021243207A1,21 WO2023076605A122) aswell as development and delivery of vaccines(WO2018170260A1,23 WO2023154818A124). Other
US based companies such as Codiak Biosciences
and Transdermal Biotechnology have filed patentapplications relating to the use of lipid-basedmaterials such as exosomes for drug and vaccine
delivery (WO2023056468A1,25 WO2020191361A226)
and transdermal delivery (US20160136169A127) andwound healing (WO2014159986A228), respectively.
The Japanese company, Konica Minolta Medical& Graphic, Inc. appears to have been more
active in the late 2000s and was focused on the

Figure 3. The top 15 research institutions in terms of average citation numbers per journal publication between 2003-2023.

Trailblazing the future with emerging biomaterials | 31

delivery of X-ray contrast agents using liposomes(JP200520654029) and the use of liposomes inphotodynamic therapy (EP2374825A130). Lipotec,
a Spanish company, has explored the use of
liposomes in cosmetics (US20130078295A1,31
EP2740484A1,32) such as for the delivery of
peptides and botulinum toxin.
Distribution for the top 15 commercial organization
appears to split between China and the USA with
9 organizations originating in China (Figure 5).
Among the non-commercial organizations in
China, Shenyang Pharmaceutical University leads
with >90 patent publications, closely followedby China Pharmaceutical University. Patents by
Shenyang Pharmaceutical University appear tobe centered around manufacturing liposomes(CN102552142A 33) as well as their applicationin drug delivery (WO2021043231A134) especiallycancer therapy (CN109718228A, 35 CN116440287A 36).
Examples of patent publications by China
Pharmaceutical University include designing
remdesivir liposomes to be administered byinhalation route (CN111991375A 37), liposomes fortargeted delivery (CN111001011A 38), as well as otherdrug delivery applications (CN107837234A 39).
Patent documents filed by the University ofCalifornia seem to be related to use of lipid
nanocarriers for drug delivery for cancer
immunotherapy (WO2021076630A140) as well as
Alzheimer's disease (WO2018081085A141) and viral
infections (WO2021207632A142).
The overall growth in patent publications acrossthe last decade shows a positive upward trend
pronounced more so for the USA, China, theRepublic of Korea, Germany, and India (IND)(Figure 5A). On the other hand, Italy and France
display a more modest growth in patents over thelast decade. Despite this upward trend, the actual
number of patents for lipid-based materials is
relatively low. Detailed analysis of patent family
data showing the complex flow of patents frompatent assignee countries or regions (left) to thepatent office wherein the first application in agiven family is filed (center) and the patent officewhere the individual patent publication activity
takes place (right) is shown in Figure 5B. Unlike
other biomaterials, for patents related to lipid-basedmaterials a majority of applications were first filed at
the European Patent Office (EPO). This is especiallytrue for the USA, Germany, Japan, Canada, Israel(ISR) and the United Kingdom (GBR) wherein nearly
half of the patent applications were filed at the EPO
first (Figure 5B). In contrast, patent applications
originating from China and Spain (ESP) appear
to show only a minor preference for home office(CHN) and EPO, respectively, while a majority ofthe patents were filed more or less evenly across
WIPO, their respective home offices as well asother patent offices across the world (Figure 5B).
For USA, the rest of the patent application filings
are split between their home office (US) and theWorld Intellectual Patent Office (WIPO). In termsof the final destination patent office, more than athird of the patents initially filed at the EPO maketheir way to the United States Patent Office (USA)followed by the EPO itself. Other important/key/major destinations offices include the Japanese,
Canadian, Chinese, Korean, Indian, Spanish,
Mexican, and Brazilian patent offices.

Trailblazing the future with emerging biomaterials | 33

Figure 4. Geographical distribution (top panel) and leading patent assignees in the field of lipid-based materials in terms of numbers of patent publications between
2003-2023. Patent assignees have been separated in to two groups: commercial and non-commercial. Bar graphs have been color coded by country/region to match color
scheme used in donut charts. Standard three letter codes used to represent countries/regions.

(A)
160

KOR

120

800

80

DEU
IND
JPN
ITA
FRA

40

2
21

-2

02

0
20

19

-2

02

8
20

20

17

-2

01

6
01
-2
15

13
20

20

20

-2

20

01

4

12

0
11
-

Number of patent publications

500

USA

CHN

400

200

2

0

02
-2
21
20

20

19

-2

02

8
-2
17
20

20

15

-2

01

01

6

4
01
-2
13
20

20

11
-

20

12

0

Publication year
(B)

USA: 11.308

USA: 23,286

EPO: 18,024

EUR: 5,398
JPN: 3,255

DEU: 2,997
JPN: 2,210
CAN: 1,743

US: 8,771

CAN: 3,218
CHN: 2,485

WIPO: 4,846

KOR: 1,362

FRA: 1,371

CHN: 1,560

IND: 1,236

CHE: 1,139

JPN: 722

ESP: 869

CAN: 711

BRZ: 853

ESP: 660

MEX: 804

ISR: 1,134
CHN: 1,100
GBR: 1,052

DEU: 586

ITA: 931

FRA: 440
ITA: 264

ESP: 833

Others: 1,212

OTH: 4,267

Figure 5. (A) Growth in patent publications over the last decade (2011-2022) in the field of lipid-based materials. (B) Sankey
graph depicting flow of patent families in the lipid-based materials field between assignee countries (left), office where the first
application in a family is filed (center) and the office where individual patent publication activities take place (right).

Key materials, forms and applications

A detailed and comprehensive exploration of
our document and substance data from the CAS
Content Collection aided in the identification of
key materials across three major categories utilized
in the development and application of lipid-basedmaterials. Broadly speaking, these include:– Lipids– Payloads– Emulsifiers
Figures 6 and 7 show a detailed breakdown ofmaterials across these categories. The category of
lipids was further sub-classified into the following
general classes:– Sphingolipids– Sterols– Phospholipids– Glycerides– Cationic lipids– Oil and waxes– PEG-lipid conjugates
In order to identify lipids that have seen an
increase in interest over time, we plotted therelative publication growth rates for >50 lipids
over 2012-2023 and used this information toshortlist key lipids shown in Figure 8. The
biggest takeaway from our data analysis wasthat of the identified lipids, cationic lipids such
as 2,3-dioleyloxy-N-[2-(sperminecarboxamido)
ethyl]-N,N-dimethyl-1-propanaminium(DOSPA; CAS number: 282533-23-7),
dimyristyloxypropyl-3-dimethyl-hydroxyethyl
ammonium (DMRIE; CAS number: 153312-64-2),
1,2-dioleoyl-sn-glycero-3-ethylphosphocholine(EDOPC; CAS number: 183283-20-7) anddioctadecylamidoglycylspermine (DOGS;
CAS number: 124050-77-7) and the PEG-lipid
conjugate DMPE-mPEG (CAS number: 47492282-2) show a sharp increase in publications
post 2018 (Figure 8A). Phospholipids such as
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(DOPE, CAS number: 4004-05-1) and
1,2-dioleoylphosphatidylserine (DOPS, CAS
Number: 70614-14-1) and sphingomyelin (CASnumber: 85187-10-6), a sphingophospholipid, also
show an increase in publications after 2018 but
the increase was of a more modest magnitude
as compared to the cationic lipids listed above(Figure 8A). Finally, publications related tothe phospholipid 1,2-dierucoyl-sn-glycero-3phosphatidylcholine (DEPC, CAS number: 5177995-4) grew rapidly from 2018 to 2020 and thenappears to have plateaued (Figure 8A).
During the COVID-19 pandemic, a number oflipids were utilized in the delivery of vaccines
being developed. The growth in interest (in termsof relative growth in publications) for these diverse
lipids belonging to classes such as cationic lipids,
PEG-lipid conjugate, phospholipids and sterols
are shown in Figure 8B. Of particular note are thecationic lipids – ALC-0315 (CAS number: 203627255-4) and SM-102 (CAS number: 2089251-47-6)– and the PEG-lipid conjugates – 2-[(Polyethylene
glycol)-2000]-N,N-ditetradecylacetamide (ALC0159, CAS number: 18496164-2-7) and DMGPEG (CAS number: 160743-62-4) which show a~5-6-fold and 3-fold increase in publications,
respectively.
The above-mentioned lipids can all be utilized toform various types of lipid nanocarriers including
liposomes, lipid nanoparticles, exosomes,
and emulsions, among others. We conducteda systematic search for the various types oflipid nanocarriers and their associated terms
and showcase their distribution and growth in
the lipid-based materials document dataset
in Figure 9. Liposomes, consisting of vesicles,
PEGylated, echogenic, stimuli-responsive, andbubble liposomes account for more than halfwhile lipid nanoparticles comprising of solid
nanoparticles (solid NPs), nanostructured lipid
carriers (nanostructured LCs), ethosomes,
cubosomes, and hexosomes account for a quarterof publications of the overall distribution (Figure
9A). Exosomes, a type of nanosized vesicles
enclosed by a lipid bilayer membrane that canbe used as drug delivery systems, and emulsions
account for about 12% and 10% of publications.
Virus-like particles (VLPs), well-ordered complex
structures composed of viral proteins that do not
retain the pathogenicity of viruses, have been
increasing explored in nanomedicine.43, 44 While
first discovered in the late 1960s,45 the use andexploration of VPNs appears to have proceeded ina modest fashion and accounts for a small fractionof overall publications in our dataset. Noteworthy,
recently a selective endogenous encapsulation
platform for cellular delivery has been developed
Trailblazing the future with emerging biomaterials | 35

based on mammalian capsid protein homologs
that form virus-like particles, and a long terminal
repeat retroviral-like protein, which preferentiallybinds and facilitates vesicular secretion of its own
mRNA.46 This modular platform, engineered
to package, secrete, and deliver specific RNAs,
has been demonstrated to be suitable fordevelopment as an efficient therapeutic delivery
unit, which potentially provides an endogenous
vector for RNA-based gene therapy. In terms ofgrowth and time trends, among the subtypes ofliposomes, stimuli-responsive liposomes47, 48 showa sharp growth after 2016 while vesicles show amore controlled/modest but sustained growth
for the last two decades (Figure 9B). Interest in
PEGylated liposomes49 appears to be more or lesssteady with neither a sharp increase nor decrease.
Finally, echogenic and bubble liposomes appear
to show a slight decline in interest around thesame time (i.e., post 2018) however the volume of
publications associated with these subtypes aremuch smaller than the others.
The diverse stimuli that have been utilized in
the context of lipid nanocarriers can be broadly
categorized into exogenous and endogenous
with the former accounting for nearly 2/3rdof publications related to stimuli-induced
release (Figure 10A). Of the various exogenous
stimuli magnetic field based50, 51 and light orphotosensitive/photo responsive52 release systems
appear to be more popular than temperature53
and ultrasound54, 55 based signaling. In termsof growth over time, publications related toendogenous stimuli, especially enzyme56, 57 andredox, 58, 59 appear to show a sharp growth after
2014 (Figure 10B) while those related to pH60
showed a more modest increase. Publications
related to exogenous stimuli show a more or lesssustained increase over the last two decades.
The diverse types and subtypes of lipid
nanocarriers are utilized for formulations forvarious routes of administration, including oral(enhancing drug absorption in the gastrointestinal
tract), topical and transdermal (improving drug
permeation through the skin), inhalation (forrespiratory diseases), and parenteral (bypassing
second pass metabolism and improving
bioavailability as well as allowing for targeted
systemic delivery). Distribution of publications

pertaining to modes of delivery show more or lesseven contributions from parenteral, transdermal,
and otic delivery routes (Figure 11A). The next
most abundant route is oral accounting for 12%of the publications, followed by comparable
contributions by inhalation, ophthalmic andnasal routes. Other routes such as rectal, vaginal,
sublingual, and buccal contribute to a smaller
extent than the rest. A further breakdownof parenteral routes indicate preference for
intravenous which accounts for nearly a third of
the parenteral data, followed by subcutaneousand intramuscular. Intraperitoneal administration(injection into the abdominal cavity) is a common
method of administration used in laboratory
animals for drug discovery research61 andprobably accounts for data corresponding totesting of lipid formulations. Intrathecal62 andepidural64 administration (injection into the spinalcord), intracerebroventricular63 administration(injection into the brain), and intracardiac65
administration (injection into the heart) are lesscommon and used in limited circumstances. A
heat map showing co-occurrences between
lipid nanocarriers, and the various routes ofadministrations are shown in Figure 11B. Listed
below are a few key observations from the heatmap:
1. Most of the lipid nanocarriers show a distinct
preference for any one administration route
over others. This was especially pronounced
for exosomes and ethosomes having highest
co-occurrences with otic and transdermalroutes of administration, respectively.
Indeed, ethosomes – soft malleable vesicles
comprising ethanol – have been specificallydeveloped to improve the delivery of various
drugs via the skin.66 Exosomes, on the other
hand have been shown to increase thedelivery efficiency of locally administeredinner ear therapies, such as the exosomeassociated adeno-associated virus.67
2. PEGylated liposomes are most appropriate
for intravenous delivery closely followed by
the otic route. Indeed, PEGylation has been
specifically invented in an effort to improvesystemic circulation time of drug carriers,
thus improving their delivery efficiency after
intravenous injection.68

3. Non-lamellar structured lipid nanoparticles
such as cubosomes and hexosomes
comprising lipids in bicontinuous cubicor hexagonal liquid crystalline phases,
respectively, are becoming popular drug
carriers for transdermal/topical delivery
because of their ability to perturb the
structure of the skin’s outermost layer – thestratum corneum, thus enhancing the drug
permeation.69
Perhaps one of the biggest applications of lipidbased materials is in the delivery of various
payloads including small molecules (drugs)70, 71
and biologics such as siRNA72, 73 as well as vaccine
delivery74, 75 and gene therapy (safe and efficientgene transfection).76, 77 Figure 12A and 12B show
the distribution of various applications and their
growth over the years for lipid-based materials.
In terms of drug delivery, lipid nanocarriers havebeen utilized in cancer therapy to reduce systemic

Lipidstoxicity and enabling targeted delivery78-80 as wellas in the treatment of infectious diseases withan aim to improve drug stability and selectively
delivery to infected tissues.81-83 Besides these,
lipid nanocarriers are employed also in thetreatment of neurological disorders (overcoming
blood-brain barrier challenges),84 ophthalmic
conditions (enhancing drug retention in theeye),85 cardiovascular therapies (improving drug
solubility and controlled release),86 and more.87
The application of LNPs has also been extended toother ﬁelds, such as medical imaging, cosmetics,
nutrition, agriculture, and other innovative areas
such as nanoreactors. Lipid nanocarriers havebeen used to deliver contrast agents in X-ray
and other types of imaging.88, 89 The use of lipid
nanocarrier in the food industry 90, 91 also shows an
upward trend (Figure 12). Cosmetics92, 93 is anothercommercial sector where the use of lipid-basedmaterials have shown a sharp increase (Figure 12).

Payloads

Emulsifiers

Figure 6. Distribution of key materials in lipid-based nanoparticles in terms of publications (journals and patents) based on dataobtained from the CAS Content Collection for the period 2012 to 2023. A further breakdown of key lipids is shown in Figure 7.

Trailblazing the future with emerging biomaterials | 37

***Sterols*

Oils &
waxes

Sphingolipids

Phospholipids

Cationic
lipidsPEG-lipid
conjugates***

Glycerides

**
**
**

*

Figure 7. Detailed distribution of lipids in terms of publications (journals and patents) based on data obtained from the CAS
Content Collection for the period 2012 to 2023. Size of the circle corresponds to number of publications (journals and patents).
The growth of materials marked with an asterisk are shown in Figure 8.

(B)

Publication year

2
20

21

-2

02

0
19

-2

02

8
20

17

-2

01

01
-2
15

01
-2

-2
21
20

20

0

6

20

20

2

40

02

0
20

19

-2

02

8
01
-2
17
20

-2
15
20

-2
13
20

01

4

0

6

15
10
5

60

4

20

80

13

40
35
30
25

ALC-0159
ALC-0315
SM-102
DMG-PEG
Cholesterol
DSPC

100

20

45

Relative publication growth (%)

DOGS
Monoolein
DOPE
DOPS
Sphingomyelin

DOSPA
DMPE-mPEG
DMRIE
DEPC
EDOPC

01

Relative publication growth (%)(A)

Publication year

Figure 8. Growth of a (A) few select lipids emerging over the last decade and (B) lipids used in COVID-19 vaccine LNPs. Data
includes journal and patent publications over the last decade (2012 to 2023) obtained from the CAS Content Collection.

(A)

(B)

Virus-like particles (0.7%)
Emulsions

20

Exosomes

Solid LNPs Bubble (0.1%)(13%)
Stimuliresponsive
3%(0.1%)
Echogenic(0.2%)PEGylated

22%

35
30

Cubosomes
Solid LNPs
Nanostructured LCs
Hexosomes
Ethosomes

25
20
15
10
5
0

05 00420 -20
07 06
20 -20
09 08
20 -20
11 10
20 -20
13 12
20 -20
15 14
20 -20
17 16
20 -20
19 18
20 -20
21 20
-2
02
2

12%

-2

Vesicles(52%)

Cubosomes (1%)
Ethosomes
Nanostructured
3%
5%
LCs

03

Hexosomes(0.2%)

20

55%

Relative growth in publication (%)

Liposomes

03
20 -20
05 04
20 -20
07 06
20 -20
09 08
20 -20
11 10
20 -20
13 12
20 -20
15 14
20 -20
17 16
20 -20
19 18
20 -20
21 20
-2
02
2

10%

Stimuli-responsive
Vesicles
PEGylated
Echogenic
Bubble20

Lipid prodrugs (0.1%)

40
35
30
25
20
15
10
5
0

30

Exosomes
Virus-like particles
Emulsions
Lipid prodrugs

25

Lipid NPs

20
15
10
5

20

20

03

-2

05 00420 -20
07 06
20 -20
09 08
20 -20
11 10
20 -20
13 12
20 -20
15 14
20 -20
17 16
20 -20
19 18
20 -20
21 20
-2
02
2

0

Publication year

Figure 9. (A) Distribution of various types and subtypes of nanocarriers comprised of lipid-based materials. Outer donut chartshows the broader classification – liposomes, lipid nanoparticles (lipid NPs), exosomes, emulsions, virus-like particles, and lipid
prodrugs, while inner pie chart depicts the breakdown across liposomes and lipid NPs. (B) Growth in publications (journals andpatents) of the different types of lipid-based materials. Data includes journal and patent publications over two decades (2003 to2023) obtained from the CAS Content Collection.

(A)

(B)

Enzyme(1%)

Magnetic
field
40%

Redox
potential (1%)
pH
18%

)
Ultrasound (4%Temperature
15%
Light
21%

Relative growth in publication (%)

Endogenous
20%

35

Enzymes
Redox
Light
pH
Ultrasound
Magnetic field
Temperature

30
25
20
15
10
5

Exogenous

20
22

0

1-

20
2

8

-2
02

19
20

6

-2
01

17
20

4
20

15

-2
01

2

-2
01

20
1

20

13

0

20
11
-

8

-2
01

09
20

6

-2
00

20

07

-2
00

05
20

20

80%

03

-2
00

4

0

Publication year

Figure 10. (A) Distribution of various types of stimuli-responsive lipid-based materials. Outer donut chart shows two major
categories of stimuli – exogenous and endogenous while inner donut chart shows the breakdown across those categories. (B)
Growth of specific stimuli utilized in stimuli-responsive lipid nanocarriers. Data includes journal and patent publications over two
decades (2003 to 2023) obtained from the CAS Content Collection.

Trailblazing the future with emerging biomaterials | 39

(B)

(A)

Vesicle

8.0
3.0
4.0
0.3
0.4
0.1
0.7
2.6
1.4
32.0
8.5
14.2
1.4
1.4
4.5
2.2
6.0
8.7
0.6

PEGylatedliposome

28.2
1.4
3.1
0.0
0.8
0.6
0.0
4.7
0.8
11.2
3.9
7.3
0.0
0.0
8.7
0.3
2.8
5.0
21.2

Modes of Delivery

Intravenous

Otic

Inhalation

Nasal

Vaginal

RectalBuccalSublingual

Oral

Ophthalmic

Transdermal/topicalIntrathecal

Intraperitoneal

Intradermal

Intracardiac

Intracerebroventricular

EpiduralSubcutaneous

Intramuscular

40.0%

20%

4%
6%

0.0%

21.1
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
15.8
10.5
5.3
0.0
0.0
0.0
0.0
0.0
10.5
36.8

0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
50.0
12.5
0.0
0.0
0.0
0.0
0.0
0.0
0.0
37.5

StimuliEchogenic
Responsive
Liposomes
Liposomes

0.1%

Otic

18%

Ophthalmic

0.0%

Oral

0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
25.0
25.0
0.0
0.0
0.0
0.0
0.0
0.0
50.0

Bubbleliposome

12%

1.1%

4.2
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
50.0
4.2
20.8
0.0
4.2
0.0
0.0
0.0
8.3
8.3

3.2
0.5
0.5
0.0
0.0
0.0
0.5
0.5
0.5
28.6
19.0
21.7
0.0
0.5
2.6
1.1
5.3
1.6
13.8

Hexosomes Cubosome

0.1%

7% Inhalation

6%

Nasal

RectalVaginal (2%)

Modes of delivery(2003-2023)
Journals and patents

23%

2.0%

Transdermal/
topicalParenteral

Sublingual (1%)
Buccal (1%)

5.4%

36%

2.8
0.6
1.1
0.1
0.2
0.0
0.3
0.3
0.2
31.5
11.2
20.3
0.1
1.0
3.4
1.0
6.7
7.6
11.7

3.6
0.6
0.8
0.0
0.1
0.0
0.1
0.6
0.0
43.9
13.4
15.8
0.1
0.5
1.7
0.5
7.2
2.0
9.0

5%
6%

0.1
0.1
0.8
0.0
0.0
0.0
0.4
0.0
0.0
84.7
1.8
3.7
0.1
0.5
0.8
1.5
1.5
0.1
3.9

Ethosomes

4.4%

3.8
1.4
2.0
0.1
0.3
0.2
0.5
1.6
1.0
5.5
2.3
3.9
0.3
0.3
0.5
0.5
2.8
1.3
71.8

Exosome23.7%

Subcutaneous

21%

8.0
8.8
11.2
0.0
0.0
0.0
2.4
5.6
0.0
17.6
2.4
8.0
3.2
2.4
1.6
3.2
12.0
4.8
8.8

Virus-likepar cles

0.7%

9.7%

1.4
0.6
1.0
0.0
0.1
0.0
0.3
0.1
0.0
53.0
11.6
10.0
0.2
0.9
1.6
1.0
5.5
3.9
8.8

14.3
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
14.3
14.3
42.9
0.0
0.0
0.0
0.0
0.0
0.0
14.3

Lipid
prodrugs

0.0%

Intramuscular

Intraperitoneal

Emulsions

17%

13%

Intrathecal

Intradermal

Intracerebroventricular (1%)

Parenteral routes(2003-2023)
Journals and patents

Solid Lipid Nanostructured
Nanoparticles Lipid Carriers

12.7%

Intravenous

Epidural (1%)
Intracardiac (0.2%)

Low

High

Figure 11. (A) Distribution of publications (journals and patents) with respect to various modes of delivery utilized for administration of lipid nanoparticles (left panel) with a further
breakdown of parenteral routes (right panel). (B) Heat map depicting co-occurrences of various types of lipid-based materials with modes of delivery in the field of lipid-based materials
based on data obtained from the CAS Content Collection for the period 2003 to 2023.

ParenteralTrailblazing the future with emerging biomaterials | 41

3%
4%
5%

Nutrition
Diagnostic
and imaging

Immunochemistry (1%)
Cosmetics

(B)

4

0
20

2
3-

6

0
20

8

0
20

1
20

0

1
20

2

1
20

4

2
4
6
8
0
4
6
8
0
2
00 200 200 201 201 201 201 201 202 202
005 07 09 11 13 15 17 19 21
20 20 20 20 20 20 20 20 20 20

0

10

20

30

Nanoreactors
Nutrition
Agriculture
Drug delivery
Diagnostic and imaging
Membrane models
Cosmetics
Immunochemistry

Publication year

16 018 020 022
0
2
2
2
2
3- 05- 07- 09- 11- 13- 15- 17- 19- 210
20
20
20
20
20
20
20
20
20
20

0

5

10

15

20

25

30

40

50

60

Figure 12. (A) Distribution of major applications of lipid-based materials (B) Growth in applications of lipid-based materials over last two decades (2003 to 2022). Data
includes journals and patent publications obtained from the CAS Content Collection.

Drug delivery

86%

Applications(2003-2023)
Journals
and patents

Membrane models (0.4%)
Agriculture (0.2%)
Nanoreactors (0.1%)(A)

Relative growth in publication (%)

Notable journal articles and patents

Table 1 consists of a set of research articles
published from 2020-2023 that are representativeof emerging trends in this field. Articles wereselected on the basis of the collective factors
such as journal impact factor, citations, andtype of study. These articles provide the usageof different forms of lipids examples including
vesicles, liposomes, cubosomes, hexosomes,
and ethosomes for varied applications. Notable
examples from Table 1 include an article titled“Theranostic combinatorial drug-loaded
coated cubosomes for enhanced targeting andefficacy against cancer cells” by the Tian groupat Jilin University, China describes assembly of
structured lipid nanoparticle known as cubosomes
encapsulating a combination of anticancer
drugs - cisplatin and paclitaxel. Cubosomes were
coated with poly-ε-lysine to avoid their prematurebursting and targeted drug release. These were
found to be nontoxic in human hepatoma HepG2cell line and exhibited anticancer activity against
HeLa cells in vitro.94
In another example, an article titled “Selective
organ targeting (SORT) nanoparticles for tissuespecific mRNA delivery and CRISPR–Cas gene
editing” by Seigwart et al. describes a Selective
Organ Targeting (SORT) strategy to selectively
target different kinds of cargoes which could
be either Cas9 mRNA, Cas-9 single guide RNA(sgRNA) or Cas9 ribonucleoproteins (RNPs) or Cre
recombinase mRNA, to target organs such as theliver, kidney, and spleen in mice. It is accomplishedby adding an additional molecule called SORT
which helps in tissue-specific delivery and editing
using CRISPR-Cas based method.95
In another recent example, an article titled “CAR
T cells produced in vivo to treat cardiac injury”
explains generation of messenger RNA (mRNA)
encoding CAR against FAP protein present on

activated fibroblasts. This mRNA is packaged inlipid nanoparticles (LNPs) targeting CD5 present
majorly on T cells. These LNPs were tested fortheir efficacy of targeting T cells in vitro, where
they improved cardiac function after injury upon
intravenous administration.96
Table 2 shows notable patents in the field of
lipid-based materials published from 2018 to2023. Patents were selected based on relevance,
novelty, applicability, and field of study. Most ofthese involve different forms of lipids, methodsof analysis and their applications. For instance,
CN110960507B97 describes synthesis of calcium
phosphate-lipid nanodrug system using lipids
like distearoylphosphatidylethanolaminepolyethylene glycol 2000 (DSPE-PEG2000) and (2,3-dioleoyl-propyl)-trimethylamine (DOTAP). These
nanoparticles encapsulate heparin and anti-breast
tumor drugs which could be co-delivered to thetumor site.
In another example, US11207269B298 describes
the liposomes for delivery of small molecule
based antitumor drug. The study describes thesynthesis of secretory phospholipase A2 (sPLA2)hydrolysable liposomes. sPLA2 levels are elevatedin cancerous or inflamed tissues, making theseliposomes potentially useful for delivering
antitumor agents.
In another recent example, CN115869262A99
provides synthesis methodology for a newpolyethylene glycol (PEG) lipid compound
which was combined with a cationic lipid,
distearoylphosphatidylcholine, and cholesterol togenerate lipid nanoparticles. These LNPs can beused for targeted drug or nucleic acid delivery.

Table 1. Notable journal publications in the field of lipid-based materials in recent years.

Research
Institute

Year

Title

JournalApplication

2020

Theranostic combinatorial drug-loaded
coated cubosomes for enhanced targetingand efficacy against cancer cells94

Nature Cell
Death & Disease

Jilin University

Combinatorial drug-loaded cubosomes
which can diagnose and treat cancer

2020

Selective organ targeting (SORT)
nanoparticles for tissue-specific mRNAdelivery and CRISPR-Cas gene editing95

NatureNanotechnology

University of
Texas

Using selective organ targeting (SORT)
strategy to engineer multiple lipid
nanoparticles each capable of selectively
delivering different cargoes to liver, spleen,
and lungs in mice.

2021

Characterization of Lipid Nanoparticles
Containing Ionizable Cationic Lipids Using
Design-of-Experiments Approach100

Langmuir

University of
British Columbia

Lipid nanoparticle -short interfering RNA
system (LNP-siRNA) and its optimization
using design of experiments (DOE)
approach.

2021

Mammalian retrovirus-like protein PEG10
packages its own mRNA and can be
pseudotyped for mRNA delivery46

Science

Massachusetts
Institute ofTechnology

Designing a retroviral-like protein, PEG-10
which binds mRNA to form capsids andsecretes it at the target site, this tunability
becomes the basis of selective endogenous
encapsidation for cellular delivery (SEND)
delivery platform.

2021

Ionization and structural properties of mRNA
lipid nanoparticles influence expression
in intramuscular and intravascularadministration101

Communication
Biology

University ofCalifornia

Using theoretical and experimental methods
to determine pKa of lipid nanoparticles
by calculating pKa of ionizable lipids tominimize off-target LNP delivery.

2022

CAR T cells produced in vivo to treat cardiac
injury96

Science

University ofPennsylvania

Anti-fibrotic CAR-T cells based on mRNAloaded LNPs directed towards cardiac CD5cells

2022

Anti-PEG Antibodies Boosted in Humans
by SARS-CoV-2 Lipid Nanoparticle mRNA
Vaccine102

ACS Nano

University of
Melbourne

Monitor Anti PEG antibody response by
SARS-CoV-2 Lipid Nanoparticle vaccine

2022

Engineered exosomes as an in situ DCprimed vaccine to boost antitumor immunity
in breast cancer103

Molecular
Cancer

Wuhan
University

Engineered breast derived cancer exosomes
to form in situ dendritic cell (DC) vaccines

2023

Glucose-Responsive Charge-Switchable
Lipid Nanoparticles for Insulin Delivery104

Angewandte
ChemieZhejiang
University

LNP-insulin complexes that can sense
glucose and exhibit prolonged glucose
releaseTrailblazing
thethefuturewithemerging
biomaterials| 43
Trailblazing
futurewithemerging
biomaterials| 43Table 2. Notable patent publications in the field of lipid-based materials in recent years.

Patent or
Publication
numberPublication year

Patent assignee

Title

Description of patented technology

US10429302B2105

2019

Scintillon Institute
For Biomedical And
Bioenergy Research, USA

Optical analyses ofparticles and vesicles

Method of analyzing vesicles based on
addition of optical labels to obtain opticalsignals for their detection.

US10851372B2106

2020

University of Ottawa,
CanadaExosome packaging of
nucleic acids

Method for packaging interfering messenger
RNA (mRNAi) into exosomes to produce
exosomes with an increased nucleic acidcontent.

WO2021262879A1107

2021

Chameleon Biosciences,
Inc., USA

Extracellular vesicles withimmune modulators

Preparation of extracellular vesicles (EVs)comprising a lipid bilayer containing
immunosuppressive agents/ immune checkpoint proteins.

US11207269B298

2021

Bio-Bedst ApS, Denmark

Medical use of sPLA2hydrolysable liposomes

Preparation of secretory phospholipase A2(sPLA2) cleavable liposomes encapsulating
cancer drug for targeted delivery of anticancer medication.

US11021745B2108

2021

Roche Sequencing
Solutions Inc. USA

Methods for forming
lipid bilayers on biochips

Assembly of biochips layered with lipid bilayer
for use in sensing applications.

CN113101280B109

2021

Harbin University of
Science and Technology,
China
Suzhou Hualancheng
New Biomaterial
Technology Co., Ltd.,
China

Solid lipid nano bacterial
cellulose eye care patch
and preparation method
and application thereof

Preparation of composite from solid lipid
nanoparticles and bacterial cellulose (1:5 ratio)
to be used for eye healthcare.

CN110960507B97

2022

Fudan University, China

Calcium phosphate-lipid
nano-drug co-delivery
system composed of
low-molecular-weight
heparin and natural
drug prodrug

Development of calcium phosphate-lipid
nano-drug co-delivery system for treatmentof breast cancer.

US11510872B2110

2022

Northwestern University,
USA

Nanoparticle-lipid
composite carriers anduses thereof

Synthesis of nanoparticles and lipid
composites which anticancer drugs inhydrophobic core. These composites canalso be derivatized and used for cancer
theranostics.

CN115894555A111

2023

Wenzhou ResearchInstitute Of Guoke,
Wenzhou Institute
Of Biomaterials And
Engineering, China

Lipid prodrug nanoassembly based on
dynamic covalentchemistry andpreparation method andapplication thereof

Construction of lipid-based prodrugs bydynamic covalent chemistry such that the
prodrug can later be attached to antibacterial/
antiviral/anticancer drugs.

CN115869262A99

2023

Guangzhou Anovent
Pharmaceutical Co. Ltd.,
China

Novel PEG lipid
compound, preparation
method, composition
and application thereof

Preparation of a novel polyethylene glycol(PEG) based lipid which could be used in drug
and nucleic acid delivery.

Challenges and perspectives

Challenges in the development of lipid
nanocarriers include drug loading andencapsulation as well as stability issues, scale-up
complexities, biocompatibility concerns, limited
drug loading capacity, drug release control,
regulatory hurdles, cost considerations, and longterm storage requirements.
1. Achieving high drug-loading capacity while
maintaining the stability of the lipid-based
system can be challenging. It is necessary
to achieve a delicate balance between highdrug loading and particle size distribution
and stability of the lipid carriers.87 It is alsoessential to ensure that the drug is uniformly
distributed within the lipid matrix.2
2. Lipid-based systems can be susceptible tophase separation and drug crystallization
over time.112 Maintaining the physical stabilityof these systems throughout their shelf life isa significant challenge.
3. Lipids are susceptible to oxidationand hydrolysis, which can lead to thedegradation of both the lipid matrix and theencapsulated drug.113 Special care is required
to prevent these reactions.
4. Controlling the release of the drug fromthe lipid carrier is essential for achieving thedesired pharmacokinetics.114 Achieving thedesired release profile can be challenging,
especially for sustained or controlled releaseformulations.
5. Although lipid-based systems can improvedrug solubility, the enhancement ofbioavailability can be variable.115 Factors suchas the type of lipid used, drug properties,
and patient-specific factors can impact theoverall bioavailability of the drug.
6. The production of lipid-based drug delivery
systems may be more complex compared
to traditional dosage forms, requiring
specialized equipment and expertise.10

7. Ensuring good compatibility between thelipid-based system and the drug, as well as
any excipients, is crucial. Incompatibilities
can lead to drug degradation, reduced
stability, or altered drug release profiles.116
8. Meeting regulatory requirements andobtaining approval for lipid-based drugdelivery systems can be challenging due tothe need for extensive safety and efficacy
data, especially if they involve novel lipid
formulations.10
9. Transitioning from laboratory-scale
production to large-scale manufacturing
can pose challenges, as maintaining productquality, consistency, and stability at alarger scale may require extensive processoptimization.117
10. Lipid-based drug delivery systems canbe more expensive to develop, andmanufacture compared to conventional
dosage forms, which can affect the overall
cost of the drug product.118
11. Traditional approach of lipid-based drug
development and testing is time consuming
and labor intensive. To overcome these
difficulties, AI and machine-learning based
approaches in conjunction with traditional
synthesis methods can help in efficientsynthesis of lipids; However, structurally
lipids are at the interface of small molecules
which have a well-defined structure andlarge polymeric molecules complicating AI
driven efforts. Despite this, in recent years
efforts have been made in this direction.119
Ongoing research and innovation in lipid-based
drug delivery systems aim to overcome thesechallenges and harness the full potential of thesesystems for improving drug delivery. This requiresa multidisciplinary approach involving combined
efforts of pharmaceutical scientists, chemists,
engineers, and clinicians.

Trailblazing the future with emerging biomaterials | 45

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Trailblazing
thethefuturewithemerging
biomaterials| 51
Trailblazing
futurewithemerging
biomaterials| 51

IV. Bioinks
Introduction

including the types of materials utilized in bioinks,
bioprinting techniques themselves, as well as
fields of applications.

Bioinks are biomaterials composed of a complex
mixture of substances, often containing desired
cell types with natural or synthetic polymers
and other supporting materials. Bioprinting,as a method, often utilizes bioinks with a goal
to fabricate biological structures in threedimensional scaffolds, tissues and organs. While
the term “bioprinting” is relatively recent, theidea itself dates back to the late 90s and was anatural extension of 3D printing in the biomedical
domain. Bioprinting has diverse applications,
including tissue engineering, wound healing,1-3
disease modeling,4-6 personalized medicine,7,8drug testing and development,9, 10 and evendrug delivery. 11-14 Interest in bioinks has been
on a steady increase in the last two decadeswith an acceleration around 2015 (Figure 1). In
general, journal publications outnumber patentpublications in this field with a ratio of 5:1 in 2022
indicating that the field is still in its nascent stages.
This continuously accelerated interest has led to an
expansion in the different aspects of bioprinting

1,400

JournalLive cells are one of the primary building blocksof bioink. They can include various cell types:(1) stem cells15-18 – highly versatile and candifferentiate into various cell types. They can bederived from sources like bone marrow, adipose
tissue, or induced pluripotent stem cells (iPSCs);(2) endothelial cells19 – essential for vascularizationand ensuring that the newly bioprinted tissue
receives an adequate blood supply; (3) tissue
specific cells – for example: keratinocytes andfibroblasts20, 21 for skin bioprinting, chondrocytes22
for cartilage bioprinting, and muscle cells forcontractile tissues. The incorporation of live cells
into bioink allows for the creation of functional
tissues because these cells can proliferate,
differentiate, and interact with the surrounding
environment, mimicking the behavior of natural
tissues.

PatentNumber of publications

1,200
1,000

*

800
600
400
200

23

20

22

21

20

20

20

19

20

20

18

17

20

16

20

15

20

20

14

13

20

20

11
12
20

20

10

09

20

08

20

07

20

20

06

05

20

04

20

20

20

03

0
Publication year
Figure 1. Number of journal and patent publications per year in the field of bioinks (shown as blue and yellow bars respectively)
over the period of the last two decades (2003-2023). * The data for 2023 only include months from Jan to Aug.

Growth factors are signaling molecules that
regulate various cellular processes, including
cell proliferation, differentiation, cell-cell/cellenvironment interaction, tissue development, andtissue repair. In bioink, growth factors are typically
added to stimulate specific cellular behaviors andenhance tissue development. Some common
growth factors used in bioprinting include:transforming growth factor-beta (TGF-β),23-25
vascular endothelial growth factor (VEGF),26,27
epidermal growth factor (EGF),28 plateletderived growth factor (PDGF),29 and fibroblast
growth factor (FGF).26, 27 These growth factors
can be incorporated into the bioink formulationin controlled concentrations to guide cell
behavior and tissue formation. They help create a
microenvironment that promotes cell proliferationand differentiation, ultimately leading to thedevelopment of functional and structured tissues.
However, live cells are fragile and lack thenecessary structural framework to grow andmaintain intricated connection and desired form.
Synthetic polymers, such as polyethylene glycol(PEG) and its derivative polyethylene glycol
diacrylate (PEGDA)30-32 and polycaprolactone(PCL),33-35 are often incorporated into bioinks toprovide the necessary mechanical strength andscaffold-like structures that help maintain thedesired tissue shape. These synthetic polymers canbe precisely tuned for properties like stiffness anddegradation rate, ensuring they match the specificrequirements of the target tissue. Meanwhile,natural polymers like collagen,36-39 fibrin,40 andgelatin41-43 offer bioactivity and biocompatibility,
closely resembling the extracellular matrix (ECM)of native tissues. Many of these polymers canform hydrogels which possess characteristics suchas oxygen and nutrient permeability, the ability
to absorb substantial amounts of water withoutcompromising their structure, biocompatibility,and biodegradability, among others. Importantly,hydrogels offer cells the freedom to migrate,
creating a dynamic environment akin to theextracellular matrix ECM, rendering themindispensable components of bioinks. Thisbiomimicry enhances cell adhesion, proliferation,and differentiation within the printed tissue. The

combination of synthetic and natural polymers
in bioinks optimally balances structural support
with the biological environment necessary for the
successful 3D bioprinting of functional tissues
and organs.
The realm of bioprinting encompasses
various established methods, including laserassisted, droplet-based, and extrusion-based
techniques.44-46 These broad methods further
branch into subcategories like inkjet, acoustic,or micro-valve droplet-based bioprinting.47
Selecting the appropriate bioink and bioprinting
technique hinges on several factors, such as theintended structure, and the mechanical design ofthe bioprinter, as well as the material's inherent
properties.44, 46, 48 For instance, while rapid gelation
is often a universal requirement, extrusionbased bioprinting proves more accommodatingof varying viscosities, contrasting with dropletbased bioprinting, which performs optimally withlow-viscosity bioinks.46 In terms of the intended
structure, whether hard (e.g., cartilage and bone)or soft (e.g., skin) tissue engineering, the demands
on bioink characteristics tend to be distinct. Softtissue engineering, for instance, necessitates
a delicate balance of elasticity, flexibility, andstructural integrity, a challenge often difficult toachieve. Light-based techniques such as photocross-linking can enhance better mechanicalproperty in existing constructs upon in-situ
crosslinking or produce a scaffold in a bioresin
reservoir using computed axial lithography.49
Within this chapter, we present our findings
stemming from a comprehensive examinationof approximately 7,000 documents, comprisingboth journal and patent publications, spanningthe period from 2003 to 2023 in the field of
bioinks. Our analysis centers on the overarching
publication trends, with a particular emphasis on
uncovering emerging materials, elucidating theirinteractions with key properties, and exploring
their potential applications.

Trailblazing the future with emerging biomaterials | 53

Journal and patent publication trends

To identify the leading research institutions in thisfield, we analyzed the average citation numbers
per publications among the top 150 organizationsin terms of total journal publications associatedwith bioinks. The top 15 research organizations
with highest average citation per paper are
shown in Figure 2. Among the 15 institutions, 6 ofthem are from the US, 4 from China, and 2 from
Korea. Harvard Medical School, with an averageof 110 citations per publication, leads the top 15
organizations.
The geographical distribution of patent assignees
across both commercial and non-commercial
entities reveals a substantial overlap, as illustrated
in Figure 3. The United States (USA) and theRepublic of Korea (KOR) dominate as leaders inboth commercial and non-commercial sectors.
China (CHN) exhibits a slightly more favorable
position in the non-commercial sector compared
to its standing in the commercial sector. Beyond
these frontrunners, other noteworthy countries/
regions include Sweden (SWE), France (FRA),
India (IND), Israel (ISR), Germany (DEU), Australia(AUS), Russia (RUS), Spain (ESP), and Switzerland(CHE). Among the top patent assignees, theSweden-based company Cellink is a leading

commercial entity in 3D bioprinting. They provide
bioinks and bioprinters tailored for applications,such as tissue engineering regenerative medicine,disease modeling, drug delivery, and so on. For
instance, patents US11186736B2, SE1950711A150, 51 by
Cellink describe important advances in the field of
bioinks. The US company Organovo is dedicatedto creating functional human tissues and organs
using 3D bioprinting techniques. Their technology
allows them to print intricate cell structures layer
by layer with the goal of ultimately creating tissues
and organs for transplantation and drug testing.
For example, WO2018035138 A1,52 EP3215603B153
patents by Organovo describe the developmentof in-vitro bioprinted human tissue models suchas tumor models and 3D printed models of skinrespectively, which could help in the assessment
fo biological responses to test drugs. Notably
Organovo has used its proprietary 3D-printed
human tissue models to develop a leadtherapeutic molecule FXR314, which is currently inPhase II clinical trials for ulcerative colitis. 54
It is not surprising to see that the growth of patentpublications prior to 2013 remained flat, probably
due to its relatively nascent stage in those years.
Over the past decade, the United States (USA),
China, and Korea have consistently demonstrated

Average number of citations per publication
Organization

Harvard Medical School
University of California
Wake Forest School of Medicine
University of Pittsburgh
Pohang University of Science and Technology
University of Florida
Nanyang Technological University
University of Wollongong
Trinity College Dublin
Zhejiang University
University of Maryland
Sungkyunkwan University
Chinese Academy of Sciences
Tsinghua University
Sichuan University

Citations per publications
Number of journal publications (USA)
Number of journal publications (KOR)
Number of journal publications (SGP)
Number of journal publications (AUS)
Number of journal publications (CHN)
Number of journal publications (IRL)

Number of journal publications
Figure 2. The top 15 research institutions in terms of average citation numbers per journal publication between 2003-2023. The
different colors of the bars represent institution’s country/region: blue (USA), red (China), yellow (Singapore), purple (Korea),brown (Australia), green (Ireland) institutions; and the yellow line represents the average number of citations per publication.

an upward trend in patent publications, asevident in Figure 4A. While countries such as
India, France, Germany, and Sweden have shown
moderate publication growth since 2017, theiroverall share of the publication volume is small.
The flow of patent activities between assignee
countries (left), the first patent filing office for agiven family (center), and the patent office forindividual patent publications (right) is shown in
Figure 4B. This analysis indicates that applicantsin China, Korea, and France typically had the first
filing in for each patent family in their national
patent offices, while applicants in the US and

16%

USA

DEU

Top 10patent assignees
2003-2023
17%

4%
8%

8%

15%

Top 10patent assignees

ESP

2% DEU
2% RUS2%
2% AUS5%

2003-2023

FRA

IND

KOR

CHN

19%

5%
6%

SWE
IND

FRA

17%

SWE

CHN

Commercial

Non-commercial

30

Others25%2% CHE2%
3% GBR
4% ISR
4%O
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Number of patent publications

To provide an overview of how research effort has
been distributed among different types of tissue,
organs, or types of cells in the field of bioinks, acomprehensive analysis was conducted with theassociated terms and their frequencies appearing
in the published documents. Figure 5A shows the
distribution of most commonly used cell types
in bioinks by counting the publications using
CAS indexed terms. Publication volumes indicatethat mesenchymal, induced pluripotent, neural,

OthersUSA 31%

KOR

Australia more frequently filed initial patents
through WIPO/PCT.

Patent assignees

Patent assignees

Figure 3. The geographic distribution of patent assignees (top panels) and the leading patent assignees in terms of the numberof patent publications (bottom panels) from 2003-2023. Leading patent assignees were presented in two groups, commercial
and non-commercial. Bar graph has been color coded by country/region to match color scheme in donut charts. Standard threeletter codes used to represent countries/regions.

Trailblazing the future with emerging biomaterials | 55

(A)

80

16

FRA

14

60

12

USA

10

IND
DEU
SWE

8
6
4

50

AUS

2

KOR
CHN

20
22

20
21

20
20

20
19

20
18

20
17

20
16

20
15

40

20
14

0
20
13

Number of patent publications

70

30
20
10

22
20

21
20

20
20

19
20

18
20

17
20

16
20

15
20

14
20

20

13

0
Publication year
(B)

USA: 1,118

WIPO: 1,284

USA: 618

KOR: 401
KOR: 487

KOR: 416

CHN: 339
CHN: 269
FRA: 128
SWE: 116
AUS: 129
DEU: 73
CAN: 92
CHE: 71
IND: 62

USA: 271
EPO: 58
TWN: 11
CAN: 10
CHN: 240
FRA: 85
SWE: 43
JPN: 7
AUS: 20
DEU: 28
JOR: 23
IND: 49

EUR: 242
JPN: 159
CAN: 109
IND: 73
AUS: 24
BRZ: 22
Others: 79
FRA: 23

Figure 4. (A) Growth in patent family publications between 2003-2022 for the top 8 most prolific countries/regions. (B) Sankey
graph depicting flow of patent families in the bioink field between assignee countries (left), office where the first application in a
family is filed (center) and the office where individual patent publication activities take place (right).

and hematopoietic stem cells are importantfor bioinks.15-18 Besides stem cells, other major
cell subtype that co-occur in the bioink dataset
include blood cells (RBCs,55 platelets,7 blood cells)
and pancreatic cells. Schwann cell,56 a type ofneuronal cell co-occurs in much smaller fraction of
publications. Figure 5B shows the distribution of
publications in the field of bioinks across cell lines
derived from different species – human, mouse,plant, hamster, rat and monkey cell lines. Our
dataset shows distribution of publications across awide variety of tissues and organs wherein bioinks
are utilized to generate tissue constructs. The
biggest contributor is the wider group of organs,(A)followed by bone, muscle, and skin. Bioinks
appear to be utilized to a smaller extent for othertissues such as nerves, joints, tendon and ligament(Figure 5C). Further breakdown of organs into
sub-categories indicates that in ~50% of cases,
bioinks are utilized in liver-related constructs. The
next most abundant categories are blood vessels,consisting of veins, arteries and capillaries, andcardiac tissue. In recent years, bioinks have also
been utilized to create tissue constructs pertaining
to other organs such as kidney, lungs, mammary
gland, pancreas, and ocular/ophthalmic (Figure
5D).

(B)
Pancreatic cell (1%)
Schwann cell (0.1%)

Hamster cell line
Plant cell line

Rat cell line
Monkey cell line (1%)

Hematopoietic stem cell (2%)
Neural stem cell
2% 3%Blood cell
8%

2% 2%

3%
Mouse
cell line

12%
15% Stromal cell

Cell Type

Mesenchymal
40%
stem cell

Humancell line

Number of publications
2003-2023

15%
16%

79%

Cell Lines

Number of publications
2003-2023

Human cell line
HUVEC

Induced pluripotent
stem cell(C)(D)
Tendon (2%)
Joint (2%)

Ligament (1%)

Eye

Nerve

3% 4%

6%
Skin

Pancreas

4%

Lung

5%

10%

5%

Tissue/Organ

Number of publications
2003-2023

Muscle 11%

24%
Bone

44% Organ

Liver

50%

Mammary gland

KidneyOrgan-wise breakdown
Number of publications
2003-2023

12% Heart17%
Blood vessel

Figure 5. Distribution of publications (journals and patents) in terms of (A) cell type, (B) cell lines, (C) organ and tissue systems(left panel) with a further breakdown across different (D) organ systems (right panel) over the time period of 2003-2023.Organ
illustrations sourced from biorender- www.biorender.com’
Trailblazing the future with emerging biomaterials | 57

Key materials, properties and applications
A deep dive into our substance and publication
data pertaining to bioinks allowed us to identify
materials that serve as components of bioinks.
Figure 6 shows identified materials for bioinksthat have been classified into 4 major categories:– Natural polymers– Synthetic polymers– Cell-based materials– Others
One of the biggest categories of materials, naturalpolymers have been further sub-divided primarily
into polysaccharide and protein-based materials.
Polysaccharides are a type of carbohydrates
composed of multiple monosaccharide units
connected by glycosidic bonds. Among them,alginate, cellulose, hyaluronic acid, and chitosan,3,57
outrank other polysaccharide materials by
a considerable margin. In the protein-basedmaterials, the distribution is slightly more evenkeeled across materials such as peptides,58, 59

silk,60, 61 agarose,62-65 fibrins, and fibrinogen,40
though gelatin41-43 and collagen36-39 appear to leadin terms of number of publications associated withthem. Live cells or cell-derived materials are atparticular interest in this field – most commonly
stem cells such as mesenchymal, pluripotent,
embryonic among others,15-18 tissue specific cells,
growth factors, and extracellular matrix (ECM) .66-69
For example, fibroblasts, a type of connective
tissue cells that are responsible for producing
collagen fibers, have been incorporated into ahydrogel-based bioink and show potential fortissue engineering.20, 21 Chondrocytes, cells that arevital for production of collagen, are of increasing
interest and have been used to bioprint 3D
constructs of human ear.22 Other cellular materials
such as human platelet lysates are still in nascentstages of development and are starting to beincorporated into bioinks.70, 71 Osteocytes havebeen incorporated into bioinks with potential
utilization in creating bone constructs.72
To shed light on the growth in popularity ofmaterials over time, the growth rates in thenumber of the publications were assessed in thoseTrailblazing the future with emerging biomaterials | 59

Protein-based

OthersPolysaccharides

Natural polymers

OthersSynthetic
polymers

Cell-based

*

*

*
*
*
*
*
*
*
*
*

Figure 6. Distribution of materials in the field of bioinks over 2003-2023 obtained from the CAS Content Collection. Size of the circle corresponds to number of publications(journals and patents). Growth of materials marked with an asterisk are shown in Figure 8.

*
*

*
*

documents mentioning the specific materials. The
number of publications or the relative publication
growth rates are shown in Figure 7. Among thedifferent cell-based materials, stem cells and ECM
show steady growth in the last decade, with anacceleration around the year 2017 (Figure 7A).
Other cell types such as chondrocytes, fibroblasts
and endothelial cells show a modest growth.
Materials based on progenitor cells and blood
cells, show a conservative but upward growthtrend. Among the polymers, polysaccharides
such as alginate73-75 and hyaluronic acid76, 77
show consistent growth in the field of bioinks
with alginate leading by a wide margin (Figure
7B). Protein-based natural polymers such as
silk and silk-based polymers60,61 and otherpeptides58, 59 have seen sustained interest in
the last decade. Synthetic derivatives of naturalpolymers, methacrylated gelatin (GelMA)78-80
and methacrylated hyaluronic acid (HAMA),81, 82
start to appear in 2016 and seem to have doubled
between 2021-2022.

(A)

(B)

200

Fibroblasts
Endothelial cells
Progenitor cells
Blood cells

500

2
02

0
20

21

-2

02

8

-2

01
20

19

-2

01

17

-2
15
20

2

0

-2
20

20

21

19

-2

02

02

8
20

17

-2

01

6
15
20

13

01

01
-2

-2
21

20

Publication year

(D)

Publication year

30
20

2
20

21

-2

02

0
20

19

-2

02

8
01
-2
17

01
-2

01
-2

-2
21
20

20

0

6

10

15

2

40

02

0
20

19

-2

02

8
01
20

17

-2

01
-2
15
20

20

13

-2

01

6

0

50

20

10

Personalized medicine
Drug testing
Wound healing
Drug delivery
Disease modeling
Antibacterial

4

20

60

13

30

Relative publication growth rate (%)

Fibroblast growth factor
Transforming growth factor
Epidermal growth factor
Vascular endothelial growth factor

20

40

4

Relative publication growth rate (%)

(C)

20

01
-2
13

100

-2

2

4

0

200

6

5

0

20

Publication year

10

300

02

0
20

19

-2

02

8
01
-2
17
20

20

15

-2

01

4
01
-2

20

13

6

100
0

HAMA
GelMA

400 1520

Number of publications

2

20

21

-2

02

0
02

8

-2

01

19

-2
17

20

01
-2

01

15

-2

20

13

20

200

4

300

0

6

50

20

Number of publications

100

400

Peptide
Silk

20

150

500

Alginate
Hyaluronic acid

25

4

600

Stem cells
ECM
Growth factor-based
Chondrocytes

Incorporating cell-based materials into bioinks is
a complex endeavor, requiring the utilization of amultitude of growth factors to foster and expedite
cell growth.83 Notably, growth factors such as
FGF84, 85 and TGF23, 24 have exhibited a significant
surge in research interest between 2020-2022,
as indicated in Figure 7C. Conversely, EGF28 and
VEGF26, 27 have experienced a more moderateincrease in relative publication growth rates during
the same period. Additionally, growth factors likeconnective tissue growth factor (CTGF),86 insulinlike growth factor (IGF), 87 hepatocyte growth
factor (HGF),88 platelet-derived growth factors

Publication year

Figure 7. Emerging trends of materials in the field of bioinks over 2013-2022 obtained from the CAS Content Collection withrespect to (A) cell-based materials and (B) natural and synthetic polymers used as components of bioinks. Increase in relative
publication growth rates for (C) growth factors used as enhancers in bioinks for optimum cell growth and (D) applications
associated with bioinks.

(PDGF)29 and others89 are still in the early stages ofpotential emergence. Each of these growth factors
possesses distinct roles and is frequently used in
combination with each other 90, 91 and specific cell
types.
While the predominant application of bioinks
remains focused on tissue engineering, it's
worth noting the existence of diverse potential
applications beyond this domain. Our dataset
unveils documents associated with a range ofapplications, including drug delivery,11, 12 woundhealing,1, 2 personalized medicine,7 antibacterial,92
drug testing and development,9, 10 and diseasemodeling4-6 as depicted in Figure 7D. For instance,a recent study for the combined applicationsof drug delivery and wound healing involved
loading gelatin-alginate hydrogel based bioink
with chlorhexidine acetate, a small moleculebactericidal agent, to allow fabrication of wounddressings.11 Another interesting application
involved loading curcumin, a naturally occurring
alkaloid isolated from Curcuma longa wellknown for its anti-inflammatory properties, as
encapsulated nanoparticles onto an alginategelatin hydrogel-based bioink with potential
applications in drug delivery.12 Self-gelling bioinks
composed of chitosan derivatives have been
designed for wound healing. 3 Platelet-rich plasma
obtained from patients containing a mixture ofseveral growth factors has been utilized to try
and create personalized bioink.7 An example
of personalized medicine is 3D printing tumor
models to test immunotherapies such as chimericantigen receptor (CAR) T-cell therapies.93
Properties of bioink have a direct influence bothon the type of structure that can be fabricated aswell as the type of printing technique that can beutilized. Broadly speaking, properties of materials
can be arranged into the following categories:– rheological– biological– surface properties– mechanical– physical– chemical– physicochemical

We generated a heat map to show connections
between materials and the various properties
that are studied in their context (Figure 8). A few
observations from the heat map include:
1. Among the selected materials, ECM, stem
cells, and cellulose seem to be the mostextensively researched materials withrespect to their properties.
2. Biological, rheological, and chemical
properties are more frequently studiedcompared to others.
3. Surface properties, encompassing aspects
like surface charge, tension, roughness,area, and wettability, appear to receive
relatively less attention.
4. Within biological properties, the following
properties are studied more extensively:– biocompatibility especially for naturalpolymers (silk, peptide, cellulose,
fibrin) as well as synthetic polymer(GelMA and PCL) and cell-basedmaterials such as extracellular matrix– cell viability more for synthetic
polymers GelMA and HAMA and cellbased materials ECM, stem cells andchondrocytes– cell adhesion more for peptide andfibrin (types of natural polymer), andsynthetic polymers GelMA, HAMAand PCL and cell-based materials
ECM and stem cells.
– Notably, the co-occurrence celldensity as a property with materials
in publications is low, despite recent
studies highlighting its importancein bioink viscosity and shear thinningbehavior.94, 95
5. Rheological properties, defined as theproperty that accounts for a material’s
deformation and flow appear to be studied
more or less evenly across the different
material types. Rheological properties
perhaps affect printability of bioinks morethan any other properties.96, 97
6. Among chemical properties, the ability to be
cross-linked appears to be studied acrossalmost all of the materials shown in Figure 8
with GelMA and HAMA (unsurprisingly) leading
and PCL trailing the pack.

Trailblazing the future with emerging biomaterials | 61

Life Science Operations106), among others.
Currently, many companies such as CELLLINK,107
MilliporeSigma,108 CollPlant,109 RegenHu,110 sellbioink and bioink based products yet mostcommercially available bioinks are used forresearch purposes or for designing pilot-scale
experiments. The accelerating commercial
availability of both bioinks as well as bioprinters is
an indicator of the interest in this area and bodes
well for future development. More efforts areneeded for translating bioink related products inclinical applications.

Rheological

Despite being a relatively new field, commerciallyavailable bioinks are already starting to appear on
the market and include gelatin-based hydrogel
bioinks such as Gel4Cell® (Amerigo Scientific98)
and BioInk® (RegenHU99), GelMA based bioinks
such as BioGel (Biobot) and Tissue Fab (Aldrich100),
alginate based CELLINK (CELLINK101), calcium
phosphate based OsteoInk™ (RegenHu102),
among others. Similarly, commercially available
bioprinters are also on the rise103 – a few example
include extrusion-based bioprinter R-Gen 200(RegenHu104), microfluidic technology based
Biopixlar (Fluicell105) and Rastrum (Inventia

6.3%

7.7%

15.0%

3.6%

9.6%

1.4%

8.8%

20.6%

22.8%

4.2%

Properties

Silk

PeptideCellulose

Fibrin

GelMA

HAMA

PCL

ECM

Stem
cells

Chondrocytes

Viscosity

3.0
3.5
3.0
17.1
4.0
0.3
1.3
0.0
3.5
4.5
1.2
1.0
0.7
0.3
0.3
0.7
0.8
1.2
2.7
8.0
2.8
1.7
1.0
0.2
4.2
2.2
2.7
0.8
1.7
1.8
1.0
2.2
1.5
11.5
4.8
0.0
1.3

3.0
2.8
2.2
13.8
3.3
0.3
1.4
0.1
4.5
8.3
0.4
1.2
2.8
0.7
1.2
0.8
0.1
0.7
2.6
4.6
0.8
0.0
2.4
2.7
0.5
0.0
1.9
1.5
1.6
5.3
0.9
2.2
0.7
10.2
4.5
0.9
8.9

5.5
4.3
3.2
12.0
3.0
0.2
2.1
0.6
4.3
3.7
1.6
0.5
1.9
0.2
1.0
0.7
0.9
0.8
2.7
2.4
2.2
1.0
1.6
2.9
2.8
0.1
6.2
5.0
2.1
4.3
1.2
1.8
2.5
8.5
3.4
1.0
0.8

5.0
4.7
5.0
12.0
2.3
0.0
0.9
1.2
6.4
7.0
0.9
1.7
0.6
0.6
0.6
1.7
0.3
0.6
1.5
2.9
0.9
0.6
2.0
2.9
1.7
1.2
2.3
0.0
4.7
4.4
0.3
2.0
2.0
9.3
5.0
0.0
3.2

5.2
3.1
3.7
13.2
2.2
0.2
1.3
0.4
7.8
6.6
0.5
1.2
0.5
0.4
0.2
0.5
0.3
0.2
0.9
2.8
1.7
0.0
3.3
0.0
2.4
0.5
4.5
0.7
2.1
7.0
0.5
1.0
4.0
14.6
3.1
0.4
0.9

3.7
2.2
3.7
0.0
2.9
0.0
0.0
0.0
8.8
11.0
0.7
0.0
1.5
0.7
0.7
0.7
1.5
1.5
0.0
6.6
2.2
0.0
1.5
8.1
2.9
0.0
1.5
0.7
2.9
5.9
0.7
2.9
2.2
16.9
0.7
0.0
1.5

1.9
1.6
2.7
10.4
6.6
0.1
1.3
0.5
4.9
8.9
1.4
1.8
1.6
1.0
0.8
1.7
0.8
0.5
2.4
2.6
1.1
0.6
3.3
3.3
1.0
4.1
7.9
1.7
2.9
7.6
0.6
0.4
1.0
4.2
4.2
0.2
1.2

3.5
2.5
2.9
12.8
2.6
0.4
1.4
0.8
6.1
7.9
0.5
1.2
0.7
0.6
0.6
1.1
0.3
0.2
0.7
3.0
0.9
0.1
3.5
2.6
1.8
1.0
3.3
0.5
3.5
7.4
0.6
2.6
1.9
10.1
5.3
0.2
3.6

4.4
3.3
3.7
4.8
3.0
0.2
1.9
1.1
7.7
8.6
0.8
1.4
0.9
0.6
0.6
1.1
0.3
0.3
1.6
2.7
1.6
0.1
0.9
3.0
2.6
0.8
2.4
0.9
4.3
8.6
0.4
2.1
2.3
10.5
5.7
0.1
3.2

4.0
3.2
4.7
4.2
2.2
1.7
1.7
0.7
8.5
4.5
0.5
0.2
0.5
0.2
0.7
1.0
0.2
0.0
1.7
4.0
0.5
0.0
6.2
3.7
2.5
0.2
3.2
1.7
4.5
9.0
0.0
1.2
4.0
10.2
3.0
0.2
3.7

Shear thinning
Yield strength/stress
Biocompatible
Biodegradable

BiologicalLow immunogenicity
Non toxic
Cell density
Cell viability
Cell adhesion
Dissolution
Bioactivity
Antimicrobial
Anti-inflammatory

Surface

Surface charge
Surface tension
Surface roughness
Surface area
Wettability

MechanicalHigh elastic modulus
Stress/strain relationshipElongation at break
Stiffness
Loss modulus
Compressive strength
Tensile strength

PhysicalDensity
Temperature responsive
Thermal stability
Gelation
Swelling

ChemicalPhysicochemical

Porosity
Crystallinity

Crosslinkable
Electroactivity
Hydrogen bondSelf-assembly

Natural polymers

Synthetic polymers

High

Low

Cell-based

Figure 8. Heat map showing co-occurrences of selected materials and properties in the field of bioinks over 2003-2023 obtained
from the CAS Content Collection. Values shown are in percentages.

Notable journal articles and patents

Table 1 consists of a set of research articles
published from 2020-2023 that are representativeof emerging trends in this field. Articles wereselected on the basis of the collective factors
such as journal impact factor, citations, andtype of study. Notable examples from the table
include the publication on volumetric additive
manufacturing (VAM) of pristine silk-based (bio)inks by Zhang et al.111 The article describes the useof silk-based bioinks made from silk sericin (SS)or silk fibroin (SF) to design silk-based constructs.
SS and SF are used across a wide range ofconcentrations in conjunction with ruthenium/
sodium persulphate (Ru/SPS) that enables
reactions between tyrosine groups of
SS and SF, under green light (wavelength)
525 nm as the photoinitiator. The resulting
formulations are printed using VAM resulting inconstructs that are biocompatible and can beused to grow C2C12 cells.
Another example is the study "titled" LightActivated Decellularized Extracellular Matrix(dECM)-Based Bioinks for Volumetric Tissue
Analogs at the Centimeter Scale by Jang et al.
at POSTECH, Republic of Korea.112 This study
relies on the use of dECM for developing bioink.
dECM is one of the most desired biomaterials
for bioinks as it can emulate the intricacy of thenative microenvironment of tissues/organs dueto the similarity in components and compositionof various biomolecules present in dECM andnative tissues. Another journal publication by
Feinberg et al. at Carnegie Mellon University,
USA,113 describes the application of the Freeform
Reversible Embedding of Suspended Hydrogels(FRESH) bioprinting technique to develop acomplete 3D human heart. To mimic the elasticityof heart tissue, a natural polymer- alginate isused as the major component of the bioink. This
breakthrough technology could further be used
to develop full-size anatomical models for organs
for ease of studying them. An exciting applicationof this down the line could be to generate artificialorgans that can be used for transplantation.
Table 2 represents notable patents in the fieldof bioinks from 2018-2023. These patents wereselected based on collective factors such as
relevance, novelty, applicability, and field ofstudy. The search was performed using CAS STN

to identify representative patents from the topcommercial and non-commercial organizations
across the globe and subsequent shortlisting
was performed by subject matter experts (SMEs)
in the field. The list reflects innovation either
in terms of the use of different materials in
preparation of bioinks or practical innovations
involving use of hybrids from these materials
for their use in 3D printing, tissue engineeringand various other applications. Patents listed
include a wide range of materials such as silk
fibroin, undenatured collagen, extracellularmatrix, derivatives of hyaluronic acid, collagen,cellulose nanofibrils etc., and their hybrids
along with different additives. For instance,
US11186736B2 (Cellink AB-Bico Group AB)51
describes the development of a double-networkhydrogel-based bioink that contains a crosslinkable polyethylene glycol (PEG) network, aphotoinitiator and a cross-linkable thickener madefrom either polyethylene oxide, polypropyleneoxide, nanofibrillar cellulose, nanocrystalline
cellulose, gelatin, collagen, glucomannon,
alginate, k-carrageenan, bentonite clay, and/or
xanthan gum. These facilitate the formation of
an interpenetrating network and the resulting
bioink can be used for a wide variety of
applications by adding different additives suchas fluorescent dyes.
Various patents pertaining to bioinks are
related to development of 3D printed tissues
such as skin, hair follicles, etc. For instance,
WO2022260583A1 (Iscaff Pharma)114 describes
the development of bioink for the reproducible
production of 3D tumor tissue scaffolds. It relieson the identification of protein compositionof tumor tissue and producing bioink with thecorresponding protein/protein domain which
can be developed into a 3D scaffold mimicking
the tumor which can be used for studying
the tumor. A closer look at patents shows thathydrogels are a commonly used form of bioink inseveral patent applications with KR102100506B1(Medifab Co., Ltd.)115 describing a thermosensitive
chitosan hydrogel comprising chitosan (a linear
polysaccharide composed of D-glucosamine andN-acetylglucosamine) cross-linked by glycerol
and phosphoric acid group. Varying the content
of phosphoric acid and glycerol in the gel can
induce the bioink to convert from liquid to gelstate. Companies like Organovo have patented
Trailblazing the future with emerging biomaterials | 63technologies for 3D printing of human tissue
models such as patent EP3215603B153 by Organovo
and L'Oreal which describes development of 3D
printed human skin model comprising a dermal
layer comprising a dermal bioink containing

fibroblasts; and an epidermal layer comprising
epidermal bioink comprising keratinocytes.
Epidermal and dermal layer are in contact toreplicate human skin-like communication in-vitro.

Table 1. Notable journal publications in the field of bioinks in recent years.
Year

Title

JournalResearch InstituteApplication

2020

Nanoengineered osteoinductive
bioink for 3D bioprinting bone
tissue116

ACS Applied
Materials
Interfaces

Texas A&M University

Nanoengineered ionic covalent entanglement(NICE) bioink formulation for 3D bone bioprinting

2020

FRESH 3D Bioprinting a Full-SizeModel of the Human Heart113

ACS Biomater.
Sci. Eng.

Carnegie Mellon
University

Hydrogel-based 3D bioprinting of human heart

2021

3D bioprinted neural tissue
constructs for spinal cord injury
repair117

Biomaterials

Chinese Academy of
Sciences

Biocompatible bioink consisting of functional
chitosan, hyaluronic acid derivatives, and Matrigel
for growth of neural stem cells (NSCs)

2021

3D bioprinted silk fibroin hydrogels
for tissue engineering118

NatureProtocols

Hallym University

Methacrylated photocurable silk fibroin (SF) bioink
for digital light processing (DLP) 3D bioprinting

2021

Light-activated decellularized
extracellular matrix-based bioinks
for volumetric tissue analogs at thecentimeter scale112

Advanced
Functional
Materials

Pohang Universityof Science andTechnology(POSTECH)

Light-activated, decellularized extracellular matrix(dECM) based bioinks with ruthenium/sodium
persulfate (dERS) for constructing bioscaffolds

2021

Programmable microbial ink for 3D
printing of living materials produced
from genetically engineered protein
nanofibers119

NatureCommunication

Harvard University,
Northeastern
University

Microbial ink that is produced entirely from thegenetically engineered E. coli biofilms

2021

3D bioprinting of high cell-density
heterogeneous tissue models
through spheroid fusion within selfhealing hydrogels120

NatureCommunication

University ofPennsylvania

Supramolecular hydrogel-based bioink comprisinghyaluronic acid (HA) modified with either
adamantane (Ad) or β-cyclodextrin (CD), used fortissue engineering

2022

Molecularly cleavable bioinks
facilitate high-performance digital
light processing-based bioprinting offunctional volumetric soft tissues121

NatureCommunication

Harvard University

Hyaluronic acid methacrylate (HAMA) mixed
gelatin methacryloyl (GelMA) bioink for digital lightprocessing (DLP) bioprinting

2022

In situ 3D bioprinting with
bioconcrete bioink122

NatureCommunication

Zhejiang University

Bioconcrete bioink comprising cell-laden
microgels aggregate and gelatin methacryloyl(GelMA) solution as the cement2022

Development of cellulose nanofibril/casein-based 3D composite
hemostasis scaffold for potential
wound-healing application123

ACS Applied
Materials
Interfaces

Jiangsu University

Cellulose nanofibrils (TCNFs), chitosan, and casein
based bioink for wound healing

2022

Orthogonally induced differentiationof stem cells for the programmatic
patterning of vascularized organoids
and bioprinted tissues124

NatureBiomedical
Engineering

Harvard University,
BostonUse of human induced pluripotent stem cells(hiPSCs) containing bioinks to generate patterned
neural tissues

2023

Volumetric additive manufacturing ofpristine silk-based (bio)inks111

NatureCommunication

Harvard Medical
SchoolSilk-based bioinks for volumetric additive
manufacturing (VAM)2023

In situ covalent reinforcement ofa benzene-1,3,5-tricarboxamide
supramolecular polymer enables
biomimetic, tough, and fibroushydrogels and bioinks125

Advanced
Materials

Maastricht University

Biomimetic bioink made from 1D fibrils made frombenzene-1,3,5-tricarboxamide (BTA) hydrogelator
with norbornene (NB)

Table 2. Notable patent publications in the field of bioinks in recent years.
Patent or
Publication
number
WO2018035138
A152

WO2018186611
A2126
WO2018071639
A1127 |
KR2556540B1

KR102156310B1/
EP3705294A1128

Publication
year

Patent assignee

Title

Description of patented technology

2018

Organovo, Inc.

Three dimensional
bioprinted tumor
models for drug testing2018

Industry Academic
Cooperation
Foundation, Hallym
University, Republicof Korea

A cancer model that accounts for the interaction of tumor
cells with surrounding stromal cells and the inherent
complexity of the tumor microenvironment by using anengineered scaffold construct. A bioink used to create theengineered constructs comprises fibroblasts, endothelial cells,
adipocytes, and preadipocytes among other cell types.

Bioink and preparation
method therefor

Bioink made of silk fibroin (SF) can help constructbiostructures using 3d printing with better stability andbiocompatibility.

2018 | 2019

Advanced
Biomatrix Inc.

Three-dimensional (3D)
printing inks made fromnatural extracellularmatrix molecules

Bioinks composed of undenatured collagen

2020

UNIST (Ulsan
National Instituteof Science andTechnology),
Republic of Korea

Manufacture of cellspheroid using bioink

KR102100506
B1129

2020

Medifab Co., Ltd.,
Korea

Thermosentitive
chitosan hydrogel
composition andbioinks composition
comprising the same

SE1950711 A150

2020

Cellink AB

3D bioprinted skintissue model

KR20200012723
A130

2020

Kyungpook
National University

Sericin-based bioink
composition for 3D
printing without photocrosslinking agent

2021

Cellink AB (BicoGroup AB)EP3215603B153

2021

Lóréal SA
Organovo Inc,
France

WO2022260583
A1114

2022

Iscaff Pharma

US11629329B2131

2023

Wake Forest
University Health
Sciences, USA

2023

POSTECH
Academy-Industry
Foundation,
Republic of Korea

2023

Commissariat al'Energie Atomiqueet aux Energies
Alternatives

US11186736B251

KR20230106369
A132

WO2023062111
A1133

US11648336
B2134

2023

Bico Group AB
Cellink Bioprinting
AB

Double network bioinks

Engineered threedimensional skintissues, arrays thereof,
and methods of making
the same
Bioink for reproducible
production of 3D tumor
tissue scaffolds
Bioink compositions
and methods ofpreparing and using thesame
Biomaterial-based
drug delivery patch,
manufacturing method
therefor, and use
thereofNovel bioink and uses
thereof for constructing
tissues
Preparation andApplications of 3D
Bioprinting Bioinks
for Repair of Bone
Defects, Based on
Cellulose Nanofibrils
Hydrogels with Naturalor Synthetic Calcium
Phosphate Particles

Method for creating spheroids using a combination of
two bioinks – the first containing alginate and the second
containing live cells – extruded one after the other. Additionof calcium chloride solution to the alginate present in the firstbioink and dissolution of the second bioink in a cell culture
medium results in formation of a cell spheroid from the cells.
Bioink containing chitosan polymer hydrogel having two
chitosan molecules form covalent and / or non-covalentbonds with glycerol and / or phosphate groups or their
combination. An example of temperature-controlled bioinkthat can interchange from a liquid state to gel state according
to the content ratio of the phosphoric acid group and theglycerol.
3D printed skin tissue that can act as model for testing in drug
development, toxicological studies, tissue engineering among
others.
Bioink comprising of protein-based material (sericin) withapplications in wound healing and tissue regeneration.
Bioink consisting of a double network including a noncrosslinkable thickener and PEG-based cross-linkablenetwork that interpenetrates each other, photoinitiator,
and/or different additives to impart desired characteristics.
Potential applications include 3D bioprinting and constructing
scaffolds.
A 3D, engineered, biological skin tissue comprising: a dermal
layer comprising a dermal bioink containing fibroblasts; andan epidermal layer comprising epidermal bioink comprisingkeratinocytes. The epidermal layer is in contact with thedermal layer to create a 3D skin tissue.
Protein-based bioinks for 3D scaffolds that mimic tumor
microenvironment and can be used to generate cancer
models to test anti-tumor therapies
Method for formulating bioink with 1:0.5 to 1:10 (thiolated
hyaluronic acid:methacrylated collagen). This composition has
an elastic modulus similar to natural tissues and can be used
for cell/tissue culture and for bioprinting.
A multilayered patch useful for drug delivery applications,containing inner and outer layers made of extracellularmatrix-based hybrid ink. Both layers have ink with different
chemical crosslinking densities and contain different growth
factors thereby allowing controlled release of drugs.
Tissue engineered esophagus via 3D bioprinting
using biodegradable polymeric materials such aspoly(caprolactone)-co-glycolide (PCG), polycaprolactone(PCL) and methylcellulose (MC).
Bioink composed of cellulose nanofibril hydrogel having
calcium containing compounds (β-tricalcium phosphate(TCP), single-phase hydroxyapatite (HA), biphasic HA-TCP,or natural bone powder). This bioink can be used for tissue
engineering/tissue replacement.

Trailblazing the future with emerging biomaterials | 65

Challenges and perspectives

An ideal bioink should possess appropriate
rheological, mechanical, chemical, and biologicalproperties of the target tissues. Despite path
breaking advances in the field of bioinks withrespect to both the materials used and their widearray of applications, there continues to be various
challenges:
1. Bioinks based on natural polymers lacksufficient mechanical strength in theabsence of additives.111, 135
2. The process of development of bioinks
focuses more on designing andcharacterizing them for their physical,
chemical, and rheological properties.
However, their interaction with live cells not
only affects the stability of bioinks but also
hampers cell viability.
3. The addition of additives, extensive printing
time, and lesser control over the printing
process can impact embedded cell viability.
4. Some synthetic polymers and additives
used in bioink preparation lackbiocompatibility/cytocompatibility,
therefore it remains a challenge to designunique bioink considering their biologicalcompetence.136 For instance hydrogels madeusing synthetic polymers without ECM
components support the cell but they do
not promote cell growth and limit cell-tocell interactions resulting in a non-native
microenvironment.135

5. Scaffold-free printing approaches withexisting bioinks such as cell pellet-based
methods often result in cellular aggregates
which could limit the supply of oxygen andnutrients to cells resulting in their loss.137
6. Bioprinting adds to the cost of the overall
procedure when used in cell/tissue culture.
7. The scale-up of the biofabrication process
to make bioprinted scaffolds for clinicalrelevance without compromising on bioink
properties and cell viability and having aminimal batch-to-batch variation thereby
highlighting a dire need for standardized
bioink formulations.138 Similarly, morework is needed in developing models andstandards to compare and evaluate theperformance of bioinks.138, 139
8. The overall lack of suitable bioinks
for generating suitable and larger 3D
constructs that mimic original tissues canhamper the translation toward clinicalapplications.
Further advancements are required in thebioink technology field to increase cell viability,
minimize cell loss, maximize cellular interactions,improve the physical, chemical, mechanical, andrheological properties of bioinks, and make themcompatible and scalable for clinical applications.

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V. Programmable materials
Introduction

Programmable materials can change theirmorphology, physical properties, and/or chemicalfunctionalities in a pre-determined sequence in
response to an external stimulus or a change inthe surrounding environment.1 Programmability
in materials is highly advantageous in some
applications, such as drug delivery, because it
enables additional, time-dependent methods ofcontrol.2 For example, mesoporous silica particles
can be programmed to release a drug cargoselectively in cancer cells by capping its pores withpolymeric structures that reconfigure in different
pH conditions. 3
Programmable materials that are used forbiomedical applications include natural andsynthetic polymers,4 as well as metal alloys, suchas Ni-Ti. The programmability of these materials
originates from their ability to respond to smallchanges in their environment, for example pH,5,
6
temperature,7 light,8, 9 electrical10 or magnetic
fields,11, 12 or a specific chemical or biologicalsignal.13

DNA-based materials represent a special classof programmable biomaterials. One reason forthis is that DNA offers precise structural tunability
through Watson-Crick base pairings.14, 15 Directed
self-assembly of single-stranded DNA can leadto diverse 2D and 3D structures, the formationand dynamics of which can be controlled at
the molecular level.16 In addition to the ability
to generate specific structures, DNA can also
be engineered to respond to specific cues or
chemical environments,17, 18 or through using
CRISPR technology.19
Programmable biomaterials have foundapplications in drug delivery, implants, sensors,and several other areas. In this chapter, we will
first review the trends in journal and patentpublications in this area, then identify the mostprominent substances used in programmablebiomaterials, and finally provide representative
examples of recent programmable biomaterial
research.

Trailblazing
thethefuturewithemerging
biomaterials| 75
Trailblazing
futurewithemerging
biomaterials| 75

Journal and patent publication trends

Figure 2 shows the top 15 research institutions interms of the number of citations per publication,from within the top 100 institutions in terms of
total journal publications. This analysis clearlyshows a trend of high research publication
activity in China. Apart from the University ofCalifornia, the top 15 institutions with the highest
number of citations per publication are in China.
The Chinese Academy of Sciences has both thehighest number of citations per publication, andthe highest number of overall publications on
programmable biomaterials.

Figure 1 shows the number of journal and patentpublications per year involving programmablebiomaterials from 2003-2023. Here, we see astrongly increasing trend in journal publications
up to 2022, and likely to include, 2023. The
frequency of patent publications has been
relatively lower, showing a flat trend from 20162022, suggesting that the results of academic
research have not yet been fully translated tocommercial applications.

3,000

JournalPatentNumber of publications

2,500

*

2,000
1,500
500

23

22

20

21

20

20

20

19

20

18

20

17

20

16

20

15

20

14

20

13

20

20

11
12
20

10

20

09

20

08

20

07

20

06

20

05

20

04

20

20

20

03

0
Publication year
Figure 1. Number of journal and patent publications per year in the programmable biomaterials field from 2003 to 2023
(journals: blue bars, patents: yellow bars). * The data for 2023 only include the months from January to August.

Average number of citations per publication
Organization

Chinese Academy of Sciences
University of California
Hunan University
Zhejiang University
Tsinghua University
Wuhan University
University of Science and Technology of China
Nanjing University
South China University of Technology
Shanghai Jiao Tong University
Sichuan University
Jilin University
Tianjin University
Beijing University of Chemical Technology
Southwest University

Citations per publications
Number of journal publications (CHN)
Number of journal publications (USA)

Number of journal publications
Figure 2. The top 15 research institutions in terms of average citations per publication (yellow line). Total publications
from 2003-2023 shown as bars; colors of the bars indicating country/region.

4%

USA 55%

NLD (1%)

CAN (1%)
CHE (1%)OthersGBR

5%2% ISR
4%KOR
4%6% DEUTop 10patent assignees

CHN 58%9% JPN

2003-2023

RUS (1%)
IND (1%)
CHE (1%)FRA
2% JPN
3% DEU3%
3% KORTop 10patent assignees
2003-2023

21%

USA

Qingdao University of Science and Technology

AUS (1%)Othersroughly a factor of 4 over the past 10 years.
Analysis of patent families, shown in Figure 4B,
indicates that the top national/regional patentoffices for filings are the US, China, EPO, Japan,
Canada, and Korea. For applicants in China,
Japan, and Korea, initial filing through the national
patent office appears to be preferred, while initial
filings through WIPO/PCT are more common for
applicants in the US, Israel, and the UK.

Massachusetts Institute of Technology

Figure 3 shows a breakdown of the top assignees
for patents related to programmable biomaterials.
The US generally has the highest amount ofpatent activity by commercial entities, led by
Boston Scientific, while patent activity by noncommercial entities is highest in China.
Furthermore, as shown in Figure 4A, patentactivity in both China and Korea has increased
significantly over time, with the number of patentfamilies filed by entities in China increasing by

13%

CHN
Non-commercial

Patent assignees

60
40

Fuzhou University

Shenzhen University

Fudan University

Tongji University

Shanghai Jiao Tong University

Donghua University

Zhejiang University

The Regents of the University of California

0

Sichuan University

20
Jiangnan University

Advanced Bio Prosthetic Surfaces, Ltd.

Ethicon, Inc.

Abbott Cardiovascular Systems, Inc.

W. L. Gore & Associates, Inc.

Medtronic, Inc.

Samsung Electronics Co., Ltd.

Cordis Corporation

St. Jude Medical, Cardiology Division, Inc.

Searete LLC

Abbott Cardiovascular Systems Inc.

Medtronic Vascular, Inc.
Shanghai National Engineering ResearchCenter for Nanotechnology Co., Ltd.
Warsaw Orthopedic, Inc.

Edwards Lifesciences Corporation0

Boston Scientific Scimed, Inc.

10

80

Harbin Institute of Technology

20

100

Guilin University of Technology

30

120

South China University of Technology

Number of patent publications

40

Cook Medical Technologies LLC

Number of patent publications

Commercial
50

Patent assignees

Figure 3. Top panel: The top 10 countries/regions in terms of number of patents published between 2003-2023. Lower
panel: The top 15 patent assignees in the field of programmable biomaterials in the same time period. Both panels are
divided into commercial and non-commercial entities. Bar graph has been color coded by country/region to match color
scheme in donut charts.

Trailblazing the future with emerging biomaterials | 77

(A)
40
35

400

30

KOR

25

DEU
JPN
ISR
GBR
CHE

15

300

10
5
2
02

0
02

-2

20

21

8

-2
19

20

01
-2

17

6
01
-2

20

01

20

20

15

4

12

-2
13

0
20

11
-

20

8

01
-2

09
20

00
-2

07

6
00
-2

05

20

00
-2

20

200

03

4

0
20

Number of patent publications

20

CHN

USA
100

2
21

-2

02

0
20

19

-2

02

8
20

17

-2

01

6
20

01
-2
15
20

01
-2

20

13

20
11
-

4

12

0
20

09

-2

01

8
20

07

-2

00

6
20

00
-2
05
20

20

03

-2

00

4

0

Publication year
(B)

WIPO: 4,710

USA: 6,869

USA: 3,361

CHN: 2,459
DEU: 605

CHN: 2,755
EUR: 1,205

CHN: 2,358

JPN: 833

JPN: 587

JPN: 383

ISR: 387

EPO: 366

KOR: 406

KOR: 318

CHE: 255

DEU: 317

GBR: 272

FRA: 83

FRA: 154

GBR: 76
CAN: 36

CAN: 140

USA: 3,881

OTH: 126

CAN: 528
KOR: 375
DEU: 120
IND: 108
BRZ: 87
ESP: 76
Others: 395

Figure 4. (A) Number of patent family publications per year between 2003-2022 for the top 8 most prolific countries/ regions.
(B) Total patent flow between assignee countries/regions (top ten countries/regions in terms of total patent filings, left),the patent filing office where the first application in the patent family was filed (center) and the destination patent office forindividual patent publication activities (right). Standard three letter codes utilized for countries/regions.

Key materials and applications

The response that happens when a programmablematerial is exposed to a specific stimulus can takeseveral forms. In some materials, the stimulus
can cause changes in noncovalent interactions
within the material that lead to reversible physicalchanges like swelling or deswelling of a material,
irreversible chemical degradation, or otherstructural changes that are required to perform
certain functions. As an example, in the case ofdrug-delivering polymeric vesicles, response toa stimulus can lead to complete disassembly. 20
These responses are commonly brought about by
temperature changes (which can be induced bydirect heating, or indirectly by photothermal ormagnetic hysteresis effects), by changes in pH orother solvent conditions that lead to protonation
or deprotonation, or through more specificchemical interactions (with glucose or enzymes,
for example).
Another class of programmable material isshape-memory substances.21 Shape memory,which is a property that can be exhibited byorganic materials and alloys, is one-way (where
the material only has one temporary form, andshape change back to its permanent form upon
stimulus is irreversible), two-way (where the shapechange is at least partially reversible), or multi-way(where the material has more than two temporary
forms).22,23 Shape-memory materials can be used
to make artificial muscles, micromachines, andimplants and medical devices that reconfigure
inside the body.24
These basic programmable functions can in turnbe used to build structures and devices withmore complex behavior. For example, actuatorscomposed of bilayer films where one layer swells
much more compared to the other2 leading toprogrammable bending or other shape-based
programming. Another example of this is localized
photothermal heating by a laser of temperatureresponsive polymers to make a wiring-freemicroactuator.25
In hydrogels, as another example, combinations ofrigid and soft programmable materials can induce
folding and other behaviors.26 “Smart” hydrogels

containing stimulus-responsive polymers makeup a large class of programmable biomaterials
and continue to be an active area of research forbiomedical applications. 27, 28,29
At an even higher level of complexity arenanorobots, which can integrate programmablematerials to make complex, active structures30
and biomimetic materials. 31,32 Programmablematerials are also used in so-called 4D printing,an emerging technology that involves 3D printing
programmable materials, which can later bephysically reconfigured, or perform actuation,
biomimetic function, or some other stimulustriggered action. 33-35
The combined bubble chart and heat map in
Figure 5 shows the substances which have beenreferenced most frequently in publications on
programmable biomaterials. These substances
are grouped into polymers (natural andsynthetic), inorganic and organic small molecules,
metallic and nonmetallic elements, minerals,
coordination compounds, and alloys. It is
important to note that not all these materials
are intrinsically programmable. Generally, thenon-programmable materials found in thesepublications serve other complementary purposesin combination with a programmable material.
Polyethylene glycol, poly(lactic acid), andpolycaprolactone are the top substances in thesynthetic polymers category. Polyethylene glycol
appears frequently due to its biocompatibility,and because it can be used in a variety of different
ways in programmable biomaterials. These include
using it to make copolymers that are responsive
to pH36, 37 (including attaching side groups thatform Schiff base bonds),38 light,39 glucose andother chemical environments,40 and as a basis for
programmable hydrogels.41
Poly(lactic acid) and polycaprolactone have similar
versatility and well-established biocompatibility
and biodegradability. Poly(lactic acid)42 hasbeen used to make materials responsive totemperature43 electric field,44 as well as a matrix
for a magnetically responsive material driven byembedded Fe3O4 particles.45 Polycaprolactone,

Trailblazing the future with emerging biomaterials | 79

notably, can be copolymerized with PEG toform thermosensitive materials for biomedical
applications.46
An important material that also appears
prominently in the data set is poly(Nisopropylacrylamide) (PNIPAM),27 a widely usedtemperature-responsive polymer. The key
property of PNIPAM is that it has a lower criticalsolution temperature (LCST) of around 32°C withwater, meaning that below this temperature, the
PNIPAM-water system is a stable single phase.
Above this temperature, hydrogen bonding
between the PNIPAM and water become lessfavorable, leading to phase separation. This
property has led to PNIPAM to be used in a wide
range of applications recently, particularly inhydrogels.47-50
Several direct and indirect sources of heatcan be used to trigger changes in PNIPAM
hydrogels, including Joule heating,51 photothermal
effects,52 and magnetic hysteresis,53 as well as
photoisomerization54 and photoionization.55
Through these methods, PNIPAM-based smart
hydrogels can be made to respond to light,
temperature, and magnetic and electric fields.
Furthermore, copolymerization with morehydrophilic or hydrophobic polymers can used
to tune the LCST temperature and the extent ofphysical changes in PNIPAM-based hydrogels. 56
The primary natural polymers that appear inprogrammable material literature are DNA,chitosan, and cellulose.
DNA is a special case, due to its precisely definedstructure and multiple types of programmability.
First, DNA can be used to make intricate,nanoscale structures through programmingbase pair sequences. This programmability been
implemented in strategies including scaffoldfree DNA self-assembly57-59 and DNA origami,60-62
which has received significant research interest
recently. In this technique, a long single stranded
DNA (the scaffold) folds into predesigned
structures determined by many short single
stranded DNA sequences (staples). The possible
applications of DNA origami include controlled
drug delivery,63, 64 biosensing,65 and biomimicry.66

DNA-based materials can also have stimulusresponse programmability similar to the synthetic
polymers described above. Several mechanisms
have been reported that lead to predictablephysical or chemical reconfigurations in DNA
molecules. Some mechanisms are physical,
which involve a change in the secondary or
tertiary structure of DNA nanostructures, throughG-quadruplex formation, triggered by pH or
metal ions,67, 68 I-switch formation, triggered by
pH,69 or duplex formation,70 in this case triggeredby the presence of Hg and glutathione.
The mechanisms can also be chemical, such
as DNA strand cleavage by DNAzymes or
restriction enzymes,71,72 or polymerase-mediatedDNA amplification.73 In addition, molecular
programming can be integrated with the
dynamics of reconfigurable DNA nanostructuresusing toehold-mediated strand displacement andtoehold exchange.74
Chitosan, the next most commonly referenced
natural polymer, is naturally pH sensitive, throughits amino and imine groups, which become
protonated at low pH.75 Thermal programmability
can be incorporated into chitosan by combining itwith thermally responsive polymers,76 for example
by grafting with PNIPAM.77
Cellulose is notable due to its abundance as a bioderived material, and because of its wide range ofproperties and functions.78 Cellulose can function
as a stimulus-responsive programmable material,
through the disruption of hydrogen-bonded
anhydroglucose units within cellulose structures
by water,79 or through chemical modificationthat enables other types of stimulus response.80
Cellulose hydrogels can also be combined withother responsive polymers, for example PNIPAM,81
to make materials that respond to multiple
stimuli.82 Nanoscale cellulose materials, suchas nanocrystals and nanofibers, have also seen
increased research activity due to their versatility,
mechanical properties, and the potential touse them as building blocks for more complex
structures.83-86
Cellulose has also been used to make biomimetic
actuators and other structures that are inspired byplant behavior.87, 88 A notable example of this is a
3D printed acrylamide-based hydrogel containing
cellulose fibrils reported by Gladman et al. 32
Anisotropic swelling of the fibrils on exposure towater caused the hydrogels to take on complex
three-dimensional shapes determined by theirplacement in the gel.
Turning to the small organic molecules, thematerial that appears most prominently
is doxorubicin, likely due to its use as arepresentative chemotherapy drug inprogrammable drug delivery materials.89, 90
N-isopropylacrylamide is used primarily as amonomer to synthesize temperature-responsive
homo- and copolymers.91, 92
Outside of organic materials, a notable
programmable material is the Ni-Ti alloy (nitinol),which has shape-memory properties triggered bytemperature, driven by the solid-state austenitemartensite phase transition. Nitinol is well known

for its use in biomedical applications,93, 94 due toits combination of shape memory properties,
biocompatibility,95 and superelasticity.
Silica is the most extensively used inorganic
substance used in programmable materials,
with particular focus on the use of mesoporous
silica for drug delivery.96 Through chemicalfunctionalization,97 mesoporous silica has been
demonstrated to release drugs in response tochanges in pH,98, 99 ultrasound,100 and other typesof stimuli.101 Within pure metals, gold and silver
are the most prominent. These materials can beused for their electrical properties, or as part ofa programming strategy where they are usedas photothermal agents.102,103 Silver can havethe added benefit of conferring antimicrobial
properties.104

Trailblazing
thethefuturewithemerging
biomaterials| 81
Trailblazing
futurewithemerging
biomaterials| 81Synthetic

NaturalPolymers

AlloysElements**

Non-metals

Inorganic

Organic

MetalsMinerals

Organic andinorganic
molecules

Coordination
compounds*

Figure 5. Bubble chart and heat maps showing distribution of substances used in programmable biomaterials in terms of number of publications (journals and patents) from 2003-2023.
Materials with a relatively high rate of growth in their use in journal and patent publications are indicated by an asterisk.

*

*

*
*

Figure 6 shows a plot of the frequency of theuse of several material terms in journal andpatent literature, normalized by their average use
frequency from 2013-2018. Materials with a highincrease in normalized frequency (identifying
them as emerging materials) were selected for thisplot.
Within this set, two materials are particularly
prominent. Lignin has seen increased
research activity due to its natural abundance,
biodegradability, and the ability to confer awide range of stimulus responses (pH, light,
temperature, electric field, ions) through chemical
modification.105,106,107,108 Metal-organic frameworks
have the dual advantages of finely controlled
pore structure and stimuli-response, making
them versatile drug delivery materials.109 Recent
work in the area of programmable MOFs includes
functionalizing them with oligonucleotides,110 andcombining MOFs with temperature-responsivehydrogels for multi-drug delivery.111 Polydopamineis also used for its combination of photothermal
and pH-responsive properties and high drug
loading capacity.112-114

14

Normalized frequency

12
10
8

Figure 7 is a heat map showing the relationshipbetween the most prominent biomedical
applications for programmable materials(top rows) and the substances used in theseapplications (left column). The green to red color
scale reflects the relative frequency that each
substance is referenced within each application.
Because DNA is not a single chemical substance,
it is treated separately in this figure. For DNA, thegreen to red color scale represents the distributionof the use of DNA-based materials across the 7
applications in the top row.
Addressing the non-DNA materials first, there
are a number of notable applications andapplication-substance pairings. First, we note that
drug delivery is the most common biomedical
application for programmable materials, due
to the potential of programmable materials to
localize drug delivery and in some cases penetrate
tissue.115-117 Within this category, silica, PEG, andchitosan are frequently referenced. (Note that
lipids are another widely used drug delivery
platform, some types of which are used clinicallyfor anticancer drug delivery.118) For silica, thisLigninMetal organic frameworks
Poly(dopamine)
Sodium carboxymethyl cellulose
Isopropylacrylamide-methylenebisacrylamide copolymer
Pentaerythritol tetra(3-mercaptopropionate)
DNA

6
4
2

22
20

21
20

20
20

19
20

18
20

17
20

16
20

15
20

14
20

20

13

0
Publication year
Figure 6. Normalized frequency of representative materials in journal and patent publications from 2013-2022.

Trailblazing the future with emerging biomaterials | 83reflects the use of functionalized mesoporous
silica as discussed above, while PEG and chitosan
are frequently used in stimuli-responsive drugdelivery hydrogels119, 120 and in composites or
copolymers.121
Within implantable devices, metallic materials
including nitinol, stainless steel, and titanium arecommonly used, due to their mechanical strengthand shape-memory properties in the case ofnitinol. Poly(lactic acid) and polycaprolactone
are also frequently used in this area. While they
are not as mechanically strong as metals, The arebioresorbable.44 Both materials can be engineered
to have stimulus response, either through shapememory,122, 123 or by incorporating other materials,
for example magnetic particles to remotely control
devices after implantation.45, 124
Sensors heavily use conductive materials

including gold, silver, copper, and graphene. Goldnanoparticles are also used as scaffolds in sensor
applications.125, 126
Based on the data in Figure 7, the most frequentuses of DNA are in drug delivery and sensors,which is likely related to the highly precise
structural characteristics and programmability of
DNA-based materials.63,65,127
The evolution in the use of DNA for
programmable biomaterial applications overtime is shown in Figure 8. Here again we see theprominence of drug delivery and sensor/diagnosis,
with sensor/diagnosis applications increasing
quickly since 2018.
Notable examples include a DNA nanorobot
developed by Ravan et al. that can simultaneously
detect the cancer biomarkers miR21 and

30.9%

26.4%

25.9%

5.7%

4.0%

3.9%

3.1%

Drug delivery

Implants

Sensors

Actuators

Genetic
engineering
2.3%

3D printing

3.7%

16.7%

(3-Aminopropyl)triethoxysilane

3.1%

0.6%

1.0%

0.2%

Tissueengineering
1.1%

Poly(lactic acid)

4.2%

8.7%

1.4%

3.6%

7.9%

0.7%

Acrylic acid

2.7%

1.4%

2.0%

2.8%

2.8%

0.6%

4.4%

Cellulose

2.7%

2.4%

3.0%

8.5%

3.7%

2.9%

6.9%

Chitosan

9.0%

2.9%

2.5%

2.0%

12.7%

16.0%

2.2%

Copper

1.2%

2.2%

4.1%

3.9%

1.1%

0.6%

2.9%

Glucose

3.6%

0.8%

5.3%

2.0%

1.7%

4.3%

1.5%

Gold

6.6%

5.0%

23.9%

8.5%

3.1%

7.7%

4.0%
6.2%

Graphene

3.0%

0.9%

7.6%

8.9%

5.7%

0.6%

Iron oxide (Fe3O4)

3.2%

0.4%

2.1%

2.0%

1.7%

1.1%

1.8%

Methylenebisacrylamide

3.4%

0.4%

2.7%

8.1%

3.1%

0.3%

5.8%

N-Isopropylacrylamide

4.2%

0.4%

2.2%

8.3%

6.2%

0.0%

4.4%

Nitinol

1.2%

18.6%

1.6%

5.3%

0.8%

0.3%

1.8%

Platinum

1.4%

3.6%

3.8%

2.8%

0.3%

1.4%

1.1%

Poly(N-isopropylacrylamide)

3.2%

0.7%

1.9%

5.9%

6.2%

0.6%

1.1%

Poly(vinyl alcohol)

2.9%

2.6%

2.5%

4.3%

1.7%

0.9%

5.1%

Polyaziridine

3.3%

0.3%

0.9%

0.4%

1.4%

20.1%

0.4%

Polycaprolactone

3.0%

5.7%

1.5%

3.4%

9.3%

1.4%

7.6%

Polyethylene glycol

9.5%

4.3%

3.8%

3.4%

11.9%

16.9%

8.0%

Polystyrene

1.9%

1.6%

1.4%

1.6%

3.1%

2.6%

1.5%

Polytetrafluoroethylene

1.0%

8.0%

1.1%

2.2%

0.8%

1.4%

0.4%

Silica

14.1%

2.1%

6.2%

2.6%

5.4%

5.4%

5.1%

Silicon

1.5%

1.7%

5.1%

3.0%

0.8%

2.3%

2.5%

Silver

1.9%

2.4%

7.4%

3.9%

1.1%

2.3%

4.0%

Stainless steel

0.7%

10.9%

1.0%

1.2%

2.3%

0.6%

0.7%

Tetraethoxysilane

4.8%

0.3%

0.7%

0.2%

0.6%

1.4%

0.7%

Titania

1.2%

2.4%

1.9%

0.4%

1.4%

0.9%

0.7%

Titanium

1.2%

8.7%

1.7%

1.0%

1.7%

1.4%

1.8%

DNA*

34.4%

2.1%

57.9%

1.5%

3.4%

0.7%

0.0%

High

Low

Figure 7. Heat map of the relationship between the most commonly used substances in programmable materials (left column)
and the most common material applications (top rows). Relative frequencies of each substance have been calculated within eachapplication category. DNA is treated separately in this figure because it is not a single chemical substance (further details in text).

miR125b.128 The nanorobot was programmed
through toehold-mediated strand displacement
and logic gate operation, where DNA cues acted
as the stimulus. Ke et al. fabricated a series of
DNA hydrogels based on a single-stranded DNA
that contained multiple domains and studied thecargo release profile.129 The hydrogel enabledcontrol of mechanical properties, thermal stability,
and cargo loading capacity through modifying thesequence and lengths of the DNA domains.
A major advantage of DNA nanovehicles for drugdelivery is that they provide several strategies ofdrug incorporation based on the nature of the
drug or therapeutic molecule. Small moleculedrugs like metal complexes130 and anthracyclines131
can be carried via intercalation within the DNA
double strand. For nucleic acid sequences such
short interfering RNAs (siRNA) or CpG motifs,
the sequences can be synthesized as a part ofa staple, or hybridized with a complementarystrand that is partially involved in forming the160

Chu et al. reported a DNA nanocarrier thatenables targeted codelivery of doxorubicin (achemotherapeutic drug) and two antisense
nucleotides in the drug-resistant cancer
cells.135 This nanovehicle is able to penetrate
the Hela/adriamycin cells and avoid lysosomal
degradation. The targeting property of thenanocarrier originated from the attachment of
MUC1 aptamers as the MUC1 protein is generally
overexpressed in several tumors. The twoantisense strands were attached to the origami via
disulfide linkage, which is cleaved by the high levelof endogenous glutathione present inside thecancer cells. Here, glutathione acts as the stimulusthat leads to the release of the antisense strands
inside the target cells.

Sensors/Diagnosis
Drug delivery
Antitumor agents
Gene therapy
Tissue engineering
Antibacterial agents

140
Normalized frequency

DNA nanostructure.132, 133 In the case of large
biomolecule cargoes and nanoparticles, the cargo
can be attached to the extensions of the staple
strands using complementary strands, or they canbe covalently attached.134

120
100
80
60
40
20

20
11
20
12
20
13
20
14
20
15
20
16
20
17
20
18
20
19
20
20
20
21
20
22

10

20

09

20

08

20

07

06

20

05

20

04

20

20

20

03

0
Publication year
Figure 8. Overall publication (Patents + Journals) trend in selected top concepts involving DNA between 2003-2022

Trailblazing the future with emerging biomaterials | 85

Notable journal articles and patents

Table 1 is a set of research articles published from2020-2023 that represents emerging trends inthe field of programmable biomaterials. These
references provide examples of the materials
and applications which appear prominently
in our analysis of the literature in this area aspresented in Section III. Selection criteria for theseexamples also included high citation count, and/or
publication in high impact factor journals.
As discussed in earlier sections, DNA-based
structures are receiving significant researchattention because of their programmability
through nucleotide base pairing. However,these structures can become destabilized due toenvironmental changes.136 In a study by Macfarlane
et al., DNA-grafted nanoparticles were stabilizedusing a polyelectrolyte hydrogel composed ofpoly(dimethylaminoethylacrylate-methylene
bis-acrylamide) (P(DMAEA-MBAAm), which
formed electrostatic bonds between positively
charged DMAEA from the hydrogel and sugar–
phosphate groups on the backbone of DNA.137
The resulting DNA-crystal-embedded hydrogelretains its crystallinity under hydration, drying,
and compressing conditions for five cycles. This
study is an example of enhancing DNA-based
programmable material through combination witha polyelectrolyte hydrogel.
Biosensors were noted as a prominent application
for programmable DNA materials in the previous
sections. An example of this is the use of atetrahedral DNA structure to detect miRNA196a, a cancer biomarker,138 through combining
it with CuS and Fe3O4@SiO2@CdS composite
particles. The fully assembled structure has a weak
photocurrent response, due to photon capture
by CuS. In the presence of the target, the Fe3O4@
SiO2@CdS particles separate from the tetrahedral
DNA and CuS through toehold-mediated strand
displacement. After additional magnetic separation,
they can be detected through photocurrent
measurements. In this study, programmability was
important in forming the tetrahedral DNA, which
has several advantages over the more commonlyused methods involving hairpin DNA, including
better sensitivity, enzyme-free use, and better
resistance to degradation.139

Bone defect repair under complex medical
conditions, such as inflammation, is challenging.140
Recently, a magnetoelectric membraneconsisting of CoFe2O4@BaTiO3 core-shell
nanoparticle embedded in poly(vinylidene
fluoride-trifluoroethylene) was reported
for bone regeneration.141 This membrane
triggers osteogenesis with its highly efficientmagnetoelectric conversion based on the core shell
CoFe2O4@BaTiO3 induced charge density increasein an external magnetic field, followed by betaphase transition in the polymer that increases themembrane surface potential. This increased surface
potential further activates bone regeneration,even when co-morbidity conditions are present.
This in vivo study provides a method to reactivateskull regeneration under medical treatments that
impede osteogenesis, or when inflammatory
conditions are present.
Trainable stimuli-responsive materials are a specialclass of programmable materials that evolve
over repeated cycling of strain, temperature, orother conditions.142, 143 An example of this type ofmaterial are dual network hydrogels whose physicalproperties change over the course of thermal
cycling in ways that depend on their design. In
a recent study, two hydrogels were constructed,
one composed of poly(N-isopropylacrylamide)(PNIPAm)/agarose, the other an interconnectedinterpenetrating network made by PNIPAm/
acrylated agarose (ac-agarose), both crosslinked
by PEGDA.144 After thermal training, the PNIPAm/
agarose hydrogel became softer and the PNIPAm/
ac-agarose became stiffer. These two thermoresponsive hydrogels can perform coopertively
as artificial muscles after thermally trained.
Furthermore, this study provides a generalapproach to build actuators using thermallytrainable materials.
One aspect of synthetic biology, another emerging
field of research, is the use of engineeredbacteria to synthesize and process chemicals. 145,146
Pokorski et al. provide an example of combining
programmability with synthetic biology, with abiocomposite material made by 3D printing anengineered cyanobacteria-alginate scaffold.147
This printed alginate scaffold can be swollen toaccommodate nutrients and gases for further

bacterial growth and the photosynthesis expressedby cyanobacteria embedded on the scaffold. The
composite material also shows its response toexternal chemical stimuli, for example plasmid
pAM4909, and forms Yellow Fluorescent Protein(YFP). Another aspect of programmability in thismaterial is controllable cell death.
Table 2 contains a set of patents and patentapplications in the field of programmable materials
from 2019-2023 that represent the material
trends discussed in Section III. For example,
US20220160901A1 describes mesoporous silica
nanoparticles loaded with a cargo, drugs orcontrast agents, where the openings of the poresare capped with stimuli-responsive polymers(including PEG and others). Under a stimulus,
which could be to light, heat, ultrasound, ormagnetic field, the polymers reconfigure toallow the cargo to be released. CN115887684A
also describes a drug delivery system. Here, arectangular DNA origami structure is complexedwith an adriamycin prodrug that is released inan acidic environment, then activated by NQO1
enzyme expressed in tumor cells. The goal of thisapproach is to improve targeting and reduce thetoxicity of anticancer drugs.

As discussed in Section III, hydrogels are commonlyused as programmable biomaterials. An example ofthis is provided in CN116474093A, which describes
a hydrogel containing a phenylboronic acidmodified hyaluronic acid/poly-N-phenylglycine
nanocomposite, crosslinked with tannic acid. Thishydrogel undergoes a gel-sol transition through a
photothermal process in the NIR II range, and also
in response to changes in pH, both of which can beleveraged for drug delivery in postoperative skincancer treatments.
Shape memory is another important class ofprogrammability. CN113683770A provides anexample of a shape-memory material which ismade of a blend of polyaryletherketones withdifferent glass transition temperatures, whichallows the material to have multiple shape memory
states corresponding to different temperatures.
This provides the ability to program more complex
or multi-step behaviors compared to standard
shape memory materials with a single transition
temperature.

Trailblazing
thethefuturewithemerging
biomaterials| 87
Trailblazing
futurewithemerging
biomaterials| 87Table 1. Notable journal publications in programmable biomaterials in recent years.
Year

Title

JournalResearch Institute

Summary

2018

Programmable Metal/
Semiconductor Nanostructures
for mRNA-Modulated Molecular
Delivery148

Nano Letters

University of Toronto

Self-assembled DNA-based metal/
semiconductor nanomaterials embeddedwith therapeutic agent; the drug release
triggered by target mRNA upon a stranddisplacement reaction

2021

Biomimetic high performance
artificial muscle built on sacrificial
coordination network andmechanical training process149

NatureCommunications

South China Universityof Technology;
Guangdong Universityof Technology

Use of poly(ethylene-propylene-dienemonomer)/lignin composite and zincdimethacrylate (ZDMA) to make an artificial
muscle2021

Dynamic Manipulation of DNAProgrammed Crystals Embedded ina Polyelectrolyte Hydrogel137

ACS Applied
Materials &Interfaces

Massachusetts Instituteof Technology

Stabilization of DNA-based structures under
different conditions using polyelectrolytehydrogel

2022

Networking of Block Copolymer
Nanoassemblies via Digital Light
Processing Four-Dimensional
Printing for Programmable
Actuation150

ACS Applied
Polymer
Materials

Nanyang Technological
University

Use of various monomers to afford
photocurable and pH-responsive copolymer,
followed by nanoassembly and digital lightprocessing to produce a pH-responsive
material

2022

Biomimetic heterodimerization oftetrapeptides to generate liquid
crystalline hydrogel in a twocomponent system151

ACS Nano

Westlake University

Controllable self-assembly of tetrapeptides
upon substitution of peptides to achieve
desired mechanical properties for specific
uses

2023

Polymer-dispersed liquid crystal
elastomers as moldable shapeprogrammable material152

NatureCommunicationsJožef Stefan InstituteShape programmability of a main-chain
liquid crystal elastomer (MC-LCE) dispersed
in a polymer matrix

2023

Phenotypically complex living
materials containing engineered
cyanobacteria147

NatureCommunications

University of California
San Diego

Engineered cyanobacteria incorporated
with alginate to form a stimuli-responsive
biocomposite material capable ofbioremediation

2023

In situ activation of flexible
magnetoelectric membraneenhances bone defect repair141

NatureCommunications

Peking University, Sun
Yat-sen University,
Huazhong University of
Science and Technology

CoFe2O4@BaTiO3/poly(vinylidene
fluoridetrifluoroethylene)-based membranewith magnetic response enhancing bone cellregeneration

2023

Thermally trainable dual networkhydrogel144

NatureCommunications

Aalto University

Two thermoresponsive polymers¬, agaroseand poly(N-isopropylacrylamide), applied toform a trainable material with establishedtraining strategy under thermal conditions

Table 2. Notable patent documents in programmable biomaterials in recent years.
Patent or
publication
numberEP3453411 A1153

publication
year

Patent assignee

Title

Description of patented technology

2019

Cook Medical
Technologies LLC

Endovascular device configured
for controlled shape memory
deployment in a body vessel

Endovascular device made of nitinol, where
the shape-memory temperature varies along
the length of the device

WO2020241819
A1154

2020

Tokyo Inst. ofTechnology;
Kawasaki Inst. ofIndustrial Promotion

Complex, medicine, therapeutic
agent for cancer, kit and conjugate(pH)

pH-responsive drug delivery material basedon PEG (or other biocompatible polymers)
modified with a boronic acid group, and acompound with a diol structure, including
tannic acid and gallic acid.

US20220160901
A1155

2020

University ofCalifornia

Stimuli-Responsive Compositions,
Imaging Systems, and Methods
for Using the Same for Biomedical
Applications

Porous silica particles loaded with active
agents (for therapy or as a contrast agent),
where the pores are capped with a stimulus
responsive polymer that is designed torelease the active agent when exposed tolight, heat, ultrasound, or magnetic field

CN112011069 A156

2020

Harbin Institute ofTechnology

Nano filler/PNIPAM compositehydrogel, preparation method
and application in smart window,
actuator and remote light control
deviceHydrogel including PNIPAM with a nanoscale filler such as MXenes, graphene, carbon
nanotubes, MoS, VO2, and others, which canbe used for near-IR irradiation triggered drugdelivery

CN113831453 A157

2021

South China
University ofTechnology

Temperature response hyaluronic
acid, hydrogel and its preparation
method and application

Hyaluronic acid based hydrogel that releases
mesenchymal stem cell-derived exosomes
for treating corneal injuries when triggeredby temperature

CN110801433 B158

2021

Jiangnan University

Targeted pharmaceutical composition
loaded with amphotericin B andadriamycin together and application
thereof (pH)

pH-responsive micelles made of mannosemodified beta-cyclodextrin, loaded withamphotericin B and adriamycin as atreatment for leishmaniasis

CN113683770 A159

2021

Harbin Institute ofTechnology

Preparation of poly(aryl ether
ketone) with multiple shape memory
effects and its application

Temperature-triggered shape memory
polyaryletherketones, mixtures of which havedifferent transition temperatures are used togenerate multiple responses

CN112980165 B160

2022

Sichuan University

Self-repairing shape memory
composite material with photomagnetic response and preparation
and application thereof

Polycaprolactone-based shape memorymaterial that responds to light or magnetic
stimuli (or to both, cooperatively) through theinclusion of Fe3O4 particles

WO2022119868
B161

2022

University ofCalifornia

Injectable biodegradable polymericcomplex for glucose-responsive
insulin delivery

Poly-L-lysine modified with 4-carboxy-3fluorophenylboronic acid, which complexes
with insulin and releases it when glucose
levels are high

US20220297374162

2022

Xerox Corporation

Structure that compresses or
expands a volume in response to an
applied magnetic field

Elastomer loaded with magnetic particles(along with compatibilizers and fillers) thatmechanically responds to magnetic field

US11219502 B2163

2022

Medtronic Advanced
Energy LLC

Transformative shape-memory
polymer tissue cavity marker devices,
systems and deployment methods

Bioresorbable, shape-memory medical
device used to mark tissue cavities aftercancer surgery to target radiation treatment
based on poly(lactic acid), poly-L-lactide,poly-L-glycolic acid, or polycaprolactone,that is inserted through a small incision, thentakes on a permanent shape as triggered bybody temperature.

CN116474093 A164

2023

Guilin University ofTechnology

Near-infrared II zone
photoresponsive hyaluronic acidbased multifunctional hydrogelfor postoperative treatment of skincancerHydrogel incorporating boronic acidmodified hyaluronic acid poly-Nphenylglycine that is light (NIR II), thermal,
pH-responsive, to be used as a postoperative
drug delivering and antimicrobial material

WO2023133546
A2165

2023

Arizona State
University

Folding mRNA into a nanoscaledelivery vehicle

DNA nanostructures as delivery vehicles formRNA and single-stranded DNA

CN115887684 A166

2023

Nanjing Universityof Posts andTelecommunications

Drug delivery nano system andmethod constructed based on DNA
origami and adriamycin prodrug

DNA origami-based drug delivery systemthat selectively releases a prodrug in acidenvironments

Trailblazing the future with emerging biomaterials | 89

Challenges and perspectives

Despite the many advantages of programmablematerials, several challenges need to beaddressed to enable their more widespread use inbiomedical devices. The challenges identified inrecent literature include:– Scale-up and cost optimization of
fabrication methods, particularly
lithography.2 Photolithography, electronand ion-beam lithography, and nanoimprint
lithography have all been used to patternprogrammable polymer materials, but
all have drawbacks. Photolithography islimited to photo-sensitive materials, while
the other two forms of lithography havepractical limitations on scaling, specificallylong processing times and issues with molddurability.
– Combining multiple independentfunctions in a single material, using
orthogonal, simultaneous responses orsequential responses to a single stimulus,
or incorporating different responses todifferent stimuli while reducing interference
between functions has proven to bedifficult.26, 167 This represents a significant
opportunity for new material development.
– Coupling the direction of the stimulus to
the direction of the response, for example
reproducing the response of plants tomove in the direction of sunlight.167 While
this continues to be a challenging area,
recent work has demonstrated that theincorporation of photoresponsive liquid
crystal elastomers in a material can enable
the selective triggering of multiple shapemorphing modes, and even continuous,
oscillating motion in actuators androbots.168-170– Low response speed and slow kinetics are
significant limitations for shape-morphinghydrogels, mainly because actuation istypically constrained by the movementof water or ions.26 Introducing porosity
on a scale conducive to generating faster
responses, as has been demonstrated byusing electrospun hydrogel fibers, and is apossible route toward a practical solution.171– Concerns exist regarding the use of
programmable materials in complex
biological systems such as the human body.
Extensive in vivo testing would be required
before proof-of-concept demonstrations
can be applied in clinical settings, as
most studies have been conducted invitro. For example, programmable folding
behavior may become unpredictable incomplex physiological environments,2 while
programmable responses may be affectedby the presence of multiple, unpredictablestimuli present in the body.
– The lack of clear evidence supporting thebiomedical effects of DNA nanostructures
and their potential immunostimulatory
properties raises concerns about their longterm safety.15, 172– Nuclease degradation in the body is acommon obstacle for all DNA-nanostructure
based in vivo applications.15 To prevent
this degradation, strategies involving
modification and encapsulation, forexample by proteins or lipids are being
explored. 173 Notably, many of thesestabilization techniques are not adaptable
to the dynamic switching needed in several
stimuli-responsive DNA nanorobots thatare as in vivo delivery vehicles.18 Althoughsome DNA nanostructures are intrinsically
nuclease resistant, their effectiveness canalso be reduced by renal filtration,15 thoughconjugation with bulky groups might help toaddress this issue.

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Trailblazing the future with emerging biomaterials | 99

VI. Protein-based materials
Introduction

has been more or less on the rise, the growthin patent publications appears to be somewhat
stagnant (Figure 1).

Materials consisting of proteinaceous components
are referred to as protein-based materials andinclude well-known examples such as silk,1-3
collagen,4, 5 keratin,6-8 etc. Desirable properties
such as biocompatibility, biodegradability, bioabsorbability and self-assembly have meant thatthe use of protein-based materials in itself is anage-old practice.1 However, the developmentof new hybrid/composite materials based onnaturally occurring protein materials12, 13 is a much
more recent endeavor. Proteins are complex
molecules consisting of long polypeptide
chains often folded to form highly complex
and dynamic structures. Classified as natural or
biopolymers, proteins possess mechanical andphysical properties with the use of protein-basedmaterials in the biomedical field. Due to theirnatural origin, proteins are biocompatible andoffer ideal mechanical and physical properties forbeing used in the biomedical field, finding a place
in applications such as drug delivery,15-17 tissue
engineering,18-21 hydrogels,13, 22, 23 wound healing,24, 25
surface functionalization of implants,26-28
electronic skin29, 30 among others. This sustained
increase interest in protein-based materials isevident in the growing number of publications(journals and patents) over the last two decades(Figure 1). While the growth in journal publications

9,000

Journal

8,000

In this report we present our findings from
evaluation of more than 122,000 documents(journals and patents) spanning across two
decades (2003-2023) in the field of protein-basedmaterials from the CAS Content Collection. Alongwith providing publication trends, our analysis
is also centered around identifying emerging
materials in the field and their applications.
The three-dimensional structures of a few protein
molecules and their corresponding amino acidcompositions are shown in Figure 2 and Table 1,
respectively. Diversity in amino acid compositionsof proteins confers characteristic properties to thematerials based on those proteins. For instance,a recent study found correlations between aminoacid compositions of silk and properties, including
wetting behavior. This could have a direct bearing
on the use and design of engineered recombinantsilk types depending on the desired applications. 31
In another study, the amino acid composition ofsilk sericin extracted from three different mothspecies was determined to be more or less similar
with all three of them displaying/possessing
antibacterial and antioxidant properties. 32

PatentNumber of publications

7,000

*

6,000
5,000
4,000
3,000
2,000
1,000

23

20

22

21

20

20

20

19

20

20

18

17

20

20

16

15

20

20

14

13

20

20

11
12
20

20

10

09

20

20

08

07

20

20

06

05

20

20

04

03

20

20

0
Publication year
Figure 1. Number of journal and patent publications per year in the field of protein-based materials (shown as blue and yellow
bars, respectively) over the period of the last two decades (2003-2023). *The data for 2023 only includes the months fromJanuary to August.

Table 1. List of commonly used proteins as materials and their amino acid compositions.
Name of protein

Organism

PDB ID

FlSp spidroin

Trichonephila clavipes

7OOM (1.80 Å)Intermediate filament proteins
keratin 1 (KRT1) and keratin 10 (KRT10)

Homo sapiens

6EC0 (2.98 Å) 10, 34

Vimentin Coil 2B fragment

Homo sapiens

1GK4 (2.30 Å) 9, 36

Serum Albumin

Homo sapiens

1AO6 (2.50 Å) 11, 37

Glutamic acid (14%), Alanine (11%), Leucine(10%), Lysine (10%)

Collagen38

mammalian source-

Glycine (33%), Hydroxyproline (22%) Proline(17%)

Elastin38

mammalian source-

Glycine (37%), Alanine (~20%), Valine(~17%), Proline (13%)

Silk Fibroin39, 40

Bombyx mori-

Glycine (43%), Alanine (30%), Serine (12%),Tyrosine (5%)

Silk Sericin41

Bombyx mori-Serine (42%), Glycine (10.5%), Threonine(7.9%)

Resilin42

Drosophila sps.

-

Glycine (27.4%), Serine (11.9%), Alanine(10.4%)(A)(B)

Abundant amino acids
14, 33Glycine (36%) and Serine (21%)
Human keratin35: Serine (13.9%), Glutamine(13.5%), Leucine (12.3 %)

(C)

(D)

Figure 2. A few representative crystal structures of protein molecules determined using X-ray crystallography: (A) humanvimentin coil 2B fragment (PDB ID: 1GK4),9 (B) coil 1b domains of human keratin 1-keratin 10 complex (PDB ID: 6EC0)10, (C)human serum albumin (PDB ID: 1AO6)11 and (D) N-terminal domain of FISp spidroin (PDB ID: 7OOM)14 determined at resolutionsof 2.3 Å, 3.0 Å, 2.5 Å and 1.8 Å, respectively.
Trailblazing the future with emerging biomaterials | 101

Journal and patent publication trends

Using the average citation per publication, weshortlisted fifteen among the top 150 institutions(in terms of number of publications) that areleading in research related to protein-basedmaterials (Figure 3). China accounts for nearly
half (7) of the 15 institutions, followed by 4 and2 institutions originating in the United Statesand Singapore, respectively. The remainder ismade up by 1 institution each from Canada andthe Republic of Korea. The leading institution
for research related to protein-based materials
appears to be Harvard Medical School with anaverage citation of ~90 per publication. A few
examples of highly cited articles from Harvard
Medical School revolve around 3D bioprintingof gelatin methacryloyl (GelMA), a synthetic
derivative of gelatin43, 44 and the use of collagen intissue engineering.45
Geographical distribution of patent assignees
across commercial and non-commercialorganizations in the field of protein-basedmaterials shows a high degree of overlap (Figure4). The United States (USA) and China (CHN)
lead in terms number of commercial and non-commercial patent assignees, respectively. Other
key countries or regions include Germany (DEU),
Republic of Korea (KOR), India (IND), Switzerland(CHE) and Italy (ITA). Japan (JPN) ranks muchhigher in number of patent commercial assignees
as compared to non-commercial ones. In termsof growth in number of patent publications overtime, China, India and Korea show an upward
trend with the volume being highest for China
in general. The USA and Germany show little
to no increase or decrease in volume of patentapplications staying more or less steady over thetwo decades. Japan on the other hand shows aslight decline in the number of patents post 2006
which holds steady 2008 onwards.
To determine leading organizations in terms ofpatent publications, we separated organizations
involved in protein-based material research into
commercial and non-commercial entities. The
geographical distribution of these organizations
shows a high degree of overlap although theexact order of leading countries of regions differs
between commercial and non-commercialorganizations (Figure 4). While the USA leadsin terms of commercial organizations, followed

Average number of citations per publication
Harvard University
Tufts University
National University of Singapore
University of California
University of Toronto
University of Michigan
Chinese Academy of Sciences
Nanyang Technological University
Seoul National University
Tsinghua University
Zhejiang University
Wuhan University
Donghua University
Fudan University
Soochow University
Number of Journal publications
Figure 3. The top 15 institutions in terms of average citation numbers per journal publication and journal publications forthe period 2003-2023. The different colors of the bars represent institution’s country/region: blue (USA), red (China), yellow(Singapore), purple (Korea), bright green (Canada); and the yellow line represents the average citation per publication.

by China (CHN) – the order is reversed for noncommercial organizations. In terms of the leading
non-commercial organizations, the group isdominated by institutions from China, accounting
for nearly 80% of the top 15 with the remaining
three members originating from the UnitedStates. For the commercial organizations, thedistribution is a little more diverse with only 4
and 3 out of the top 15 organizations originating
in USA and China, respectively. The remainderof the leading organizations comprised of one
organization each from: Switzerland, India,
Denmark (DNK), Republic of Korea, Germany,

Japan and France (Figure 4). Patent publications
from the US based company Allergan, Inc. related
to the use of silk fibroin in drug delivery (WO
2019006098 A146), hydrogels (WO 2010123946
A247) and medical devices (US 20150148823 A148).
The University of California, the leading noncommercial organization, had patent publications
with diverse applications of protein-basedmaterials including tissue engineering (WO
2012002986 A249), drug delivery (WO 2020092229
A150) and hydrogels (US20230158149 A151) among
others.

Others16%

USA 27%19%

GBR

3% ITA2%
2% CHE
3% FRATop 10patent assignees4%2003-2023

5%

CHN

25%

5%
8%

CHN 34%IND

2003-2023

KOR

DEU

19%

USA

JPN
Commercial

Non-commercial
rsity
Number of patent publications
Si of
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Ph Zh n orar eji Un nia
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KOR

DEU
FRA

ive

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4%

Ch

100

5%

3% JPN
3% RUS
3% ITA
3% CHE
3%
IND
4%

Un

iot
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hn
Tia
olo
Number of patent publications
Gr njigy
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tin haen rmnt P ac Ne , Incha eu ste .
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wt
Or velo ion
tho pm
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c.

150

Top 10patent assignees

OthersPatent assignees

Patent assignees

Figure 4. Geographical distribution of patent assignees (top panel – donut charts) and leading patent assignees, presented ascommercial and non-commercial, in terms of the number of patent publications (bottom panels – bar charts) from 2003-2023.
Bar graph has been color coded by country/region to match color scheme in donut charts. Standard three letter codes used torepresent countries/regions.
Trailblazing the future with emerging biomaterials | 103

(A)

1,800

CHN

Number of patent publications

1,500

1,200
USA

900

600

KOR
IND
JPN
DEU

300

2

20

21

-2

02

0
19

-2

02

8
20

20

17

-2

01

6
15

-2

01

4
20

-2
13
20

20
11
-

01

12

0
20

09

-2

01

8
20

07

-2

00

6
20

00
-2
05
20

20

03

-2

00

4

0

Publication year
(B)

USA: 28,928
USA: 61,898

WIPO: 61,817

CHN: 21,827
CHN: 18,798
DEU: 10,147

USA: 21,137

CHN: 17,765

JPN: 8,454
CHE: 6,148
FRA: 5,306
KOR: 5,767
GBR: 5,217
ISR: 4,064
IND: 3,649

EUR: 13,337
JPN: 9,950
CAN: 7,456

DEU: 5,542

KOR: 5,561

JPN: 4,529

IND: 4,028

KOR: 4,441

BRZ: 2,619

FRA: 3,670

MEX: 2,240

EPO: 3,084

ESP: 1,903

IND: 2,273
GBR: 768

Others: 12,602

OTH: 3,922

Figure 5. (A) Yearly growth in patents for selected leading countries in terms of patent publications in the field of protein-basedmaterials over 2003-2023 from the CAS Content Collection. (B) Sankey graph depicting flow of patent families in the proteinbased materials field between assignee countries (left), office where the first application in a family is filed (center) and the officewhere individual patent publication activities take place (right). Others and OTH includes more than 80 worldwide patent offices.

Key materials and applications

We performed an extensive search across both
the document and substance dataset in the CAS
Content Collection and identified and categorized
protein-based materials into one of the following:– Structural– Elastomeric– Adhesive– Others
The system of classification was based on thefunctionality of proteins. One of the biggest
classes was structural proteins, comprising ofmembers such as collagen, silk and keratin among
others as seen in Figure 6. This was followed byelastomeric proteins, elastin, and resilin with the
publications related to the former outnumbering
those for the latter. The next most abundantgroup of protein-based materials was adhesive
proteins with mussel foot proteins (MFPs)
accounting for most of the publications.
Among structural proteins, collagen represents
the highest number of publications (Figure 6).
Publications related to collagen have shown asteady increase over the years with a steeper
increase post 2019 (Figure 7A). Collagen is oneof the most abundantly found proteins in theextracellular matrix (ECM) and collagen-based
biomaterials can be derived from the acellularform of collagen. Extracted collagen can becomplexed with other biomolecules such as
chitosan, elastin, and glycosaminoglycans.52
Collagen-based materials can be widely used
as tissue scaffolds, in wound dressing, tissue
repair, and in drug delivery systems.53, 54 Gelatin, aprotein derived from collagen hydrolysis, exhibits
numerous advantages over collagen such as
low immunogenicity, better water solubility, andsol-gel transition. 53, 55, 56 A closer look at the CAS
data shows that gelatin, an important protein fordeveloping gelatin-based materials, has showna steep increase in the number of publications
post 2017. Gelatin-based hydrogels are used forvarious biomedical applications such as tissue
engineering, and medical scaffold preparation.
An engineered gelatin-based material, gelatinmethacryloyl (GelMA) exhibits crosslinkability
making it useful for developing hydrogels forbiomedical applications. In addition GelMA is also
widely used for 3D printing and drug delivery.57, 58
Another important category is silk-basedmaterials, which have shown a steady rise inpublications since 2003, indicating their wideusage (Figure 7A). Recombinantly produced silk
protein has shown high versatility and can bemade into various forms such as films, coatings,
capsules, particles, foams, fiber mats, etc. allowing
them to have diverse applications in fields suchas tissue engineering and wound dressing.59, 60
Recombinant systems have been utilized to obtainsilk in large quantities61-63 with the insect Bombyx
mori64, 65 having the most number of publications
associated with it in our dataset (Figure 8A). This isfollowed by the prokaryote Escherichia coli which
has been used to produce spider silk.66, 67 Other
expression systems that appear to have been
used, albeit to a much smaller extent, include
plant-based systems such as Nicotiana tobacum,68
eukaryotic Pichia pastoris,69-71 animal-based
system Mus musculus72 as well as the prokaryote
Salmonella typhimurium.73 Silk-based materials
are also used in bioelectronic applications suchas developing electronic skin (also known asE-skin) (Figure 8B).74 Silk fibroin can be used toprepare hydrogels either individually or they canbe combined with other proteins like elastin to
generate silk-elastin-like protein polymer (SELP)
hydrogels that can be used for controlled releaseof molecules such as cytochrome, vitamin B12,
DNA, etc.75-78
In addition to structural proteins, adhesive
proteins like mussel foot proteins (MFP) (Figure
6 and 7B) contain a modified form of tyrosine,
3,4-dihydroxyphenylalanine (Dopa). The presenceof Dopa provides attachment ability to MFP,
allowing it to bind to solid surfaces, including awide variety of hydrophilic surfaces such as glass,metals, and hydrophobic surfaces such as plastics.
Studies have shown MFP attaches to metalpresenting surfaces (e.g., TiO2).79 and graphene
oxide (GO),80 forming composite materials thatcan be used for engineering and antimicrobial
applications.81-83 Due to these diverse applications,publications related to MFP have shown a steadyincrease over the last two decades (Figure 7B).

Trailblazing the future with emerging biomaterials | 105

Structuralfunction***

Elastomeric

OthersAdhesive

Figure 6. Distribution of protein-based materials based on functionality over two decades (2003 to 2023) from the CAS Content Collection. Size of the circle corresponds to numberof publications (journals and patents). Growth of materials marked with an asterisk are shown in Figure 7.

*
**
*
*

*

Elastomeric proteins like elastin and resilin
have shown a steady increase in the growthof publications related to them. Interestingly,
publications related to resilin show a rapid
acceleration 2019 onwards (Figure 7B). Elastin is
an extracellular protein that provides elasticity
to tissues and has been used in various forms
such as soluble fibers, recombinant tropoelastin(precursor protein of elastin), elastin-like peptides(EPLs), elastin-like recombinamers (ELRs).

Applications of elastin-based materials include
use in skin grafts, vascular grafts, heart valves,
biomedical devices, drug delivery systems etc.84-86
Resilin is an elastomeric protein which possesses
ideal mechanical properties in addition to its
self-assembly and ability to undergo phasetransition making it ideal/useful for developing
smart materials.87 Resilin mimetics such asresilin-like polypeptides (RLPs) have sequencerich in hydrophilic amino acids and possess high

(A)

(B)

5

2
02

0
02
20

21

-2

8
01

-2

20

19

6

-2

20

17

4

01

01
20

15

-2

12
20

13

-2

0

20

01
20

11
-

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-2

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00

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00

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00

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03

6

0

10

00

5

15

-2

10

20

07

15

Osteopontin
LamininOsteocalcin

25

20

Relative growth in publication (%)

20

20

SMA
KeratinElastinVimentin
Resilin
MFP

CollagenFibrin25

4Relative growth in publication (%)

Silk
GelatinPublication year

Publication year

(C)

Drug delivery
Hydrogels
Wound healing
Tissue engineering

8000

Bone
Bioprinting
Skin
Bioelectronics

2000

1200

0

900

-2
20 00
07 6
-2
20 00
09 8
-2
20 01
11 0
-2
20 01
13 2
-2
20 01
15 4
-2
20 01
17 6
-2
20 01
19 8
-2
20 02
21 0
-2
02
2

1500

04

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20
05

-2
0

1800

20
03

Number of publications

6000

600
300

20
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-2
20 00
05 4
-2
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07 6
-2
20 00
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20 01
11 0
-2
20 01
13 2
20 201
15 4
-2
20 01
17 6
-2
20 01
19 8
-2
20 02
21 0
-2
02
2

0

Publication year

Figure 7. Emerging trends of (A) and (B) protein-based materials and (C) their applications based on data from the CAS Content
Collection for 2003-2023.
Trailblazing the future with emerging biomaterials | 107

elastomeric potential expanding the application ofresilin in fields such as biosensors, bioelectronics,
bioprinting in addition to applications in tissue
engineering, biomedical applications and drugdelivery.87-89

the last four years, indicating the importance of
ECM-based biomaterials (Figure 7B).
The overall distribution of biomedical applications
for protein-based materials are shown in Figure
8B in the outer donut chart. The inner pie chartshows the distribution of the same biomedical
applications for silk-based materials in particular.
Both the overall protein-based and silk-specificapplications follow similar trends, the exceptions
being that silk-based materials have a relatively
higher number of publications associated with
their use in tissue engineering,95 hydrogels,96, 97
and bioelectronics.98, 99 Growth in publications
over the last two decades indicates an upward
trend across the broad with a particularly sharp
increase in bioprinting100-102 and electronic skin103,
104
after 2014 and 2020 (Figure 7C). On the other
hand, wound healing105, 106 and hydrogels107, 108 are
the other applications that show a less sharp but
still considerable growth.

Extracellular matrix-based biomaterials are used
for tissue regeneration, cell growth, drug delivery,
and various other biomedical applications. Thisis made possible due to ECM’s ability to act as anatural scaffold for designing various biomaterials
owing to their natural biocompatibility andbiodegradability.90 In addition to major ECM
proteins such as elastin, collagen, trace ECM
proteins like osteopontins, vimentins and laminins
have been used to promote cell growth, adhesion,and maintaining cytoskeletal function.91-94 The
CAS Content Collection data shows that these
proteins show a moderate increase in the last two
decades except for osteopontin, which shows asteep increase in the number of publications over

(A)

(B)
Nicotiana tobacum (0.3%)
Others (0.5%)

Salmonella typhimurium (0.3%)
Pichia pastoris (0.4%)
Mus musculus (0.5%)

Bioelectronics
Skin (0.4%)

0.7%
5% 4%

20%

Drug delivery 37%
Recombinant systems
in silk production
2003-2023
Journals and Patents

Bioprinting

2% 3%Escherichia coli
20%

31%

Hydrogels

12%

14%

12% Wound healing

9%
16%
15%

78%

19%

Bombyx moriTissue engineering

Bone related

Figure 8. Distribution of (A) recombinant systems used for silk production and (B) applications for protein-based materials
overall (outer donut chart) and for silk-based materials (inner pie chart).

Notable journal articles and patents

Table 2 encompasses a set of research articles
published from 2020-2023 that represents
emerging trends in the field of protein-basedmaterials. These references were selected
to provide examples of the materials andapplications that appear prominently in our
analysis of the protein-based material literature aspresented in section III. They were also selectedbased on other factors, including the impact
factor of journal and the number of other articles
citing the reference. The listed examples include
publications related to silk, gelatin, collagen,elastin, keratin, resilin, MFP, peptides, antibodies,
etc.
Notable examples from Table 2 include an article
titled “Thermoplastic Molding of Regenerated
Silk” which describes a method for transforming
solid-state regenerated silk fibroin (derived from
Bombyx mori) into structural materials. By tuning
the processing conditions, these materials canbe used to construct biomedical devices such as
medical screws for bones, ear plugs etc.109
Another example is the study titled “Liquid metaltailored gluten network for protein-based e-skin”
by Ye, Shen, et al. at Fudan University, China,
which describes the method for the constructionof gluten-based electronic skin. Gluten protein iscross-linked using gallium indium alloy (EGaIn),generating a gluten network that can be used
to generate electronic skin (e-skin) due to highstretchability, self-healing, biocompatibility,
biodegradability.110
In another example, gelatin/gelatin methacryloyl(gelMA) and carboxymethylcellulose (CMC) areused to design dual-network microporous PAM(Protein-based Annealed Microgel) scaffolds via
extrusion printing. PAM scaffolds were checked
for their strength, biocompatibility, rheologicalproperties, and degradability. Eventually,
encapsulation in the scaffolds was tested using
recombinant Escherichia coli DH5α to examine
cell viability and cell leakage from these scaffolds.
Further, Saccharomyces cerevisiae encapsulated
PAM scaffolds were used for testing ethanol
fermentation, indicating that these scaffolds canbe functionalized with different microorganisms tocarry out various functions.111

Furthermore, researchers at Westlake University
have developed a green and efficient methodwith scaling-up potential for modifying nativesilk fibroin to silk acid with a tunable modification
degree. Upon subcutaneous implantation, thesilk acid materials with a high carboxylation
degree exhibited enhanced degradation, a mild
foreign-body response, and pro-angiogenic
properties, demonstrating great potential for silk
acid as a new implantable biomaterial for tissue
regeneration.112
Table 3 shows notable patents in the field ofprotein-based materials published from 2018 to2023. Patents were selected based on relevance,
novelty, applicability, and field of study. Most ofthese involve different proteins in their various
forms focusing on their applications in thefield as described in section III. For instance,
JP6807089B2113 by Spiber Inc. explains thesynthesis of modified silk fibroin with reduced
overall glutamine content which reduces theoverall hydrophobicity of the protein leading
to a reduction in shrinkage of silk fibroin.
Modified fibroin fibers, in their various forms like
nanofibers, films, and coatings can be used fordiverse biomedical applications.
In another example, US20220142936A1114
discusses protein-based nanoparticles that canbe used for treating cancer. These nanoparticles
could be composed of water-soluble proteinssuch as albumin, mucin, transferrin, insulin,lysozyme, hemoglobin, collagen, catalase,horseradish peroxidase, glucose oxidase, and/or their combinations in specific ratios and they
are synthesized using electrodynamic jetting
method. They can contain active nucleic acid asa therapeutic agent and can be functionalized tosuit different cancer types.
In a recent example, US11578106B2115 explains thecomposition of a coating composition based on
the use of surfactant adhesive proteins (mostly
mussel-derived adhesive proteins) that areversatile and exhibit an excellent affinity to thehydrophilic or lyophilic surfaces. The proteins usedin the composition can be modulated to give riseto anticancer, antibacterial, antifungal, or antiviralcoating.

Trailblazing the future with emerging biomaterials | 109

Table 2. Notable journal articles in the field of protein-based materials in recent years.

Year

Title

JournalResearch InstituteApplication

2020

Cation-induced shape programmingand morphing in protein-basedhydrogels116

Science Advances

University of
WisconsinMilwaukee (UWM)

Human serum albumin-based hydrogels
which can undergo temporary shape andmorphology changes in response to metal
ion stimulus.

2020

A bioinspired and hierarchicallystructured shape-memory material117

Nature Materials

Harvard University

A keratin-based system that exhibits
hydration-controlled shape memory
properties.

2020

Thermoplastic Molding ofRegenerated Silk109

Nature Materials

Tufts University

Thermal processing method to transform
solid-state regenerated natural silk intosilk-based bulk material.

2021

Photopatterned biomolecule
immobilization to guide threedimensional cell fate in naturalprotein-based hydrogels118

Proceedings of the
National Academy of
Sciences

University ofWashington

Natural hydrogel materials decorated withbioactive proteins which could be used intissue engineering.

2021

Adhesive protein-based
angiogenesis-mimicking
spatiotemporal sequential releaseof angiogenic factors for functional
regenerative medicine119

Biomaterials

Pohang Universityof Science andTechnology

Mussel adhesive protein (MAP) based
platform fabricated to spatially separate
the release of (vascular endothelial growth
factor (VEGF) and platelet-derived growth
factor (PDGF).

2021

Nanoengineered PeptideBased Antimicrobial Conductive
Supramolecular Biomaterial for
Cardiac Tissue Engineering120

Advanced Materials

Tel Aviv University

A composite hydrogel containing Arg–Gly–
Asp (RGD) peptide used for DNA binding
and antimicrobial activity.

2021

Elastin-like polypeptide modified
silk fibroin porous scaffold promotes
osteochondral repair121

Bioactive Materials

Northwest University

Porous scaffold made from elastinlike polypeptide (ELP) bound to Silk
fibroin (SF) which can mimic 3D cellular
microenvironment.

2021

Accelerated polymerization of
N-carboxyanhydrides catalyzed bycrown ether122

NatureCommunication

University of Illinois

Method for rapid synthesis of polypeptides
by accelerated polymerization (catalyzed bycrown ethers (CEs)) of N-carboxyanhydrides(NCAs)

2022

Liquid metal-tailored gluten network
for protein-based e-skin110

NatureCommunication

Fudan University

Gluten-based electronic skin, which is selfhealing, stretchable, and biocompatible.

2023

Silk-based hydrogel incorporated
with metal-organic framework
nanozymes for enhanced
osteochondral regeneration97

Bioactive Materials

Nanjing Medical
University

Silk hydrogel with nanozymes which can beused to accelerate Osteochondral defects(OCD) repair

2023

Bioprinting microporous functional
living materials from protein-based
core-shell microgels111

NatureCommunication

University ofCambridge

Gelatin/gelatin methacryloyl (gelMA) andcarboxymethylcellulose (CMC) based
protein annealed microgel (PAM) for
culturing separate microbial consortia
simultaneously.

2023

Silk Acid as an Implantable
Biomaterial for Tissue Regeneration112

Advanced Healthcare
Materials

Westlake University

Silk acid materials can be used to fabricate
new implantable biomaterials for tissue
regeneration.

Table 3. Notable patent publications in the field of protein-based materials in recent years.

US9925301B2

Publication
year
2018

JP6807089B2123

2021

Spiber, Inc., Japan

Modified fibroin

It describes method for producing artificially modified
fibroin fiber with reduced shrinkage for use in industrial
applications.

US11180541B2124

2021

Geltor, Inc., USA

Recombinant collagenand elastin molecules
and uses thereof

It explains the preparation of non-naturally occurring
truncated forms of collagen and elastin that can beused for industrial and tissue engineering applications

CN108348577B125

2021

Bengt I Samuelsson
Institute of Life
Science Co Ltd, China

Mussel mucin productand application
thereof in inhibiting
skin inflammation

It demonstrates the use of mussel mucin (MAP)
known as mussel foot protein (Mefp) as an active
ingredient in treating skin inflammation

US11065365B2126

2021

Allergan Australia
Pty Ltd Allergan
Pharmaceuticals
International Ltd,
Ireland

Preparation and/or formulation ofproteins cross-linked
with polysaccharides

It describes formulations based on Tropoelastin andalbumin crosslinked using saccharide-based linker,
these could be used for therapeutic purposes.

US20220142936A1114

2022

University of Michigan,
USA

Therapeutic proteinbased nanoparticles
for treating cancer

It describes nanoparticles comprising water-soluble
proteins. These nanoparticles have a mesh structure
encapsulating the inhibitor of the transcription factor
and can be used for treating cancer.

CN110951096B127

2022

Guangdong
Institute of Medical
Instruments, China

GelMA-oxidized
glucan doublenetwork hydrogel andpreparation method
thereof

It describes a method for preparing hydrogel using
methacrylate gelatin (GelMA)-oxidized glucan doublenetwork hydrogel which has improved mechanicalproperties as compared to normal gelatin-basedhydrogel.

WO2022178409A2128

2022

The Regents of the
University of Colorado,
The University ofNorth Texas Health
Science Center, USA

Protein-based
therapies for ocularconditions

It demonstrates therapies developed using peptides
derived from a heat shock protein, including Hsp20
and/or αΒ-crystallin which could help in ocularconditions.

CN114748707A129

2022

Sichuan University,
China

Degradable
anticoagulant
and rapid
endothelialization
coating of occluder
and preparation
method thereof

It describes the method for preparing degradable,
protein-based occluder anticoagulants where proteins
like laminin, elastin, gelatin, and RGD peptides areused for promoting endothelial repair.

CN113527895B130

2022

Westlake University

A degradable andsuper-tough silk
protein-basedmaterial and its
preparation method
and application

It describes method of fabricating degradable andsuper-tough silk protein-based materials.

US20230158149A1131

2022

University of California

Wafer-Scale Protein
Patterning of Hydrogel
Devices

It describes method of performing extracellular matrix
proteins patterning on silicon or glass-based wafer.

US11603393B2132

2023

Bondwell Technologies
Lp, USA

Self-assembly ofprotein-based
biomaterials withmultiple morphologies

It describes the composition of protein-based
biomaterial composed of ultrabithorax (Ubx) protein
which can be used to form sheets, fibers, films, etc.

US11578106B2115

2023

Tme Therapeutics Co
Ltd, Korea

Surfactant adhesivecomposition

It relates to the formation of mussel adhesive proteinbased biofunctional adhesive which can be used todevelop antibacterial/a antimicrobial films.

Patent number
122

Patent assignee

Title

Description of patented technology

Trustees of Tufts
College, USA

Methods of producing
and using silk
microfibers

It describes preparation of silk microfiber-reinforced
scaffolds which can be used for bone graft applications.

Trailblazing the future with emerging biomaterials | 111

Challenges and perspectives

Protein-based biopolymeric materials findapplication in various realms. Advances inproteomics and next-generation sequencing
technologies in the past decade have enabled
the identification and characterization of new
proteins, thereby accelerating the developmentof new protein-based materials. Despite theseadvancements, some challenges still remain:
1. The biggest challenge occurs during the
production of proteins using recombinantsources arising from excessive metabolic
burden due to the over-expression of certain
non-native genes, which directly impacts
the yield of the target proteins. Anotherchallenge is the discrepancy in codon usage
arising from the use of different expression
hosts as compared to natural sources; forinstance, bacterial expression systems
exhibit a low tolerance for sequence repeats
and eliminate such sequences, leading
to altered protein sequences. More work
is needed for widespread success in thisarea to overcome host-organism-related
challenges encountered during recombinant
protein production.134-136
2. Native protein sequences might containdomains with immunogenicity, and it isimportant to engineer or modify these
proteins by removing these domains for
efficient use in protein-based materials.137
3. Proteins are natural polymers, and can lacksufficient mechanical strength, resorbability,
functionality, or access to functionality for
their intended use in tissue engineering.
Developing new approaches, such as
sequence engineering or hybridizationof proteins with other synthetic/naturalpolymers, are needed to increase theirusability.137

4. Engineered protein-based materials showpoor neovascularization - the ability toform new blood vessels. Also, controllable
mechanical and low/lack of self-healing
properties in engineered protein scaffolds/
constructs affect their use in tissue
engineering applications.110, 137 Efforts arebeing made to modify these materials or
use them as composites, this could help
in enhancing the mechanical/physicalproperties of protein-based materials.
5. Proteins are not completely hydrophobic
in nature. They have low water-barrier
properties, as compared to synthetic
materials like plastics, therefore, structuralmodifications can help in enhancing proteinhydrophobicity.138
6. While proteins are being used for tissue
engineering applications, they are not an
ideal choice for antimicrobial applications
due to their susceptibility to proteasehydrolysis.111 Mapping the protein sequenceand linking it to the proteolytic stability
profile of the protein can help modulate thesequence to improve its proteolytic stability.
Protein-based materials have advanced in tissue
engineering, drug delivery, and regenerative
medicine owing to their biocompatibility,
cytocompatibility, biodegradability, andbioactivity. However, continued advancements
are needed in translating more protein-basedmaterials into various clinical applications.

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Trailblazing the future with emerging biomaterials | 119

VII. Self-healing materials
Introduction

Self-healing materials are defined by theirability to recover from mechanical, thermal,
and chemical-induced damage to restore their
original properties, without external assistance.
For example, a self-healing polymer-based gel
can be designed with reversible crosslinks that arebroken when it experiences shear forces during
injection, allowing it to flow like a liquid through anarrow needle. After the material is at rest inside
the body, the crosslinks are re-formed, restoring
its gel-like rheological properties.1
The same approach can be used to repair cracks,
cuts, or breaks in a bulk material under static
conditions. When two disconnected faces of a selfhealing material are placed into contact, reversible
bonds can be re-formed, which combined withinterdiffusion results in joining of the two faces.
In the context of biomedical applications, thiscan make wound dressings, implanted devices,and scaffolds2 more resilient, robust, and reliable,
since the damage they can experience due tothe dynamic conditions of the body cannot be
repaired by natural processes. 3, 4
As an example, both types of self-healing aredemonstrated by a biocompatible poly(vinyl
alcohol) (PVA) based hydrogel containing tannic
acid.5 This material contains a high densityof strong hydrogen bonds between PVA andtannic acid which can be repeatedly broken
and re-formed, giving the material self-healing
properties. When two cut pieces of this material
are placed in contact, the bond formed between
the pieces recovers to 87% of its initial tensile
strength within 2 hours. On a microscopic level,
dynamic rheological testing showed that crosslinks
were disrupted at high shear strain, with the gel-like properties being mostly restored within 70
seconds of removing the high shear strain.
In a broader context, various synthetic selfhealing concepts have been developed, basedon different physical processes and chemistries.
Self-healing has been extensively studiedin polymers, polymer composites, ceramics,
concrete materials, and metals. Self-healing
polymers are the most widely used, primarily
because of the ease of chemical functionalizationand modification of polymeric systems and therelatively low temperature required to induce
the mobility over short length scales required
for self-healing.6 Polymers are even more heavily
represented in biomedical applications due to thebiocompatibility of many polymers and the ability
to engineer them to have mechanical properties
similar to biological tissue.
In this report, we will first examine trends in thefrequency of journal and patent publicationsin the field of self-healing biomaterials from2003-2023. Next we will discuss the chemicalmechanisms that are used to impart self-healing
properties to biomaterials, which are closely
connected to the specific chemical substances andfunctionalities used. We will then analyze trends
extracted from the CAS Content Collection related
to the substances used in this area, and their mostprominent applications. Finally, we will highlight a
selection of journal and patent publications that
represent emerging trends.

Journal and patent publication trends

Figure 3 presents a breakdown of patentpublications by country, from commercial andnon-commercial assignees. Chinese assignees
make up about 80% of the patent publications
in both the commercial and non-commercial
categories, followed by the US with around 7-8%
share of the patents in both the categories. Japan,
Korea, and Israel follow the US in the commercial
category, while Korea, India, and France are
the next highest assignee countries in the noncommercial category.

Figure 1 shows the number of journal and patentpublications during the period 2003-2023. There
has been a steady growth in the number ofjournal publications in the past 20 years whichappears likely to continue in 2023. The numberof patent publications has also shown steady
growth, with some deceleration from 2020-2022.
Like most other emerging materials, the numberof journal publications is significantly higher than
the number of patents. The increase in the journal
to patent ratio in 2021 and 2022 suggests that
research into self-healing materials is focusedon early-stage research rather than commercial
development.

The trend of patent publications over time broken
down by country/region is shown in Figure 4.
Here again we see the high number of patentpublications originating from assignees in
China. Patent activity in the area of self-healingmaterials began to increase in around 2012, withmost activity taking place after 2016, and still
increasing as of 2023. The other trend we see inthis plot is a significant rise in the patent activity
from assignees in Korea starting in 2016, leading
to Korea originating the second-most patentpublications after China from 2016-2023.

The institutions with the highest number ofjournal publications and the average number ofcitations per publication are presented in Figure
2. Overall, the majority of publications in thisarea originate from research institutions in China,
along with one institution each from the UnitedStates and Netherlands. The University of Illinois
has generated the most citations per publication,
followed by Xi’an Jiaotong University and Harbin
Institute of Technology.

1,400

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1,200

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23

0
Publication year

Figure 1. Number of journal and patent publications per year in the self-healing biomaterials field, 2003-2023. * = partial year
data for 2023.
Trailblazing the future with emerging biomaterials | 121

Figure 4B shows the flow of patent activities
through national patent offices and the Patent
Cooperation Treaty (PCT) system. Here, an activity
is defined as an event where a patent document,
either an application or a granted patent, ispublished. The left column shows the top ten
patent assignee countries/regions in terms ofnumber of patent activities. The right column
shows the patent office where the patent activity
took place. The center column, connecting thetwo, indicates the office where the first patent in
the family was filed.
The data in Figure 4B indicates that almost allpatents filed in China have the first in the family
filed in the China national patent office. In the US,
first patents in the family also generally are filed in
the US, with a smaller portion filed through PCT.
This trend is generally observed for assignees inJapan and Korea.

Average number of citations per publication
Organization

University of Illinois at Urbana-Champaign
Xi'an Jiaotong University
Harbin Institute of Technology
Sichuan University
Northwestern Polytechnical University
Chinese Academy of Sciences
Zhejiang University
Tsinghua University
South China University of Technology
Tongji University
Tianjin University
Jilin University
Southeast University
Beijing University of Chemical Technology
Delft University of Technology

Citations per publications
Number of journal publications (CHN)
Number of journal publications (USA)
Number of journal publications (NLD)

Number of journal publications
Figure 2. The top 15 research institutions in terms of average citations per publication (yellow line). Total publications from 20032023 shown as bars; colors of the bars indicating country/region of the institution.

Others3%

ISR (1%)
KOR (1%)
JPN

5%

7%

USA

Others7%

FRA (1%)
IND (2%)
KOR

4%

8%

CHN 84%

Top 5 commercial
patent assignees
2003-2023

USA

Top 5 non-commercial
CHN 78%patent assignees
2003-2023

Figure 3. The top countries/regions in terms of number of self-healing biomaterials patent publications between 2003-2023, forcommercial (left) and non-commercial (right) entities. (Reduced from the top 10 as shown in other chapters due to the relatively
low number of patent publications below the top 5 assignee countries.)(A)Number of patent publications

200

CHN

150

100

50

10
20
11
20
12
20
13
20
14
20
15
20
16
20
17
20
18
20
19
20
20
20
21
20
22

09

20

08

20

07

20

06

20

05

20

04

20

20

20

03

0

KOR USA
JPN
IND
DEU

Publication year
(B)

CHN: 1,387

CHN: 1,385

CHN: 1,364

USA: 351

WIPO: 290

USA: 242

US: 124

KOR: 71

KOR: 77
JPN: 37
DEU: 33

OTH: 7

EUR: 54

KOR: 75

JPN: 52

IND: 32

IND: 33

IND: 31
CAN: 18
BRZ: 4
Others: 18
TWN (a province of CHN): 6
DEU: 7

ITA: 28
NLD: 23
FRA: 14
CHE: 15

JPN: 37
EPO: 30
DEU: 16

Figure 4. (A) Number of patent publications from the top six patent assignee countries/regions from 2003 to 2022. (B) Total
patent flow between assignee countries/regions (top ten countries/regions in terms of total patent filings, left), the patent filingoffice where the first application in the patent family was filed (center) and the destination patent office for individual patentpublication activities (right). Standard three letter codes utilized for countries/regions.

Trailblazing the future with emerging biomaterials | 123

Self-healing mechanisms, materials, andapplications
Chemical Mechanisms
A variety of chemical interactions can be used
to impart self-healing properties to polymers.
Hydrogen bonding, as described in the example
in Section I, is one type of reversible interactionthat is commonly used.7, 8 Hydrogen bonds are
weaker than covalent bonds and so, for thisstrategy to be effective, there must be a sufficientspatial density of hydrogen bonds. However,hydrogen bonding is a particularly convenientself-healing chemistry since it can be incorporated
through several types of chemistry, allowing
flexibility in material choice, and because brokenhydrogen bonds can be re-formed at room
temperature.9
Other commonly used non-covalent interactions
to provide self-healing properties in polymers
include hydrophobic,10 host-guest,11 electrostatic,
π-π stacking,12 and metal-ligand coordinationinteractions, notably those between catechols andiron(III) ions.13
Dynamic covalent interactions can be used
in a similar way to give materials self-healing
properties. Within this group, dynamic Schiffbase linkages are widely used for biomaterials,14
with their use growing significantly in the last
5 years. These linkages are based on reactions
between a nucleophile and an aldehyde or ketone
to form a bond, typically an imine or oxime,
which is reversible in the presence of water. An
example of this is a self-healing hydrogel basedon a mixture of dialdehyde-modified hyaluronic
acid and cystamine.15 Schiff base linkages are
well-suited for biomaterial applications because
they are easily formed at room temperature withno catalyst, and because the required chemicalfunctionalities can be incorporated into hydrogelforming polymers. Furthermore, the Schiffreaction is pH-sensitive, which can be used tofurther control the mechanical properties of gel
structures based on their chemical environment,
for example, to cause them to release a drug
selectively in acidic environments.16
Self-healing properties can also be engineered

through the use of polymer side chains thatparticipate in thermally induced reversible
crosslinking via Diels-Alder reactions17, 18 andMichael additions.19 With these mechanisms,
higher temperatures (>100 °C) are generally
required to induce self-healing, which limits theirapplications, but also provides an additional route
to control their mechanical properties. Disulfide20
and borate ester bonds21 are other reversible
covalent bonds used in self-healing biomaterials.
A common approach in this field is to use multiple
self-healing chemistries in the same material,
to cover a range of mechanical properties andself-healing time scales. Recent examples include
wound healing hydrogels that achieve self-healing
through combinations of catechol-Fe coordinationand Schiff base bonds,22 and a combinationof Schiff base, hydrogen bonding, and pi-pi
interactions,23 and a hydrogel for wearable sensor
applications that uses a combination of hydrogenbonding and boronic ester bonds.24
Self-healing chemistry can also be synergisticallycombined with other polymer physicsdriven processes to create multifunctional
materials. An example of this is a hydrogel
based on interpenetrating polyaniline/poly(4styrenesulfonate) (PANI/PSS) that combines astrain-dependent electrical conductivity with
self-healing abilities, and can be used for humanmotion sensing and other applications. 25 Selfhealing properties were incorporated into thehydrogel by adding hydrogen bond linkages to
the PSS before forming the interpenetrating
network, in the form of 2-ureido-4[1H]pyrimidinone groups.
A second example is a system developed by Bao
et al. consisting of alternating layers of immiscible
polydimethylsiloxane (PDMS) and polypropylene
glycol (PPG), which re-align and heal themselves
after being misaligned by cross-layer damage.26
Macroscopic realignment of the 3-15 µm thick layers
is driven by their immiscibility, which causes the layers
to minimize interfacial contact between PDMS and
PPG and reestablish the PDMS-PPG stratification.
Molecular-level self-healing, as well as planaradhesion between the dissimilar layers, is achieved byadding H-bonding groups to both polymers.

coordination compounds.

Analysis of the CAS database shows theprevalence of hydrogels in the field of selfhealing biomaterials. Hydrogels are employed
as scaffolds for tissue regeneration,1, 27, 28 aswound dressings,29-32 for drug delivery,33 andseveral other applications. Hydrogels can beengineered to have other functional properties
in addition to being self-healing. For example,
Zhang et al. 34 fabricated a polymer hydrogel
based on the thermo-responsive polymer poly(Nisopropylacrylamide) which swells around 20%
in response to a temperature change of 20 °C.
The material is also self-healing, based on hostguest orthogonal assembly that takes place in the
mixture of star and linear forms of the polymer.

Because hydrogels are a particularly active
area of research in the context of self-healing
biomaterials, we have also analyzed the subset ofmaterials within our reference set that are used inself-healing hydrogels, shown in Figure 6.
The top natural polymers used in self-healinghydrogels include chitosan, hyaluronic acid,sodium alginate, and cellulose. 39-42 The existenceof multiple functional groups in these molecules,
as well as the ability to chemically functionalize or
modify them, help them to effectively crosslink,providing gel-like mechanical properties and selfhealing ability.43 Notable examples of chemicallymodified natural polymers are quaternizedchitosan, which combines crosslinking sites andantimicrobial activity,44 and oxidized hyaluronic
acid, which contains aldehyde groups that canform Schiff base linkages.45

In general, self-healing materials can be classified
in two ways: autonomic versus non-autonomic(based on whether an external stimulus isrequired to initiate healing), and intrinsic versus
extrinsic (based on whether the material itself canself-heal, or an additional component is needed
to initiate healing). 35 In the case of extrinsic
self-healing materials, healing can be achieved
thought the release of material from insideembedded capsules, 36 hollow fibers,36 or vascular
networks37, 38 that rupture under stress. Based on
the published literature on this topic, the vast
majority of modern self-healing biomaterials use
intrinsic mechanisms. Both autonomous and nonautonomous approaches are used, depending on
the demands of the application (for example, if
thermal or pH-responsiveness is useful to provide
additional local control over self-healing).
Materials and Substances
The substances used most commonly in selfhealing biomaterials research and development
are presented in Figure 5. Polymers make up
the largest group, with synthetic and naturalpolymers being used roughly equally. The next
major categories are organic and inorganic
molecules, followed by the pure elements, which
can be further categorized into metals and nonmetals. Other categories of substances foundin self-healing materials are minerals such ashydroxyapatite, alloys such as stainless steel, andSimilarly, most of the top synthetic polymers in
self-healing biomaterials, including polyethylene
glycol, poly(vinyl alcohol) and poly(acrylic acid)are also used in hydrogels.46-48 Self-healing
biomedical hydrogels can also use a mixtureof gel-forming polymers in the same material
to optimize performance, for example sodium
alginate/PVA,49 gelatin/PVA,50 gelatin/chondroitin
sulfate,51 and dialdehyde carboxymethyl cellulose/chitosan/poly(acrylic acid). 52
Within the non-metallic elements, forms of carbon
including carbon fibers, carbon nanotubes,53
graphene, and graphite fillers are used to impart
specific mechanical and electrical properties. Silver, in
powder form as well as silver nanoparticles, is used in
medical dressings due to its antimicrobial properties,54,
55
while both materials are used in sensors.56
Organic small molecules, including glycerol andacrylic acid, are primarily the starting materials
for the polymers used in self-healing hydrogels
and other applications. 57 Silica is the most widelyused inorganic material; it can form a gel structure
when chemically modified,58, 59 or can be used as
an encapsulant for drug delivery.60 Most othermaterials in this category are used in synthesis ofself-healing materials, with the exception of iron

Trailblazing the future with emerging biomaterials | 125

Synthetic

NaturalPolymer

Metals*Non-metals

Elements

Organic andinorganic molecule

Minerals

AlloysInorganic

Organic***

Figure 5. Bubble chart showing distribution of substances used in self-healing biomaterials in terms of number of publications (journals and patents) from 2003-2023. Size of the circles
correspond to number of publications.

**

*
*

Coordination
compounds

Trailblazing the future with emerging biomaterials | 127

Organic andinorganic molecules
Polymers

Synthetic

NaturalFigure 6. Bubble chart showing distribution of materials used in hydrogels in terms of number of publications (journals and patents) in self-healing materials over two decades (20032023). Size of the circles correspond to number of publications.

Inorganic

Organicchloride, which can also be used to form dynamic
crosslinks.
Among the minerals, hydroxylapatite is frequently
used due to its biocompatibility and is widelyused as filler in hydrogel and in bone related
applications.61 The other notable minerals aretalc, borax, montmorillonite, and gypsum. Borax,
in particular, can be used to generate dynamic
crosslinks leading to self-healing behavior inpolymer systems.62, 63 Stainless steel and titaniumbased alloys are the most commonly used alloys
due to their inertness and mechanical strength.
In addition, we have also identified substances
which showed the highest relative growth intheir usage in journal and patent publications
the last 5 years, to determine trends inemerging substances, as shown in Figure 7.
The major category of substances in this list are
diisocyanates, followed by alcohols, the naturalpolymers chitosan and sodium alginate, andgraphene.
Diisocyanates are used in the synthesis ofpolyurethanes, which in turn indicates thatpolyurethanes are generally an emerging classof substance in the self-healing biomaterials.64,
65
Polyurethanes are commonly used as a basis
for materials that use hydrogen bonding,66 DielsAlder reactions67 and other mechanisms for selfhealing. Polyurethanes are well-precedented inpolymer chemistry, so their handling, reactivity,and limitations are well-known. The alcohols inthis list are commonly used as starting materials
for polymers, including polyoxyalkylenes.
Chitosan, sodium alginate, and graphene arecommon materials in self-healing hydrogels.
Overall, these emerging substances suggest thatpolymers, primarily polyurethanes, and hydrogels
are the most actively researched in self-healing
biomaterial applications.
In a similar way, we can identify self-healingmechanisms that are increasingly being usedin biomedical applications.1, 6, 68, 69 As discussed
earlier in this section, there are a variety ofchemical mechanisms used for self-healing, which
can involve non-covalent or reversible covalentinteractions.
The plot in Figure 8 shows how frequently
different self-healing mechanisms have beenreferenced in journal and patent publications overtime, from 2013-2023. From this analysis, we seethat the most frequently mentioned mechanisms
involve hydrogen bonding, Schiff base formation,and metal coordination bonding.
Applications
The development of self-healing materials has
significantly contributed to the advancementof several biomedical applications. Specifically,
they have found applications in medical devices,
drug delivery systems, and tissue engineering,

200
160
140
120
100

3
2

80
60

Publication year

Figure 7. Normalized frequency of representative materials
in journal and patent publications from 2013-2022.

Publication year

Figure 8. Count of journal and patent publications
referencing self-healing mechanisms from 2013-2022.

22
20

21
20

20
20

19
20

18
20

17
20

16
20

20

13
20

20
22

21
20

20
20

20
19

20
18

20
17

20
16

0
20
15

0
20
14

20

15

40

1

14

4

Isophorone diisocyanate
Diphenylmethane diisocyanate
Poly(vinyl alcohol)
Hexamethylene diisocyanate
Graphene
Polyethylene glycol
ChitosanSodium alginate

Hydrogen bond
Schiff base linkage
Metal coordination
Electrostatic interaction
Disulfide bondHost-guest
Borate ester
Hydrophobic interaction
Diels-Alder

20

5

20
13

Normalized frequency

6180
Number of publications

7

eventually improving patient outcomes andenhancing the quality of life. These applications,and the substances most commonly associatedwith them, are shown in Figure 9 as a heat map.
One prominent application area for self-healing
coatings and polymers is tissue regeneration
and wound care. 30, 70 Self-healing coatings andpolymers are not only injectable, but can also
be engineered to have antibacterial properties
based on photothermal response,13 or through theincorporation of antibacterial materials such asquaternized chitosan,71 moxifloxacin,72 or Mxenes.73
Through these combined effects, self-healing
wound dressings reduce patient suffering, speed
up the healing process, and lower the chance of
infection.
An example of the use of self-healing materials forwound healing is a hydrogel developed by Zhang
et al. that can be injected into irregular deep burnwound beds.74 This hydrogel is fabricated fromcarboxymethyl chitosan (CMC) and dialdehydemodified cellulose nanocrystals (DACNC), which(±)-Propylene glycol
Acrylamide
Acrylic acid
Ammonium persulfate
Calcium chloride
CarbonCellulose
ChitosanDibutyltin dilaurate
Diphenylmethane diisocyanate
Ethanol
GlycerolGraphene
Hexamethylene diisocyanate
Hyaluronic acid
Hydrochloric acid
Iron chloride (FeCl3)
Isophorone diisocyanate
Poly(acrylic acid)
Poly(dimethylsilanediol)Poly(vinyl alcohol)
Polycaprolactone
Polyethylene glycol
SilicaSilverSodium alginate
Sodium chloride
Sodium hydroxide

27.6%
25.7%
Wound healing /Drug delivery
dressings
0.6%
0.6%
2.6%
0.6%
6.3%
3.1%
5.2%
0.9%
0.9%
2.5%
2.9%
3.1%
1.4%
6.2%
15.5%
7.8%
1.4%
3.7%
1.7%
1.9%
1.4%
3.7%
2.9%
4.4%
3.4%
3.7%
2.3%
2.8%
10.6%
6.9%
2.0%
3.4%
2.9%
2.2%
2.0%
3.1%
1.4%
3.7%
1.4%
2.5%
3.7%
5.0%
0.6%
3.4%
9.2%
6.2%
1.7%
5.3%
4.0%
3.7%
5.4%
4.4%
1.4%
1.6%
5.2%
3.4%

17.7%
Sensors
0.4%
5.6%
6.9%
4.3%
1.7%
5.6%
3.9%
3.9%
3.5%
0.0%
0.4%
2.6%
6.5%
2.2%
1.3%
3.0%
3.9%
1.3%
3.0%
3.9%
5.2%
2.6%
9.1%
5.6%
5.6%
2.6%
1.3%
3.9%

are derived from the naturally occurring polymers
chitosan and cellulose. Dynamic Schiff baselinkages between the amine groups of CMC andthe DACNC allows this material to immediately
self-heal after injection to form an integratedhydrogel that completely fills the wound andprotects it from the external environment.
In a second example, Luo et al. developed a seriesof N-carboxyethyl chitosan- and sodium alginatebased injectable self-healing antibacterialhydrogels containing CuS nanoparticles.75 The
physical properties of this material could befurther tuned by adjusting the oxidized sodium
alginate (OA) content, with the storage modulus
increasing at higher OA content due to the higher
density of imines. Conductive, self-healing gels forwound treatment have also been demonstrated.
For example, Jiang et al. reported an injectable,
biocompatible, self-healable, and conductive
material made from poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and guarslime for healing wounds in parts of the body that
undergo stretching such as knees and elbows.76

9.8%
Pharmaceuticalhydrogels
0.8%
3.2%
2.4%
3.2%
0.8%
0.8%
6.3%
17.5%
0.8%
0.8%
1.6%
3.2%
3.2%
0.8%
15.9%
1.6%
2.4%
0.8%
0.8%
0.0%
5.6%
0.0%
9.5%
4.0%
1.6%
8.7%
0.8%
3.2%

8.3%
Prosthetics /Implants
0.0%
0.0%
3.8%
0.0%
3.8%
2.8%
2.8%
7.5%
1.9%
1.9%
1.9%
2.8%
4.7%
2.8%
5.7%
6.6%
4.7%
1.9%
2.8%
1.9%
1.9%
1.9%
7.5%
9.4%
5.7%
4.7%
4.7%
3.8%

6.7%
Tissueengineering
0.0%
2.3%
8.0%
4.6%
4.6%
3.4%
3.4%
11.5%
0.0%
0.0%
0.0%
1.1%
4.6%
0.0%
12.6%
4.6%
2.3%
0.0%
0.0%
0.0%
0.0%
0.0%
13.8%
8.0%
1.1%
5.7%
4.6%
3.4%

4.1%
3D printing
0.0%
1.9%
3.7%
9.3%
1.9%
7.4%
3.7%
7.4%
1.9%
3.7%
0.0%
1.9%
7.4%
3.7%
7.4%
1.9%
1.9%
3.7%
0.0%
1.9%
1.9%
0.0%
5.6%
3.7%
1.9%
11.1%
5.6%
0.0%

High

Low

Figure 9. Heat map of the relationship between the most commonly used substances in self-healing materials and the mostcommon material applications. Relative frequencies of each substance have been calculated within each application category.

Trailblazing the future with emerging biomaterials | 129

Since 2015, biomedical hydrogels with self-healing
properties have gained attention as promising
options for tissue engineering and regenerative
medicine. Self-healing scaffolds that can repair
themselves after damage are being investigatedin regenerative medicine to promote thedevelopment of tissues and organs in vitro and invivo.77, 78

responsive injectable drug delivery gels, whichhave been designed to break down in acidic
environments, allowing for targeted local delivery
for cancer and infection treatment. 58 In theseapplications, the self-healing property of the gelallows it to recover its rheological properties after
injection, and to repair itself macroscopically if it
breaks apart.

Hwang et al. developed a mechanically compliant
interpenetrating polymer network (IPN) hydrogel
using polyacrylamide (PAAM) and gelatin.
The PAAM/gelatin hydrogel matched with thenative vocal fold tissue in physical and chemical
properties, and thus, functioned as an adhesive
artificial tissue implant for voice recovery.79

Mooney et al. developed an alternate drug
release strategy which uses ultrasound to disrupt
ionically crosslinked hydrogels.87 In this study,
the chemotherapy drug mitoxantrone wasselectively released from a self-healing injectedalginate hydrogel in vivo using an ultrasonichorn. The researchers also demonstrated
similar ultrasonically-driven drug release withother molecules, proteins, and condensed
oligonucleotides using alginate and chitosanbased gels. In 2019, Ji et al. reported a structureswitchable coating based on poly(ε-caprolactone)poly(ethylene glycol)-poly(ε-caprolactone) triblock
copolymer network.88 After absorbing water andfreeze-drying, this coating adopted a microporous
morphology. However, on mild heating (~40 °C),
it switched back to a pore-free structure within as
little as 5 seconds.

The development of medical implants anddevices is another use of self-healing materials
in biomedicine. In recent years, injectable selfhealing hydrogels have shown promise as partof minimally invasive surgical approaches totreating issues in the brain and nervous system.80,
81
For example, Hsu et al. developed a semiinterpenetrating network polymer composed ofhyaluronan and chitosan to make an injectable,
self-healing hydrogel to deliver neural stem cells
as a treatment for traumatic brain injury.82
Implants such as vascular stents, prosthetic joints,
and pacemakers undergo constant wear in the
body. The longevity of these devices can beincreased by using materials and coatings which
can self-heal microscale damage from corrosion
or mechanical forces. This improves the reliability
and safety of these devices while reducing theneed for frequent replacements.83, 84
Using injectable self-healing materials for drugdelivery is an interesting new direction of research
and application. Self-healing materials can beloaded with drugs, for example via microcapsules,and designed to release them gradually, intargeted locations, or in response to an external
stimulus. Here, self-healing properties aid incontrolling the properties of the drug-releasing
medium after injection, improving therapeutic
efficacy.85, 86 One common example is pH-

Self-healing materials can also be used inbiomedical sensing applications.89, 90 In 2020, Youet al. reported autonomously ultrafast self-healing
poly(sebacoyl 1,6-hexamethylenedicarbamate
diglyceride) (PSeHCD) elastomers forbioelectronics91 that could also be re-processed
into different shapes. Similar to the naturally
occurring peptidoglycan structure, PSeHCD wasdesigned with repeating units that contained
both ester and urethane groups. The ester groups
conferred biodegradability, while the urethanegroups enabled the formation of extensive anduniformly distributed hydrogen bonds, whichgave the elastomers the ability to rapidly selfheal. The material was also easily reprocessed into
different shapes by placing it in a mold at elevatedtemperatures. This reprocessibility was possible
due to the high density of H-bonds in the polymer
network, which controlled the structure but could
be dissociated on heating.

Notable journal articles and patents

Table 1 is a set of research articles published from2020-2023 that represents emerging trends in thefield of self-healing biomaterials. These articles
were selected to represent the range of materials
and applications being studied today today, in
combination with other factors including journal
impact factor and number of citations.
Notable examples from the table include aquaternized chitosan-based self-healing hydrogelthat possesses protocatechualdehyde–ferriciron as a crosslinker to enhance the reversibilityof pH-responsive aldehyde-Fe bond and Schiffbase bond formation developed by Guo etal.22 This hydrogel demonstrates injectability,
biocompatibility, reversible adhesion, and effective
wound healing in a rat model. The adhesivestrength of the hydrogel in the presence andabsence of deferoxamine mesylate (a chelating
agent) provides evidence for the reversibilityof adhesion. The antimicrobial property of thischitosan-based hydrogel is also significant, andis based on a photothermal effect. This dual
cross-linked chitosan-based hydrogel sealant
has potentials to be broadly applied to infected
wound healing.
Earlier in 2023, Fu et al. described a composite
material based on a soft self-healing polyurea(SSPU) coupled with the gallium–indium–tin
eutectic alloy Galinstan. SSPU was obtained fromthe reaction of bis(3-aminopropyl)-terminatedpoly(dimethylsiloxane) (PDMS, Mn=3000),trimethyl hexamethylene diisocyanate (THI), and3,3’-dimethyl-4,4’-biphenylene diisocyanatge(DBI). The self-healing activity is driven by the
dynamic hydrogen bonding between THI an DBI,
while Galinstan increases the fracture toughness
to prevent mechanical failure without softness
loss. This approach can effectively prevent thematerials from crack propagation. This material
could be further used in capacitive strain-sensors
in human-machine interfaces, bioelectronics, andeven soft robotics for applications of biomimicry.
92

Maxillofacial hard tissue regeneration suchas dentin and bone is challenging because ofmaterial expense, the risks of autologous or
allogeneic transplantation, and the ineffectivenessof mineral materials alone. To resolve this issue,

Guo et al. synthesized a mineralized hydrogel,polyacrylic acid (PAA)-carboxymethyl chitosan(CMC)-treated dentin matrix (TDM), which isself-repairable and injectable.93 This hydrogel
composite contains amorphous calcium
phosphate forming reversible coordination bonds
between CMC and PAA, followed by dynamic
ionic and hydrogen bonds formation within thestabilized TDM structure. This study showed that
this PAA-CMC-TDM hydrogel retains its bioactivity
and promotes the regeneration of dentin/bone
hard tissue.
Table 2 lists notable patent documents (granted
patents and applications) in the field of selfhealing biomaterials published from 2018 to 2023.
Patents were selected based on relevance, novelty,
applicability, and field of study.
Notable examples include CN114246982A,
assigned to Nanjing Drum Tower Hospital. Thispatent application discloses an injectable hydrogel
based on a mix of a 4-arm benzaldehydeterminated PEG with carboxymethyl chitosan to
improve the delivery of mesenchymal stem cells to
specific parts of the body
CN111068107A (Shanghai Jiaotong University)
describes a fiber-hydrogel composite scaffold foruse in regeneration of tissues such as muscle. The
fiber is electrospun from a mixture of graphene,
melatonin, and a biocompatible polymer suchas polylactic acid or polycaprolactone, while ahyaluronic acid derivative is used as the hydrogel
matrix.
In WO2023084521A1 (Technion Research andDevelopment Foundation Limited), a self-healing(disulfide based) wound dressing is described that
also contains embedded sensors for measuring
glucose level, pH, and temperature.
The prevalence of hydrogel-based self-healingmaterials in these patent examples is a reflectionof the growing use of hydrogels in this area.
However, CN116284671B provides a recent example
of a non-hydrogel based self-healing biomaterial.
This patent describes the synthesis of a heparinfunctionalized polyurethane, which has selfhealing properties based on hydrogen bonding
and disulfide bonds. This material is intended foruse in medical implants.
Trailblazing the future with emerging biomaterials | 131

Table 1. Notable journal publications in self-healing biomaterials in recent years.

Research
Institute

Year

Title

JournalSummary

2020

Muscle-Inspired Self-Healing Hydrogels for
Strain and Temperature Sensor94

ACS Nano

Nanjing Tech
University

Polyaniline nanofibers (PANI NFs) areincorporated into a poly(acrylic acid) (PAA)
hydrogel to fully mimic the microstructuresand multifunctionalities of human muscle

2020

Physical Double-Network Hydrogel
Adhesives with Rapid Shape Adaptability,
Fast Self-Healing, Antioxidant and NIR/pH
Stimulus-Responsiveness for MultidrugResistant Bacterial Infection and Removable
Wound Dressing13

Advanced
Functional
Materials

Xi’an Jiaotong
University

A hydrogel adhesive made up of catechol–
Fe3+ coordination cross-linked poly(glycerol
sebacate)-co-poly(ethylene glycol)-gcatechol and quadruple hydrogen bonding
cross-linked ureido-pyrimidinone modified
gelatin

2020

Resilient yet entirely degradable gelatinbased biogels for soft robots andelectronics95

Nature Materials

Johannes Kepler
University Linz

A versatile self-adhering gelatin-based
biogel derived entirely from natural andfood-safe constituents

2021

Dual-Dynamic-Bond Cross-Linked
Antibacterial Adhesive Hydrogel Sealants
with On-Demand Removability for PostWound-Closure and Infected Wound
Healing22

ACS Nano

Xi’an Jiaotong
University

A series of adhesive antioxidant
antibacterial self-healing hydrogels
fabricated through dual-dynamic-bondcross-linking among ferric iron (Fe),protocatechualdehyde (PA) containing
catechol and aldehyde groups andquaternized chitosan (QCS)

2022

Molecular Design and Preparation ofProtein-Based Soft Ionic Conductors with
Tunable Properties96

ACS Applied
Materials &Interfaces

Westlake
University

Silk-based soft ionic conductors fabricatedusing silk proteins and calcium chloride

2023

Bioactive self-healing hydrogel based ontannic acid modified gold nano-crosslinker
as an injectable brain implant for treating
Parkinson’s disease97

Biomaterials
Research

National Taiwan
University

A bioactive self-healing hydrogel
comprising chitosan crosslinked by theoxidized tannic acid-modified gold nanocrosslinker

2023

Biomineralization-inspired mineralizedhydrogel promotes the repair andregeneration of dentin/bone hard tissue93

NPJ Regenerative
Medicine

Sichuan
University

A composite mineral matrix hydrogel PAACMC-TDM containing amorphous calcium
phosphates (ACPs), polyacrylic acid (PAA),
carboxymethyl chitosan (CMC) and dentin
matrix (TDM)

2023

A self-healing electrically conductive
organogel composite98

NatureElectronics

Carnegie Mellon
University

A poly(vinyl alcohol)–sodium borate-basedorganogel composite embedded with silver
microflakes and gallium-based liquid metal
microdroplets

2023

Vascular smooth muscle-inspiredarchitecture enables soft yet tough selfhealing materials for durable capacitive
strain-sensor92

NatureCommunications

Nanjing
University of
Science andTechnology

A class of core-shell structured liquid
droplets, i.e., gallium–indium–tin eutectic
alloys (Galinstan) wrapped with thin oxide
layer introduced into a soft self-healing
polyurea (SSPU) through robust interfacialcoordination interactions, forming a
synthetic structure similar to that of vascularsmooth muscles

2023

Ultrarobust subzero healable materials
enabled by polyphenol nano-assemblies99

NatureCommunications

Sichuan
University

An ultrarobust subzero healable glassy
polymer fabricated by incorporating
polyphenol nano-assemblies withnumerous end groups into polymerizable
deep eutectic solvent (PDES) elastomers

Table 2. Notable patent documents in self-healing biomaterials in recent years.

Patent or
Publication number

Publicationyear

CN114479124B100

Patent assignee

Title

Description of patented technology

2023

Chinese Academy ofMedical Sciences andPeking Union Medical
College

Preparation of selfhealing hydrogel withgood antibacterial
activity for preparing
wound dressing

Self-healing, antibiotic, non-cytotoxic hydrogel
based on quaternized chitosan and glucomannan
used for wound healing

CN114246982A101

2022

Nanjing Drum Tower
Hospital

Injectable self-healinghydrogel loaded withmesenchymal stem cells(MSCs), its preparation
method and application

Injectable hydrogel consisting of a mixture of
4-arm benzaldehyde-terminated PEG withcarboxymethyl chitosan, intended to improve thedelivery of mesenchymal stem cells to specificparts of the body

CN113583262B102

2022

Sichuan University

Near-infrared response
hyaluronic acid hydrogel
for articular cartilage
repair and preparation
method thereof

Hydrogel used for cartilage repair, based on a
mixture of azobenzene-modified hyaluronic
acid and cyclodextrin-modified hyaluronic acid.
The non-covalent crosslinking density of the gel
is reduced by exposure to near-infrared light,
causing it to change its mechanical properties andfriction coefficient.

CN113384754B103

2022

First Affiliated Hospitalof Jinan University

Preparation method of
injectable self-healinghydrogel for promoting
regeneration of
periodontal tissues

Mixed aldehyde-modified hyaluronic acid /hydroxyethyl chitosan hydrogel used to fill defects
and promote periodontal tissue regeneration. The
hydrogel releases drugs and converts from a gel
to a solution slowly over time.

WO2023084521A1104

2023

Technion Researchand Development
Foundation Limited

Biocompatible selfhealing polymers anduses thereof“Smart”, self-healing wound dressing material
based on an aliphatic disulfide-containing
polyurethane containing embedded sensor formeasuring glucose, pH, or temperature.

CN111068107A105

2020

Shanghai Jiaotong
University

Three-dimensionalbionic self-healinghydrogel fiber scaffold
composition andpreparation method andapplication thereof

A fiber-hydrogel composite scaffold where thefiber is electrospun from a mixture graphene,
melatonin, and a biocompatible polymer(polylactic acid, polycaprolactone given as
examples), and the hydrogel is a hyaluronic acidderivative.

WO2023009830A1106

2023

Becton, Dickinson andCompany

Self-healing
thermoplastic elastomer
composition

A membrane containing a styrenic block
copolymer that prevents leaks and re-seals whenpunctured with a needle for medical applications.

CN116284671B107

2023

Suzhou Xinrui Medical
Technology Co., Ltd.

Production of heparinlike polyurethanes with
self-repairing property
using polyether polyols

Synthesis of a heparin-functionalized
polyurethane with self-healing properties basedon hydrogen bonding and disulfide bonds

CN116440066A108

2023

Zhengzhou University

Strong antioxidant
and rapid antibacterial
wound repair self
healing pharmaceuticalhydrogels with strong
adhesion and promoting
blood vessels

Gel containing PVA, oligomeric procyanidine,borax, and Fe3+. Self-healing properties are
based on hydrogen bonds, B-O bonds, and Fe3+
coordination complexes.

US20190298852A1109

2019

Industry-University
Cooperation
Foundation Hanyang
University

Glycol chitosan-basedhydrogel capableof exhibiting selfhealing behavior in
the presence of ironoxide nanoparticles
without the use of toxic
crosslinkers, and use in
drug delivery

Hydrogel consisting of only naturalpolysaccharides (glycol chitosan and oxidized
hyaluronate) and iron oxide nanoparticles, with nocrosslinkers. The self-healing mechanism in thismaterial can be controlled using a magnetic field
through the nanoparticles.

Trailblazing the future with emerging biomaterials | 133

Challenges and perspectives

Self-healing materials have emerged as apromising class of materials with applications inseveral aspects of biomedicine, and significant
attention has been focused on the development
and characterization of these materials with a view
toward these applications.
One of the applications where self-healingmaterials have shown significant potential iswound healing. While several types of wounddressings with self-healing properties have alreadybeen developed, obstacles remain to developing
smart wound dressings.4
According to our analysis, as shown in Figure 9,
in the natural polymer category, cellulose-basedmaterials are used in wound healing researchat a relatively lower level compared to chitosan,
hyaluronic acid, and alginate. Cellulose and its
derivatives have received research attention inother fields because of its widespread availability,
low cost, and mechanical strength. However, themechanical properties of cellulose, including its
Young’s modulus ranging from 20 to 355 GPa,110
may impede its application in wound healing
as a soft and injectable material without further
modification. The stiffness of cellulose makes it
unsuitable for soft tissues/organs like skin andother parts of the body that are frequently inmotion.
Instead, in recent years cellulose has been utilized
as a reinforcing agent to modify the stiffness of
self-healing base materials such as chitosan,74, 111,
112
poly(vinyl alcohol),113 and poly(vinyl alcohol)borax (PB).114, 115 Nanocrystalline cellulose, cellulose
nanofibers, and their modified species increases
the stretchability of self-healing compositehydrogels significantly. Recently, injectable, selfhealing cellulose-containing hydrogels havebeen reported for wound healing applications.116,
117
These examples suggest that, while theuse of cellulose in wound healing materials ischallenging, it has the potential to become oneof the primary natural materials in this field, as areinforcing agent or a base material.

Due to their use in highly dynamic environments,
flexible biosensors can benefit from theincorporation of self-healing materials94, 118 (this isreflected by the prominence of sensor applications
as shown in Figure 9). Materials used in flexible
biosensors have several other key requirements,
including stretchability, conductivity, durability,
softness, and biocompatibility.119-121 The analysis
presented in Section III indicates that the use ofnatural polymers in sensors remains challenging,likely due to poor conductivity and stretchability.122
For this reason, natural polymers like chitosan
have been combined with synthetic polymers andionic compounds to form self-healing compositehydrogels with metal coordination bonds andhydrogen bonds that results in electroconductive,
durable, stretchable, and sufficiently soft materials
for biosensor use.122, 123 These examples indicate
the potential of using natural polymers withnovel modifications to achieve multifunctional
biosensors and other biomedical devices,in addition to incorporating self-healing
properties.120
Another potential future research direction is thedevelopment of self-healing wound dressingsthat are also stimulus-responsive, making themcapable of responding to changing conditions
such as temperature and pH. While new selfhealing materials and novel mechanisms havebeen introduced into wound dressings124 thesafety and toxicity of the materials needs to bethoroughly investigated.4
The use of self-healing hydrogels in many
applications (as shown in Figure 9) has driven
research into their rheological properties andtheir responsiveness to external stimuli such as
pH, temperature, and stress, and into theoreticalmodels of their properties.1 125, 126 The use ofmachine learning to develop more detailed
models of polymer dynamics, including their noncovalent bond interactions, has been reported
recently.127-129 In this area, more extensive use ofcomputational tools to predict the properties ofmultifunctional composites should reduce theexperimental costs of developing self-healingmaterials.

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VIII. Bioelectronic materials
Introduction

Bioelectronics is an interdisciplinary field in whichelectronic devices are integrated into biologicalsystems, including the human body.1-5 Integration
can take the form of implantation or attachment
to the skin. The emergence of bioelectronics asan active research topic has led to a new realm of
possibilities that bridge the gap between microand nano-electronics and living organisms.
Bioelectronics involves the development of
new devices, often using novel materials andmethodologies, that allow electronic systems
to interface with biological components at
the molecular, cellular, and organ levels. Thisapproach capitalizes on the intrinsic ability ofliving organisms to sense, process, and respond toexternal stimuli, in combination with the precisionand speed of modern electronic components.
This combination has unlocked a diverse range ofapplications that hold significant promise acrossvarious sectors, such as real-time monitoring of
brain activity or heart rate, delivering therapeutic
electrical signals or drugs, chemical sensing, andnew prosthetic devices.
Bioelectronics heavily relies on an array of
specialized materials that enable effective
integration with biological tissue. One example
is organic electronics,6-8 including organic
semiconductors and conductive polymers. Thesematerials can offer advantages such as flexibility
and biocompatibility, making them ideal for
creating interfaces that seamlessly interact withbiological tissues. Biodegradable materials
which can be resorbed by the body and used
to make transient bioelectronic devices, are asecond important class of materials which appear
prominently in the literature.4, 9, 10

The materials used in bioelectronic devices
are engineered to have specific, applicationdependent properties that are critical to theirperformance. Examples of these properties
include:a. Softness and stretchability
b. Adhesion to biological tissues
c. Biocompatibility, non-toxicity, resistance tofouling, and reduced inflammatory response
d. Bioresorbability
e. Mechanical durability
f. Large response to physical stimuli(piezoelectric response, for example)
g. Large electrical response to chemical
environmenth. Electrical and ionic conductivity
i. Effective ionic-electronic transduction
The requirements for these properties areoften beyond what is typically found in otherapplications. For example, since electrical signals
are usually carried by ions in biological systems,
materials that form the interface between
electronics and living tissue must effectively
convert from electron- to ion-based signaling.11-13
In addition, these materials must simultaneously
have mechanical properties that are well matchedto the biological material they are in contact with,so that they can move with the body and maintainphysical comfort. For example, a low Young’s
modulus may be needed for a bioelectronicmaterial that is used at an organ interface.14 Anymaterials implanted in the body must also bebiocompatible, and resist biofouling over time.15
In this report, we will analyze substance, function,
and application data from approximately 50,000
journal and patent publications from 2003-2023
to examine trends and connections in these areas.
In addition, we will focus on identifying emerging
trends and materials.

Trailblazing the future with emerging biomaterials | 143

Journal and patent publication trends

Among the top 100 research institutions in termsof number of journal publication, the top 15
based on the average number of citations per
publication are shown in Figure 2. This statistic
provides a measure of the average impact per
publication. Most of the top institutions basedon this ranking are in the US or China, with the
top institutions in terms of average number ofcitations and total number of publications being
Massachusetts Institute of Technology and theChinese Academy of Sciences, respectively.
Figures 3 and 4 summarize patent activity in

The number of bioelectronics-related journaland patent publications between 2003 and 2023
is shown in Figure 1. Two notable trends areobserved in this data. First, we see a substantial
increase in the number of journal publications
from 2017 to 2022. Second, the ratio of journal
to patent publications also increased during
this period. This trend suggests an increasein the amount of academic research in thelast five years which has not yet resulted incommercialization.

5,000

Journal

4,500

Patent*Number of publications

4,000
3,500
3,000
2,500
2,000
1,500
1,000
500
23

22

20

21

20

20

20

19

20

18

20

17

20

16

20

15

20

14

20

13

20

20

11
12
20

10

20

09

20

08

20

07

20

06

20

05

20

04

20

20

20

03

0
Publication year
Figure 1. Number of journal and patent publications per year in the bioelectronics field from 2003 to 2023 (journals: blue bars,
patents: yellow bars). * The data for 2023 only include months from Jan to Aug.
Average number of citations per publication
Massachusetts Institute of Technology
University of Michigan
Nanyang Technological University
University of California
Chinese Academy of Sciences
Tsinghua University
Zhejiang University
Seoul National University
Sichuan University
Stanford University
Peking University
Nanjing University
Huazhong University of Science and Technology
Fudan University
Central South University
Southwest University

Citations per publication
Number of journal publications (USA)
Number of journal publications (CHN)
Number of journal publications (SGP)
Number of journal publications (KOR)

Number of journal publications

Figure 2. The top 15 research institutions in terms of average citations per publication (yellow line). Total publications from 20032023 shown as bars; colors of the bars indicating country/region location (blue: USA, red: China, dark green: Singapore, purple:
Korea).

the area of bioelectronic materials. In Figure
3, the top patent assignees are separated into
commercial and non-commercial entities. This
analysis shows that the most commercial patentactivity has been generated by companies in
the US, in terms of number of patent families
generated, while non-commercial patent activity
is driven more by institutions in China. A notable
exception to this is the University of California,
which has been listed as the assignee on more
patent publications than any other research
institution. Part of the reason for this is that
University of California is an assembly of 10
separate public universities.

grown more significantly in China compared to
the US, particularly since 2017. The relative amountof patent publications has also grown significantly
in Korea in the last 10 years.
Figure 4B shows the flow of patent activities
through national patent offices and the Patent
Cooperation Treaty (PCT) system. Here, an activity
is defined as an event where a patent document,
either an application or a granted patent, ispublished. The left column shows the top ten
patent assignee countries/regions in terms ofnumber of patent activities. The right column
shows the patent office where the patent activity
took place. The center column, connecting thetwo, indicates the office where the first patent in
the family was filed.

The trend of patent publications over time shownin Figure 4A indicates that patent activity has

OthersOthers13%

USA 44%

Top 10patent assignees
2003-2023

FRA (2%)
NLD (2%)
GBR (2%)2%
2% ISR
3% CHE
4%
6%

6%
16%

CHN 38%KOR

2003-2023

JPN

9%

DEU

USA

Commercial

60

100

50

80

40

60

30

40

20

20

10

0

an

El

Bo

Un

ro

mo

M
du edtr
lat onion icC
IB orpM .
SaComsun De rp.
Bi g El xco
os ec mW ens tronar e
sa W ics
w eb
Or stetho r
Me P ped
dtr ace ic
on se
ic
t
Mi ter
niM
Ad
Se ed
Bi
va
otr
a
nc
on Gre reteedika
Ne Car Se tba
ur dia & tch
om c P Co
od ac . K
ula em G
tio akInt n S ers
el ys
Co tem
rp s
or
ati
on

0

eu
cN
tifi
ien

ive
rsi
t
Number of patent publications
Z yo
g
ec
ha heji f CaM
tro
asi J an lif
iao g U orn
sa
nic
ch
sa
To niv ia
us
nd
ng er
e
tts
Te
U s
F
Ins ud niv ity
lecomtitu an ers
U
ity
te
mu
of nivenic
ati Ti Tec rsity
Ko
a
on
h
re
s R njin noloaA
es Un gydv
iv
ean
St arch ers
ce
ity
an
Na
dI
I
n
f
o
nji Ko nssng re tit
Un rd u titu
iv ni teUn a I ute
ive nst of Ts ersi vers
rsi itut Sc ing ty o ityty e o ien hu f Jofac
Po f Sc e a Un inansts ien nd ivecan e a Tec rsitSo
d T nd hn yuthele Te oloCh
co ch gymm no
ina
Un Har un logyv
ive a ica
rsi rd U tiontyof nive s
Te rs
ch ity
no
log
y
70

120

Sc

Non-commercial
80

Sh

Number of patent publications

140

KOR

25%

CHN

sto
n

TWN (1%) (a province of CHN)
JPN (2%)RUS
2% DEU
2%
2% NLDTop 103% IND
patent assignees 4%
FRA
12%

Patent assignees

Patent assignees

Figure 3. Top panel: The top 10 countries/regions in terms of number of patents published between 2003-2023. Lower panel: The
top 15 patent assignees in the field of bioelectronics in the same time period. Both panels are divided into commercial and noncommercial entities. Bar graph has been color coded by country/region to match color scheme in donut charts.
Trailblazing the future with emerging biomaterials | 145

(A)

600

80

KOR

70

50
40

DEU
JPN
CHE
FRA
GBR

30

400

20
10

300

0

USA

20
0
20 3
0
20 4
0
20 5
0
20 6
0
20 7
0
20 8
0
20 9
10
20
1
20 1
12
20
1
20 3
1
20 4
1
20 5
1
20 6
1
20 7
1
20 8
1
20 9
2
20 0
2
20 1
22

Number of patent publications

CHN

60

500

200

100

KOR
DEU

10
20
11
20
12
20
13
20
14
20
15
20
16
20
17
20
18
20
19
20
20
20
21
20
22

20

09

08

20

07

20

20

06

05

20

20

04

20

20

03

0

JPN
CHE
FRA
GBR

Publication year
(B)

USA: 8,242

USA: 9,389

USA: 14,015

WIPO: 8,882

CHN: 4,617

CHN: 3,993
KOR: 1,345
DEU: 1,214
JPN: 1,514
ISR: 786
GBR: 690
CHE: 638
FRA: 593
NLD: 470

CHN: 3,853
EPO: 650
JPN: 720
KOR: 1,209
DEU: 587
ESP: 114
GBR: 149
FRA: 355
Others: 137

EUR: 2,465
JPN: 1,470
KOR: 1,175
CAN: 832
IND: 196
DEU: 252
BRZ: 109
GBR: 135
FRA: 123
OTH: 507

Others: CAN, MEX, ISR, TWN (a province of CHN), AUS, IND
OTH: ISR, AUS, MEX, HKN, ESP, AST, TWN (a province of CHN), RUS
Figure 4. (A) Number of patent family publications per year between 2003-2022 for the top 8 most prolific countries/ regions.
(B) Total patent flow between assignee countries/regions (top ten countries/regions in terms of total patent filings, left), thepatent filing office where the first application in the patent family was filed (center) and the patent office where individual patentpublication activities took place (right). Standard three letter codes utilized for countries/regions.

For example, a patent application filed by a USbased assignee in the Japan national patentoffice might first have been filed as a PCT/WIPO
application. In this diagram, that patent activity
would flow from the United States, to WIPO, then to
JP.
From this figure, we see that in the US, France,
and Switzerland, the initial filings for a given
family are roughly split evenly between PCT
and the home country/region patent office.
For assignees in Germany, Korea, and Japan, asignificant fraction of initial filings are done in the
USPTO. UK-based companies more heavily favor
PCT applications, while China-based companies
file the majority of first applications in the Chinese
national patent office.
Figure 5A depicts the locations within the humanbody that bioelectronic devices are used, as
discussed in journals and patents publishedfrom 2003 to 2023. Analysis was performed bycounting the total number of publications thatreferenced specific organs or regions of the body,
including synonyms, then normalizing by the total
publication count.

Devices targeted at the facial region constituteroughly 37% of total applications. In some cases,
this research has progressed to the point ofcommercialization, for example the Argus II
Retinal Prosthesis System, which in 2013 became
the first retinal implant approved by the FDA.16,
17
This device uses platinum electrodes, titanium,
and niobium, with many of the components
encased in polydimethylsiloxane (PDMS).18 Later
research on retinal implants investigated replacing
platinum in the electrode with materials that havea higher charge injection limit (the amount ofcharge that can be delivered without exceeding
voltage that leads to irreversible and possibly
damaging chemical reactions, primarily waterelectrolysis), such as conductive polymers andnanocomposites.19 A recent example is a retinal
implant based on iridium oxide, insulated with SiC
and SiO2.20
The brain and nervous system closely follow,
making up 30% of applications. Applications inthis area include deep brain stimulation (DBS),
which can significantly improve the quality oflife for Parkinson's disease patients by delivering
precise electrical pulses to mitigate motor

Brain and nervous system (30% )Spinal cord (4.83% )Synovial fluid (0.4%)
Amniotic fluid (0.3%)

Semen (1.2%)
Facial region (37.2% )Lungs (1.7% )Tear (1.7%)
Milk(3.1%)
Saliva
(5.1%)

Heart (3.9% )Arms (6.3% )Spleen (0.4% )Skin (4.4% )Bile (0.2%)

Sweat(5.3%)
Body fluid(7.1%)

Liver (5.2% )

Blood
(63%)

Stomach (1.2% )Urine(12.5%)

Pancreas (0.7% )Intestines (1.7% )Legs (2.4% )Figure 5. (A) Human silhouette illustrating the distribution of publications (2003-2023) concerning bioelectronic devices indifferent regions of the body(Illustrations sourced from Biorender-www.biorender.com). (B) Pie chart displaying the distributionof various biofluids in publications related to bioelectronic applications.
Trailblazing the future with emerging biomaterials | 147

symptoms.21-23 The materials used in commercial
DBS devices include Pt-Ir electrodes withpolyurethane or PDMS encapsulation. 24, 25 In
addition, devices to deliver electrical stimulation
to the spinal cord, for example as a treatment forchronic pain, have been on the US market since2015.
Devices and materials which replicate componentsof the nervous system, such as neuromorphic
devices and artificial nerves, are notable as
having increased research activity recently. These
include materials based on conductive hydrogels
that can be used to repair peripheral nerves,26
neuromorphic devices that interface with thebrain, which have been made using a variety ofmaterials,27 and a sensor that can replicate tactile
and other senses using poly(3-hexylthiophene)/polyethylene glycol nanowires printed on soft
silicone.28

In the heart, bioelectronic devices have been used
to monitor and deliver electrical signals, or evenreplace cardiac tissue.29 Other major application
areas include myoelectric limb prosthetics, where
bioelectronic devices enable amputees to control
artificial limbs with residual muscle signals,30
and sensors used for continuous monitoring
inside the body, for example in the liver,31 or skin,which represents a particularly emerging area ofdevelopment. 32, 33
Figure 5B shows an overview of the various
biofluids that are referenced in combination withbioelectronic devices, using an analysis similar tothat described for figure 5A.
Blood and urine account for roughly 75% of thesereferences, in applications that include real-time
glucose level tracking,34, 35 and implanted or
prosthetic devices to monitor and control urine. 36
The other 25% of references include biofluid,37
sweat, 38 saliva,39 and milk.40

Key material substances, forms, andfunctions

There are several possible methods to classify
biomaterials when analyzing research trends. In
this report, we will classify them in three ways:• Chemical Substance. For this classification,
we can leverage the indexing of chemical
substances by name and CAS Registry
Number, which is done for all journal andpatent publications in the CAS Content
Collection. Examples of this classification
include gold, graphene, and poly(3,4ethylenedioxythiophene) (PEDOT).
• Form. This can be considered as a related,but orthogonal method to chemical
substance classification. Examples arehydrogels, nanoparticles, and composites.
• Function. Most bioelectronic devices are
hybrids, composed of several materials withdifferent properties and functions. Breaking
bioelectronic materials down by function
will allow us to examine the materials usedin each individual component of a device.
Examples of functions are electrodes, sensor
materials, and encapsulation materials.
Figures 6-9 are focused on classifying andidentifying trends in bioelectronic materials
by their chemical substance. The first groupof chemical substances, metals and inorganic
compounds (Figure 6) were found to be themost frequently mentioned type of substances inbioelectronic material literature from 2003-2023.

Included within this class are several important
sub-classifications. The first is noble metals, which
include gold, silver, platinum group metals, andtheir alloys. These materials are used primarily
for their high electronic conductivity, chemical
stability, and the ability to form them intofunctional nanomaterials using well-developed
methods.41, 42
The next are transition metals, primarily iron,titanium, copper, and nickel, as well as their alloys,
including stainless steel and nitinol. Several ofthese materials are used in part due to theirknown biocompatibility, particularly titanium,43
while other metals are encapsulated usinginert polymers or other materials to prevent
degradation by the body.44, 45
In general, the use of noble and transition
metals has not increased significantly relative toother materials discussed here, and as such areindicated by gray circles in Figure 6.
Biodegradable and bioresorbable metals, which
include zinc, magnesium, and molybdenum, areof unique interest for bioelectronic applications
that involve temporary placement of an electronic
device.9 These materials combine the electricalproperties of a metal with the ability to be safely
broken down and absorbed by the body overtime. Full transient bioelectronic devices havebeen constructed by combining these metals
with biodegradable encapsulating polymers, forexample an electronic nerve stimulator electrodeand power receiver antenna consisting of Mo
encapsulated in a biodegradable polyurethane.46

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Oxides

Transition metals

Bioactive ceramics
Piezoelectric ceramics

Functional alloys

Liquid metals

Nitrides andcarbides*Figure 6. Bubble chart and heat maps showing frequency of the use of metals and inorganic compounds in the field of bioelectronics. Bubble size
corresponds to the number of bioelectronics-related publications mentioning the material type (both patents and journals) between 2003-2023. The asterisk
indicates emerging materials (see Fig. 9).

Noble metals
and alloys

Other
inorganics

Bioresorbable
metalsMetal oxides are a broad class of material thatcan serve several functions, from insulating layers
for electrical isolation or semiconductor device
purposes (SiO2, TiO2, and HfO2 for example),or as charge conductors (SnO2, ITO, IrOx). Of
these, IrOx, or “SIROF” (sputtered iridium oxidefilm), a mixture of iridium and iridium oxides,
is commonly used as a bioelectronic electrodeinterface material due to its low impedance,
relatively high charge injection limit, anddurability.20, 47 Among the nitrides found inbioelectronic devices, TiN stands out as being ahighly studied material for brain interface multielectrode arrays (MEAs).48
Another notable material in this category ishydroxyapatite, which is included in the bioactive
ceramics group, and can be used as a scaffolding
material for integrating bioelectronics into humanbone.49

As shown in Figure 7, polymers make up asecond class of bioelectronic materials, and also
serve a variety of functions. The most commonlyreferenced functional polymers are conductive,
notably PEDOT, polypyrrole, and polyaniline.
PEDOT:PSS is the most commonly usedconductive polymer material in bioelectronics
research.1 In our analysis, we found that PEDOT
appears in journal and patent publicationsat roughly double the frequency of the othercommon conductive polymers polypyrrole andpolyaniline. This may be due to concerns over the
long-term stability and potential toxicity of these
two materials in the body, respectively.50, 51
The second and third most referenced classesof functional polymers are those that are used
to form hydrogels, notably poly(lactic acid),
polyethylene glycol, and poly(vinyl alcohol),and biodegradable polymers including
polycaprolactone and poly(glycolic acid). As
discussed in other sections of this report,**
Conductive
polymers

Biodegradable
synthetic
polymers***
Natural polymers

Inert polymers*

Hydrogel-forming
synthetic polymers**

Figure 7. Bubble chart and heat maps showing frequency of the use of various polymers in the field of bioelectronics. Bubble
size corresponds to the number of bioelectronics-related publications mentioning the material type (both patents and journals)
between 2003-2023. Asterisks indicate emerging materials (See Figure 9).

Trailblazing the future with emerging biomaterials | 151

hydrogels are heavily used in bioelectronic
applications due to their physical similarity
to biological tissues. 52 Polycaprolactone andpoly(glycolic acid) are safely resorbed into thebody and used in other biomedical applications,53
so they have advantages as encapsulationmaterials for bioelectronic devices that are meantfor only temporary use.
Another notable class of polymers are thosethat are derived from natural sources including
cellulose, chitosan, and alginate.54 These polymers
have attracted significant research attention due
to their biocompatibility and resorbability. A recent
example is the combination of biodegradable
MoOx and sodium alginate gel to make aresorbable supercapacitor to power transiently
implanted bioelectronic devices.55
Silk-based materials are particularly notable
due to their versatility, biocompatibility, andmechanical strength.4,56 A recent example isthe use of silk to encode encrypted data in an
implanted device.57 In this case, the tunable
electrical and biodegradation properties of silk
were used to encode electronic and opticalbased data simultaneously on a single device
which degraded over time in a rat model. Parallel
efforts are underway to generate spider silkfrom alternate sources, for example transgenic
silkworms,58 and to synthesize artificial materials
inspired by the structure of spider silk. 59
The class of polymers that appear most frequently
in bioelectronics references are inert or passive,
and are used for encapsulation, as substrates, or
as a matrix material in functional composites. In

Carbonnanomaterials

this area, poly(dimethyl siloxane) (PDMS) is themost commonly used material.
PDMS has several advantageous properties that
explain its widespread use in bioelectronics. First,
its tunable flexibility and elasticity enables thecreation of flexible and stretchable electronic
devices that can mechanically integrate withbiological tissues. PDMS-based substrates arecommonly used for the fabrication of flexible
electrodes,60, 61 sensors,62 and wearable devices.63
Moreover, PDMS is optically transparent in visible
and near-infrared wavelengths, making it suitablefor optical applications, enabling real-timemonitoring and imaging of biological processes.
The biocompatibility of PDMS is also importantfor bioelectronic implants. PDMS-sheathed neuralinterfaces, for instance, can be implanted into
the brain or peripheral nervous system to record
neural activity or deliver electrical stimulation
without causing significant tissue damage or
immune response.64, 65 Additionally, PDMS isrelatively easy to process and fabricate into
complex structures using techniques such as soft
lithography and replica molding, which allows for
rapid prototyping, customization, and potential
for high-volume manufacturing.
The unique properties of carbon nanomaterials,
shown in Figure 8, makes them particularly
useful for bioelectronic materials. Carbon
nanotubes (CNTs), including single-walled(SWCNTs) and multi-walled (MWCNTs), are used
to improve electrical and mechanical propertiesof bioelectronic composites,66, 67 and as sensor
components.68 Similarly, graphene can be used
as a conductive filler,69 or in tissue engineering, by

Carbon bulk
materials

Figure 8. Bubble chart and heat maps showing frequency of the use of carbon its allotropes in the field of bioelectronics. Bubble
size corresponds to number of publications (both patents and journals) between 2003-2023.

serving as the basis for biocompatible scaffolds
for regenerating bone,70 and neural tissue.71
Graphene oxide (GO), a water-dispersible
graphene derivative, can also be used for
drug delivery,72 acting as a carrier for targeted
therapeutic agent delivery.

materials mentioned in at least 20 publicationsin 2022. Gold and silicon are shown as a basis
for comparison, and their use has not increased
significantly over this time. This analysis shows thatthe highest growth rates are in:– Hydrogel-forming polymers: polyacrylamide,poly(vinyl alcohol) and cellulose– Inert polymers: poly(vinylidene fluoride),poly(dimethyl siloxane), poly(ethylene
terephthalate)– Conductive polymers: poly(3,4ethylenedioxythiophene) andpoly(styrenesulfonic acid)– Titanium nitride

The data shown in Figures 6-8 are aggregatedfrom 2003-2023, and therefore represent a timeaveraged view of the substances used over thattime. To identify substances that that have beenused more frequently in recent years (emerging
substances), we counted the number of times anindividual substance was mentioned each year
from 2013-2022, then normalized these counts
by the average number of times the substance
was referenced per year between 2013-2018. This
allowed us to identify substances that are growing
in use over the last 5 years.

Beyond their chemical composition, we can alsoclassify bioelectronic materials by their physicalform, as shown in Figure 10. Here, we see thatthe materials used in bioelectronic applications
are roughly split between gels (mainly hydrogels),
nano-scale materials, macromolecules, thin films/
coatings, and composites (note that there is

The plot in Figure 9 shows the substances withthe highest normalized growth rate in termsof mentions over the last 5 years, limited to

7

7.00

6

Normalized frequency

6.00

5

Normalized frequency

5.00

4

4.00

3

3.00

Polyacrylamide
Poly(vinyl alcohol)
Cellulose
Poly(vinylidene fluoride)
Poly(dimethyl siloxane)
Poly(styrene sulfonic acid)Titanium nitride
Poly(ethylene terephthalate)Poly(3,4-ethylenedioxythiophene)
Silicon
Gold

2

2.00

1

2

2022

20
2

1

2021

20
2

0

2020

20
2

9

2019

20
1

8
20
1

7

2017

6

2016

20
1

5

2015

20
1

4

2014

20
1

3

2013

20
1

Publica on year

20
1

0

0.00

2018

1.00

Publication year
Figure 9. Normalized frequency of representative materials in journal and patent publications from 2013-2022.

Trailblazing the future with emerging biomaterials | 153significant overlap between some of these forms
in single devices or materials).
The data shown in Figure 9 indicates thathydrogel-forming polymers are a particularly
emerging class of substances, which is also
reflected in the forms classification shown in
Figure 10 Furthermore, combining hydrogels withnanoscale materials can be particularly useful.
This approach takes advantage of the biologicaltissue compatibility of hydrogels and the uniqueelectrical and mechanical properties, potential
for functionalization, and high surface area ofnanoscale materials.
The forms in Figure 10 that have a particularlyhigh ratio of mentions in patent publications
compared to journal articles, suggesting thatthese materials have progressed further towards
commercialization, are highlighted in color.
The final method to classify bioelectronic materials

is by their function in a device, shown as a heat
map in Figure 11. Here, individual material
functions are shown in the top row, and the top
materials associated with these functions arelisted in the left column. This figure indicates thatthe primary function of individual bioelectronicmaterials are active sensor components, interface
materials between electronic components andbiological tissues (including electrical sensing/mapping/stimulation applications), optoelectronicmaterials, signal processing components, andmechanical sensors. In general, the heat map
reflects the frequent use of noble metals, as wellas ITO, graphene, titanium, and the polymers
PDMS, PEDOT, PET, and PMMA.
A major function of biomaterials is to form aphysical and electrical interface between an
electrical device and biological tissue. This cantake the form of an electrode, electrode coating,bioadhesive, or combination of these things.

Hydrogel

Gels
OrganogelNano-scale materials

Macromolecules

DNA
RNA

Nanoparticles
Nanowires
Nanorods
Nanosheets
Nanoporous materials
Nanotubes
Other

Protein
Carbohydrates

FORMS
Thin films/coatings

Number of
publications>5000

Composites
Others

3001-5000

Liquid metals
Ionic liquids
Microsphere1001-3000
501-1000
101-500
0-100

Figure 10. Trend map showing distribution of various forms in the field of bioelectronics. The size of colored circle corresponds
to number of publications (journal and patent) over 2003-2023. Topics with high patent-to-journal ratio are highlighted using
colored rounded rectangles.

The primary function of these components is
to maintain low-impedance electrical contact
for electrical sensing and/or stimulation, while
maintaining a compliant and durable attachment
to tissue.
This combination of properties is often achievedin modern bioelectronic devices using composites
where one component provides the desired
mechanical characteristics, and the other provides
the desired electron and/or ion conductivity.
Notable examples include percolated silver /polyacrylamide-alginate hydrogel,73 graphene
oxide / PVA hydrogel,74 carbon nanotube / PDMS
bottlebrush elastomers,66 PEDOT:PSS mixed
with a supramolecular solvent,75 bicontinuous
PEDOT:PSS / polyurethane hydrogel,76 and
PEDOT/functionalized graphene oxide/polyacrylamide hydrogel.77
A conformal, well-adhered interface between
bioelectronic materials and biological tissues
is important for stable and reliable functioningof bioelectronic devices. However, this can bechallenging to realize in soft, wet, dynamic biointerfaces. To this end, Zhao et al. developed anelectrical bioadhesive interface by a graphenePVA nanocomposite material, demonstratingsuperior biocompatibility, applicability,
mechanical and electrical stability, as well as theability to trigger detachment of the material.74
In another example, an ionic-conductive

dopamine-containing polymer film based on
copolymerization of dopamine methacrylamide(DMA), acrylic acid (AA), and methoxyethyl
acrylate (MEA), p(DMA-co-AA-co-MEA), wasintegrated with Au/PDMS bilayer films to create
water-resistant electrodes, which could be used
for monitoring electrocardiography (ECG) signals
underwater as they could maintain conductivity
and firm adhesion to skin.78 In this material, theDMA component provided the water-resistantadhesive properties. Recently, a bioelectronic
patch was developed for precise cardiac
monitoring, which used an ionically conductive
catechol-conjugated alginate (Alg-CA) hydrogel
to provide instantaneous adhesion to the
dynamic cardiac tissues. This material was used todemonstrate measurement of ECG signals in live
rat models for up to 4 weeks.79
Bioelectronic materials are also incorporated
into biomedical sensor devices,2, 11 where they
are designed for applications such as detecting,chemical environments80 or sensing pressure.81
For example, Lee et al.,68 developed a sensor
based on single-walled carbon nanotubes
modified with a human olfactory receptor protein,which could detect the presence of an odorantat concentrations as low as 1 femtomolar withhigh sensitivity. Doped carbon nanomaterials,
such as nitrogen-doped graphene, are used
as electrochemical biosensors for molecules
including DNA, proteins, glucose, and hydrogen
peroxide.82-84

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9.6%
5.1%

12.4%

5.8%

GrapheneIndium tin oxide

Iron

2.6%
1.4%
1.6%
0.3%
1.3%
1.5%
1.1%
0.2%
1.0%
0.5%
7.1%
7.0%
0.4%
2.0%
3.7%
0.5%
2.0%

0.6%

1.0%

0.1%

0.9%

1.5%

0.7%

0.0%

0.6%

0.4%

4.8%

5.9%

0.4%

2.2%

2.1%

0.2%

2.4%

Poly(3,4-ethylenedioxythiophene)

Poly(dimethylsiloxane)

Poly(ethylene terephthalate)Poly(lactic acid)

Poly(methyl methacrylate)Poly(styrenesulfonic acid)

Poly(vinylalcohol)

Polycaprolactone

Polyethylene glycol

Quartz

SiliconSilverTin oxide

Titania

Titanium

Zinc

Zinc oxide

2.2%

0.7%

2.6%

2.3%

0.4%

7.1%

15.7%

0.7%

1.8%

0.2%

1.8%

1.8%

3.7%

0.6%

2.8%

2.4%

2.2%

3.6%

1.3%

0.4%

7.5%

5.8%

18.4%

4.2%

2.0%

1.1%

4.4%

2.5%

Optoelectronicmaterial

2.9%

1.8%

0.5%

6.1%

2.8%

1.0%

9.6%

15.0%

0.9%

1.0%

0.1%

1.1%

0.9%

2.6%

0.3%

1.6%

0.8%

1.4%

8.9%

2.8%

0.8%

4.1%

4.3%

15.9%

6.1%

0.6%

0.4%

4.8%

2.2%

0.9%

2.9%

0.7%

0.1%

13.2%

5.0%

1.2%

0.4%

0.3%

4.2%

2.5%

2.0%

0.3%

5.8%

6.6%

3.4%

3.6%

1.9%

1.1%

3.2%

9.3%

13.0%

7.4%

1.7%

2.0%

3.4%

1.7%

MechanicalsensorSignalprocessing
3.6%

2.4%

2.6%

5.4%

0.2%

2.9%

0.8%

0.0%

6.1%

9.6%

4.0%

0.8%

0.2%

2.1%

1.5%

1.9%

1.0%

3.1%

2.7%

2.7%

6.3%

1.5%

0.4%

3.1%

4.2%

26.8%

3.3%

1.9%

0.8%

5.7%

1.1%

Piezoelectric

1.0%

0.7%

1.4%

3.6%

1.1%

0.5%

10.7%

9.3%

0.7%

0.9%

0.2%

3.6%

1.4%

2.7%

0.7%

5.9%

2.7%

2.7%

8.9%

3.0%

1.4%

1.8%

6.4%

13.9%

7.5%

1.1%

2.0%

4.1%

1.1%

Temperature
sensor

0.8%

1.0%

0.5%

3.5%

1.5%

0.0%

7.5%

9.0%

1.0%

1.5%

1.0%

2.5%

4.5%

3.0%

2.0%

4.5%

1.0%

6.0%

11.1%

3.5%

1.5%

1.0%

4.0%

13.6%

4.0%

3.0%

3.0%

3.5%

1.5%

Actuator

0.6%

0.4%

1.9%

0.2%

6.9%

0.6%

0.0%

4.4%

26.5%

1.3%

1.7%

0.2%

1.0%

0.2%

1.0%

0.6%

0.8%

2.7%

0.4%

11.0%

2.9%

0.4%

1.3%

0.8%

22.3%

2.9%

0.6%

0.6%

4.6%

2.1%

Microelectro
mechanicalsystems

Low

High

Figure 11. Heat map of the relationship between the most commonly used substances in bioelectronic materials (left) and the most common material applications (top). Relative
frequencies of each substance have been calculated within each application category. Note that the electronic/tissue interface category also includes electrical sensing and stimulation.

10.2%

9.9%

2.3%

Platinum

Nickel

26.5%

32.2%

Gold

0.6%

3.6%

2.6%

Copper

1.8%

4.0%

6.3%

Chitosan

0.4%

0.5%

0.3%

Cellulose

1.7%

1.8%
2.1%

1.3%

1.1%

Alumina

Electronic /tissue interface

Chemical sensors /immunosensors

Aluminum

31.1%

58.3%

Notable journal articles and patents

Table 1 is a set of research articles published from2020-2023 that represents emerging trends inthe field of bioelectronics. These references wereselected to provide examples of the materials
and applications which appear prominently in
our analysis of the bioelectronics literature aspresented in Section III. They were also selectedbased on other factors including journal impact
factor and the number of other articles citing
the reference. The examples include the useof IrOx, PEDOT:PSS, PEG, silk-based materials,
carbon nanotubes, hydrogels, and PDMS, forapplications including retinal implants, microelectrocorticography, wearable devices, tissue/
electrode interfaces, and neural interfaces.
Notable examples from Table 1 include aphotovoltaic-based subretinal implant that
achieved a visual resolution of 28 microns,
matching the limiting visual resolution in rats.
In this system, images are projected using nearinfrared light onto a photovoltaic array implantedin the eye, which directly transmits electricalsignals to the retinal neural network. The arrayconsists of silicon-based photovoltaic pixels, using
IrOx / Ti / Pt stack electrodes, with SiO2 and SiC
as encapsulating materials. In this application,use of IrOx, in the form of sputtered iridium oxide
film or SIROF, is important due to its high charge
injection capacity relative to other electrodematerials.
In a second example, Jiang et al.86 developed
and optimized a mixture of PEDOT:PSS anda functionalized polyrotaxane for use as astretchable, patternable conductive material.
The key structure to optimize in this material
is the polyrotaxane, which consisted of a PEG
backbone with encircling cyclodextrin. The
primary function of the cyclodextrin was toprevent crystallization of the PEG, a process thatwould degrade the mechanical properties ofthe mixed material. In addition, a fraction of thecyclodextrins were functionalized with PEG andmethacrylate groups, to control water solubility
and enable photopatterning of the material.
They also demonstrated the use of this optimized
material on human and octopus skin for surface
electromyography, and as an electrode array forstimulating and mapping the rat brain. Pokorski etal. have also developed a method for 3D printing
PEDOT:PSS using direct ink writing (DIW), andused it to print a flexible, cortex-wide microelectrocorticography array for stimulating andcalcium imaging a mouse brain.87
Chen et al.88 reported a silk-based electrode foradvanced wearable devices and on-skin sensors
that utilizes an electrospun silk fiber mat coatedwith PEDOT:PSS, featuring high stretchability andcomfort against sweat on the skin. The electrodematerial can be stretched more than 250%, has
low evaporative resistance (10 times lower thancommercially available gel electrodes) and highwater-vapor transmission (2 times higher than therate of water loss from the skin). This electrodealso demonstrates no apparent disturbanceduring data collection under sweaty conditions.
Another recent example of composite materials
in bioelectronic devices is a mixture of single-wallcarbon nanotubes (SWCNTs) with PDMS-based
bottlebrush elastomers (PDMS BBEs).66 The PDMS
BBEs can be made ultra-soft by optimizing thepolymer side chain length, grafting density andnetwork strand length, making them suitable
for applications in cardiac muscle and the brain.
SWCNTs (incorporated at 0.4–0.6 wt%) provide
conductivity.
A soft interlayer in an electric thin film can makea high modulus thin film more stretchable ona low modulus substrate. This approach leads
to more applications of the existing stretchable
electronic materials to tissue-like modulus devices,such as sensors on cardiac muscle. Wang etal. reported a polystyrene-ethylene-butylenestyrene (SEBS) as the interlayer that acts as anadhesive for electronic materials and low modulus

Trailblazing the future with emerging biomaterials | 157

substrates.14 The design of SEBS interlayer on
the polyacrylamide (PAAm) hydrogel is ultrasoft, around two orders of magnitude lower thanpolydimethylsiloxane (PDMS) and SEBS. This
design is further utilized for PEDOT:PSS-based
electrodes, with mechanical tests demonstrating
increased stretchability and softness of theinterlayer-inserted electrode.
Table 2 shows notable patents in the field ofbioelectronics published from 2018 to 2023.
Patents were selected based on relevance, novelty,
applicability, and field of study. Most of these
involve implantable devices for organ stimulation,
pain management, monitoring, and/or analysis ofbioelectronic data.
For instance, US 10898718B2, ‘Sensor-based pain
management systems and methods’ (Boston
Scientific Neuromodulation Corp, USA) describesa system for measuring and managing pain. The
system first collects data from the patient, forexample a galvanic skin response, electrodermal
activity, electromyogram, electroencephalogram,
blood pressure, heart sounds, or saliva production

rate, then uses this data to generate a quantitative
pain score. This can then be reported to a clinician
or used to control an automated pain control
system. This invention can be helpful for patients
who do not have the ability to communicate asubjective pain score, or do not have immediate
access to medical care.
In recent years, hydrogels, natural polymers andconductive polymers such PEDOT: PSS havebeen cited in patents in the bioelectronic field.
US 11633589B2 (QV Bioelectronics Ltd.) describes
an injectable electrode material consisting of a
mixture of solid PEDOT:PSS particles dispersed ina PEDOT:PSS-containing gel or liquid phase. This
material can be injected into a tumor resection
cavity, then used to deliver electrotherapy
treatments targeting residual cancer cells left at
the edge of the cavity after surgery. The biphasic
material allows the electrode to conform to
the edges of the cavity, which can move due toswelling, while generating electric fields close
to the tumor site at lower voltages compared toexternally mounted electrodes.

Table 1. Notable journal publications in bioelectronic materials in recent years.

Year

Title

JournalResearch Institute

Summary

2020

Muscle-Inspired Self-Healing
Hydrogels for Strain and Temperature
Sensor89

ACS Nano

Nanjing Tech
University

Self-healing sensor based on a poly(acrylicacid) hydrogel with polyaniline nanofibers

2020

Functionalized helical fibre bundles ofcarbon nanotubes as electrochemicalsensors for long-term in vivo
monitoring of multiple diseasebiomarkers90
Enhancement-mode ion-basedtransistor as a comprehensive
interface and real-time processing
unit for in vivo electrophysiology 91

Nature BiomedEng.

Fudan University

CNTs modified with different materials(Pt nanoparticles, glucose oxidase, ZnO,PEDOT:PSS) for sensing H2O2, glucose, andions; CNTs were insulated using PDMS

Nature Materials

Columbia University

PEDOT:PSS/polyethyleneimine mixture
as the active channel in an ion-gatedelectrochemical transistor for in vivo
electrophysiological sensor

2021

Electrical bioadhesive interface forbioelectronics74

Nature Materials

Southern University.
of Science andTechnology

Electrically conductive bioadhesive using a
PVA hydrogel with reduced graphene oxide
filler, and poly(acrylic acid) modified with
N-hydroxysuccinimide ester for adhesion

2021

An electrically conductive silver–
polyacrylamide–alginate hydrogel
composite for soft electronics73

NatureElectronics

Carnegie Mellon
University

Polyacrylamide-alginate hydrogel withpercolated silver to make a soft, conductive
electrode

2021

Permeable superelastic liquid-metal
fibre mat enables biocompatible andmonolithic stretchable electronics92

Nature Materials

Hong Kong
Polytechnic
University

Poly(styrene-block-butadiene-block-styrene)
fiber mixed with eutectic gallium-indium alloy(EGaIn) as a conductive, stretchable material

2022

A transient, closed-loop network of
wireless, body-integrated devices forautonomous electrotherapy10

Science

Northwestern
University, USA

Bioresorbable, temporary wireless cardiac
implant made of dynamic covalentpolyurethane, Mo, and Si

2022

A double-layer carbon nanotubes/
polyvinyl alcohol hydrogel with highstretchability and compressibility forhuman motion detection67
Topological supramolecular network
enabled high-conductivity, stretchable
organic bioelectronics86

Engineered
Science

Beijing Universityof Posts andTelecommunications

Flexible strain sensor based on a carbon
nanotube/PVA hydrogel mixture

Science

Stanford University,
Tianjin University

Mix of PEDOT:PSS and a PEG/MAfunctionalized PEG-backbone polyrotaxane asa stretchable, photo-patternable conductive
material

2022

Electronic photoreceptors enable
prosthetic visual acuity matching thenatural resolution in rats20

Nature Comm.

Stanford University

Subretinal implant using IrOx electrodes with
SiO2 and SiC encapsulation

2022

Three-dimensional printing of softhydrogel electronics93

NatureElectronics

University of
Adelaide, Westlake
University

3D printing of conductive Ag-based networks
inside of an alginate-polyacrylamide hydrogel
matrix; rheological properties of the matrix
are engineered to allow printing, followed bycuring to form a stretchable, covalently boundstructure2023

3D printable high-performance
conducting polymer hydrogel for allhydrogel bioelectronic interfaces76

Nature Materials

Massachusetts
Institute. ofTechnology, Jiangxi
Science andTechnology Normal
Univ.

Use of a bicontinuous PEDOT:PSS/hydrophilic
polyurethane structure to optimize the
combination of electrical and mechanicalproperties of a hydrogel; material can beformed by 3D printing, electrospinning, spin
coating, or micro-molding

2023

Zinc hybrid sintering for printed
transient sensors and wirelesselectronics9

Npj Flexible
Electronics

Ecole Polytechnique
fédérale deLausanneZn particle ink printed onto polyimide, paper,
PLA, as bioresorbable pressure sensors andwireless power receivers

2023

Conductive and elastic bottlebrush
elastomers for ultrasoft electronics66

NatureCommunicafions.

University of Toronto

Soft electrode based on PDMS bottlebrush/
single wall carbon nanotube mixture2023

Achieving tissue-level softness on
stretchable electronics through ageneralizable soft interlayer design14

NatureCommunicafions.

University of Chicago

Use of a polystyrene-ethylene-butylenestyrene adhesion interlayer with PAAm
hydrogel/PEDOT:PSS

2023

Graphene and Poly(3,4ethylenedioxythiophene)-Polystyrene
Sulfonate Hybrid Nanostructures for
Input/Output Bioelectronics94

ACS Applied
Nano Materials

Carnegie Mellon
University

High surface area PEDOT:PSS formed ongraphene/Si nanowire composite as electrodematerial

2020

2022

Trailblazing the future with emerging biomaterials | 159

Table 2. Notable patent publications in bioelectronic materials in recent years.
Patent or
publication
numberUS 10065036B295

Publication
year

Patent assignee

Title

Description of patented technology

2018

Second Sight Medical
Products, Inc., USA

A system to pre-condition and measure the impedanceof electrode-tissue interfaces for an implanted visual
prosthesis

US 10668290B296

2020

Medtronic Inc., USA

Method for measuring
stable and reproducible
electrode-tissue
impedance
Delivery of pacing
therapy by a cardiac
pacing device

CN 111363097 A97

2020

Wenzhou ResearchInstitute of Chinese
Academy Of Sciences,Wenzhou Institute
Of Biomaterials And
Engineering, China

Preparation methodof bioelectronichydrogel, product, andapplication thereof

US 11517238B298

2022

University of Illinois,
Northwestern
University, USA

Encapsulated flexible
electronics for longterm implantation

US 10898718B299

2021

Boston Scientific
Neuromodulation
Corporation, USA

Sensor-based pain
management systems
and methods

CN 214175051U100

2021

Huashan Hospitalof Fudan University,
China

US 11633589B2101

2023

QV Bioelectronics
Ltd., UK

Movement intention
identification systemof exoskeleton glove
equipment based onbrain plasticity
Biphasic injectableelectrode

WO2023154259A2102

2023

Cz Biohub Sf, LLC,
The Regents Of
The University Of
California, USA

Woven fabricbioelectronic device

WO2023038703A1103

2023

Obsidio, Inc., USA

Piezoelectric shearthinning material
compositions andmethods for use

WO2023075689A2104

2023

Nanyang
Technological
University, Singapore

Bioinspired water shrink
film for shape-adaptive
bioelectronics

Implantable medical device to deliver pacing signals(pacemaker, defibrillator for example) combined with
ECG sensors for closed-loop cardiac resynchronization
therapy.
A bioelectronic hydrogel made by photopolymerizing
a mixture of carboxylic acid monomers (acrylic andmethacrylic acid), calcium nitrate, PVA, gold nanorods,
distilled water, and a photoinitiator. IR irradiation heats
the nanorods to kill bacteria on the surface of the gel.
Processes for optimizing the encapsulation of
implantable electronic devices, including bendable,
stretchable, or flexible devices. Cited encapsulation andcoating materials include SiO2, diamond, SiC, Al2O3,
HfO2, parylene, PDMS, polyimide, SU-8, and PMMA.
Sensors use physiological signals from patients(galvanic skin response, electrodermal activity,
electromyogram, electroencephalogram, bloodpressure, heart sounds, or saliva production) togenerate pain scores and deliver treatment.
A human-computer interaction device to identify
intended movements using myoelectric signals for a
prosthetic glove.

A biphasic injectable electrode material consistingof solid particles of PEDOT: PSS in a PEDOT:PSScontaining liquid or gel phase, used for delivering
electrical treatments to the edges of a surgical tumor
resection cavity.
Implantable devices consisting of two or moretypes of threads woven together, to be used fortissue repair. Threads can be made from polymer
fiber (polypropylene, PVC, polyethylene, PEEK,
polycarbonate, polyetherimide (PEI), polysulfone,
polyurethane, cellulose, chitosan), metal wire,or permeable tubing, in conjunction with othercomponents.
Shear-thinning hydrogels containing piezoelectric
nanoparticles (laponite, bentonite, kaolinite, ormontmorillonite-smectite nanoclay, quartz, ZnO, or
AlN). These materials can be injected into the bodyand used to stimulate cells/tissues using wirelessimpulses (ultrasound, RF, or microwave). Polymers in
the hydrogels include gelatin, collagen, chitosan, silk,poly(lactic acid), cellulose, alginate, agarose, starch,
PVDF, PEG, lignin, karatin, PVA, and PTFE.
A thin film which contracts by more than 50% of its
original length upon exposure to water. The film
contains crystalline inclusion complex domains formed
from poly(pseudo)rotaxanes or a-cyclodextrin/PEG
polyrotaxanes, crosslinked with polyethylene oxide,with electrically conductive layers (gold, silver, copper,
IrOx, or TiN) and passive insulating layers (PDMS, selfhealing styrene-ethylene/butylene-styrene given as
examples). The conductive layers can be formed on thethin film in its dry, rigid state, then the film transforms
to a soft, stretchable state after implantation.

Challenges and perspectives

As discussed in this report, the field ofbioelectronics has seen a surge in scientific papers
introducing advanced materials and devices,
particularly in the last five years. The focus ofmuch of this work has been combining highly
engineered materials into hybrid and composite
devices, mainly to impart these devices with theunique properties needed for bioelectronics
applications. These properties, such as softness,
electrical conductivity, biodegradability, andpiezoelectricity, are highly diverse and not foundtogether in conventional materials used in otherapplications.
While this approach has resulted in remarkableadvances in this area, it has also introduced
several new challenges.1-3, 5, 52, 105 Based on a surveyof recent bioelectronics literature, the mostsignificant current challenges in this field are:
– Biocompatibility / toxicity / immune
response of materials used in bioelectronics
materials, including nano-scale materials
and composites whose properties vary withsynthesis and other processing conditions.
Device materials interacting with skin cancause skin contamination, irritation, andinfection. When a bioelectronic device
is implanted inside the body, a foreign
body reaction can be activated by the
immune system, which might lead to theformation of a fibrotic capsule covering theimplanted device. This can isolate it from thesurrounding tissues, causing it to become
inactive.106– Long-term chemical and physical stability ofmaterials in the dynamic environment of thebody, including adhesion to and compliancewith biological tissue, is also a challenge.1– Difficulties with converting electron to ion
current at the interface between electrodes
and biological tissue while avoiding
irreversible chemical reactions.12, 107– Matching the physical characteristics ofexisting electronic device materials, which
are generally planar and rigid, having
elastic modulus approximately >1GPa, withcurvilinear, soft, low elastic modulus <100kPa tissues.108 This mechanical mismatch
between the skin and device can cause
injury.109– The performance of the implanted device
can degrade owing due to physicaldeterioration, such as mechanical damage
to the electrode components or probe.110, 111– Poor adhesion and abrupt mechanicalstresses can also result in cracking anddelamination of devices. The most common
outcome in these cases is the damage tothe insulating layer, leading to the exposureof metallic interconnections. Thus, parasitic
current pathways can be set up between thetissue and any electronic processing system,
resulting in unintended cross-talks.112

Trailblazing
thethefuturewithemerging
biomaterials| 161
Trailblazing
futurewithemerging
biomaterials| 161

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DOI: 10.1088/1741-2560/12/1/011001.

IX. Sustainable materials for biomedical applications
Introduction

Sustainability is defined by the United Nations
Brundtland Commission as “meeting the needsof the present without compromising the abilityof future generations to meet their own needs”.1
Sustainability is a multi-faceted topic, withenvironmental, economic, and social aspects.
In materials science, the environmental andeconomic aspects are most relevant, and include
pollution prevention, use of renewable resources,
cost saving, and energy efficiency.2
Increasing the use of sustainable materials
in biomedical applications can significantly
contribute to enhancing the sustainability ofthe overall global economy. 3, 4 In the context ofbiomedical applications, sustainability involves
using materials that have one or more of thefollowing characteristics:– Biodegradable or compostable-theydegrade in natural conditions without
human intervention– Made from bio-based, naturally abundant,or renewable raw material sources– More environmentally benign than thematerials they replace
Bio-based substances are either obtained directlyor are derived from biological systems such as
plants or agricultural waste. Bio-based polymers
are considered sustainable since they can beobtained from renewable bio-resources, though
not all bio-based polymers are biodegradable.
Examples of sustainable materials used inbiomedical applications include various types of
personal protective equipment (PPE),5, 6 medical
packaging,7-9 textiles,10, 11 and other single-use,
disposable lab or clinic supplies used in health andlife science settings.12
In general, the desired properties of thesematerials include biocompatibility, non-toxicity,mechanical and thermal stability, processability, as
well as other application-specific functionality.13, 14
A major theme in this area is adapting, modifying,or combining intrinsically sustainable materials(such as biodegradable polymers and naturallyderived materials) with other substances to givethem these required properties.

In recent years, sustainability has become more
important due to the limited availability of fossil
fuels from which some synthetic polymers are
made, and growing concern about the impact of
non-biodegradable waste on the environment.12
One recent example is the environmental impact
of PPE made from non-biodegradable plastics
during the COVID-19 pandemic,15-18 whichhighlighted the importance of biodegradable
plastics in health care and motivated research inthis area.19, 20 The use of sustainable materials forface masks has been widely studied due to theirubiquity during the COVID-19 pandemic andbecause sustainable nanoscale fibers are available
and can substitute for the traditional materials in
face mask filters. 5
Single-use biomedical packaging materials
have stringent requirements, such as durability,
strength, resistance to various environments,and low weight. To meet these requirements,
conventional packaging is made from fossil fuelbased polymers that are not easily biodegradable.
Overall, packaging accounts for nearly 40%
of all plastics produced.21 For these reasons,research attention has been directed towards
developing sustainable packaging for biomedical
applications.7
In this chapter, we describe the publishing trends,
most prominent and emerging materials, andapplications of sustainable materials in biomedical
settings. Polymers represent the majority ofthese materials, and include natural polymers,22,23
and synthetic polymers which can be further
categorized as bio-based, biodegradable, orboth, with polylactic acid as a key example.24, 25
In addition to developing new materials to meetrequired specifications, there are other significant
challenges involved in the growth of this area.
These include matching existing materials withappropriate applications (often displacing existing,less expensive non-sustainable materials), supply
chain establishment, and obtaining regulatory
approvals. To illustrate how these challenges canbe overcome, we will also provide examples ofsustainable biomedical materials that have beencommercialized for a range of applications.

Trailblazing the future with emerging biomaterials | 169

Journal and patent publication trends

The time trend of journal and patent publicationsin the area of sustainable materials is shown in
Figure 1. Journal publication frequency has showna steady increase from 2003, with a particularlyhigh growth after 2017. Patent publication
activity has also generally increased since 2003,
but not as steadily or quickly. However, a rise inpatent activity from 2019 to 2021 was observed.
Comparing these trends with the journal andpatent publication trends in the other chapters,
the overall number of journal and patentpublications is lower, but growing quickly since
2015.
Figure 2 shows the top 10 institutions in termsof publication count in the area of sustainable
materials, ranked by the average number ofcitations per publication. Based on this analysis,
there is significant research interest in this area

Number of publications

350

Journalin China. Among the institutions with the mostpublications, Sichuan University has the highest
average citations, and the Chinese Academyof Sciences has the highest number of total
publications.
Figure 3 shows a geographical distributionof patent publication assignees. China has
the highest share of patent publications fromcommercial entities, followed by almost equalshare from the United States and Japan. For noncommercial assignees, China has roughly 49%,
followed by the United States, Korea, and Japan.
Figure 4 shows the patent publication frequency
time for the 5 countries which have generated themost patent publications overall. Besides China,patent activity has been relatively flat, indicatingthat organizations in China are largely driving
patent activity in this area.

Patent

300

*

250
200
150
100
50

20

03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
20
15
20
16
20
17
20
18
20
19
20
20
20
21
20
22
20
23

0
Publication year
Figure 1. Number of journal and patent publications per year in the sustainable biomedical materials field from 2003 to 2023
(journals: blue bars, patents: yellow bars). * The data for 2023 only include months from Jan to Aug.

Average number of citations per publication

Organization
Sichuan University
Donghua University
Wuhan University
Beijing University of Chemical Technology
South China University of Technology
Nanjing Forestry University
Chinese Academy of Sciences
Universiti Sains Malaysia
Zhejiang University
Institute of Chemical Technology

Citations per publications
Number of journal publications (CHN)
Number of journal publications (MYS)
Number of journal publications (IND)

Number of journal publications
Figure 2. The top 10 research institutions in terms of average citations per publication (yellow line). Total publications from 20032023 shown as bars; colors of the bars indicating country/region location.

Others10%

CHN 37%

Top 10 commercial
patent assignees

CHE (1%)
FIN (1%)
FRA (2%)
ITA (2%)GBR
7%
4% DEU
6% KOR

2003-2023

Others20%2% ITATop 10 non-commercial 2% CHE
2% IND49%
CHN
patent assignees
2% FRA
2% DEU2%

2003-2023

5%

17%

JPN

18%

USA

8%

USA

5%

RUS

JPN

KOR

Figure 3. Geographical distribution of 2003-2023 patent publication assignees for commercial (left) and non-commercial (right)
entities.

Trailblazing the future with emerging biomaterials | 171

90

Number of patent publications

80
70

CHN

60
50
40
30
20
USA
KOR
JPN
DEU

10

10
20
11
20
12
20
13
20
14
20
15
20
16
20
17
20
18
20
19
20
20
20
21
20
22

20

09

20

08

07

20

06

20

20

05

04

20

20

20

03

0

Publication year
Figure 4. Number of patent family publications per year between 2003-2022 for the top five most prolific countries/ regions.

Key material substances, forms, andapplications

The substances that appear most frequently
in sustainable materials-related publications
are shown in Figure 5, grouped as polymers(natural and synthetic), inorganic and organic
small molecules, salts, elements (metals andnonmetals), alloys, minerals, and coordination
compounds.
Natural polymers, primarily cellulose, starch,and chitosan, appear prominently in this data
set. Cellulose, a highly abundant and renewablebiopolymer, is present in plant and algae cell walls,
as well as in bacterial biofilms. Cellulose has been
identified in several of the preceding chapters
as being used in various types of emerging
biomaterial applications.
In addition to those applications, cellulose has also
been studied as a replacement for nonrenewable
synthetic polymers such as polypropylene for
medical supplies.26 These medical applications canalso benefit from the inclusion of antimicrobial
components, such as embedded copper27
or silver28 nanoparticles, naturally derived
antimicrobials (for example, Murraya koenigii
extract29) or covalently grafted antimicrobial
polymers and drugs. 30 It is important to note
that, for many of these applications, chemical
modification of cellulose to further enhanceor otherwise modify its properties is required.
To this end, a wide array of possible chemical
modifications have been developed, with newenvironmentally benign, non-toxic or “green”
techniques being an active area of research. 31
A strong trend identified in the data set is theuse of cellulose nanomaterials7, 32, 33 (cellulose
nanofibers, cellulose nanocrystals, and bacterial
nanocellulose) and fibrillated cellulose34 inbiomedical applications and packaging. Theseemerging materials have multiple, abundantsources, including biomass and cellulosecontaining waste,35, 36 and are significantly lower
cost options compared to alternatives such ascarbon nanotubes, petroleum-based materials,
ceramics, and others.
For this reason, cellulose nanomaterials havewidely been used as fillers to improve the barrier

and mechanical properties of other polymers, 37, 38
including poly(lactic acid) and polycaprolactone,
which are also frequently used sustainable
materials. Notably, cellulose nanocrystals havebeen demonstrated to reduce the oxygen andwater permeability of poly(lactic acid) composites,
which is important in their use as packaging
materials. 39 The macroscopic properties of thesecomposites are strongly dependent on coupling
between the cellulose nanomaterials and thematrix, which can be controlled by chemicallymodifying the cellulose surface.40 Conversely,
materials such as lignin,41 PEG,29 and graphene42
have been incorporated into cellulose-basedmaterials to further enhance their mechanical andbarrier properties.
Starch, a plant-derived polysaccharide, is alsoa fully biodegradable, nontoxic, and low-costresource for sustainable biomedical materials.43, 44
Limitations of starch-based films related tomoisture sensitivity and mechanical properties canbe addressed through the inclusion of fillers suchas zinc oxide,45 copper oxide,46 montmorillonite,47
and silver nanoparticle-immobilized cellulose
nanofibrils.48 As with cellulose, antibacterial
additives such as silver49 or chemically graftedbiocides49 can also be incorporated into
starch. Chitosan is another abundant naturalpolysaccharide that has generated significant
interest in the field of sustainable biomedical
materials because of its high biodegradability
and biocompatibility.50, 51 For example, chitosan
has been chemically modified and combined withother naturally derived materials to make strong,
self-healing materials with antibiotic effects. 52
Poly(lactic acid) (PLA) is the most frequently usedpolymer in this field, because it can be synthesizedfrom a variety of naturally abundant sources, andis both biocompatible and biodegradable.24, 53
However, along with these major advantages,
PLA has a number of weaknesses related to its
processability and material properties.
These weaknesses can largely be addressed
through physical blending with other polymers or
naturally derived substances (such as cardanol),54
chemical modification, nanomaterial fillers(including silica55 and graphene56), and even
CO2 treatments. 57 Alternate synthesis methods
Trailblazing the future with emerging biomaterials | 173

for PLA, for example in situ self-nucleating
polymerization,58 can also provide routes toimproving manufacturability and physicalproperties. A subset of these additives has beenstudied for their ability to confer antimicrobial
properties to PLA.59
Similarly, polycaprolactone (PCL) is also acommonly used biodegradable polymer thatis frequently referenced in publications onsustainable biomedical materials. In addition tobiocompatibility, PCL-based materials have also
been engineered to have shape-memory (asPCL-polyurethane-chitosan composite60) andphotocurable properties (as polycaprolactone
diacrylate61), enabling them to be formed using
stereolithography and 3D printing via digital lightprocessing.
Other notable materials that appear in Figure 5
are graphene,62, 63 silica,64, 65 zinc oxide (ZnO),66, 67
and silver,68 which are used as fillers to improvefunctional properties and, in the case of ZnO andsilver, to confer antibacterial properties. Thesematerials are often used in the biodegradable
polymers discussed here.
In Figure 6, we have identified several emerging
materials, the use of which has increased
significantly since 2018. These include materials
that have been discussed above, including
graphene, ZnO, starch, and cellulose. A notable
additional material is the biodegradable polyester,
adipic acid-1,4-butanediol-terephthalic acidcopolymer (also known as polybutylene adipate
terephthalate or PBAT). Examples of its use include
blending PBAT with PLA and reinforcing fillers
to make medical equipment,69 combining PBAT
nanofibrils with PLA to improve barrier properties
for medical packaging,70 and melt-blending
PBAT with used coffee grounds containing
lignocellulosic material as a reinforcement in abiodegradable composite.71
From this document data set, the prevalent
biomedical applications of sustainable materials
can be broken into three major areas:– Disposable medical clinic and laboratory
supplies, such as face masks, gloves, surgicalgowns, bandages, and labware– Packaging used in medical settings– Materials used for a variety of medical
purposes, manufactured using alternative
or novel methods which are environmentallybenign compared to traditional methods
In the first category, there are several examplesof new materials and methods for making
personal protective equipment, particularly facemasks, motivated by the increase in the use of
these masks during the COVID-19 pandemic.15,72
Materials for these applications include PLA,73,
74
poly(butylene succinate),75 cellulose,26
and chitosan.76 For mask filter applications,electrospinning is a prominent technique forforming nanoscale fibers from these materials,5, 77, 78
which can be used to make fine particle filters. In
some cases, these biodegradable, electrospun
fiber-based filters have comparable or better
particle removal characteristics compared to
traditional N95 masks, which are typically madeusing melt-blown polypropylene fibers. The
performance of these materials can be further
enhanced by embedding antimicrobials,79 or
through the incorporation of polar functionality inthe filter, for example by adding chitosan.74
Beyond personal protective equipment,sustainable materials such as algae-derived starch,
PLA, and lignin have been used to make medical
packaging materials44, 70, 80 and single-use medical
diagnostic equipment.81, 82
Examples of the third category include
environmentally benign or “green” methods
to synthesize materials used in biomedical
applications, including gold,83 silver, platinum,84
and ZnO85-87 nanoparticles, MXenes,88 andpolyesters (through the use of lipase catalysts).89

Trailblazing the future with emerging biomaterials | 175

Synthetic

NaturalPolymer

Nonmetals

Elements

MetalsMinerals*

Inorganic

Organic

Coordination
compounds

AlloysOrganic andinorganic molecule

Salts

Figure 5. Bubble chart showing distribution of substances used in sustainable biomedical materials in terms of number of publications (journals and patents) from 2003-2023.

*
*
**
*

**

Alloys6

Adipic acid-1,4-butanediol-terephthalic acid copolymer
Graphene
Poly(butylene succinate)
Butanedioic acid, polymer with 1,4-butanediol
Zinc oxide
StarchCellulose

Normalized frequency

5
4
3
2
1

22
20

21
20

20
20

19
20

18
20

17
20

16
20

15
20

14
20

20

13

0
Publication year
Figure 6. Normalized frequency of representative emerging sustainable biomedical materials in journal and patent publications
from 2013-2022.

Notable journal articles and patents

Table 1 is a set of research articles published from2020-2023 that represents emerging trends in thefield of sustainable biomedical materials. These
references provide examples of the materials
and applications which appear prominently
in our analysis of the literature in this area aspresented in Section III. Selection criteria for theseexamples also included high citation count, and/or
publication in high impact factor journals.
A notable example from Table 1 is a single-use
face mask reported by Choi et al.,75 which contains
a poly(butylene succinate)-based filter material
coated with chitosan nanomaterials that leverages
the polar groups present on the chitosan surface.
This nanofiber/microfiber integrated filter provides
a high particulate matter removal efficiency(98% of 2.5 µm PM, similar to an N95 filter) witha low pressure differential across the filter, which
is important for breathing comfort. This filter
material further retains its performance after
exposure to moisture. Biodegradability of thematerial was also demonstrated, with complete
decomposition within four weeks after the mask is
disposed in a composting soil.
Novel biomedical materials have also been
designed specifically to be recyclable. A notable
example of this is an electronic skin (an importantmaterial in human-computer interfaces90, 91)
developed by Li et al.92. This material, whichis composed of cellulose nanofibrils (CNFs),
poly(vinyl alcohol), and EGaIn liquid metal
droplets, can be recycled by simply cutting it
into small pieces, dissolving it in water, thenre-casting it. Notably, this e-skin also addresses
limited stretchability,93 a common issue with theuse of liquid metals in electronic skin, by forming
the material into a Kirigami structure. Throughdifferent cutting methods, these structures
can perform various stretching types while
maintaining consistent electrical properties.
Gold nanoparticles (AuNPs) are used for drugdelivery,94 biosensing,95 catalysis,96 and otherapplications. Sustainable synthesis of AuNPs
has become an active area of research,97 withbiosynthesis approaches being one importantclass. As an example, Subbulakshmi et al98 utilizeda type of marine red seaweed, Gelidiella acerosa,
to produce AuNPs that showed antibacterial

properties against gram positive bacteria,
photocatalytic degradation of commercial dyes.
Notable patents and patent applications onsustainable biomedical materials published from2018-2023 are listed in Table 2. Some of these
involve matching existing sustainable materials,
such as poly(lactic acid), polycaprolactone, andcellulose, with biomedical applications where nonsustainable materials are currently used. Examples
include US20200189230A1 (multilayer abrasive
medical wipe made using cellulose, poly(lacticacid), or other biodegradable materials),
AU2021106722A4 (biodegradable medical
gloves made from polycaprolactone, starch,and glycerol), and WO2022026784A1 (recyclable
absorbent packaging containing cellulose).
The list also contains examples of modifying
sustainable materials to give them additionalfeatures (such as antimicrobial, anti-wetting, or
specific mechanical properties), allowing them tomeet the requirements of an existing commercial
application. These include CN114349940A, which
discloses a method for copolymerizing PLA andPCL to make biodegradable protective gloves. The
use of PCL softens and lowers the melting point of
the PCL, both important for the application, andeliminates the need for phthalate plasticizers.
A second example is WO2023089562A1, which
discloses a method to deposit bio-basedsaccharide fatty acid esters onto cellulosebased materials to make them hydrophobic andlipophobic. This approach can replace the use offluorocarbons, silicone, and petroleum-derived
materials as surface treatments.
A notable application discussed in previous
sections was the use of sustainable materials
treated with antimicrobial materials for facemasks. As an example, CN115704183A describes
forming a face mask filter using melt-blown PLA
fibers, then treating the filter with a suspension ofcarbon nitride and nanoscale TiO2 particles, which
can inhibit bacteria and virus activity throughphotocatalytic effects.
Table 3 contains a list of products that incorporate
sustainable materials, and the companies thatmake each product, with references to productliterature. The products in the table can be
Trailblazing the future with emerging biomaterials | 177grouped into PPE (including gloves and facemasks), pharmaceutical packaging, general
medical packaging, and other applications.
The materials represented in the table include
poly(lactic acid),48, 99 cellulose,50, 100-102 as well asother plastics derived from natural sources suchas sugarcane103 and castor oil,104 and sustainable
materials with antimicrobial coatings.101
In many cases, the sustainable materials in
Table 3 are meant to replace non-sustainable
materials that are used currently. These
include plant material-derived face masks,105
biodegradable examination gloves,106 andpharmaceutical packaging that can be recycled

or composted.100, 107 An illustrative example is areusable pharmaceutical container combinedwith a compostable refill pouch.108 Beyond
these examples, medical packaging and devices
have been designed to reduce the amount ofwaste they generate, through product design or
recycling programs.109, 110
A final important aspect to the examples in Table 3is that they represent a range of company sizes,
from large, established chemical and medical
supply companies to smaller startup operations.
For startups, the amount of investment raised todate, where available, has been included in the“company” column of Table 3.

Table 1. Notable journal articles on sustainable biomedical materials in recent years.

Research
Institute

Year

Title

JournalApplication

2020

Polylactic acid based biocomposite
films reinforced with silanizednanocrystalline cellulose111

International
Journal of
Biological
Macromolecules

Zhejiang Sci-Tech
University

Addition of nanocrystalline cellulose (NCC) to PLA
to improve its barrier, thermal, and mechanicalproperties. Modification of the NCC with
3-aminopropyltriethoxysilane significantly improved
the thermal stability of the composite material.

2020

Sonication amplitude andprocessing time influence thecellulose nanocrystals morphology
and dispersion112

Nanocomposites

Western New
England
University

Cellulose nanocrystals were dispersed in a PVA-water
matrix using sonication. The effect of sonication timeand amplitude on the shape, size, and crystallinity of
the cellulose was characterized.

2020

Antibacterial Al-doped ZnO
coatings on PLA films113

Journal of
Materials
Science

Italian National
Agency for New
Technologies

Al-doped ZnO / PLA film composites for foodpackaging and biomedical applications. The purposeof the Al-doped ZnO is to provide antibacterial andUV-blocking properties while maintaining hightransparency in the visible range.

2020

A sustainable synthetic route forbiobased 6-hydroxyhexanoic acid,adipic acid, and ε-caprolactone
by integrating bio- and chemical
catalysis114

Green Chemistry

Lund University

Sustainable, bio-based process to synthesize
ε-caprolactone, a precursor for polycaprolactone by
first oxidizing 1,6 hexanediol to 6-hydroxyhexanoic
acid using the bacteria Gluconobacter oxydans,followed by conversion of 6-hydroxyhexanoic acid toε-caprolactone using zeolites and acidic ion exchange
resin as catalysts

2021

Biodegradable, Efficient, andBreathable Multi-Use Face Mask
Filter75

Advanced
Science

Korea ResearchInstitute ofChemicalTechnology

Biodegradable, moisture-resistant, highly breathable,
and high-performance fibrous mask filters withbiodegradable fibers coated with cationic chitosan.

2021

Needleless electrospun
phytochemicals encapsulated
nanofibre based 3-ply
biodegradable mask for combating
COVID-19 pandemic79

ChemicalEngineering
JournalIndia Ministry of
Defence

Design of a three-layered face-mask by using
biodegradable poly(lactic acid) and cotton withencapsulated phytochemicals in the inner-filtration
layer.

2021

Lead-free nanocomposite
piezoelectric nanogenerator
film for biomechanical energy
harvesting115

Nano Energy

Cadi Ayyad
University

Self-poled, lead-free, biocompatible, and bio-flexible
piezoelec. nanogenerator (BF-PNG), Ba0.85Ca0.15Zr0.10Ti0.90O3
nanoparticles, are functionalized with polydopamine andembedded in biodegradable poly(lactic acid).

2022

System-level integrative analyses
for production of lignin hydrogels116

Green
Chemistry

Kyung Hee
University

Two strategies for the synthesis of a biomedical ligninhydrogel. While choosing the raw materials, native vs.
methacrylated, these strategies consider the overall
technoeconomic analysis and life-cycle assessment of
the process.

2022

A Self-Supporting, ConductorExposing, Stretchable, Ultrathin,
and Recyclable KirigamiStructured Liquid Metal Paper for
Multifunctional E-Skin92, 116

ACS Nano

Zhengzhou
University

The traditional liquid metal electrodes has low
performance of electrophysiological monitoring due tolimited direct skin contact. This study reported a kindof LM electrode which is self-supporting, conductorexposing, stretchable, ultrathin, and recyclable formultifunctional E-skin.

2023

Tough, anti-drying andthermoplastic hydrogels consistingof biofriendly resources for a wide
linear range and fast response
strain sensor117

Journal of
Materials
Chemistry A

Wuyi University

To overcome the challenges of nonlinearity andlong response time in wearable devices, this study
presented a wide linear range and fast response
strain sensor based on ionic conductive hydrogels,composed of biodegradable PVA, chitosan, andbiogenic phytic acid.

2023

Biogenic gold nanoparticles fromGelidiella acerosa: bactericidal andphotocatalytic degradation of twocommercial dyes 98

AppliedNanoscience

Alagappa
University

Investigation of marine red seaweed generated gold
nanoparticles (AuNPs), which showed activity against
bacteria Staphylococcus aureus and can be degradedupon exposure to sunlight.
Trailblazing the future with emerging biomaterials | 179

Table 2. Notable patent publications on sustainable biomedical materials in recent years.

Patent or Pub.
numberPub.
year

CN107629424A118

Patent assignee

Title

Description

2018

Toray Advanced
Materials ResearchLaboratories China
Co LtdMicroporous polylactic
acid membrane

Biodegradable poly(lactic acid) film that has 1-3000
nm pores on its interior, and on one surface, but
not the other surface, for use in packaging andbiomedical applications

US20200189230A1119

2020

North Carolina State
University

Composite sheet
comprisingbiodegradable orcompostable materials
and uses thereof

Biodegradable, multi-layer sheet where the outerabrasive layer is made by melt-blowing polymer
fibers, for use as a medical wipe

CN112521663A120

2021

Hubei Guanghe Biotech Co., Ltd.

Fully degradable medical
packaging bag andpreparation method
thereofMelt-blended biodegradable material
for medical packaging containing silanemodified polyhydroxybutyrate/alginate, starch,polycaprolactone, poly(lactic acid), TiO2, and otheradditives.

AU2021106722A4121

2021

Mohanty et al.

Biodegradable
disposable gloves

Biodegradable polycaprolactone gloves with apatterned ergonomic design

CN113512185A122

2021

Jiangnan University

Preparation ofthermoplastic
biodegradable glove
material with excellent
tensile recovery
performance andmechanical properties

Gloves made by melt blending two biodegradable
polyesters, followed by a transesterification reaction

CN114349940A123

2022

Shandong
Hengchang Medical
Technology Co., Ltd.,

Preparation method ofpolylactic acid-based
self-plasticized fully
biodegradable gloves

Method for reducing the rigidity of poly(lacticacid) by copolymerizing it with ε-caprolactone foruse in gloves, eliminating the need for phthalate
plasticizers

WO2022026784A1124

2022

The Procter &Gamble Company

Absorbent article package
material with natural
fibersAn absorbent material that contains natural fibers:
cellulose-based fibers, bamboo based fibers, cotton,
for packaging purposes

KR2436259B1125

2022

Ecoclean Platform
Corp

Hazardous substanceadsorption member
comprisingbiodegradable polymer
to which natural productderived composition isappliedAbsorbent material made using melt-blown
poly(lactic acid) fibers, porous silica, and naturally
derived antibacterial and antiviral substances,that can be used for gauze, bedding, and otherbiomedical applications

WO2023089562A1126

2023

Greentech Global
Pte. Ltd

Water-insoluble, highmelting point saccharide
fatty acid esters (SFAE)

Method for treating cellulose based materials withrenewably sourced coating compositions to makethem hydrophobic and lipophobic

ZA2022011225A127

2023

Anhui Polytechnic
University

Chitosan-starchcomposite film,
preparation method andapplication thereof

Method for synthesizing a chitosan-starchcomposite film, where the amino groups of chitosan
are first protonated using acetic acid before
combining it with starch; the film can be used for
medical packaging

CN115594962A128

2023

Shandong Intech
Medical Technology
Co., Ltd.

Biodegradable surgicalgown and preparation
thereof

Biodegradable, low cost surgical gown material
made by melt blending polyhydroxyalkanoate,poly(lactic acid), and other additives

CN115704183A129

2023

Dahe Technology
Development(Nanjing) Co., Ltd.

Biodegradable polylactic
acid antibacterial meltblown cloth for mask

Poly(lactic acid) based face mask that contains
photocatalytically antibacterial TiO2 particles

Table 3. Examples of commercial sustainable materials for biomedical applications.

Application

Personal
protective
equipment(PPE)

Pharmaceuticalpackaging

Generalmedicalpackaging

Other / generalapplications

Company

Product summary

Reference

Location

Ahlstrom

100% bio-based, biodegradable face mask made from PLA
fibers (outer layers) and cellulose-based fibers (filter)a,b

130, 131

FinlandG95

100% plant-based KN95 face maska,b

105

USA

Inovenso

Electrospun fiber materials for face mask filters made frompolycaprolactone, PVA, and collagenb

132

USA

Kingfa Science andTechnology

Biodegradable PLA and nitrile gloves, surgical masks, and other
PPEa,b133

China

Platinum Health

Biodegradable nitrile examination glovesb

106

USA

Amcor

Recyclable pharmaceutical blister packagingb

107

Switzerland

AstellasBiomass-derived plastic for pharmaceutical blister packaging(claimed to be the world’s first)a

103

Japan

Cabinet HealthCompostable pharmaceutical packaging made of cellulose andother bio-sourced materialsa,b

134

USA

Grounded

Compostable, recyclable pharmaceutical packaginga,b108Australia

Körber

Paper and cardboard-based pharmaceutical packaging andrapid testsa,b100

Germany

Billerud

Medical packaging paper, recyclable and sourced throughsustainable forestrya

102, 135

SwedenBiorigin

Medical paper products with antimicrobial and hydrophobic
coatings, made using recycled/compostable materialsa,b

101

USA

CoverisSustainable and recyclable medical packagingb

136

Austria

MedlineCompostable poly(lactic acid) patient belonging bagb
Endoscope transport tray made from recycled sugar pulpa

99, 137, 138

USA

Qingdao Fullsun
Biotechnology

Biodegradable corn starch / poly(lactic acid) blend biohazard
medical waste bagsa,b

139

China

ArkemaRilsan® MED, a polyamide produced from castor oil is used inhealthcare applicationsa

104, 140

FranceEastmanEastar Renew 6763, a recyclable polyester-based material used
for rigid medical packaginga

141, 142

USA

Henan Lantian
Medical Supplies Co.

Poly(lactic acid) and cellulose-based biodegradable medical
textilesa,b143-145

China

Mediclo

Medical apparel made using plant-based or recycled polyester
fibersa146

USA

NewGen Surgical

Sugarcane bagasse-based surgical suppliesa,b

147

USA

a. Made using sustainably sourced or bio-based materials; b. Engineered to be recyclable, biodegradable in the environment or
landfills. Raised amounts are from Pitchbook (my.pitchbook.com, accessed Nov. 20, 2023.

Trailblazing the future with emerging biomaterials | 181

Challenges and perspectives

Challenges to wider adoption of sustainable
materials for biomedical applications include
their sensitivity towards common sterilization
methods,148 high cost of synthesis and fabricationcompared to the conventional,5, 149 faster
degradation in performance of the materials,
hydrophilicity, difficulty with processing,5, 150 andenvironmental sensitivity (PLA, for example, isprone to degradation under certain enzymaticconditions).5 Fabrication of sustainable materials
can be complicated,5 in part due to complex
extraction process from the natural sources, which
in turn increases the cost. Addressing these issues
is an active area of research. For example, thesensitivity of polylactic acid towards sterilization
methods can be overcome by using additives suchas zinc oxide.148
PLA is widely used in sustainable packaging
applications across several industries. While PLA isbiodegradable and made from abundant natural
sources, environmental analysis of processes used
to make it must also take into account energy
input requirements, as was recently done for aprocess used to make PLA using wheat straw as
a feedstock.151 If these processes are significantly
more energy-intensive compared to processes
used to make alternative, non-sustainable
materials, then the overall environmental effectmay not be positive.
As discussed in previous sections, PLA has
drawbacks such as brittleness, degradation under
specific conditions, high gas permeability and low
thermal resistance.152, 153 Composites of polylactic
acid with other biodegradable polymers, nonbiodegradable polymers and oxides are understudy to overcome these drawbacks.152, 154 Copolymerizing PLA with other sustainable polymers
is also reported to overcome the drawbacks of
PLA.155
Polyhydroxyalkanoates (PHA) are another groupof biodegradable polymers which are challenging
to synthesize due to high cost, difficulty incustomizing properties, and complexity associatedwith its synthesis from the bacteria.149, 156 To
avoid this, alternate methods for the synthesis
of PHA are under development.157, 158 PHA lacks
intrinsic antibacterial activity, impact resistance,

and thermal stability, which can be overcome byforming composites with graphene.159 Anotherstrategy to improve the properties of PHA is theuse of multi-PHA blends.160
One of the problems associated with cellulose
nanocrystal based materials is their hydrophilic
surface properties, and difficulty with theirdispersion when using them in polymer matrix
composites. 37 To decrease the hydrophilicity ofcellulose nanocrystals, surface modifications withhydrophobic functional groups and coatings areunder development.161
Succinate polyesters are a group of bio-based
synthetic biodegradable polymers which facechallenges due to the use of metallic catalysts
during their synthesis,162 making them difficult
to use for biomedical applications.163 In addition,
the high temperature used in this method also
leads to large variations in chain lengths. To
overcome these issues, biotechnological synthesis
routes like enzymatic catalysis methods are underdevelopment.164, 165
In terms of manufacturing methods, as discussed
earlier in this chapter, electrospinning can be used
to make biodegradable nanofibers and othermaterials from sustainable materials. However,many electrospinning processes use a significant
amount of solvents which are not environmentallyfriendly.5 Greener alternatives to electrospinning
are under development which will help in
reducing the impact of such methods.166, 167
PPE and packaging are applications with highinterest for sustainable materials development.
However, practical challenges related to material
properties remain. For example, cellulose-based
face masks have difficulty matching the filtration
efficiency and breathability of conventional nonbiodegradable face masks.6 In addition, large
scale production of cellulose based masks remainsa challenge.6 It is desirable to achieve a balance
between the desired mechanical properties andthe biodegradability.168 Various organizations
are working on the development of cellulose
based materials for sustainable applications, withproduction expected to grow once manufacturing
processes become more affordable.13

For sustainable packaging materials, obstacles
to more widespread use include high cost, poor
barrier and mechanical properties.169 To overcome
these challenges, composites of multiple
sustainable materials are under development
for packaging applications.170, 171 Furthermore,higher level design strategies can help in
addressing some of the inherent drawbacks of thematerials.172, 173

Often, sustainable materials must also displace
incumbent non-sustainable options for agiven application. Sustainable materials facedifficulties in replacing current materials; thecosts of sustainable materials are in many cases
higher than those of current materials, resilient
supply chains need to be established for them,and for some uses regulatory approval for the
replacements must be obtained which requires
additional testing and resources.

Trailblazing
thethefuturewithemerging
biomaterials| 183
Trailblazing
futurewithemerging
biomaterials| 183

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X. Conclusions
In this section, we will first summarize therecent journal and patent publication trends
observed across the eight topic areas, thendiscuss prominent themes in the applications
and challenges found throughout this report,
and finally identify the major material types thatare currently being researched to address thesecomplex applications and challenges.
By examining journal publication trends, we canroughly classify the eight topic areas as either having
rapid and exponential growth from 2013-2023, oras having research activity even before that time
which has steadily increased until now. The former
category, which includes bioinks and self-healingmaterials, has seen a roughly tenfold increasein publication frequency in the last 10 years. The
latter category, which includes the other six topics,
has increased in journal publication frequency by
between two- and fourfold since 2013, indicating
continued strong interest in these topics.
Most of the topic areas have seen a correlating
increase in the frequency of patent publications.
The exceptions to this are programmable,
protein-based, and to a lesser extent lipid-basedmaterials, where patent activity has been relatively
flat. While the data does not point to a specificcause for this, the trend indicates that university
research activity has increased more rapidly
compared to commercialization over the last 5-10
years. This may indicate that there are perhaps
fundamental materials challenges preventing
more widespread commercialization that still need
to be solved through scientific research.
For each of the eight topic areas, we identified alist of the 15 most influential research institutionsin terms of number of publications and theaverage number of times each publication wascited. In most cases, the leading institution by
these measures was different for each topic.
There were, however, several institutions whichappeared frequently across multiple topic
chapters, including the Chinese Academy of
Sciences, the University of California, Zhejiang
University, Tsinghua University, Sichuan University,
and Nanyang Technological University. The set ofcommercial entities with the largest number ofpatents tends to be quite different from chapter tochapter, indicating a high degree of specialization
within commercial research and development inthese fields.
The most prominent applications discussed in thisreport across all topic areas were drug delivery,
wound healing, tissue engineering, and sensors.
Drug delivery, in particular, was discussed in
the majority of the chapters, being a primary
application for lipid-based, programmable, selfhealing, and protein-based materials, and asecondary application for bioinks. The prominenceof drug delivery as a research area in this report
appears to reflect a larger, interdisciplinary effort
to improve the targeting of drugs, especiallyanticancer drugs, while minimizing side effects
due to nonspecific drug release.
The emergence of sensors as an application area
is also related to an interdisciplinary trend, in
this case to monitor and collect data from thehuman body and to use that data for diagnosis
and treatment. Within this report, the types ofmaterials that are used in sensor applications
are used for their high chemical specificity,mechanical resilience, or their ability to connect
key parts of the body with electronic devices (asdiscussed in the programmable, self-healing, andbioelectronic materials chapters).
While the materials described in this report
have the potential to significantly improve thediagnosis and treatment of disease through theseapplications, in many cases a significant amountof research and development work remains before
widespread clinical use is possible.
A major challenge across many of these emerging
areas is the need for more extensive in vivo andclinical testing to identify and resolve possible
issues with toxicity, immune response, andlong-term biocompatibility of materials thatare implanted or injected into the body. Thatchallenge is made more complex by the useof materials that are not traditionally foundin biomedical applications, and materials
whose structure and properties are affected byconditions used in their synthesis. Regulatory
agencies such as the FDA, CFDA, or EMA do
not traditionally issue approvals for individualbiomaterials. Instead, testing of full medical
devices or drugs made using these materials will
be done in coordination with these agencies.1
A second challenge identified in multiple chaptersis the need for materials that combine highly
controlled and specific functions with durability,
resilience, and predictable functioning in body.
Examples include flexible bioelectronic interface
materials, sensors, and implants that must movealong with dynamic organs such as the heart,and stimulus-responsive drug delivery materials
intended to respond to a specific chemical
stimulus in an environment with many overlapping
potential stimuli.
Challenges to more widespread uses of thematerials discussed in this report also exist
outside of the applications themselves. For
example, for some of the materials discussed
here, economically viable, high quality, high yield
manufacturing processes do not yet exist. This isparticularly true for composites made specificallyfor highly demanding applications that require
multiple, orthogonal properties (electricalconductivity and self-healing properties, forexample).
As shown by the data presented in this report,these potential applications and challenges
are currently being addressed through thedevelopment of a wide range of both novel
materials, and materials that are being inventively
repurposed for biomedical applications. Material
types that were referenced across several chapters
include:– Naturally-derived polymers, such as
chitosan, cellulose, hyaluronic acid, alginate,collagen, gelatin, and silk, which have theadvantages of biocompatibility and naturalabundance. There are also well-developedroutes to chemically modify these materials
to change their properties and add novel
functions such as self-healing or stimulus
response.
– Biocompatible and biodegradable synthetic
polymers, including polyethylene glycol,
poly(lactic acid), polyvinyl alcohol, andpolycaprolactone.

– Hydrogels, often made using the polymers
listed above. In addition to their similarity
to human tissue, this report contains many
examples of hydrogels that are engineered
to perform complex functions, includinghydrogel-based actuators, sensors, and drugdelivery systems.
– Nanoscale materials, including graphene,carbon nanotubes, and metal nanoparticles.
Stimulus response was also observed in multiple
topic areas, in the programmable material
chapter where this was a focus, as well as in thelipid-based, self-healing, and bioinks chapters.
The stimuli engineered into these materials wereboth endogenous (pH, enzyme, redox, and otherspecific chemical triggers) and exogenous (light,
temperature, magnetic field, ultrasound). In some
applications, multiple materials were combinedto generate a stimulus response, for example
combining a photothermally responsive material
with a temperature-responsive polymer. In the
majority of cases, the responses involved releaseof a drug or gene therapy material, or some othertherapeutic function.
Another strong trend was the combinationof multiple functional polymers, or polymers
with other materials (carbon nanomaterials,
hydroxyapatite, cells, and metal nanoparticles, forexample). This is typically done to precisely control
mechanical properties or to incorporate multiple
overlapping functions in a single material.
A less explored area, but one with immense
potential, is the use of artificial intelligence,computational modeling, and other computing
tools to aid in the development of biomaterials,
as an extension of how these tools are presently
being used for drug discovery.2 With theastonishing speed that AI is currently evolving, it
is not surprising that these tools are already being
used to understand and predict the dynamics
of self-healing polymers using image analysis
from healing experiments,3 to virtually screen
libraries of lipids for use in mRNA-delivery lipid
nanoparticles,4 to model the release of drugs
from programmable hydrogels in the presenceof multiple stimuli,5 and to identify peptides thathave the ability to form hydrogels by combining

Trailblazing the future with emerging biomaterials | 195

machine learning with selected experiments.6(Notably, in this final example, a tetrapeptidehydrogel developed using the machine learningmodel was demonstrated to improve the immune
response of a COVID-19 vaccine.) These examples
illustrate the potential for AI tools to speed up thedevelopment of new biomaterials by processing
and extracting information from large data sets,
and reducing experimental iterations.
The exploration of biomaterials across the various
chapters demonstrates both the advancements
and obstacles in this evolving field. Increasing
academic interest contrasts with a lag incommercial patent activity, pointing to hurdles
in translating research into practical applications.
These materials hold promise in drug delivery,
sensors, and other applications, with the potential
to refine and revolutionize areas of healthcare.
However, challenges persist in rigorous in vivo
testing and establishing feasible manufacturingmethods. The use of diverse material types,
coupled with engineered stimuli and AI tools,
represent multifaceted approaches to addressthese challenges, paving the way to reshape
healthcare practices through the use of newmaterials.

References(1) Safety of Metals and Other Materials Used in Medical Devices. https://www.fda.gov/medical-devices/
products-and-medical-procedures/safety-metals-and-other-materials-used-medical-devices(accessed 8 January 2024).
(2) Dara, S.; Dhamercherla, S.; Jadav, S. S.; Babu, C. H. M.; Ahsan, M. J. Machine Learning in Drug
Discovery: A Review. Artificial Intelligence Review 2022, 55 (3), 1947-1999. DOI: 10.1007/s10462-02110058-4.
(3) Anwar Ali, H. P.; Zhao, Z.; Tan, Y. J.; Yao, W.; Li, Q.; Tee, B. C. K. Dynamic Modeling of Intrinsic SelfHealing Polymers Using Deep Learning. ACS Applied Materials & Interfaces 2022, 14 (46), 52486-52498.
DOI: 10.1021/acsami.2c14543.
(4) Xu, Y.; Ma, S.; Cui, H.; Chen, J.; Xu, S.; Wang, K.; Varley, A.; Lu, R. X. Z.; Wang, B.; Li, B. AGILE Platform:
A Deep Learning-Powered Approach to Accelerate LNP Development for mRNA Delivery. bioRxiv 2023,
2023.2006.2001.543345. DOI: 10.1101/2023.06.01.543345.
(5) Boztepe, C.; Künkül, A.; Yüceer, M. Application of artificial intelligence in modeling of the doxorubicinrelease behavior of pH and temperature responsive poly(NIPAAm-co-AAc)-PEG IPN hydrogel.
Journal of Drug Delivery Science and Technology 2020, 57, 101603. DOI: https://doi.org/10.1016/j.
jddst.2020.101603.
(6) Xu, T.; Wang, J.; Zhao, S.; Chen, D.; Zhang, H.; Fang, Y.; Kong, N.; Zhou, Z.; Li, W.; Wang, H. Accelerating
the prediction and discovery of peptide hydrogels with human-in-the-loop. Nature Communications
2023, 14 (1), 3880. DOI: 10.1038/s41467-023-39648-2.

XI. Methods
For this report, eight topic areas were selectedthat represent the most active and promising
fields of research within biomaterials. The
selection of these topic areas was a multi-stage
process. First, a broad survey of the biomaterials
field was conducted using natural language
processing to identify concepts with a particularlyhigh rate of growth in journal and patentpublications between 2020-2022. This analysis was
combined with citation graph cohesiveness, which
is a measure of how many times publications
containing a particular concept have been cited byother publications, to generate a list of candidate
topics. Next, final topics were selected from thesecandidates for a Phase I1 and Phase II report (thisdocument) through collaboration between subject
matter experts at CAS and Westlake University.
The data used in this report is drawn from the
CAS Content Collection™, a repository of diverse
scientific knowledge containing over 59 million
records from chemistry, biomedical sciences,material sciences, and other topics, which has
been extensively curated by subject matter
experts (SMEs). The substances referenced ineach publication are indexed based on their CAS
registry numbers, as well as their functional rolein the document and substance classification.
More than 35 roles exist, with examples including
therapeutic use, pharmacological activity, andtechnical and engineered material use. Substanceclasses include organic/inorganic small molecules,
protein/peptide sequences, polymers, elements,
and alloys, among others. The key concepts ineach document were also manually indexed,similarly classified, and included in the data set.
For each of the eight topic areas, a search query
to identify the relevant document set from the
CAS Content Collection was developed, theniteratively adjusted by SMEs to minimize noisebased on manual quality checks. This resulted
in sets of between roughly 4,000 and 120,000
for each topic, published from 2003-2023.
The data extracted from these documents
was comprehensive, consisting of four types:
substance, concept (both as described above),document, and patent activity data. Document
data includes title, abstract, publication year,

the number of times cited (for journal articles),as well as information on the authors, research
institutions, and patent assignees.
Patent activity data includes detailed information
about patent families and individual patents
filed in 97 patent offices worldwide. From thisdata, leading assignees and time trends basedon patent families were identified. This data also
allowed for the determination of chronologicalflow of filing initial patent applications within
patent families through national patent offices,
the World Intellectual Property Organization(WIPO), and the European patent office (EPO),
leading eventually to individual patent publication
activities within national patent offices. In thiscontext, an activity is defined as an event that
leads to the publication of a patent document,
for example application publications, issuing ofpatents, and certain other events.
Data from the document sets was analyzed
by performing searches and filtration based
the title, abstract, claims, CAS indexed terms
and for CAS registry numbers in the substancedata unless otherwise specified. To ensure
accurate and complete analysis, the searchedkeywords included multiple synonyms as well as
abbreviations, while taking care to minimize thenumber of incorrectly identified documents. Data
analysis was performed using Tableau, and figures
were prepared using a combination of Tableau,
Microsoft Excel, and Adobe illustrator.
When defining the countries/regions andorganizations associated with a given document,
the affiliation of the first author or the patentassignee was taken as the affiliation of the
document. When multiple organizations wereaffiliated with a particular journal or patentpublication, only the first author or first patentassignee’s affiliated organization was considered.
The countries/regions of origin were designatedas the location associated with the first author’s orfirst patent assignee’s location.
Each chapter was reviewed by at least one
independent subject matter expert in the relevant
topic area, in order to confirm technical accuracy

Trailblazing the future with emerging biomaterials | 197

and completeness. Additional discussion andreferences were added to several of the chapters
based on guidance and feedback from theseexperts.
Overall, the methodology described above
encompasses a substantial volume of indexedscientific content, advanced data analytics skills,
and a diverse array of biomaterials subject matter

experts. The utilization of modern tools to analyze
millions of documents, seamlessly guided andinterpreted by subject matter experts, was madefeasible through the exceptional resources
dedicated to this project. Importantly, this project
also involved collaborative efforts between teams
at Westlake University and CAS, operating at
a detailed technical level, and leveraging thecomprehensive CAS Content Collection.

References(1) https://www.cas.org/resources/cas-insights/emerging-science/top-10-emerging-trends-biomaterials.

Westlake University

CAS, a division of the American Chemical SocietyAbout Westlake University
Established in 2018, Westlake University is a new type of research university,
a first in the history of modern China. We enjoy strong public support
and aim to be a reformer in our higher education system. Founded byprominent scientists and scholars, Westlake University is committed tobuilding a truly international, world leading, research-focused university.
Connect with us at westlake.edu.cn

About CASSYNTHETICCHEMISTRYRESEARCH
TRENDS REPORTCAS connects the world’s scientific knowledge to accelerate breakthroughs that
improve lives. We empower global innovators to efficiently navigate today’scomplex data landscape and make confident decisions in each phase of theinnovation journey. As a specialist in scientific knowledge management, ourteam builds the largest authoritative collection of human-curated scientific
data in the world and provides essential information solutions, services,and expertise. Scientists, patent professionals, and business leaders acrossindustries rely on CAS to help them uncover opportunities, mitigate risks, andunlock shared knowledge so they can get from inspiration to innovation faster.
CAS is a division of the American Chemical Society.
Connect with us at cas.org

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