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# Degradable Self-healable Networks for Use in Biomedical Applications

Mathilde Grosjean, Louis Gangolphe, Benjamin Nottelet

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Mathilde Grosjean, Louis Gangolphe, Benjamin Nottelet. Degradable Self-healable Networks for Use in Biomedical Applications. Advanced Functional Materials, 2023, pp.2205315. 10.1002/adfm.202205315. hal-03992019

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HAL
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# Degradable Self-healable Networks for Use in Biomedical Applications

Mathilde Grosjean, Louis Gangolphe, Benjamin Nottelet

► To cite this version:

Mathilde Grosjean, Louis Gangolphe, Benjamin Nottelet. Degradable Self-healable Networks for Use in Biomedical Applications. Advanced Functional Materials, 2023, pp.2205315. 10.1002/adfm.202205315. hal-03992019

HAL Id: hal-03992019

https://hal.science/hal-03992019v1

Submitted on 12 Jan 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Degradable Self-healable Networks for Use in Biomedical Applications

Mathilde Grosjean, Louis Gangolphe, and Benjamin Nottelet*

Among biomaterials, 3D networks with capacities to absorb and retain large quantities of water (hydrogels) or withstand significant deformation and stress while recovering their initial structures at rest (elastomers) are largely used in biomedical applications. However, when damaged, they cannot recover their initial structures and properties. To overcome this limitation and satisfy the requirements of the biomedical field, self-healable hydrogels and elastomers designed using (bio)degradable or bioeliminable polymer chains have been developed and are becoming increasingly popular. This review presents the latest advances in the field of self-healing degradable/bioeliminable networks designed for use in health applications. The strategies used to develop such networks based on reversible covalent or physical cross-linking or their combination via dual/multi-cross-linking approaches are analyzed in detail. The key parameters of these hydrogels and elastomers, such as mechanical properties, repair and degradation times, and healing efficiencies, are critically considered in terms of their suitabilities in biomedical applications. Finally, their current and prospective uses as biomaterials in the fields of tissue engineering, drug/cell delivery, and medical devices are presented, followed by the remaining challenges faced to ensure the further success of degradable self-healable networks.

## 1. Introduction

Self-healing polymers were first developed almost fifty years ago.[1] Initially, the main objective was to increase the lifespans of these materials or reprocess them. To this end, scientists began to exploit the interplay between chains to enable repair and restoration of the properties of the original material. The concept was in its infancy, and the starting point for self-repairing polymers was in 2001 when White et al. reported the repair of a fracture in an epoxy resin following the introduction of a repair agent (dicyclopentadiene) and a platinum

catalyst.[2] This strategy for incorporating reversible interactions into the polymer chains has since been abandoned. Most strategies to develop self-repairing polymers rely on a single type of reversible covalent bond, sometimes referred to as a dynamic covalent bond (e.g., Diels-Alder (DA) adducts [3] and imine,[4] disulfide,[5] and acylhydrazone bonds [6,7]), or physical noncovalent bond (e.g., hydrogen bonds,[8] hydrophobic, electrostatic,[9] metal-ligand,[10] and host-guest interactions,[11] and $\pi-\pi$ stacking [12]). However, a novel generation of dual/multi-cross-linked self-healing materials with several types of chemical and/or physical cross-links has begun to emerge. This is particularly true for degradable polymers that are used in biomedical applications.

Moreover, the use of degradable polymers has been increasing rapidly, scientifically and economically, in the biomedical sector recently, for example, to control the release of drugs or mimic the elastic properties of living tissue.[13–15] In the medical field, they are anticipated to register a compound annual growth rate of 15.7% from 2021 to 2028.[16] Of particular interest are degradable 3D polymer networks with the capacity to absorb and retain large quantities of water (hydrogels) or withstand significant deformation and stress while recovering their initial structures at rest (elastomers).[17–19] The 3D network is formed via physical (hydrogen bonding, dipolar forces, crystalline regions) or chemical (covalent bonding) cross-linking. One advantage of a chemically cross-linked degradable 3D network is its capacity to maintain its 3D structure and lose its mechanical properties homogeneously during degradation (surface erosion). However, when these materials are damaged (cracking, cutting, or scratching), recovering their initial structures and properties is almost impossible.[1] Therefore, introducing self-healing properties into this class of biomaterials is of considerable interest.

Self-healable hydrogels and elastomers have therefore increased in popularity recently, as indicated by the numerous reviews regarding this topic.[1,20–24] However, to date, no review has focused on hydrogels or elastomers with self-healing properties and based on biodegradable or bioeliminable polymer chains, and thus, this review aggregates the latest advances in this field. Readers' attention is drawn to the notion of degradation. Although the networks presented here may be considered degradable, their degradations do not rely on the

M. Grosjean, L. Gangolphe, B. Nottelet
Polymers for Health and Biomaterials
IBM
Univ Montpellier
CNRS, ENSCM, 34090 Montpellier, France
E-mail: benjamin.nottelet@umontpellier.fr

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm.202205315.

© 2023 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

DOI: 10.1002/adfm.202205315
# Degradable Self-healable Networks for Use in Biomedical Applications

Mathilde Grosjean, Louis Gangolphe, and Benjamin Nottelet*

Among biomaterials, 3D networks with capacities to absorb and retain large quantities of water (hydrogels) or withstand significant deformation and stress while recovering their initial structures at rest (elastomers) are largely used in biomedical applications. However, when damaged, they cannot recover their initial structures and properties. To overcome this limitation and satisfy the requirements of the biomedical field, self-healable hydrogels and elastomers designed using (bio)degradable or bioeliminable polymer chains have been developed and are becoming increasingly popular. This review presents the latest advances in the field of self-healing degradable/bioeliminable networks designed for use in health applications. The strategies used to develop such networks based on reversible covalent or physical cross-linking or their combination via dual/multi-cross-linking approaches are analyzed in detail. The key parameters of these hydrogels and elastomers, such as mechanical properties, repair and degradation times, and healing efficiencies, are critically considered in terms of their suitabilities in biomedical applications. Finally, their current and prospective uses as biomaterials in the fields of tissue engineering, drug/cell delivery, and medical devices are presented, followed by the remaining challenges faced to ensure the further success of degradable self-healable networks.

## 1. Introduction

Self-healing polymers were first developed almost fifty years ago.[1] Initially, the main objective was to increase the lifespans of these materials or reprocess them. To this end, scientists began to exploit the interplay between chains to enable repair and restoration of the properties of the original material. The concept was in its infancy, and the starting point for self-repairing polymers was in 2001 when White et al. reported the repair of a fracture in an epoxy resin following the introduction of a repair agent (dicyclopentadiene) and a platinum

catalyst.[2] This strategy for incorporating reversible interactions into the polymer chains has since been abandoned. Most strategies to develop self-repairing polymers rely on a single type of reversible covalent bond, sometimes referred to as a dynamic covalent bond (e.g., Diels-Alder (DA) adducts [3] and imine,[4] disulfide,[5] and acylhydrazone bonds [6,7]), or physical noncovalent bond (e.g., hydrogen bonds,[8] hydrophobic, electrostatic,[9] metal-ligand,[10] and host-guest interactions,[11] and $\pi-\pi$ stacking [12]). However, a novel generation of dual/multi-cross-linked self-healing materials with several types of chemical and/or physical cross-links has begun to emerge. This is particularly true for degradable polymers that are used in biomedical applications.

Moreover, the use of degradable polymers has been increasing rapidly, scientifically and economically, in the biomedical sector recently, for example, to control the release of drugs or mimic the elastic properties of living tissue.[13–15] In the medical field, they are anticipated to register a compound annual growth rate of 15.7% from 2021 to 2028.[16] Of particular interest are degradable 3D polymer networks with the capacity to absorb and retain large quantities of water (hydrogels) or withstand significant deformation and stress while recovering their initial structures at rest (elastomers).[17–19] The 3D network is formed via physical (hydrogen bonding, dipolar forces, crystalline regions) or chemical (covalent bonding) cross-linking. One advantage of a chemically cross-linked degradable 3D network is its capacity to maintain its 3D structure and lose its mechanical properties homogeneously during degradation (surface erosion). However, when these materials are damaged (cracking, cutting, or scratching), recovering their initial structures and properties is almost impossible.[1] Therefore, introducing self-healing properties into this class of biomaterials is of considerable interest.

Self-healable hydrogels and elastomers have therefore increased in popularity recently, as indicated by the numerous reviews regarding this topic.[1,20–24] However, to date, no review has focused on hydrogels or elastomers with self-healing properties and based on biodegradable or bioeliminable polymer chains, and thus, this review aggregates the latest advances in this field. Readers' attention is drawn to the notion of degradation. Although the networks presented here may be considered degradable, their degradations do not rely on the

M. Grosjean, L. Gangolphe, B. Nottelet
Polymers for Health and Biomaterials
IBM
Univ Montpellier
CNRS, ENSCM, 34090 Montpellier, France
E-mail: benjamin.nottelet@umontpellier.fr

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm.202205315.

© 2023 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

DOI: 10.1002/adfm.202205315
same mechanism, and thus, two types of degradable networks are considered in this review. First, degradable networks undergoing real degradation, i.e., degradation at the molecular level of the polymer chains (e.g., via hydrolysis in degradable networks or enzymatic reactions in biodegradable networks) that is independent of the reversible/dynamic bonds responsible for the self-healing properties. Second, bioeliminable networks that lose their 3D structures, and whose polymer chains may be excreted by the body without scission of the polymer backbones (e.g., soluble polyethylene glycol (PEG) chains). This review therefore only focuses on networks with (bio)degradable and/or bioeliminable polymers and self-healing properties provided by reversible covalent or dynamic physical cross-linking or dual/multi-cross-linking. In each of these sections, we focus on the mechanical properties, repair and degradation times, and healing efficiencies of the materials, and the last section presents the biomedical applications of these self-healing degradable networks and their prospective uses.

**2. Self-Healing Mechanism and Evaluation**

Self-healing is based on the presence of reversible bonds and may occur via different mechanisms that may be divided into two main categories: dynamic chemical bonding and reversible physical interactions (Figure 1). Reversible covalent bonds include imine, boronate ester, hydrazone, and disulfide bonds and DA adducts. Reversible noncovalent bonding includes hydrogen bonding, hydrophobic, host-guest, electrostatic or ionic interactions, and metal coordination. Self-repairing materials may, therefore, exhibit self-healing properties owing to one or several of these bonds and interactions.

The key process in self-healing is the interpenetration and bond reformation of the polymer chains, with dynamic bonds around the healing interface. Therefore, the incorporation of reversible bonds is not the only prerequisite in preparing a self-healing material, and other factors should be considered. Self-healable materials rely on three principles: 1) localization, 2) temporality, and 3) mobility.[1] First, the concept of localization

corresponds to the nature and state (size and position) of the damage, and the latter exhibits an essential effect on the capacity of the material to self-repair (superficial or deep). The repair pathways should be adapted according to the expected damage and application of the material. Second, self-healing is time-dependent, and temporality is defined as the time required for the material to fill the damaged area and regain its initial properties. To accelerate self-healing, the mobility of the chains within the material and the reactivity between the chain ends resulting from the dissociation should be increased, and numerous external factors (pH, temperature, UV light, redox, and mechanical stimuli) are used to realize this.[9,25] The mobility of the polymer chains enables molecular and macroscopic reorganization of the material. At the molecular level, the mobility of the chains enables the dissociation and recombination of cleaved bonds via the diffusion of repairing agents or interplay between the functions involved in the repair process. At the macroscopic level, this mobility results in the visible repair of the damage.[20,26] The necessity of the mobility of the polymer chains and reactivity between the dissociated moieties was clearly established in recent modeling studies, with the polymer chains diffusing across the interface to reform the dynamic bonds, as modeled using diffusion-reaction theory.[27] This theory is based on chain reptation and involves a curvilinear diffusion coefficient combined with the association-dissociation kinetics of dynamic bonds. This enables the prediction of self-healing times and efficiencies as functions of the chain mobility and length distribution, in addition to the bond dynamics (Figure 2), and thus, the external stimuli generally used in self-healing.

Notably, the type of damage initially generated varies considerably, rendering the comparison of the self-healing performances of different materials that are also used in a variety of applications challenging.[22] Nevertheless, over the period considered, similar analytical methods were used to evaluate and quantify self-healing macroscopically and at the molecular level. In terms of damage (Figure 3), a common method used to macroscopically demonstrate the self-healing capacity of a material is the contact method, which involves cutting the sample into several pieces and placing them in contact to permit self-healing.

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Covalent and non-covalent bonds that allow self-healing properties in hydrogels and elastomers.</figcaption></figure>
same mechanism, and thus, two types of degradable networks are considered in this review. First, degradable networks undergoing real degradation, i.e., degradation at the molecular level of the polymer chains (e.g., via hydrolysis in degradable networks or enzymatic reactions in biodegradable networks) that is independent of the reversible/dynamic bonds responsible for the self-healing properties. Second, bioeliminable networks that lose their 3D structures, and whose polymer chains may be excreted by the body without scission of the polymer backbones (e.g., soluble polyethylene glycol (PEG) chains). This review therefore only focuses on networks with (bio)degradable and/or bioeliminable polymers and self-healing properties provided by reversible covalent or dynamic physical cross-linking or dual/multi-cross-linking. In each of these sections, we focus on the mechanical properties, repair and degradation times, and healing efficiencies of the materials, and the last section presents the biomedical applications of these self-healing degradable networks and their prospective uses.

## 2. Self-Healing Mechanism and Evaluation

Self-healing is based on the presence of reversible bonds and may occur via different mechanisms that may be divided into two main categories: dynamic chemical bonding and reversible physical interactions (Figure 1). Reversible covalent bonds include imine, boronate ester, hydrazone, and disulfide bonds and DA adducts. Reversible noncovalent bonding includes hydrogen bonding, hydrophobic, host-guest, electrostatic or ionic interactions, and metal coordination. Self-repairing materials may, therefore, exhibit self-healing properties owing to one or several of these bonds and interactions.

The key process in self-healing is the interpenetration and bond reformation of the polymer chains, with dynamic bonds around the healing interface. Therefore, the incorporation of reversible bonds is not the only prerequisite in preparing a self-healing material, and other factors should be considered. Self-healable materials rely on three principles: 1) localization, 2) temporality, and 3) mobility.[1] First, the concept of localization

corresponds to the nature and state (size and position) of the damage, and the latter exhibits an essential effect on the capacity of the material to self-repair (superficial or deep). The repair pathways should be adapted according to the expected damage and application of the material. Second, self-healing is time-dependent, and temporality is defined as the time required for the material to fill the damaged area and regain its initial properties. To accelerate self-healing, the mobility of the chains within the material and the reactivity between the chain ends resulting from the dissociation should be increased, and numerous external factors (pH, temperature, UV light, redox, and mechanical stimuli) are used to realize this.[9,25] The mobility of the polymer chains enables molecular and macroscopic reorganization of the material. At the molecular level, the mobility of the chains enables the dissociation and recombination of cleaved bonds via the diffusion of repairing agents or interplay between the functions involved in the repair process. At the macroscopic level, this mobility results in the visible repair of the damage.[20,26] The necessity of the mobility of the polymer chains and reactivity between the dissociated moieties was clearly established in recent modeling studies, with the polymer chains diffusing across the interface to reform the dynamic bonds, as modeled using diffusion-reaction theory.[27] This theory is based on chain reptation and involves a curvilinear diffusion coefficient combined with the association-dissociation kinetics of dynamic bonds. This enables the prediction of self-healing times and efficiencies as functions of the chain mobility and length distribution, in addition to the bond dynamics (Figure 2), and thus, the external stimuli generally used in self-healing.

Notably, the type of damage initially generated varies considerably, rendering the comparison of the self-healing performances of different materials that are also used in a variety of applications challenging.[22] Nevertheless, over the period considered, similar analytical methods were used to evaluate and quantify self-healing macroscopically and at the molecular level. In terms of damage (Figure 3), a common method used to macroscopically demonstrate the self-healing capacity of a material is the contact method, which involves cutting the sample into several pieces and placing them in contact to permit self-healing.

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Covalent and non-covalent bonds that allow self-healing properties in hydrogels and elastomers.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Figure 2.** Illustration of the predicted equilibrium healing time based on diffusion-reaction theory in a function of a) the chain length distribution via average chain length b) the chain mobility via the Rouse friction coefficients and c) the bond dynamics via the reverse reaction rates (from dissociated to associated state). Adapted with permission.[27] Copyright 2018, Elsevier.</figcaption></figure>

Punch – a hole is excavated in the material – and crack methods – a crack is generated at the surface of the sample – are two other types of methods reported (Figure 3). Optical evaluation of self-healing includes macroscopic observations, optical microscopy, and scanning electron microscopy (SEM).

At the molecular level, spectroscopic analyses, such as nuclear magnetic resonance spectroscopy, Fourier transform infrared (IR) spectroscopy, and X-ray photoelectron spectroscopy, are historically used to assess dissociation and rebonding. Molecular repair affects the mechanical properties of materials, and self-healing is also assessed by quantifying the mechanical recoveries of materials via static or dynamic mechanical studies. Mechanical evaluations include rheological, tensile, compressive, stretching, bending, and gravity resistance studies. The extent and quality of self-repair are expressed via the self-healing efficiency (SHE), which is obtained by comparing the performance of the healed material with that of the pristine material.

To facilitate a comparison between the networks discussed in this review, readers are invited to refer to the tables in each section, which aggregate the main characteristics listed above (mechanical properties, self-healing evaluation and conditions, SHE, and degradation).

### 3. (Bio)Degradation versus Bioelimination

This review focuses on hydrogels and elastomers based on (bio)degradable and/or bioeliminable polymers (Figure 4). (Bio)degradation refers to the cleavage of the covalent bonds of the polymer backbone (e.g., hydrolysis in degradation and enzymatic lysis in biodegradation), which is accompanied by a decrease in molar mass. Bioelimination refers to the possible excretion of the polymer chains from the body after the loss of the 3D structure of the network but without a decrease in molar mass.

<figure><img src="image_5.png" /><figcaption>**Figure 3.** Various methods used to evaluate the self-healing properties.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Figure 2.** Illustration of the predicted equilibrium healing time based on diffusion-reaction theory in a function of a) the chain length distribution via average chain length b) the chain mobility via the Rouse friction coefficients and c) the bond dynamics via the reverse reaction rates (from dissociated to associated state). Adapted with permission.[27] Copyright 2018, Elsevier.</figcaption></figure>

Punch – a hole is excavated in the material – and crack methods – a crack is generated at the surface of the sample – are two other types of methods reported (Figure 3). Optical evaluation of self-healing includes macroscopic observations, optical microscopy, and scanning electron microscopy (SEM).

At the molecular level, spectroscopic analyses, such as nuclear magnetic resonance spectroscopy, Fourier transform infrared (IR) spectroscopy, and X-ray photoelectron spectroscopy, are historically used to assess dissociation and rebonding. Molecular repair affects the mechanical properties of materials, and self-healing is also assessed by quantifying the mechanical recoveries of materials via static or dynamic mechanical studies. Mechanical evaluations include rheological, tensile, compressive, stretching, bending, and gravity resistance studies. The extent and quality of self-repair are expressed via the self-healing efficiency (SHE), which is obtained by comparing the performance of the healed material with that of the pristine material.

To facilitate a comparison between the networks discussed in this review, readers are invited to refer to the tables in each section, which aggregate the main characteristics listed above (mechanical properties, self-healing evaluation and conditions, SHE, and degradation).

### 3. (Bio)Degradation versus Bioelimination

This review focuses on hydrogels and elastomers based on (bio)degradable and/or bioeliminable polymers (Figure 4). (Bio)degradation refers to the cleavage of the covalent bonds of the polymer backbone (e.g., hydrolysis in degradation and enzymatic lysis in biodegradation), which is accompanied by a decrease in molar mass. Bioelimination refers to the possible excretion of the polymer chains from the body after the loss of the 3D structure of the network but without a decrease in molar mass.

<figure><img src="image_5.png" /><figcaption>**Figure 3.** Various methods used to evaluate the self-healing properties.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Figure 4.** Self-healing versus biodegradation and bioelimination.</figcaption></figure>

Different degradation mechanisms are observed for polymers used in the biomedical field, including hydrolysis, enzymatic degradation, and oxidation.[28] In hydrolysis, the hydrolyzable bonds of polymer chains react with water molecules and dissociate, yielding smaller chains and resulting in polymer degradation. Hydrolytic degradation is thus a combination of water diffusion within the polymer network and random scission of hydrolyzable bonds. Chemical groups that may react with water and undergo hydrolysis mainly contain oxygen, nitrogen, sulfur, and phosphorus atoms. Therefore, polymers that may degrade via this mechanism include polyesters, polyamides, polycarbonates, polyorthesters, and polyanhydrides, and these materials may undergo different degradation processes, such as surface erosion, bulk degradation, and, more rarely, autocatalytic degradation. Surface erosion occurs when hydrolysis is faster than water diffusion. During degradation, the material loses mass progressively but maintains its initial molecular weight and shape. Bulk degradation occurs when water diffusion within the polymer matrix is faster than hydrolysis. The material progressively degrades, eroding from the center to the surface and becoming porous. Oligo- and monomers may diffuse through the material and escape, and thus, the material loses mass. Finally, autocatalytic degradation occurs when bulk degradation leads to the generation of oligomers within the core of the material, which diffuse very slowly but bear functional groups (e.g., carboxylic acid) with the capacity to catalyze hydrolysis. This type

of degradation is rare and typical of polylactide species with dimensions of >1 mm.

Degradation via oxidation, which is due to the generation of oxidants by tissues, is caused by the biological defensive action of the immune system. After the implantation of biomedical devices in the body, inflammatory cells may produce oxidative agents (e.g., peroxides) that diffuse into polymeric implants and degrade them. Polymers that are more likely to degrade via oxidation display structures wherein free radicals may be easily generated (e.g., polyethers or polyamines). Degradation via oxidation may also include photodegradation, wherein oxidative agents are generated via exposure to UV or visible radiation.[29]

Enzymatic biodegradation occurs as a defense mechanism in response to the implantation of foreign materials within the body. When acted upon by enzymes, the long polymer chains are reduced to small chains or monomers. Polymer composition is critical in enzymatic degradation, and polymers that may be degraded via this type of reaction include collagens, polysaccharides, proteins, some polyesters, and several polycarbonates. As the enzymes responsible for biodegradation originate from the biological systems of the patients, biodegradation may differ from one individual to another. In the same individual, biodegradation may vary over time and depends on the surrounding tissues. Various enzymes, such as dehydrogenase, oxidase, hydrolase, cutinase, lipase, and protease, play key roles in the biodegradation of polymers.[30]
<figure><img src="image_6.png" /><figcaption>**Figure 4.** Self-healing versus biodegradation and bioelimination.</figcaption></figure>

Different degradation mechanisms are observed for polymers used in the biomedical field, including hydrolysis, enzymatic degradation, and oxidation.[28] In hydrolysis, the hydrolyzable bonds of polymer chains react with water molecules and dissociate, yielding smaller chains and resulting in polymer degradation. Hydrolytic degradation is thus a combination of water diffusion within the polymer network and random scission of hydrolyzable bonds. Chemical groups that may react with water and undergo hydrolysis mainly contain oxygen, nitrogen, sulfur, and phosphorus atoms. Therefore, polymers that may degrade via this mechanism include polyesters, polyamides, polycarbonates, polyorthesters, and polyanhydrides, and these materials may undergo different degradation processes, such as surface erosion, bulk degradation, and, more rarely, autocatalytic degradation. Surface erosion occurs when hydrolysis is faster than water diffusion. During degradation, the material loses mass progressively but maintains its initial molecular weight and shape. Bulk degradation occurs when water diffusion within the polymer matrix is faster than hydrolysis. The material progressively degrades, eroding from the center to the surface and becoming porous. Oligo- and monomers may diffuse through the material and escape, and thus, the material loses mass. Finally, autocatalytic degradation occurs when bulk degradation leads to the generation of oligomers within the core of the material, which diffuse very slowly but bear functional groups (e.g., carboxylic acid) with the capacity to catalyze hydrolysis. This type

of degradation is rare and typical of polylactide species with dimensions of >1 mm.

Degradation via oxidation, which is due to the generation of oxidants by tissues, is caused by the biological defensive action of the immune system. After the implantation of biomedical devices in the body, inflammatory cells may produce oxidative agents (e.g., peroxides) that diffuse into polymeric implants and degrade them. Polymers that are more likely to degrade via oxidation display structures wherein free radicals may be easily generated (e.g., polyethers or polyamines). Degradation via oxidation may also include photodegradation, wherein oxidative agents are generated via exposure to UV or visible radiation.[29]

Enzymatic biodegradation occurs as a defense mechanism in response to the implantation of foreign materials within the body. When acted upon by enzymes, the long polymer chains are reduced to small chains or monomers. Polymer composition is critical in enzymatic degradation, and polymers that may be degraded via this type of reaction include collagens, polysaccharides, proteins, some polyesters, and several polycarbonates. As the enzymes responsible for biodegradation originate from the biological systems of the patients, biodegradation may differ from one individual to another. In the same individual, biodegradation may vary over time and depends on the surrounding tissues. Various enzymes, such as dehydrogenase, oxidase, hydrolase, cutinase, lipase, and protease, play key roles in the biodegradation of polymers.[30]
Notably, these (bio)degradation mechanisms do not rely on reversible or dynamic bonds, which are responsible for the self-healing properties (Figure 4).

# 4. Degradable Networks With Self-healing Properties Based on Dynamic/Reversible Chemical Bonds

## 4.1. Imine bond/Schiff base

The imine bonds formed via Schiff-base reactions between amine and aldehyde groups are the most used dynamic covalent bonds in preparing self-healing networks, particularly hydrogels. Examples of self-healing networks based on Schiff-base reactions are shown in **Table 1**, which also shows their mechanical, self-healing, and degradation properties.

Unsurprisingly, among imine bond-containing self-healable degradable hydrogels, most are based on chitosan and its derivatives because of the presence of primary amines within these biopolymers and their good cytocompatibility.[31–38] Conversely, the source of the aldehydes varies, with both synthetic and semi-synthetic biopolymers used. This provides numerous polymer combinations, resulting in chitosan-based self-healable biomaterials with healing times varying from a few minutes to one day and storage modulus $G'$ ranging from a few hundred pascals to a few hundred kilopascals. Although scarcely reported, small aldehydes have also been used, e.g., fluorescent 5-(benzo[d]thiazol-2-yl)-4-hydroxyisophthalaldehyde was associated with chitosan to yield a soft self-healing hydrogel that exhibited a low $G'$ (<100 Pa) and short healing time (<1 h) when exposed to moisture-saturated air.[39]

### 4.1.1. Schiff-base hydrogels prepared using chitosan and synthetic polymers

Most chitosan/synthetic polymer combinations contain telchelic α,ω-benzaldehyde PEG (PEG-BA). Soft hydrogels with $G'$ values and self-healing times of 0.5–30 kPa and 1–24 h, respectively, were prepared using various chitosan derivatives. For example, Huang et al. [43] developed hydrogels with $G'$ values of up to 3 kPa, high SHEs (94%), and slow healing rates (12 h at 37 °C) using 4-arm PEG-BA and N-carboxymethyl chitosan (CMC). Four-arm PEG-BA was also combined with quaternized methacryloyl chitosan to produce hydrogels that could self-heal within 2 h and exhibited rapid in vivo degradation within 7 d.[44] Depending on the composition of the gel, $G'$ could be tuned between 0.9 and 8 kPa.

Stiffer imine-based hydrogels with high $G'$ values (>10 kPa) were obtained using zwitterionic 1-glutamic acid-functionalized chitosan and 4-arm PEG-BA.[45] Following injection through a 22-gauge needle, hydrogels left for 1 h in air and 2 h in phosphate-buffered saline (PBS) exhibited complete self-healed network structures. Increasing the amount of 4-arm PEG-BA cross-linker increased $G'$ from 4 kPa at a chitosan-glutamic acid:PEG-BA ratio of 1:0.33 (w:w) to 31 kPa at a ratio of 1:2. The self-healed samples subjected to mechanical compression

displayed mechanical behaviors similar to those of the original hydrogels. The degradation of the hydrogels was investigated at pH values of 6.5 and 7.4. Faster degradation was observed under acidic conditions, with 60% mass remaining after 30 d at pH 7.4 compared to 44% mass remaining after 30 d at pH 6.5.

Other chitosan derivatives associated with PEG-BA include phenol-functionalized chitosan,[40] glycated chitosan with [42] or without [41] fibrin, a chitosan-g-aniline tetramer,[33] and N-(carboxyethyl)chitosan (CEC).[46] Finally, polyether dibenzaldehyde Pluronic was proposed as an alternative to PEG-BA. In combination with N-[3-(4-hydroxyphenyl)propanamido]chitosan, hydrogels with $G'$ values in the range 0.4–1.2 kPa and healing times of 1 h were prepared.[47]

### 4.1.2. Schiff-base Hydrogels Prepared Using Chitosan and Biopolymers

Self-healable chitosan/biopolymer hydrogels represent the largest class of Schiff-base hydrogels. The biopolymers used include derivatives of hyaluronic acid (HA), dextran, alginate, and cellulose. In contrast to Schiff-base hydrogels based on synthetic polymers, this family of self-healable hydrogels is limited to soft hydrogels with moduli rarely superior to 1 kPa, but with faster self-healing, which is generally observed in <2 h. Hydrogels with healing in minutes (<15 min) were obtained by combining CEC and oxidized sodium alginate (A-Alg) [32] or bisaldehyde-functionalized carboxymethyl cellulose and CMC.[37] Hydrogels with healing times of <2 h were obtained by mixing glycated chitosan and an oxidized dextran (A-Dex),[35] CMC and A-Dex,[48] or acrylamide-modified chitin with 2% amino groups and A-Alg.[38] Slower self-healing was only reported for injectable electroactive soft degradable hydrogels based on dextran-g-aniline tetramer-g-4-formylbenzoic acid and CEC, which required 12 h at 37 °C in a humid atmosphere to recover their mechanical properties after damage.[34] With respect to stiffer hydrogels, only three examples with $G'$ values of >1 kPa have been reported recently. These hydrogels were composed of N-succinyl-chitosan and multi-aldehyde chondroitin sulfate [31] or CEC and aldehyde-modified HA (A-HA).[36] In the latter example, N-(furfural) chitosan was combined with A-Dex in the presence or absence of bismaleimide-PEG to increase the acid resistances of the imine-containing hydrogels by combining the imine bonds with DA adducts.[49]

Regarding biodegradability, all gels exhibited degradation, but with large discrepancies depending on their chemical natures. Whereas several were fully degraded within a few days,[32] others were only partially degraded after a few weeks,[31,35,36] even in the presence of enzymes, such as lysozyme.[37,49]

### 4.1.3. Schiff-base Hybrid Hydrogels Prepared Using Chitosan and Particles

Using chitosan as a component of the hydrogels, the incorporation of different types of particles also reportedly enhanced the biological and mechanical properties but also slowed the degradation of hydrogels. For example, hydroxyapatite (HAp) nanoparticles and calcium carbonate microparticles were embedded in a self-healing hydrogel composed of CMC and A-Alg.[50]
Notably, these (bio)degradation mechanisms do not rely on reversible or dynamic bonds, which are responsible for the self-healing properties (Figure 4).

# 4. Degradable Networks With Self-healing Properties Based on Dynamic/Reversible Chemical Bonds

## 4.1. Imine bond/Schiff base

The imine bonds formed via Schiff-base reactions between amine and aldehyde groups are the most used dynamic covalent bonds in preparing self-healing networks, particularly hydrogels. Examples of self-healing networks based on Schiff-base reactions are shown in **Table 1**, which also shows their mechanical, self-healing, and degradation properties.

Unsurprisingly, among imine bond-containing self-healable degradable hydrogels, most are based on chitosan and its derivatives because of the presence of primary amines within these biopolymers and their good cytocompatibility.[31–38] Conversely, the source of the aldehydes varies, with both synthetic and semi-synthetic biopolymers used. This provides numerous polymer combinations, resulting in chitosan-based self-healable biomaterials with healing times varying from a few minutes to one day and storage modulus $G'$ ranging from a few hundred pascals to a few hundred kilopascals. Although scarcely reported, small aldehydes have also been used, e.g., fluorescent 5-(benzo[d]thiazol-2-yl)-4-hydroxyisophthalaldehyde was associated with chitosan to yield a soft self-healing hydrogel that exhibited a low $G'$ (<100 Pa) and short healing time (<1 h) when exposed to moisture-saturated air.[39]

### 4.1.1. Schiff-base hydrogels prepared using chitosan and synthetic polymers

Most chitosan/synthetic polymer combinations contain telchelic α,ω-benzaldehyde PEG (PEG-BA). Soft hydrogels with $G'$ values and self-healing times of 0.5–30 kPa and 1–24 h, respectively, were prepared using various chitosan derivatives. For example, Huang et al. [43] developed hydrogels with $G'$ values of up to 3 kPa, high SHEs (94%), and slow healing rates (12 h at 37 °C) using 4-arm PEG-BA and N-carboxymethyl chitosan (CMC). Four-arm PEG-BA was also combined with quaternized methacryloyl chitosan to produce hydrogels that could self-heal within 2 h and exhibited rapid in vivo degradation within 7 d.[44] Depending on the composition of the gel, $G'$ could be tuned between 0.9 and 8 kPa.

Stiffer imine-based hydrogels with high $G'$ values (>10 kPa) were obtained using zwitterionic 1-glutamic acid-functionalized chitosan and 4-arm PEG-BA.[45] Following injection through a 22-gauge needle, hydrogels left for 1 h in air and 2 h in phosphate-buffered saline (PBS) exhibited complete self-healed network structures. Increasing the amount of 4-arm PEG-BA cross-linker increased $G'$ from 4 kPa at a chitosan-glutamic acid:PEG-BA ratio of 1:0.33 (w:w) to 31 kPa at a ratio of 1:2. The self-healed samples subjected to mechanical compression

displayed mechanical behaviors similar to those of the original hydrogels. The degradation of the hydrogels was investigated at pH values of 6.5 and 7.4. Faster degradation was observed under acidic conditions, with 60% mass remaining after 30 d at pH 7.4 compared to 44% mass remaining after 30 d at pH 6.5.

Other chitosan derivatives associated with PEG-BA include phenol-functionalized chitosan,[40] glycated chitosan with [42] or without [41] fibrin, a chitosan-g-aniline tetramer,[33] and N-(carboxyethyl)chitosan (CEC).[46] Finally, polyether dibenzaldehyde Pluronic was proposed as an alternative to PEG-BA. In combination with N-[3-(4-hydroxyphenyl)propanamido]chitosan, hydrogels with $G'$ values in the range 0.4–1.2 kPa and healing times of 1 h were prepared.[47]

### 4.1.2. Schiff-base Hydrogels Prepared Using Chitosan and Biopolymers

Self-healable chitosan/biopolymer hydrogels represent the largest class of Schiff-base hydrogels. The biopolymers used include derivatives of hyaluronic acid (HA), dextran, alginate, and cellulose. In contrast to Schiff-base hydrogels based on synthetic polymers, this family of self-healable hydrogels is limited to soft hydrogels with moduli rarely superior to 1 kPa, but with faster self-healing, which is generally observed in <2 h. Hydrogels with healing in minutes (<15 min) were obtained by combining CEC and oxidized sodium alginate (A-Alg) [32] or bisaldehyde-functionalized carboxymethyl cellulose and CMC.[37] Hydrogels with healing times of <2 h were obtained by mixing glycated chitosan and an oxidized dextran (A-Dex),[35] CMC and A-Dex,[48] or acrylamide-modified chitin with 2% amino groups and A-Alg.[38] Slower self-healing was only reported for injectable electroactive soft degradable hydrogels based on dextran-g-aniline tetramer-g-4-formylbenzoic acid and CEC, which required 12 h at 37 °C in a humid atmosphere to recover their mechanical properties after damage.[34] With respect to stiffer hydrogels, only three examples with $G'$ values of >1 kPa have been reported recently. These hydrogels were composed of N-succinyl-chitosan and multi-aldehyde chondroitin sulfate [31] or CEC and aldehyde-modified HA (A-HA).[36] In the latter example, N-(furfural) chitosan was combined with A-Dex in the presence or absence of bismaleimide-PEG to increase the acid resistances of the imine-containing hydrogels by combining the imine bonds with DA adducts.[49]

Regarding biodegradability, all gels exhibited degradation, but with large discrepancies depending on their chemical natures. Whereas several were fully degraded within a few days,[32] others were only partially degraded after a few weeks,[31,35,36] even in the presence of enzymes, such as lysozyme.[37,49]

### 4.1.3. Schiff-base Hybrid Hydrogels Prepared Using Chitosan and Particles

Using chitosan as a component of the hydrogels, the incorporation of different types of particles also reportedly enhanced the biological and mechanical properties but also slowed the degradation of hydrogels. For example, hydroxyapatite (HAp) nanoparticles and calcium carbonate microparticles were embedded in a self-healing hydrogel composed of CMC and A-Alg.[50]
<table><caption>**Table 1.** Self-healing hydrogels and elastomers based on imine bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Phenol-functionalized chitosan/PEG-BA</td><td>G' = 0.5 kPa</td><td>Cut, Syringe injection</td><td>6 h</td><td>—</td><td>—</td><td>[40]</td></tr><tr><td>Hydrogel</td><td>Glycolated chitosan/PEG-BA</td><td>G' = 0.8 kPa at 25 °C<br>G' = 1.5 kPa at 37 °C</td><td>Hole</td><td>12 h</td><td>—</td><td>—</td><td>[41]</td></tr><tr><td>Hydrogel</td><td>Glycolated chitosan/PEG-BA</td><td>G' = 1.2 kPa</td><td>Hole</td><td>6 h</td><td>—</td><td>In vitro, 30 d</td><td>[42]</td></tr><tr><td>Hydrogel</td><td>Chitosan-g-aniline/PEG-BA</td><td>G' = 2 kPa</td><td>Cut</td><td>Immediately</td><td>—</td><td>In vivo, 45 d</td><td>[33]</td></tr><tr><td>Hydrogel</td><td>CMC/PEG-BA</td><td>G' up to 3 kPa</td><td>Cut</td><td>12 h, 37 °C</td><td>94%</td><td>—</td><td>[43]</td></tr><tr><td>Hydrogel</td><td>Quaternized methacryloyl chitosan/PEG-BA</td><td>G' = 0.9 to 8 kPa</td><td>Cut</td><td>120 min, 37 °C</td><td>—</td><td>In vivo, 7 d</td><td>[44]</td></tr><tr><td>Hydrogel</td><td>Zwitterionic L-GA-chitosan/PEG-BA</td><td>G' = 4 to 31 kPa</td><td>Syringe injection</td><td>1 h in air, 2 h in PBS</td><td>—</td><td>In vitro, 40% mass loss after 30 d at pH 7.4, 56% at pH 6.5</td><td>[45]</td></tr><tr><td>Hydrogel</td><td>CEC/PEG-BA<br>Polyacrylamide</td><td>σ<sub>max</sub> = 460 kPa<br>ε<sub>max</sub> = 4600%</td><td>Cut</td><td>24 h<br>35 °C, alkaline conditions</td><td>84% (σ<sub>max</sub>)<br>93% (ε<sub>max</sub>)</td><td>—</td><td>[46]</td></tr><tr><td>Hydrogel</td><td>N-[3-(4-hydroxyphenyl)propanamido] chitosan/Dibenzaldehyde Pluronic</td><td>G' = 0.4 to 1.2 kPa</td><td>Syringe injection</td><td>1 h</td><td>> 95% (G')</td><td>—</td><td>[47]</td></tr><tr><td>Hydrogel</td><td>CEC/A-HA</td><td>G' = 2 to 6 kPa</td><td>Crack</td><td>3 min</td><td>—</td><td>In vitro, 34% mass loss in 10 d</td><td>[36]</td></tr><tr><td>Hydrogel</td><td>N-succinyl-chitosan/Chondroitin sulfate multiple aldehydes</td><td>G' = 4 kPa</td><td>Cut</td><td>2 h, moisture</td><td>—</td><td>In vivo, 60% degradation in 7w</td><td>[31]</td></tr><tr><td>Hydrogel</td><td>CEC/A-Alg</td><td>G' = 0.08 to 2 kPa</td><td>Syringe injection</td><td>5 min, physiological conditions</td><td>—</td><td>In vitro, 100% degradation in 3 to 14 d</td><td>[32]</td></tr><tr><td>Hydrogel</td><td>CMC/Aldehyde-functional carboxymethyl cellulose</td><td>G' = 200 to 600 Pa</td><td>Cut</td><td>6 to 15 min</td><td>65-83% (G')</td><td>In vitro, 50 to 75% mass loss in 3w with lysozyme, 40 to 60% without</td><td>[37]</td></tr><tr><td>Hydrogel</td><td>Glycolated chitosan/A-Dex</td><td>G' = 30 Pa to 1 kPa</td><td>Syringe injection</td><td>120 min</td><td>80% (G')</td><td>In vitro, 40 to 80% mass loss in 2 weeks</td><td>[35]</td></tr><tr><td>Hydrogel</td><td>CMC/A-Dex</td><td>G' = 11 Pa</td><td>Cut, Hole</td><td>30 min<br>90 min</td><td>—</td><td>In vivo, 21 d</td><td>[48]</td></tr><tr><td>Hydrogel</td><td>CEC/Dextran-g-aniline tetramer-g-4-formylbenzoic acid</td><td>G' = 0.3 to 0.65 kPa</td><td>Cut</td><td>12 h, 37 °C, humid atmosphere</td><td>—</td><td>In vitro, 74% to 91% degradation in 8 d</td><td>[34]</td></tr><tr><td>Hydrogel</td><td>Acrylamide modified chitin/A-Alg</td><td>G' = 600 Pa</td><td>Crack</td><td>60min</td><td>—</td><td>—</td><td>[38]</td></tr><tr><td>Hydrogel</td><td>N-furfural chitosan/A-Dex<br>Bismaleimide-PEG</td><td>G' = 0.6 to 3 kPa</td><td>Cut</td><td>3 h<br>25 °C</td><td>100% (G')</td><td>In vitro, 20 to 50% degradation with lysozyme</td><td>[49]</td></tr><tr><td>Hydrogel</td><td>CMC/A-Alg<br>HAp<br>CaCO<sub>3</sub></td><td>G' = 2 to 6 kPa</td><td>Syringe injection</td><td>—</td><td>—</td><td>In vitro, 40 to 86% weight loss in 2 weeks</td><td>[50]</td></tr><tr><td>Hydrogel</td><td>CMC/A-Alg<br>MGMs</td><td>G' = 3 to 10 kPa</td><td>Cut</td><td>2 h</td><td>97% (G')</td><td>In vitro, 10 to 30% mass loss in 2 weeks</td><td>[51]</td></tr><tr><td>Hydrogel</td><td>Chitosan/PEG-BA<br>Fe<sub>3</sub>O<sub>4</sub> particles</td><td>G' up to 2 kPa</td><td>Hole</td><td>1 h</td><td>—</td><td>—</td><td>[52]</td></tr><tr><td>Hydrogel</td><td>CEC/A-HA<br>Carbonyl iron magnetic particles</td><td>G' = 1 to 30 Pa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, 30 to 75% mass loss in 4d</td><td>[53]</td></tr><tr><td>Hydrogel</td><td>L-arginine conjugated chitosan/PEG-BA<br>pDA-NPs</td><td>G' = 230 to 1100 Pa</td><td>Cut</td><td>5min</td><td>—</td><td>In vitro, 50 to 75% degradation in 14d</td><td>[54]</td></tr><tr><td>Hydrogel</td><td>CMC/Poly(dextran-g-4-formylbenzoic acid)<br>Peptide nanofibers</td><td>G' = 91 to 700 Pa</td><td>Cut</td><td>2min</td><td>—</td><td>In vitro, 70 to 90% mass loss with lysozyme after 9d</td><td>[55]</td></tr><tr><td>Hydrogel</td><td>Chitosan/Aldehyde functional polyurethane nanoparticles</td><td>G' = 700 Pa</td><td>Cut</td><td>1 h, RT</td><td>—</td><td>In vitro, 5 to 20% mass loss in 1m</td><td>[56]</td></tr><tr><td>Hydrogel</td><td>Ethylenediamine functional gelatin/Dialdehyde carboxymethylcellulose</td><td>G' up to 60 kPa</td><td>Cut</td><td>1h</td><td>90%</td><td>In vitro, 75% mass loss after 12d, 80% after 2m</td><td>[57]</td></tr></tbody></table>
<table><caption>**Table 1.** Self-healing hydrogels and elastomers based on imine bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Phenol-functionalized chitosan/PEG-BA</td><td>G' = 0.5 kPa</td><td>Cut, Syringe injection</td><td>6 h</td><td>—</td><td>—</td><td>[40]</td></tr><tr><td>Hydrogel</td><td>Glycolated chitosan/PEG-BA</td><td>G' = 0.8 kPa at 25 °C<br>G' = 1.5 kPa at 37 °C</td><td>Hole</td><td>12 h</td><td>—</td><td>—</td><td>[41]</td></tr><tr><td>Hydrogel</td><td>Glycolated chitosan/PEG-BA</td><td>G' = 1.2 kPa</td><td>Hole</td><td>6 h</td><td>—</td><td>In vitro, 30 d</td><td>[42]</td></tr><tr><td>Hydrogel</td><td>Chitosan-g-aniline/PEG-BA</td><td>G' = 2 kPa</td><td>Cut</td><td>Immediately</td><td>—</td><td>In vivo, 45 d</td><td>[33]</td></tr><tr><td>Hydrogel</td><td>CMC/PEG-BA</td><td>G' up to 3 kPa</td><td>Cut</td><td>12 h, 37 °C</td><td>94%</td><td>—</td><td>[43]</td></tr><tr><td>Hydrogel</td><td>Quaternized methacryloyl chitosan/PEG-BA</td><td>G' = 0.9 to 8 kPa</td><td>Cut</td><td>120 min, 37 °C</td><td>—</td><td>In vivo, 7 d</td><td>[44]</td></tr><tr><td>Hydrogel</td><td>Zwitterionic L-GA-chitosan/PEG-BA</td><td>G' = 4 to 31 kPa</td><td>Syringe injection</td><td>1 h in air, 2 h in PBS</td><td>—</td><td>In vitro, 40% mass loss after 30 d at pH 7.4, 56% at pH 6.5</td><td>[45]</td></tr><tr><td>Hydrogel</td><td>CEC/PEG-BA<br>Polyacrylamide</td><td>σ<sub>max</sub> = 460 kPa<br>ε<sub>max</sub> = 4600%</td><td>Cut</td><td>24 h<br>35 °C, alkaline conditions</td><td>84% (σ<sub>max</sub>)<br>93% (ε<sub>max</sub>)</td><td>—</td><td>[46]</td></tr><tr><td>Hydrogel</td><td>N-[3-(4-hydroxyphenyl)propanamido] chitosan/Dibenzaldehyde Pluronic</td><td>G' = 0.4 to 1.2 kPa</td><td>Syringe injection</td><td>1 h</td><td>> 95% (G')</td><td>—</td><td>[47]</td></tr><tr><td>Hydrogel</td><td>CEC/A-HA</td><td>G' = 2 to 6 kPa</td><td>Crack</td><td>3 min</td><td>—</td><td>In vitro, 34% mass loss in 10 d</td><td>[36]</td></tr><tr><td>Hydrogel</td><td>N-succinyl-chitosan/Chondroitin sulfate multiple aldehydes</td><td>G' = 4 kPa</td><td>Cut</td><td>2 h, moisture</td><td>—</td><td>In vivo, 60% degradation in 7w</td><td>[31]</td></tr><tr><td>Hydrogel</td><td>CEC/A-Alg</td><td>G' = 0.08 to 2 kPa</td><td>Syringe injection</td><td>5 min, physiological conditions</td><td>—</td><td>In vitro, 100% degradation in 3 to 14 d</td><td>[32]</td></tr><tr><td>Hydrogel</td><td>CMC/Aldehyde-functional carboxymethyl cellulose</td><td>G' = 200 to 600 Pa</td><td>Cut</td><td>6 to 15 min</td><td>65-83% (G')</td><td>In vitro, 50 to 75% mass loss in 3w with lysozyme, 40 to 60% without</td><td>[37]</td></tr><tr><td>Hydrogel</td><td>Glycolated chitosan/A-Dex</td><td>G' = 30 Pa to 1 kPa</td><td>Syringe injection</td><td>120 min</td><td>80% (G')</td><td>In vitro, 40 to 80% mass loss in 2 weeks</td><td>[35]</td></tr><tr><td>Hydrogel</td><td>CMC/A-Dex</td><td>G' = 11 Pa</td><td>Cut, Hole</td><td>30 min<br>90 min</td><td>—</td><td>In vivo, 21 d</td><td>[48]</td></tr><tr><td>Hydrogel</td><td>CEC/Dextran-g-aniline tetramer-g-4-formylbenzoic acid</td><td>G' = 0.3 to 0.65 kPa</td><td>Cut</td><td>12 h, 37 °C, humid atmosphere</td><td>—</td><td>In vitro, 74% to 91% degradation in 8 d</td><td>[34]</td></tr><tr><td>Hydrogel</td><td>Acrylamide modified chitin/A-Alg</td><td>G' = 600 Pa</td><td>Crack</td><td>60min</td><td>—</td><td>—</td><td>[38]</td></tr><tr><td>Hydrogel</td><td>N-furfural chitosan/A-Dex<br>Bismaleimide-PEG</td><td>G' = 0.6 to 3 kPa</td><td>Cut</td><td>3 h<br>25 °C</td><td>100% (G')</td><td>In vitro, 20 to 50% degradation with lysozyme</td><td>[49]</td></tr><tr><td>Hydrogel</td><td>CMC/A-Alg<br>HAp<br>CaCO<sub>3</sub></td><td>G' = 2 to 6 kPa</td><td>Syringe injection</td><td>—</td><td>—</td><td>In vitro, 40 to 86% weight loss in 2 weeks</td><td>[50]</td></tr><tr><td>Hydrogel</td><td>CMC/A-Alg<br>MGMs</td><td>G' = 3 to 10 kPa</td><td>Cut</td><td>2 h</td><td>97% (G')</td><td>In vitro, 10 to 30% mass loss in 2 weeks</td><td>[51]</td></tr><tr><td>Hydrogel</td><td>Chitosan/PEG-BA<br>Fe<sub>2</sub>O<sub>4</sub> particles</td><td>G' up to 2 kPa</td><td>Hole</td><td>1 h</td><td>—</td><td>—</td><td>[52]</td></tr><tr><td>Hydrogel</td><td>CEC/A-HA<br>Carbonyl iron magnetic particles</td><td>G' = 1 to 30 Pa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, 30 to 75% mass loss in 4d</td><td>[53]</td></tr><tr><td>Hydrogel</td><td>L-arginine conjugated chitosan/PEG-BA<br>pDA-NPs</td><td>G' = 230 to 1100 Pa</td><td>Cut</td><td>5min</td><td>—</td><td>In vitro, 50 to 75% degradation in 14d</td><td>[54]</td></tr><tr><td>Hydrogel</td><td>CMC/Poly(dextran-g-4-formylbenzoic acid)<br>Peptide nanofibers</td><td>G' = 91 to 700 Pa</td><td>Cut</td><td>2min</td><td>—</td><td>In vitro, 70 to 90% mass loss with lysozyme after 9d</td><td>[55]</td></tr><tr><td>Hydrogel</td><td>Chitosan/Aldehyde functional polyurethane nanoparticles</td><td>G' = 700 Pa</td><td>Cut</td><td>1 h, RT</td><td>—</td><td>In vitro, 5 to 20% mass loss in 1m</td><td>[56]</td></tr><tr><td>Hydrogel</td><td>Ethylenediamine functional gelatin/Dialdehyde carboxymethylcellulose</td><td>G' up to 60 kPa</td><td>Cut</td><td>1h</td><td>90%</td><td>In vitro, 75% mass loss after 12d, 80% after 2m</td><td>[57]</td></tr></tbody></table>
<table><caption>**Table 1. Continued.**</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Aldehyde-modified xanthan gum/Phosphatidylethanolamine liposomes</td><td>G' = 1 to 100 Pa</td><td>Syringe injection<br>Cut</td><td>10 min<br>15min</td><td>—</td><td>In vitro, in presence of histidine or papain</td><td>[58]</td></tr><tr><td>Hydrogel</td><td>Polyethylenimine/Aldehyde and ammonium functional copolymer poly(4-formylphenyl methacrylate-co-2-(methacryloyloxy)ethyl trimethylammonium chloride)<br>PNIPAM</td><td>G' = 1 to 2 kPa</td><td>Cut</td><td>30 min, RT</td><td>—</td><td>In vitro, 80% mass loss in 24 h at pH 5.4, 37% at pH 7.4</td><td>[59]</td></tr><tr><td>Elastomer</td><td>Synthetic polyester based on terephthaldehyde, tri(2-aminoethyl) amiben trioxatridecanediamine, and dehamethylediamine monomers</td><td>E = 1–20 MPa<br>σ<sub>max</sub> = 4.2–16.7 MPa</td><td>Crack</td><td>3 min, 55 °C</td><td>100% (Visual)</td><td>In vitro, 100% degradation after 48 h at pH = 1</td><td>[60]</td></tr></tbody></table>

A-Alg, aldehyde-modified alginate; A-Dex, aldehyde-modified dextran; A-HA, aldehyde-modified hyaluronic acid; CEC, carboxyethyl chitosan; CMC, carboxymethyl chitosan; E, Young's modulus; G', storage modulus; HAp, hydroxyapatite; L-GA, L-glutamic acid; MGMs, magnetic gelatin microspheres; PDA-NPs, polydopamine nanoparticles; PEG, poly(ethylene glycol); PEG-BA, benzaldehyde poly(ethylene) glycol; PNIPAM, poly(N-isopropylacrylamide); ε<sub>max</sub>, strain at break; σ<sub>max</sub>, stress at break.

This led to an increase in G' to 6 kPa compared with that of 2 kPa without particles. It also stabilized the network, which displayed a limited mass loss of 40% compared to that of 86% without particles after 2 weeks. Various magnetic particles have been incorporated to produce hydrogels with magnetic field-dependent rheological properties. To this end, magnetic gelatin microspheres (MGMs) loaded with Fe₃O₄ nanoparticles were added to a CMC/A-Alg hydrogel,[51] Fe₃O₄ particles were mixed into a chitosan/PEG-BA matrix,[52] and carbonyl iron magnetic particles were added to CEC/A-HA.[53]

To improve the mechanical properties and increase the stabilities of hydrogels, Ling et al. [54] prepared hydrogels with L-arginine-conjugated chitosan and PEG-BA containing polydopamine nanoparticles (pDA-NPs) that enabled an increase in G' of ≈400%. Conversely, an increase of 66% was reported by Qiu et al. [55] upon reinforcement of CMC/poly(dextran-g-4-formylbenzoic acid) hydrogels with peptide nanofibers. Finally, a hybrid system composed of chitosan and aldehyde-functional polyurethane (PU) nanoparticles yielded Schiff-base self-healing hydrogels.[56] PU was obtained via the reaction of polycaprolactone (PCL) diol and poly(1,4-butylene adipate) (HTPBA) diol with isophorone diisocyanate (IPDI) and modified with glyoxal. After damage, the gel fully healed after 1 h at room temperature and could endure stretching without breaking, whereas, under repeated damage-healing cycles under oscillatory strain, it fully recovered its initial G' at ≈700 Pa. The latter example displayed the slowest in vitro degradation, with a limited mass loss of 20% after one month.

### 4.1.4. Other Schiff-base hydrogels

Other examples of self-healable hydrogels based on Schiff bases but without chitosan as the source of primary amine groups have been reported. Lei et al. [57] prepared a stiff self-repairing hydrogel using ethylenediamine-functionalized gelatin that reacted with dialdehyde carboxymethyl cellulose. Such hydrogels exhibited high G' values compared to those of the other systems, with G' values of up to 60 kPa, high SHEs

of 90% after 1 h, and rapid initial degradation, with 25% mass remaining at day 12. Ma et al. [58] developed a biodegradable, injectable polymer-liposome hydrogel based on aldehyde-modified xanthan gum cross-linked with phosphatidylethanolamine liposomes. The hydrogel exhibited rapid self-healing (<15 min) but a low G' of 1–100 Pa. Remarkably, degradation depended on the environment. It was rapid in the presence of histidine, due to substitution within the original Schiff-base linkages, or papain, due to xanthan enzymatic degradation, but no degradation was observed in water.

Finally, using fully synthetic, potentially eliminable polymers, Wang et al. [59] reported an injectable Schiff base-containing hydrogel with thermoresponsive and antimicrobial properties obtained by combining aldehyde- and ammonium-functionalized poly(4-formylphenyl methacrylate-co-2-(methacryloyloxy) ethyl trimethylammonium chloride), poly(N-isopropylacrylamide) (PNIPAM), and polyethylenimine.

### 4.1.5. Schiff-base elastomers

As demonstrated by these examples, Schiff-base dynamic cross-linking is a powerful, widely used approach in designing degradable, self-healing hydrogels. However, this strategy remains in its infancy in yielding degradable, self-healing elastomers for use in biomedical applications, with only one example reported to date. Li et al. designed dynamic covalent elastomers using terephthaldehyde, various diamines, and tri(2-aminoethyl)amine as cross-linking agents.[60] The networks obtained displayed glass transition temperatures (T<sub>g</sub>) of 7–60 °C, strain at break (ε<sub>max</sub>) values of up to 170%, and stress at break (σ<sub>max</sub>) values of 1–20 MPa. However, they exhibited mostly plastic behaviors rather than elastomeric behaviors, with marked plastic deformations. Self-healing was realized upon heating to enable chain motion, which was applied to the scratched samples, with healing temperatures ranging from 20 to 55 °C. Although not composed of degradable precursors, this material could fully disintegrate within 48 h under acidic conditions.
<table><caption>**Table 1. Continued.**</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Aldehyde-modified xanthan gum/Phosphatidylethanolamine liposomes</td><td>G' = 1 to 100 Pa</td><td>Syringe injection<br>Cut</td><td>10 min<br>15min</td><td>—</td><td>In vitro, in presence of histidine or papain</td><td>[58]</td></tr><tr><td>Hydrogel</td><td>Polyethylenimine/Aldehyde and ammonium functional copolymer poly(4-formylphenyl methacrylate-co-2-(methacryloyloxy)ethyl trimethylammonium chloride)<br>PNIPAM</td><td>G' = 1 to 2 kPa</td><td>Cut</td><td>30 min, RT</td><td>—</td><td>In vitro, 80% mass loss in 24 h at pH 5.4, 37% at pH 7.4</td><td>[59]</td></tr><tr><td>Elastomer</td><td>Synthetic polyester based on terephthaldehyde, tri(2-aminoethyl) amiben trioxatridecanediamine, and dehamethylediamine monomers</td><td>E = 1–20 MPa<br>σ<sub>max</sub> = 4.2–16.7 MPa</td><td>Crack</td><td>3 min, 55 °C</td><td>100% (Visual)</td><td>In vitro, 100% degradation after 48 h at pH = 1</td><td>[60]</td></tr></tbody></table>

A-Alg, aldehyde-modified alginate; A-Dex, aldehyde-modified dextran; A-HA, aldehyde-modified hyaluronic acid; CEC, carboxyethyl chitosan; CMC, carboxymethyl chitosan; E, Young's modulus; G', storage modulus; HAp, hydroxyapatite; L-GA, L-glutamic acid; MGMs, magnetic gelatin microspheres; PDA-NPs, polydopamine nanoparticles; PEG, poly(ethylene glycol); PEG-BA, benzaldehyde poly(ethylene) glycol; PNIPAM, poly(N-isopropylacrylamide); ε<sub>max</sub>, strain at break; σ<sub>max</sub>, stress at break.

This led to an increase in G' to 6 kPa compared with that of 2 kPa without particles. It also stabilized the network, which displayed a limited mass loss of 40% compared to that of 86% without particles after 2 weeks. Various magnetic particles have been incorporated to produce hydrogels with magnetic field-dependent rheological properties. To this end, magnetic gelatin microspheres (MGMs) loaded with Fe₃O₄ nanoparticles were added to a CMC/A-Alg hydrogel,[51] Fe₃O₄ particles were mixed into a chitosan/PEG-BA matrix,[52] and carbonyl iron magnetic particles were added to CEC/A-HA.[53]

To improve the mechanical properties and increase the stabilities of hydrogels, Ling et al. [54] prepared hydrogels with L-arginine-conjugated chitosan and PEG-BA containing polydopamine nanoparticles (pDA-NPs) that enabled an increase in G' of ≈400%. Conversely, an increase of 66% was reported by Qiu et al. [55] upon reinforcement of CMC/poly(dextran-g-4-formylbenzoic acid) hydrogels with peptide nanofibers. Finally, a hybrid system composed of chitosan and aldehyde-functional polyurethane (PU) nanoparticles yielded Schiff-base self-healing hydrogels.[56] PU was obtained via the reaction of polycaprolactone (PCL) diol and poly(1,4-butylene adipate) (HTPBA) diol with isophorone diisocyanate (IPDI) and modified with glyoxal. After damage, the gel fully healed after 1 h at room temperature and could endure stretching without breaking, whereas, under repeated damage-healing cycles under oscillatory strain, it fully recovered its initial G' at ≈700 Pa. The latter example displayed the slowest in vitro degradation, with a limited mass loss of 20% after one month.

### 4.1.4. Other Schiff-base hydrogels

Other examples of self-healable hydrogels based on Schiff bases but without chitosan as the source of primary amine groups have been reported. Lei et al. [57] prepared a stiff self-repairing hydrogel using ethylenediamine-functionalized gelatin that reacted with dialdehyde carboxymethyl cellulose. Such hydrogels exhibited high G' values compared to those of the other systems, with G' values of up to 60 kPa, high SHEs

of 90% after 1 h, and rapid initial degradation, with 25% mass remaining at day 12. Ma et al. [58] developed a biodegradable, injectable polymer-liposome hydrogel based on aldehyde-modified xanthan gum cross-linked with phosphatidylethanolamine liposomes. The hydrogel exhibited rapid self-healing (<15 min) but a low G' of 1–100 Pa. Remarkably, degradation depended on the environment. It was rapid in the presence of histidine, due to substitution within the original Schiff-base linkages, or papain, due to xanthan enzymatic degradation, but no degradation was observed in water.

Finally, using fully synthetic, potentially eliminable polymers, Wang et al. [59] reported an injectable Schiff base-containing hydrogel with thermoresponsive and antimicrobial properties obtained by combining aldehyde- and ammonium-functionalized poly(4-formylphenyl methacrylate-co-2-(methacryloyloxy) ethyl trimethylammonium chloride), poly(N-isopropylacrylamide) (PNIPAM), and polyethylenimine.

### 4.1.5. Schiff-base elastomers

As demonstrated by these examples, Schiff-base dynamic cross-linking is a powerful, widely used approach in designing degradable, self-healing hydrogels. However, this strategy remains in its infancy in yielding degradable, self-healing elastomers for use in biomedical applications, with only one example reported to date. Li et al. designed dynamic covalent elastomers using terephthaldehyde, various diamines, and tri(2-aminoethyl)amine as cross-linking agents.[60] The networks obtained displayed glass transition temperatures (T<sub>g</sub>) of 7–60 °C, strain at break (ε<sub>max</sub>) values of up to 170%, and stress at break (σ<sub>max</sub>) values of 1–20 MPa. However, they exhibited mostly plastic behaviors rather than elastomeric behaviors, with marked plastic deformations. Self-healing was realized upon heating to enable chain motion, which was applied to the scratched samples, with healing temperatures ranging from 20 to 55 °C. Although not composed of degradable precursors, this material could fully disintegrate within 48 h under acidic conditions.
<table><caption>**Table 2.** Self-healing hydrogels based on boronate ester bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials<br>Boronate polymer/Diol polymer</th><th>Mechanical<br>properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Poly(methacryloyloxyethyl phosphorylcholine) functionalized with benzoxaborole or catechol pendant groups</td><td>G' = 0.1 kPa</td><td>Cut</td><td>1 min</td><td>—</td><td>In vitro, 20 min in the presence of fructose, immediately with HCl 0.1 M</td><td>[61]</td></tr><tr><td>Hydrogel</td><td>5-methacrylamido-1,2-benzoxaborole<br>3-gluconamidopropyl methacrylamide<br>Acrylamide</td><td>G' = 1 kPa</td><td>Cut</td><td>5 min</td><td>—</td><td>—</td><td>[62]</td></tr><tr><td>Hydrogel</td><td>MAABO/Nopoldiol<br>2-glucoamidoethylmethacrylamide<br>PEG methyl ether methacrylate</td><td>G' = 10 Pa to 4 kPa</td><td>Cut</td><td>20 s</td><td>—</td><td>In vitro, in the presence of H<sub>2</sub>O<sub>2</sub></td><td>[63]</td></tr><tr><td>Hydrogel</td><td>Poly(DMA-st-MAABO)<br>2-lactobionamidoethyl methacrylamide,<br>exhibiting galactose residues on the surface</td><td></td><td>Cut</td><td>1 min</td><td>—</td><td>In vitro, in the presence of fructose, ATP, H<sub>2</sub>O<sub>2</sub>, or in acidic conditions</td><td>[64]</td></tr><tr><td>Hydrogel</td><td>Phenylboronic acid modified 4-armed PEG/<br>Dopamine functionalized 4-armed PEG</td><td>G' = 20 kPa</td><td>Cut</td><td>30 s</td><td>—</td><td>In vitro, acidic or basic conditions, in the presence of glucose or dopamine</td><td>[65]</td></tr><tr><td>Hydrogel</td><td>Poly(aspartic acid) derivatives with boronic acid groups/PVA</td><td>G' = 200 to 400 Pa</td><td>Cut</td><td>1 min, 1 h, or 12 h depending on the composition</td><td>100% (G')</td><td>—</td><td>[66]</td></tr><tr><td>Hydrogel</td><td>Alginate grafted with phenylboronic acid/PVA</td><td>G' = 1 kPa</td><td>Cut</td><td>30 s</td><td>100% (G')</td><td>—</td><td>[67]</td></tr><tr><td>Hydrogel</td><td>Carboxyethyl cellulose grafted with phenylboronic acid/PVA</td><td>G' = 40 to 1000 Pa</td><td>Cut</td><td>12 h</td><td>>95% (σ<sub>max</sub>)<br>100% (G')</td><td>—</td><td>[68]</td></tr><tr><td>Hydrogel</td><td>3-aminophenylboronic acid modified sodium alginate/Methacrylated hyaluronic acid</td><td>G' = 300 Pa</td><td>Cut, Hole</td><td>10 min</td><td>100% (G')</td><td>In vivo</td><td>[69]</td></tr><tr><td>Hydrogel</td><td>Poly(acrylamide-co-dopamine methacrylamide)<br>bis(phenylboronic acid carbamoyl) cystamine/PVA</td><td>G' = 1 kPa</td><td>Cut</td><td>1 to 5 min</td><td>100% (G')</td><td>—</td><td>[70]</td></tr><tr><td>Hydrogel</td><td>CTL<br>Boric acid<br>Mannitol</td><td>G' = 20 Pa</td><td>Cut</td><td>5 min</td><td>—</td><td>In vitro, in the presence of lysozyme</td><td>[71]</td></tr></tbody></table>

CTL, lactose modified chitosan; DMA, N-N-dimethylacrylamide; G', storage modulus; MAABO, 5-methacrylamido-1,2-benzoxaborole; nopoldiol, (1R)-(-)-nopol-methacrylamido-diol; PVA, poly(vinyl alcohol); σ<sub>max</sub>, stress at break.

## 4.2. Boronate Ester Bond

The use of reversible boronate ester bonds is another method of preparing self-healing degradable hydrogels, as indicated by the larger number of biomaterials developed recently containing these bonds (Table 2). Boronate ester bonds are formed via the complexation of boronic acid and diol, and their stabilities depend on the pH and concentration of free alcohol groups acting as binding competitors (e.g., glucose in vivo). If the pH is higher than the pKa of the diol (generally below alkaline pH), the ionization of the diol may be initiated, leading to the formation of a stable borate ester. Numerous boronic acid derivatives have been developed, but oxa- and benzoxaboroles are the most common, whereas sugar derivatives or catechol groups are classically used as diols/polyols.

Two strategies yield boronate ester-based self-healable materials, depending on the natures of the partners bearing the complementary reactive groups, which may be two polymers (synthetic or biopolymers) or a polymer and low-molecular-

weight compound. These distinctions are used to classify the various examples. Notably, owing to the reversibility of the boronate ester bond under various conditions (competitors, pH, oxidation), it is a bond of choice in designing networks using non-degradable polymers while guaranteeing their bioelimination.

### 4.2.1. Boronate Ester-based Hydrogels Prepared Using Synthetic Polymers

Among the synthetic polymers, polyacrylic derivatives bearing (benz)oxaborole groups have mainly been used to yield boronate ester-based hydrogels. Such hydrogels are soft and typically exhibit rapid self-healing times of <5 min, e.g., very soft catechol-based hydrogels (G' = 0.1 kPa) were designed using zwitterionic copolymers of poly(methacryloyloxyethyl phosphorylcholine) functionalized with benzoxaborole or catechol pendant groups.[61]
<table><caption>**Table 2.** Self-healing hydrogels based on boronate ester bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials<br>Boronate polymer/Diol polymer</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Poly(methacryloyloxyethyl phosphorylcholine) functionalized with benzoxaborole or catechol pendant groups</td><td>G' = 0.1 kPa</td><td>Cut</td><td>1 min</td><td>—</td><td>In vitro, 20 min in the presence of fructose, immediately with HCl 0.1 M</td><td>[61]</td></tr><tr><td>Hydrogel</td><td>5-methacrylamido-1,2-benzoxaborole<br>3-gluconamidopropyl methacrylamide<br>Acrylamide</td><td>G' = 1 kPa</td><td>Cut</td><td>5 min</td><td>—</td><td>—</td><td>[62]</td></tr><tr><td>Hydrogel</td><td>MAABO/Nopoldiol<br>2-glucoamidoethylmethacrylamide<br>PEG methyl ether methacrylate</td><td>G' = 10 Pa to 4 kPa</td><td>Cut</td><td>20 s</td><td>—</td><td>In vitro, in the presence of H<sub>2</sub>O<sub>2</sub></td><td>[63]</td></tr><tr><td>Hydrogel</td><td>Poly(DMA-st-MAABO)<br>2-lactobionamidoethyl methacrylamide,<br>exhibiting galactose residues on the surface</td><td></td><td>Cut</td><td>1 min</td><td>—</td><td>In vitro, in the presence of fructose, ATP, H<sub>2</sub>O<sub>2</sub>, or in acidic conditions</td><td>[64]</td></tr><tr><td>Hydrogel</td><td>Phenylboronic acid modified 4-armed PEG/<br>Dopamine functionalized 4-armed PEG</td><td>G' = 20 kPa</td><td>Cut</td><td>30 s</td><td>—</td><td>In vitro, acidic or basic conditions, in the presence of glucose or dopamine</td><td>[65]</td></tr><tr><td>Hydrogel</td><td>Poly(aspartic acid) derivatives with boronic acid groups/PVA</td><td>G' = 200 to 400 Pa</td><td>Cut</td><td>1 min, 1 h, or 12 h depending on the composition</td><td>100% (G')</td><td>—</td><td>[66]</td></tr><tr><td>Hydrogel</td><td>Alginate grafted with phenylboronic acid/PVA</td><td>G' = 1 kPa</td><td>Cut</td><td>30 s</td><td>100% (G')</td><td>—</td><td>[67]</td></tr><tr><td>Hydrogel</td><td>Carboxyethyl cellulose grafted with phenylboronic acid/PVA</td><td>G' = 40 to 1000 Pa</td><td>Cut</td><td>12 h</td><td>>95% (σ<sub>max</sub>)<br>100% (G')</td><td>—</td><td>[68]</td></tr><tr><td>Hydrogel</td><td>3-aminophenylboronic acid modified sodium alginate/Methacrylated hyaluronic acid</td><td>G' = 300 Pa</td><td>Cut, Hole</td><td>10 min</td><td>100% (G')</td><td>In vivo</td><td>[69]</td></tr><tr><td>Hydrogel</td><td>Poly(acrylamide-co-dopamine methacrylamide)<br>bis(phenylboronic acid carbamoyl) cystamine/PVA</td><td>G' = 1 kPa</td><td>Cut</td><td>1 to 5 min</td><td>100% (G')</td><td>—</td><td>[70]</td></tr><tr><td>Hydrogel</td><td>CTL<br>Boric acid<br>Mannitol</td><td>G' = 20 Pa</td><td>Cut</td><td>5 min</td><td>—</td><td>In vitro, in the presence of lysozyme</td><td>[71]</td></tr></tbody></table>

CTL, lactose modified chitosan; DMA, N-N-dimethylacrylamide; G', storage modulus; MAABO, 5-methacrylamido-1,2-benzoxaborole; nopoldiol, (1R)-(-)-nopol-methacrylamido-diol; PVA, poly(vinyl alcohol); σ<sub>max</sub>, stress at break.

## 4.2. Boronate Ester Bond

The use of reversible boronate ester bonds is another method of preparing self-healing degradable hydrogels, as indicated by the larger number of biomaterials developed recently containing these bonds (Table 2). Boronate ester bonds are formed via the complexation of boronic acid and diol, and their stabilities depend on the pH and concentration of free alcohol groups acting as binding competitors (e.g., glucose in vivo). If the pH is higher than the pKa of the diol (generally below alkaline pH), the ionization of the diol may be initiated, leading to the formation of a stable borate ester. Numerous boronic acid derivatives have been developed, but oxa- and benzoxaboroles are the most common, whereas sugar derivatives or catechol groups are classically used as diols/polyols.

Two strategies yield boronate ester-based self-healable materials, depending on the natures of the partners bearing the complementary reactive groups, which may be two polymers (synthetic or biopolymers) or a polymer and low-molecular-

weight compound. These distinctions are used to classify the various examples. Notably, owing to the reversibility of the boronate ester bond under various conditions (competitors, pH, oxidation), it is a bond of choice in designing networks using non-degradable polymers while guaranteeing their bioelimination.

### 4.2.1. Boronate Ester-based Hydrogels Prepared Using Synthetic Polymers

Among the synthetic polymers, polyacrylic derivatives bearing (benz)oxaborole groups have mainly been used to yield boronate ester-based hydrogels. Such hydrogels are soft and typically exhibit rapid self-healing times of <5 min, e.g., very soft zwitterionic copolymers of poly(methacryloyloxyethyl phosphorylcholine) functionalized with benzoxaborole or catechol pendant groups.[61]
Among the acrylic monomers containing oxaborole groups used to yield self-healable hydrogels, 5-methacrylamido-1,2-benzoxaborole (MAABO) is commonly used. MAABO was copolymerized with 3-gluconamidopropyl methacrylamide and acrylamide.[62] Poly(ethylene glycol) methyl ether methacrylate was also copolymerized with MAABO, (1R)-(-)-nopol-methacrylamido-diol and 2-gluconamidoethyl methacrylamide to prepare dual-cross-linked hydrogels that exhibited self-healing properties in a wide range of pH values (8.5–1.5) and degradabilities under oxidative conditions.[63] Finally, cross-linked nanogels of NIPAM, N,N-methylenebisacrylamide, and 2-lactobionamidoethyl methacrylamide, bearing galactose residues on their surfaces, were used as cross-linkers to form a hydrogel network via the formation of dynamic adducts with the benzoxaborole groups of hydrophilic poly(dimethylacrylamide (DMA)-co-MAABO) copolymers.[64]

In addition to polyacrylics, a few examples of fully synthetic boronate ester-based hydrogels, which were prepared using PEG or polyvinyl alcohol (PVA), have been reported. Injectable hydrogels based on dopamine-functionalized 4-arm PEG and phenylboronic acid-modified 4-arm PEG exhibited G' values of 20 kPa and short self-healing times of 30 s.[65] In another example, PVA was mixed with poly(aspartic acid) derivatives bearing quaternary ammonium groups with bactericidal properties and boronic acid groups to yield materials with G' values of 200–400 Pa with fast (1 min) or slow (up to 12 h) healing times.[66]

In addition to their rapid self-healing properties, these boronate ester-based hydrogels displayed good cytocompatibility and could be easily degraded under competitive exchange (e.g., with fructose, adenosine triphosphate, or dopamine), oxidative (e.g., with hydrogen peroxide), or acidic conditions.

### 4.2.2. Boronate Ester-based Hydrogels Prepared Using Biopolymers

Biopolymers have been used to develop boronate ester-based hydrogels by exploiting the ease of functionalization provided by the reactive groups on their backbones. PVA was combined with alginate grafted with phenylboronic acid to yield a hydrogel that healed in only 30 s,[67] whereas its association with carboxyethyl cellulose grafted with phenylboronic acid led to gels requiring 12 h to heal.[68] In another example, methacrylated HA was associated with 3-aminophenylboronic acid-modified sodium alginate to develop soft hydrogels (G' = 300 Pa) with short self-healing times of 10 min.[69]

### 4.2.3. Boronate ester-Based Hydrogels Formed via the Associations of Polymers and Low Molecular Weight Cross-linkers

Low-molecular-weight polyboronic or polyol compounds have been used as cross-linkers to yield boronate ester-based hydrogels. Using a bis(phenylboronic acid carbamoyl) cystamine cross-linker with PVA and poly(acrylamide-co-dopamine methacrylamide), Guo et al. prepared soft gels, which displayed G' values of 1 kPa and rapid self-repair times of <5 min.[70] Boric acid and lactose-modified chitosan (CTL) were combined in the presence of the polyol competitor mannitol to reduce the very fast kinetics of CTL/boron self-assembly and avoid syneresis to

form homogeneous but weak gels (G' ≈ 20 Pa) under physiological conditions.[71] These CTL-boric acid gels were repaired after 5 min and stretched by >500%.

## 4.3. Hydrazone Bond

Hydrazone bonds are reversible covalent bonds formed via reactions between aldehyde and hydrazine groups. Owing to their sensitivities to pH, they are the cornerstones of numerous biodegradable self-healing hydrogels. Similar to imine bond-based materials, most systems described include at least one biopolymer in their design, whereas only a few examples of fully synthetic materials are reported in the recent literature (Table 3).

### 4.3.1. Hydrazone-based Hydrogels Prepared Using Biopolymers

Qin et al. contributed to the development of such hydrazone-based hydrogels with a light-emitting self-healable hydrogel prepared using tetraphenylethylene-poly(N,N-dimethylacrylamide-stat-diacetone acrylamide)$_2$ and acylhydrazide-functionalized pectin [72] and a hydrogel composed of pectin aldehyde and acylhydrazide-functionalized poly(NIPAM-stat-acylhydrazide).[73] Both hydrogels could heal in 24 h, degraded upon exposure to a pectinase solution, and exhibited G' values of ≈ 1 kPa, regardless of the concentrations or ratios investigated. Stiffer hydrogels with G' values of >3 kPa were obtained by mixing aldehyde- and hydrazide-functionalized HAs.[74] Softer hydrogels (G' < 1 kPa) were prepared by mixing adipic dihydrazide-grafted carboxyethyl chitin and PEG-BA,[75] cross-linking oxidized xanthan with an 8-arm PEG-hydrazine,[76] or mixing hyperbranched PEG-based multi-hydrazide, A-HA, and gelatin.[77] These soft gels healed within 2–24 h and displayed slow mass losses when incubated in buffer solutions. For instance, a maximum degree of degradation of 9.2% after 30 d at pH 7.4 and 36.8% at pH 5.5 were obtained for the xanthan-PEG system. However, degradation could be significantly increased in the presence of collagenase [74] or lysozyme.[75]

Finally, two self-healing hydrogels that exhibited degradabilities under specific conditions were reported. Chen et al. fabricated hydrogels using pectin acylhydrazide and poly(DMA-stat-4-formylphenyl acrylate (FPA)).[78] When exposed to sodium carbonate, the gels degraded in 24 h, whereas degradation required ≈ 1 week with sodium bicarbonate. In another example, hydrogels prepared using A-HA and 3,3'-dithiobis(propionic hydrazide) were developed to provide a variety of degradation kinetics ranging from 4 h to 5 weeks, depending on the redox and enzymatic conditions.[79] Both gels exhibited G' values of ≈ 2 kPa and self-healed within a few hours.

### 4.3.2. Hydrazone-based Hydrogels Prepared Using Synthetic Polymers

Qin et al. developed fully synthetic hydrazone-based self-healing hydrogels with G' values of ≈ 1 kPa. Acylhydrazone-containing hydrogels were prepared by cross-linking P(NIPAM-FPA-DMA) copolymers with 3,3'-dithiobis(propionohydrazide) or
Among the acrylic monomers containing oxaborole groups used to yield self-healable hydrogels, 5-methacrylamido-1,2-benzoxaborole (MAABO) is commonly used. MAABO was copolymerized with 3-gluconamidopropyl methacrylamide and acrylamide.[62] Poly(ethylene glycol) methyl ether methacrylate was also copolymerized with MAABO, (1R)-(-)-nopol-methacrylamido-diol and 2-gluconamidoethyl methacrylamide to prepare dual-cross-linked hydrogels that exhibited self-healing properties in a wide range of pH values (8.5–1.5) and degradabilities under oxidative conditions.[63] Finally, cross-linked nanogels of NIPAM, N,N-methylenebisacrylamide, and 2-lactobionamidoethyl methacrylamide, bearing galactose residues on their surfaces, were used as cross-linkers to form a hydrogel network via the formation of dynamic adducts with the benzoxaborole groups of hydrophilic poly(dimethylacrylamide (DMA)-co-MAABO) copolymers.[64]

In addition to polyacrylics, a few examples of fully synthetic boronate ester-based hydrogels, which were prepared using PEG or polyvinyl alcohol (PVA), have been reported. Injectable hydrogels based on dopamine-functionalized 4-arm PEG and phenylboronic acid-modified 4-arm PEG exhibited G' values of 20 kPa and short self-healing times of 30 s.[65] In another example, PVA was mixed with poly(aspartic acid) derivatives bearing quaternary ammonium groups with bactericidal properties and boronic acid groups to yield materials with G' values of 200–400 Pa with fast (1 min) or slow (up to 12 h) healing times.[66]

In addition to their rapid self-healing properties, these boronate ester-based hydrogels displayed good cytocompatibility and could be easily degraded under competitive exchange (e.g., with fructose, adenosine triphosphate, or dopamine), oxidative (e.g., with hydrogen peroxide), or acidic conditions.

### 4.2.2. Boronate Ester-based Hydrogels Prepared Using Biopolymers

Biopolymers have been used to develop boronate ester-based hydrogels by exploiting the ease of functionalization provided by the reactive groups on their backbones. PVA was combined with alginate grafted with phenylboronic acid to yield a hydrogel that healed in only 30 s,[67] whereas its association with carboxyethyl cellulose grafted with phenylboronic acid led to gels requiring 12 h to heal.[68] In another example, methacrylated HA was associated with 3-aminophenylboronic acid-modified sodium alginate to develop soft hydrogels (G' = 300 Pa) with short self-healing times of 10 min.[69]

### 4.2.3. Boronate ester-Based Hydrogels Formed via the Associations of Polymers and Low Molecular Weight Cross-linkers

Low-molecular-weight polyboronic or polyol compounds have been used as cross-linkers to yield boronate ester-based hydrogels. Using a bis(phenylboronic acid carbamoyl) cystamine cross-linker with PVA and poly(acrylamide-co-dopamine methacrylamide), Guo et al. prepared soft gels, which displayed G' values of 1 kPa and rapid self-repair times of <5 min.[70] Boric acid and lactose-modified chitosan (CTL) were combined in the presence of the polyol competitor mannitol to reduce the very fast kinetics of CTL/boron self-assembly and avoid syneresis to

form homogeneous but weak gels (G' ≈ 20 Pa) under physiological conditions.[71] These CTL-boric acid gels were repaired after 5 min and stretched by >500%.

### 4.3. Hydrazone Bond

Hydrazone bonds are reversible covalent bonds formed via reactions between aldehyde and hydrazine groups. Owing to their sensitivities to pH, they are the cornerstones of numerous biodegradable self-healing hydrogels. Similar to imine bond-based materials, most systems described include at least one biopolymer in their design, whereas only a few examples of fully synthetic materials are reported in the recent literature (Table 3).

#### 4.3.1. Hydrazone-based Hydrogels Prepared Using Biopolymers

Qin et al. contributed to the development of such hydrazone-based hydrogels with a light-emitting self-healable hydrogel prepared using tetraphenylethylene-poly(N,N-dimethylacrylamide-stat-diacetone acrylamide)$_2$ and acylhydrazide-functionalized pectin [72] and a hydrogel composed of pectin aldehyde and acylhydrazide-functionalized poly(NIPAM-stat-acylhydrazide).[73] Both hydrogels could heal in 24 h, degraded upon exposure to a pectinase solution, and exhibited G' values of ≈ 1 kPa, regardless of the concentrations or ratios investigated. Stiffer hydrogels with G' values of >3 kPa were obtained by mixing aldehyde- and hydrazide-functionalized HAs.[74] Softer hydrogels (G' < 1 kPa) were prepared by mixing adipic dihydrazide-grafted carboxyethyl chitin and PEG-BA,[75] cross-linking oxidized xanthan with an 8-arm PEG-hydrazine,[76] or mixing hyperbranched PEG-based multi-hydrazide, A-HA, and gelatin.[77] These soft gels healed within 2–24 h and displayed slow mass losses when incubated in buffer solutions. For instance, a maximum degree of degradation of 9.2% after 30 d at pH 7.4 and 36.8% at pH 5.5 were obtained for the xanthan-PEG system. However, degradation could be significantly increased in the presence of collagenase [74] or lysozyme.[75]

Finally, two self-healing hydrogels that exhibited degradabilities under specific conditions were reported. Chen et al. fabricated hydrogels using pectin acylhydrazide and poly(DMA-stat-4-formylphenyl acrylate (FPA)).[78] When exposed to sodium carbonate, the gels degraded in 24 h, whereas degradation required ≈ 1 week with sodium bicarbonate. In another example, hydrogels prepared using A-HA and 3,3'-dithiobis(propionic hydrazide) were developed to provide a variety of degradation kinetics ranging from 4 h to 5 weeks, depending on the redox and enzymatic conditions.[79] Both gels exhibited G' values of ≈ 2 kPa and self-healed within a few hours.

#### 4.3.2. Hydrazone-based Hydrogels Prepared Using Synthetic Polymers

Qin et al. developed fully synthetic hydrazone-based self-healing hydrogels with G' values of ≈ 1 kPa. Acylhydrazone-containing hydrogels were prepared by cross-linking P(NIPAM-FPA-DMA) copolymers with 3,3'-dithiobis(propionohydrazide) or
<table><caption>**Table 3.** Self-healing hydrogels based on hydrazone bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials<br>Aldehyde polymer/Hydrazine polymer</th><th>Mechanical<br>properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Tetraphenylethylene-poly(DMA-stat-diacetone acrylamide)<sub>2</sub>/Acylhydrazide<br>functionalized pectin</td><td>G' = 0.6 to 2 kPa</td><td>Cut</td><td>24 h, moisture</td><td>—</td><td>—</td><td>[72]</td></tr><tr><td>Hydrogel</td><td>Pectin aldehyde/<br>Poly(NIPAM-stat-acylhydrazide)</td><td>G' = 1 kPa</td><td>Cut</td><td>24 h</td><td>—</td><td>In vitro, in the presence of pectinase<br>or by microbes from the air</td><td>[73]</td></tr><tr><td>Hydrogel</td><td>A-HA/Hydrazide-HA</td><td>G' > 3kPa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, increased in the presence of<br>collagenase</td><td>[74]</td></tr><tr><td>Hydrogel</td><td>PEG-BA/Adipic dihydrazide-grafted<br>carboxyethyl chitin<br>Phe-NH<sub>2</sub></td><td>G' = 1 to 13 Pa</td><td>Cut</td><td>6 h, 37 °C, humid<br>environment</td><td>95% (compres-<br>sive load)</td><td>In vitro, increased in the presence of<br>lysozyme</td><td>[75]</td></tr><tr><td>Hydrogel</td><td>Oxidized xanthan/8-arm<br>PEG-hydrazine</td><td>G' = 190 to 770 Pa</td><td>Cut</td><td>24 h, 37 °C</td><td>—</td><td>In vitro, 9% degradation after 30 d at<br>pH 7.4, 37% at pH 5.5</td><td>[76]</td></tr><tr><td>Hydrogel</td><td>A-HA/Multi-hydrazide PEG<br>Gelatin</td><td>G' = 200 to 400 Pa</td><td>Cut</td><td>2h</td><td>—</td><td>—</td><td>[77]</td></tr><tr><td>Hydrogel</td><td>Poly(DMA-stat-4-FPA)/Pectin<br>achylhydrazide</td><td>G' = 2 kPa</td><td>Cut</td><td>12 h, moisture</td><td>—</td><td>In vitro, 24 h in Na<sub>2</sub>CO<sub>3</sub>, 1 week in<br>NaHCO<sub>3</sub></td><td>[78]</td></tr><tr><td>Hydrogel</td><td>A-HA/3,3'-dithiobis(propionic<br>hydrazide)</td><td>G' = 2.2 kPa</td><td>Cut</td><td>2 h</td><td>100% (G')</td><td>In vitro, 5 weeks in PBS, 4 h in dithio-<br>threitol, 12 to 17 h in H<sub>2</sub>O<sub>2</sub>, 12 to 16 h<br>in hyaluronidase, or under UV-light</td><td>[79]</td></tr><tr><td>Hydrogel</td><td>P(NIPAM-FPA-DMA)/3,3'-dithiobis<br>(propionohydrazide), PEO dihydrazide</td><td>G' = 30 Pa to 5kPa</td><td>Hole</td><td>24 h</td><td>—</td><td>In vitro, 24 h in Na<sub>2</sub>CO<sub>3</sub> and TEA</td><td>[6]</td></tr><tr><td>Hydrogel</td><td>Dialdehyde-PEG/PAEH</td><td>G' = 1 kPa</td><td>Cut</td><td>24 h</td><td>—</td><td>In vitro, 7d in Na<sub>2</sub>CO<sub>3</sub>, 1m in NaHCO<sub>3</sub></td><td>[80]</td></tr></tbody></table>

A-HA, aldehyde-modified hyaluronic acid; DMA, N-N-dimethylacrylamide; FPA, formylphenyl acrylate; G', storage modulus; HA, hyaluronic acid; NIPAM, N-isopropylacrylamide; PAEH, poly(aspartic acid) derivatives with hydrazide functional groups; PEG, poly(ethylene glycol); PEG-BA, benzaldehyde poly(ethylene glycol); PEO, poly (ethylene oxide).

PEG-dihydrazide of various molecular weights.[6] They also prepared hydrogels using hydrazide-functionalized poly(aspartic acid), which was reacted with PEG-dialdehyde.[80] All hydrogels self-healed in 24 h and degraded in sodium carbonate solutions after 24 h (the former) or 7 d (the latter).

## 4.4. Disulfide Bond

Disulfide bonds are among the most commonly used reversible covalent bonds because of their natural occurrence in proteins, and they are critical in protein bioactivities. Disulfide bonds are the oxidized partners of the thiol/disulfide redox couple, and thus, they are easily converted to their thiol counterparts upon reaction with thiols at neutral pH or nucleophilic thiolates at alkaline pH. In contrast to the previously discussed dynamic chemical bonds, disulfide bonds are rarely used in designing degradable self-healing hydrogels. Only one example has been reported in the recent literature, whereas several self-healable disulfide-based elastomers have been reported (Table 4).

### 4.4.1. Disulfide Bond-based Hydrogels

Zhang et al. [81] developed an inherently biodegradable self-healing hydrogel based on bovine serum albumin (BSA), wherein the network structure could reversibly form via the reduction of the disulfide bonds in BSA, followed by re-oxidation.

The gels were soft, with G' values of 1 kPa, could fully self-heal in 2 min in the presence of hydrogen peroxide, and were bio-compatible, as demonstrated using MCF-7 cells.

### 4.4.2. Disulfide Bond-based Elastomers

Although disulfide bonds are not commonly reported in self-healable hydrogels, they have been investigated for their self-healing properties in elastomers. This approach is a component of the general trend aimed at reducing chemical and plastic waste, as these self-healable elastomers are considered sustainable because of their reprocessabilities. Soft elastomers were prepared using a bis(acrylate) monomer (bis(2-(acryloyloxy)ethyl)octadic-9-enedioate) mixed with copolymers of polydimethylsiloxane containing 4–6% (mercaptopropyl)methylsiloxane to formulate an ink for use in 3D printing technology.[82] Thin films with thicknesses of 1 mm exhibited respective E, σ<sub>max</sub>, and ε<sub>max</sub> values of 0.2 MPa, 52 kPa, and 24% at room temperature. Self-healing was realized via heating at 80 °C for 8 h, which led to SHEs of 86% and 100% in terms of tensile strain and strength, respectively. In another example, Yuan et al. prepared self-healing elastomers via the polycondensation of dicarboxylic acids, 1,4-butanediol, glycerol, and 3,3'-dithiodipropionic acid (DTPA).[83] Glycerol and DTPA were used to modulate the properties of the soft elastomers, with E, σ<sub>max</sub>, and ε<sub>max</sub> values in the ranges 0.2–0.9 and 0.4–1.5 MPa and 550–1700%, respectively, as functions of the compositions. Self-healing at 30 °C
<table><caption>**Table 3.** Self-healing hydrogels based on hydrazone bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials<br>Aldehyde polymer/Hydrazine polymer</th><th>Mechanical<br>properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Tetraphenylethylene-poly(DMA-stat-diacetone acrylamide)<sub>2</sub>/Acylhydrazide<br>functionalized pectin</td><td>G' = 0.6 to 2 kPa</td><td>Cut</td><td>24 h, moisture</td><td>—</td><td>—</td><td>[72]</td></tr><tr><td>Hydrogel</td><td>Pectin aldehyde/<br>Poly(NIPAM-stat-acylhydrazide)</td><td>G' = 1 kPa</td><td>Cut</td><td>24 h</td><td>—</td><td>In vitro, in the presence of pectinase<br>or by microbes from the air</td><td>[73]</td></tr><tr><td>Hydrogel</td><td>A-HA/Hydrazide-HA</td><td>G' > 3kPa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, increased in the presence of<br>collagenase</td><td>[74]</td></tr><tr><td>Hydrogel</td><td>PEG-BA/Adipic dihydrazide-grafted<br>carboxyethyl chitin<br>Phe-NH<sub>2</sub></td><td>G' = 1 to 13 Pa</td><td>Cut</td><td>6 h, 37 °C, humid<br>environment</td><td>95% (compres-<br>sive load)</td><td>In vitro, increased in the presence of<br>lysozyme</td><td>[75]</td></tr><tr><td>Hydrogel</td><td>Oxidized xanthan/8-arm<br>PEG-hydrazine</td><td>G' = 190 to 770 Pa</td><td>Cut</td><td>24 h, 37 °C</td><td>—</td><td>In vitro, 9% degradation after 30 d at<br>pH 7.4, 37% at pH 5.5</td><td>[76]</td></tr><tr><td>Hydrogel</td><td>A-HA/Multi-hydrazide PEG<br>Gelatin</td><td>G' = 200 to 400 Pa</td><td>Cut</td><td>2h</td><td>—</td><td>—</td><td>[77]</td></tr><tr><td>Hydrogel</td><td>Poly(DMA-stat-4-FPA)/Pectin<br>achydrazide</td><td>G' = 2 kPa</td><td>Cut</td><td>12 h, moisture</td><td>—</td><td>In vitro, 24 h in Na<sub>2</sub>CO<sub>3</sub>, 1 week in<br>NaHCO<sub>3</sub></td><td>[78]</td></tr><tr><td>Hydrogel</td><td>A-HA/3,3'-dithiobis(propionic<br>hydrazide)</td><td>G' = 2.2 kPa</td><td>Cut</td><td>2 h</td><td>100% (G')</td><td>In vitro, 5 weeks in PBS, 4 h in dithio-<br>threitol, 12 to 17 h in H<sub>2</sub>O<sub>2</sub>, 12 to 16 h<br>in hyaluronidase, or under UV-light</td><td>[79]</td></tr><tr><td>Hydrogel</td><td>P(NIPAM-FPA-DMA)/3,3'-dithiobis<br>(propionohydrazide), PEO dihydrazide</td><td>G' = 30 Pa to 5kPa</td><td>Hole</td><td>24 h</td><td>—</td><td>In vitro, 24 h in Na<sub>2</sub>CO<sub>3</sub> and TEA</td><td>[6]</td></tr><tr><td>Hydrogel</td><td>Dialdehyde-PEG/PAEH</td><td>G' = 1 kPa</td><td>Cut</td><td>24 h</td><td>—</td><td>In vitro, 7d in Na<sub>2</sub>CO<sub>3</sub>, 1m in NaHCO<sub>3</sub></td><td>[80]</td></tr></tbody></table>

A-HA, aldehyde-modified hyaluronic acid; DMA, N-N-dimethylacrylamide; FPA, formylphenyl acrylate; G', storage modulus; HA, hyaluronic acid; NIPAM, N-isopropylacrylamide; PAEH, poly(aspartic acid) derivatives with hydrazide functional groups; PEG, poly(ethylene glycol); PEG-BA, benzaldehyde poly(ethylene glycol); PEO, poly (ethylene oxide).

PEG-dihydrazide of various molecular weights.[6] They also prepared hydrogels using hydrazide-functionalized poly(aspartic acid), which was reacted with PEG-dialdehyde.[80] All hydrogels self-healed in 24 h and degraded in sodium carbonate solutions after 24 h (the former) or 7 d (the latter).

## 4.4. Disulfide Bond

Disulfide bonds are among the most commonly used reversible covalent bonds because of their natural occurrence in proteins, and they are critical in protein bioactivities. Disulfide bonds are the oxidized partners of the thiol/disulfide redox couple, and thus, they are easily converted to their thiol counterparts upon reaction with thiols at neutral pH or nucleophilic thiolates at alkaline pH. In contrast to the previously discussed dynamic chemical bonds, disulfide bonds are rarely used in designing degradable self-healing hydrogels. Only one example has been reported in the recent literature, whereas several self-healable disulfide-based elastomers have been reported (Table 4).

### 4.4.1. Disulfide Bond-based Hydrogels

Zhang et al. [81] developed an inherently biodegradable self-healing hydrogel based on bovine serum albumin (BSA), wherein the network structure could reversibly form via the reduction of the disulfide bonds in BSA, followed by re-oxidation.

The gels were soft, with G' values of 1 kPa, could fully self-heal in 2 min in the presence of hydrogen peroxide, and were bio-compatible, as demonstrated using MCF-7 cells.

### 4.4.2. Disulfide Bond-based Elastomers

Although disulfide bonds are not commonly reported in self-healable hydrogels, they have been investigated for their self-healing properties in elastomers. This approach is a component of the general trend aimed at reducing chemical and plastic waste, as these self-healable elastomers are considered sustainable because of their reprocessabilities. Soft elastomers were prepared using a bis(acrylate) monomer (bis(2-(acryloyloxy)ethyl)octadic-9-enedioate) mixed with copolymers of polydimethylsiloxane containing 4–6% (mercaptopropyl)methylsiloxane to formulate an ink for use in 3D printing technology.[82] Thin films with thicknesses of 1 mm exhibited respective E, σ<sub>max</sub>, and ε<sub>max</sub> values of 0.2 MPa, 52 kPa, and 24% at room temperature. Self-healing was realized via heating at 80 °C for 8 h, which led to SHEs of 86% and 100% in terms of tensile strain and strength, respectively. In another example, Yuan et al. prepared self-healing elastomers via the polycondensation of dicarboxylic acids, 1,4-butanediol, glycerol, and 3,3'-dithiodipropionic acid (DTPA).[83] Glycerol and DTPA were used to modulate the properties of the soft elastomers, with E, σ<sub>max</sub>, and ε<sub>max</sub> values in the ranges 0.2–0.9 and 0.4–1.5 MPa and 550–1700%, respectively, as functions of the compositions. Self-healing at 30 °C
<table><caption>**Table 4.** Self-healing hydrogels and elastomers based on disulfide bonds or Diels-Alder adducts (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Disulfide bonds</td><td>BSA</td><td>G' = 1 kPa</td><td>Cut</td><td>2 min, H<sub>2</sub>O<sub>2</sub></td><td>100% (σ<sub>max</sub>)</td><td>—</td><td>[81]</td></tr><tr><td rowspan="2">Elastomer</td><td rowspan="2">Disulfide bonds</td><td>Polyester based on bis(acrylate) monomer (bis(2—(acryloyloxy)ethyl) octadic-9-enedioate) with [4–6% (Mercaptopropyl)-methylsiloxane]-dimethyl siloxane</td><td>E = 0.23 MPa<br>σ<sub>max</sub> = 52 kPa<br>ε<sub>max</sub> = 24%</td><td>Cut</td><td>8 h, 80 °C</td><td>86% (ε<sub>max</sub>)<br>100% (σ<sub>max</sub>)</td><td>—</td><td>[82]</td></tr><tr><td>Polyester via polycondensation of dicarboxylic acids, 1,4-butanediol, glycerol, and DTPA</td><td>E = 0.16–0.86 MPa<br>σ<sub>max</sub> = 0.36–2.42 MPa<br>ε<sub>max</sub> = 542–1728%</td><td>Cut</td><td>2 h, 30 °C</td><td>100% (scratch)<br>95–98%<br>(σ<sub>max</sub>/ε<sub>max</sub>)</td><td>—</td><td>[83]</td></tr><tr><td>Elastomer</td><td>Disulfide bonds</td><td>Polyurethane block copolymers: hydroxy-terminated poly(1,4-butylene adipate) (HTPBA), IPDI, and PCL diol as a soft segment</td><td>E = 7.2 MPa<br>σ<sub>max</sub> = 4.6 MPa</td><td>Cut</td><td>5 h, RT<br>2 h, 40 °C</td><td>95% (σ<sub>max</sub>)</td><td>In vitro, 50% mass loss (8d, pH 14)</td><td>[84]</td></tr><tr><td>Elastomer</td><td>Diels-Alder</td><td>PCL-furan/PCL-maleimide</td><td>E = 75–159 MPa<br>ε<sub>max</sub> = 202–536%</td><td>Cut</td><td>1 h, 100 °C then<br>24 h, 50 °C</td><td>100% (Visual)<br>60–100% (E)</td><td>—</td><td>[90]</td></tr><tr><td>Elastomer</td><td>Diels-Alder</td><td>PCL-furan/PCL-maleimide</td><td>E = 19.6–347.9 MPa<br>σ<sub>max</sub> = 0.79–27.1 MPa<br>ε<sub>max</sub> = 17–36%</td><td>Scratch</td><td>24 h, 60 °C</td><td>91–100% (E)</td><td>—</td><td>[89]</td></tr></tbody></table>

BSA, bovine serum albumin; DTPA, dithiopropionic acid; E, Young's modulus; G', storage modulus; HTPBA, hydroxy-terminated poly(1,4-butylene adipate); IPDI, isophorone diisocyanate; PCL, polycaprolactone; ε<sub>max</sub>, strain at break; σ<sub>max</sub>, strain at break.

was realized visually after 1 h, whereas σ<sub>max</sub> recovery required 2 h (Figure 5.1). Using a similar polycondensation strategy in the design of a conductive skin device, Li et al. synthesized PUs with disulfide bonds in their backbones using hydroxy-terminated HTPBA, IPDI, and PCL diol.[84] Optimization of the composition enabled E and σ<sub>max</sub> to reach 7.2 and 4.6 MPa, respectively, while self-healing was realized after 2 h at 40 °C with a SHE in terms of tensile strength of 95%.

## 4.5. DA Adducts

DA cycloaddition reactions have been investigated to extend the service lifetimes of materials. This is a reversible reaction between furan and maleimide groups under a thermal stimulus. Despite the covalent nature of DA chemistry, its bond strength is lower than those of other covalent bonds. Therefore, upon crack initiation, the DA adducts could cleave via

<figure><img src="image_7.png" /><figcaption>**Figure 5.** 1) a) Theoretical mechanism for self-healing of a disulfide-based elastomer b) Image showing self-healing of recombined cut elastomers after being kept at room temperature (30 °C) for 10 s, c) stress-strain curves of the original and healed elastomers with different healing times at room temperature. 2) a) Schematic depiction of the Diels-aldere-based shape memory-assisted self-healing process in a polyurethane material based on furan-maleimide chemistry b) Optimal microscopy of sample cut with a razor blade before (left) and after (right) healing at 50 °C for 24 h. Adapted with permission.[83,90] Copyright 2020, American Chemical Society. Copyright 2014, American Chemical Society.</figcaption></figure>
<table><caption>**Table 4.** Self-healing hydrogels and elastomers based on disulfide bonds or Diels-Alder adducts (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Disulfide bonds</td><td>BSA</td><td>G' = 1 kPa</td><td>Cut</td><td>2 min, H<sub>2</sub>O<sub>2</sub></td><td>100% (σ<sub>max</sub>)</td><td>—</td><td>[81]</td></tr><tr><td rowspan="2">Elastomer</td><td rowspan="2">Disulfide bonds</td><td>Polyester based on bis(acrylate) monomer (bis(2—(acryloyloxy)ethyl) octadic-9-enedioate) with [4–6% (Mercaptopropyl)-methylsiloxane]-dimethyl siloxane</td><td>E = 0.23 MPa<br>σ<sub>max</sub> = 52 kPa<br>ε<sub>max</sub> = 24%</td><td>Cut</td><td>8 h, 80 °C</td><td>86% (ε<sub>max</sub>)<br>100% (σ<sub>max</sub>)</td><td>—</td><td>[82]</td></tr><tr><td>Polyester via polycondensation of dicarboxylic acids, 1,4-butanediol, glycerol, and DTPA</td><td>E = 0.16–0.86 MPa<br>σ<sub>max</sub> = 0.36–2.42 MPa<br>ε<sub>max</sub> = 542–1728%</td><td>Cut</td><td>2 h, 30 °C</td><td>100% (scratch)<br>95–98%<br>(σ<sub>max</sub>/ε<sub>max</sub>)</td><td>—</td><td>[83]</td></tr><tr><td>Elastomer</td><td>Disulfide bonds</td><td>Polyurethane block copolymers: hydroxy-terminated poly(1,4-butylene adipate) (HTPBA), IPDI, and PCL diol as a soft segment</td><td>E = 7.2 MPa<br>σ<sub>max</sub> = 4.6 MPa</td><td>Cut</td><td>5 h, RT<br>2 h, 40 °C</td><td>95% (σ<sub>max</sub>)</td><td>In vitro, 50% mass loss (8d, pH 14)</td><td>[84]</td></tr><tr><td>Elastomer</td><td>Diels-Alder</td><td>PCL-furan/PCL-maleimide</td><td>E = 75–159 MPa<br>ε<sub>max</sub> = 202–536%</td><td>Cut</td><td>1 h, 100 °C then<br>24 h, 50 °C</td><td>100% (Visual)<br>60–100% (E)</td><td>—</td><td>[90]</td></tr><tr><td>Elastomer</td><td>Diels-Alder</td><td>PCL-furan/PCL-maleimide</td><td>E = 19.6–347.9 MPa<br>σ<sub>max</sub> = 0.79–27.1 MPa<br>ε<sub>max</sub> = 17–36%</td><td>Scratch</td><td>24 h, 60 °C</td><td>91–100% (E)</td><td>—</td><td>[89]</td></tr></tbody></table>

BSA, bovine serum albumin; DTPA, dithiopropionic acid; E, Young's modulus; G', storage modulus; HTPBA, hydroxy-terminated poly(1,4-butylene adipate); IPDI, isophorone diisocyanate; PCL, polycaprolactone; ε<sub>max</sub>, strain at break; σ<sub>max</sub>, strain at break.

was realized visually after 1 h, whereas σ<sub>max</sub> recovery required 2 h (Figure 5.1). Using a similar polycondensation strategy in the design of a conductive skin device, Li et al. synthesized PUs with disulfide bonds in their backbones using hydroxy-terminated HTPBA, IPDI, and PCL diol.[84] Optimization of the composition enabled E and σ<sub>max</sub> to reach 7.2 and 4.6 MPa, respectively, while self-healing was realized after 2 h at 40 °C with a SHE in terms of tensile strength of 95%.

### 4.5. DA Adducts

DA cycloaddition reactions have been investigated to extend the service lifetimes of materials. This is a reversible reaction between furan and maleimide groups under a thermal stimulus. Despite the covalent nature of DA chemistry, its bond strength is lower than those of other covalent bonds. Therefore, upon crack initiation, the DA adducts could cleave via

<figure><img src="image_7.png" /><figcaption>**Figure 5.** 1) a) Theoretical mechanism for self-healing of a disulfide-based elastomer b) Image showing self-healing of recombined cut elastomers after being kept at room temperature (30 °C) for 10 s, c) stress-strain curves of the original and healed elastomers with different healing times at room temperature. 2) a) Schematic depiction of the Diels-aldere-based shape memory-assisted self-healing process in a polyurethane material based on furan-maleimide chemistry b) Optimal microscopy of sample cut with a razor blade before (left) and after (right) healing at 50 °C for 24 h. Adapted with permission.[83,90] Copyright 2020, American Chemical Society. Copyright 2014, American Chemical Society.</figcaption></figure>
<table><caption>**Table 5.** Self-healing hydrogels and elastomers based on hydrogen bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Cytosine and guanosine-modified HA<br>1,6-hexamethylenediamine</td><td>G' = 0.85 to 99.80 kPa</td><td>Cut</td><td>24h</td><td>—</td><td>In vitro, 40% mass loss in 7 d</td><td>[91]</td></tr><tr><td>Hydrogel</td><td>BSA<br>Epychlorhydrin</td><td>G' = 10 to 10 000 Pa</td><td>Cut</td><td>24h</td><td>—</td><td>In vitro, 70% degradation in 72 h<br>with trypsin, only 12% in PBS</td><td>[92]</td></tr><tr><td>Elastomer</td><td>PLA-PEB-UPy</td><td>E = 4.4 to 156 MPa<br>σ<sub>max</sub> = 2.2 to 9.4 MPa<br>ε<sub>max</sub> = 125 to 691%</td><td>Cut</td><td>20 min, UV-light,<br>76 °C</td><td>97% (E)</td><td>—</td><td>[93]</td></tr><tr><td>Elastomer</td><td>PDLLA-UPy</td><td>E = 594 to 900 MPa<br>σ<sub>max</sub> = 8.0 to 9.6 MPa</td><td>Cut</td><td>270 s, 37 °C</td><td>100% (Visual)</td><td>—</td><td>[94]</td></tr><tr><td>Elastomer</td><td>PLA-co-PTHF with UPy</td><td>E = 56.9 MPa<br>σ<sub>max</sub> = 1.1 to 14.8 MPa</td><td>Cut<br>Crack</td><td>24 h, 80 °C</td><td>99% (σ<sub>max</sub>)</td><td>—</td><td>[95]</td></tr><tr><td>Elastomer</td><td>UPy to telechelical PTMEG<br>4-arm star-shaped PCL</td><td>E = 44 to 117 MPa<br>σ<sub>max</sub> = 3.24 to 8.25 MPa<br>ε<sub>max</sub> = 18 to 54%</td><td>Cut</td><td>48 h, 40 °C</td><td>88% (σ<sub>max</sub>)</td><td>—</td><td>[96]</td></tr><tr><td>Elastomer</td><td>Dimethacrylate PCL<br>Methacrylates bearing UPy<br>function</td><td>E = 170 to 203 MPa<br>σ<sub>max</sub> = 10 to 14 MPa<br>ε<sub>max</sub> = 200 to 450%</td><td>Deep scratch</td><td>1 h, 80 °C</td><td>80% (σ<sub>max</sub>)</td><td>—</td><td>[97]</td></tr><tr><td>Elastomer</td><td>PGS with UPy</td><td>E = 0.4 to 32.8 MPa<br>σ<sub>max</sub> = 0.2 to 4.6 MPa<br>ε<sub>max</sub> = 63 to 260%</td><td>Cut</td><td>12 h, 55 °C</td><td>85% (σ<sub>max</sub>)</td><td>In vitro, 88% mass loss with<br>enzyme after 84h</td><td>[98]</td></tr><tr><td>Elastomer</td><td>PSeD with UPy</td><td>E = 1.9 to 10.6 MPa<br>σ<sub>max</sub> = 1.9 to 2.7 MPa<br>ε<sub>max</sub> = 121 to 215%</td><td>Cut</td><td>30 min, 60 °C</td><td>98% (σ<sub>max</sub>)</td><td>In vitro, 79% mass loss with<br>enzyme after 48h</td><td>[99]</td></tr></tbody></table>

BSA, bovine serum albumin; E, Young's modulus; G', storage modulus; HA, hyaluronic acid; PCL, polycaprolactone; PDLLA, poly(d,L-lactic acid); PGS, poly(glycerol-co-sebacate); PLA, poly(lactic acid); PSeD, poly(sebacoyl diglyceride); PTHF (poly(tetrahydrofuran); PTMEG, poly(tetramethylene ether) glycol; UPy, 2-ureido-4[1H]-pyrimidinone; ε<sub>max</sub>, stress at break; σ<sub>max</sub>, strain at break.

retro reaction, resulting in crack propagation.[85] This strategy has been used in the field of degradable polymers for >10 y, but research was mainly focused on shape-memory and/or reproducible materials, with only recent interest in self-healing elastomers (Table 4).[86–88]

The first example reported by Rivero et al. was a DA-based elastomer obtained via the chain-end functionalization of PCL with furan and maleimide moieties.[89,90] They combined PCL-bearing furan/maleimide groups and PCL diol with hexamethylene diisocyanate (HDI) hard segments to produce self-healable PUs (Figure 5.2).[90] The elastomers exhibited E and ε<sub>max</sub> values in the ranges 75–159 MPa and 200–540%, respectively, depending on the HDI content. This elastomer was limited in terms of self-healing, with only partial healing observed even after inducing the retro-DA reaction via heating to 100 °C (above the PCL melting temperature (T<sub>m</sub>)) for 1 h and then maintaining the temperature at 50 °C for 24 h. A much-enhanced SHE was obtained for an elastomer based on bismaleimidic and bisfuranic PCL chains with urethane-thiourethane networks.[89] The elastomers exhibited E values of 20–350 MPa, depending on the content of the PCL cross-linker. At 60 °C (T<sub>m</sub> of PCL), molecular rearrangements were promoted, and the healing time for scratches ranged from 2 to 72 h, depending on the PCL content. A faster and higher SHE was obtained at higher PCL contents, with SHEs of up to 91% in terms of E and σ<sub>max</sub>.

## 5. Degradable Networks with Self-Healing Properties Based on Noncovalent Interactions/Physical Bonds

The preceding sections discuss the various dynamic covalent bonds used to design self-healing, degradable/bioeliminable networks. In addition to this approach, self-healing networks may also be produced via noncovalent interactions, such as hydrogen bonds, hydrophobic, host-guest, electrostatic interactions, or metal coordination.

### 5.1. Hydrogen Bonds

Hydrogen bonding occurs between a hydrogen atom covalently bound to an electronegative atom, such as nitrogen, oxygen, or fluorine, and a lone pair of electrons of another electronegative atom. Although hydrogen bonds are largely present within hydrogels, only a few examples of hydrogels and elastomers based solely on hydrogen bonding with self-healing properties have been reported, and the data are shown in **Table 5**. As will be discussed in section V, hydrogen bonds are mostly combined with other mechanisms.

A recent example of a self-healing hydrogel involving only hydrogen bonds was reported by Ye et al.[91] These hydrogels were based on cytosine- and guanosine-modified HA and
<table><caption>**Table 5.** Self-healing hydrogels and elastomers based on hydrogen bonds (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Cytosine and guanosine-modified HA<br>1,6-hexamethylenediamine</td><td>G' = 0.85 to 99.80 kPa</td><td>Cut</td><td>24h</td><td>—</td><td>In vitro, 40% mass loss in 7 d</td><td>[91]</td></tr><tr><td>Hydrogel</td><td>BSA<br>Epychlorhydrin</td><td>G' = 10 to 10 000 Pa</td><td>Cut</td><td>24h</td><td>—</td><td>In vitro, 70% degradation in 72 h<br>with trypsin, only 12% in PBS</td><td>[92]</td></tr><tr><td>Elastomer</td><td>PLA-PEB-UPy</td><td>E = 4.4 to 156 MPa<br>σ<sub>max</sub> = 2.2 to 9.4 MPa<br>ε<sub>max</sub> = 125 to 691%</td><td>Cut</td><td>20 min, UV-light,<br>76 °C</td><td>97% (E)</td><td>—</td><td>[93]</td></tr><tr><td>Elastomer</td><td>PDLLA-UPy</td><td>E = 594 to 900 MPa<br>σ<sub>max</sub> = 8.0 to 9.6 MPa</td><td>Cut</td><td>270 s, 37 °C</td><td>100% (Visual)</td><td>—</td><td>[94]</td></tr><tr><td>Elastomer</td><td>PLA-co-PTHF with UPy</td><td>E = 56.9 MPa<br>σ<sub>max</sub> = 1.1 to 14.8 MPa</td><td>Cut<br>Crack</td><td>24 h, 80 °C</td><td>99% (σ<sub>max</sub>)</td><td>—</td><td>[95]</td></tr><tr><td>Elastomer</td><td>UPy to telechelic PTMEG<br>4-arm star-shaped PCL</td><td>E = 44 to 117 MPa<br>σ<sub>max</sub> = 3.24 to 8.25 MPa<br>ε<sub>max</sub> = 18 to 54%</td><td>Cut</td><td>48 h, 40 °C</td><td>88% (σ<sub>max</sub>)</td><td>—</td><td>[96]</td></tr><tr><td>Elastomer</td><td>Dimethacrylate PCL<br>Methacrylates bearing UPy<br>function</td><td>E = 170 to 203 MPa<br>σ<sub>max</sub> = 10 to 14 MPa<br>ε<sub>max</sub> = 200 to 450%</td><td>Deep scratch</td><td>1 h, 80 °C</td><td>80% (σ<sub>max</sub>)</td><td>—</td><td>[97]</td></tr><tr><td>Elastomer</td><td>PGS with UPy</td><td>E = 0.4 to 32.8 MPa<br>σ<sub>max</sub> = 0.2 to 4.6 MPa<br>ε<sub>max</sub> = 63 to 260%</td><td>Cut</td><td>12 h, 55 °C</td><td>85% (σ<sub>max</sub>)</td><td>In vitro, 88% mass loss with<br>enzyme after 84h</td><td>[98]</td></tr><tr><td>Elastomer</td><td>PSeD with UPy</td><td>E = 1.9 to 10.6 MPa<br>σ<sub>max</sub> = 1.9 to 2.7 MPa<br>ε<sub>max</sub> = 121 to 215%</td><td>Cut</td><td>30 min, 60 °C</td><td>98% (σ<sub>max</sub>)</td><td>In vitro, 79% mass loss with<br>enzyme after 48h</td><td>[99]</td></tr></tbody></table>

BSA, bovine serum albumin; E, Young's modulus; G', storage modulus; HA, hyaluronic acid; PCL, polycaprolactone; PDLLA, poly(d,L-lactic acid); PGS, poly(glycerol-co-sebacate); PLA, poly(lactic acid); PSeD, poly(sebacoyl diglyceride); PTHF (poly(tetrahydrofuran); PTMEG, poly(tetramethylene ether) glycol; UPy, 2-ureido-4[1H]-pyrimidinone; ε<sub>max</sub>, stress at break; σ<sub>max</sub>, strain at break.

retro reaction, resulting in crack propagation.[85] This strategy has been used in the field of degradable polymers for >10 y, but research was mainly focused on shape-memory and/or reproducible materials, with only recent interest in self-healing elastomers (Table 4).[86–88]

The first example reported by Rivero et al. was a DA-based elastomer obtained via the chain-end functionalization of PCL with furan and maleimide moieties.[89,90] They combined PCL-bearing furan/maleimide groups and PCL diol with hexamethylene diisocyanate (HDI) hard segments to produce self-healable PUs (Figure 5.2).[90] The elastomers exhibited E and ε<sub>max</sub> values in the ranges 75–159 MPa and 200–540%, respectively, depending on the HDI content. This elastomer was limited in terms of self-healing, with only partial healing observed even after inducing the retro-DA reaction via heating to 100 °C (above the PCL melting temperature (T<sub>m</sub>)) for 1 h and then maintaining the temperature at 50 °C for 24 h. A much-enhanced SHE was obtained for an elastomer based on bismaleimidic and bisfuranic PCL chains with urethane-thiourethane networks.[89] The elastomers exhibited E values of 20–350 MPa, depending on the content of the PCL cross-linker. At 60 °C (T<sub>m</sub> of PCL), molecular rearrangements were promoted, and the healing time for scratches ranged from 2 to 72 h, depending on the PCL content. A faster and higher SHE was obtained at higher PCL contents, with SHEs of up to 91% in terms of E and σ<sub>max</sub>.

**5. Degradable Networks with Self-Healing Properties Based on Noncovalent Interactions/Physical Bonds**

The preceding sections discuss the various dynamic covalent bonds used to design self-healing, degradable/bioeliminable networks. In addition to this approach, self-healing networks may also be produced via noncovalent interactions, such as hydrogen bonds, hydrophobic, host-guest, electrostatic interactions, or metal coordination.

**5.1. Hydrogen Bonds**

Hydrogen bonding occurs between a hydrogen atom covalently bound to an electronegative atom, such as nitrogen, oxygen, or fluorine, and a lone pair of electrons of another electronegative atom. Although hydrogen bonds are largely present within hydrogels, only a few examples of hydrogels and elastomers based solely on hydrogen bonding with self-healing properties have been reported, and the data are shown in **Table 5**. As will be discussed in section V, hydrogen bonds are mostly combined with other mechanisms.

A recent example of a self-healing hydrogel involving only hydrogen bonds was reported by Ye et al.[91] These hydrogels were based on cytosine- and guanosine-modified HA and
<figure><img src="image_8.png" /><figcaption>**Figure 6.** Synthesis of PGS-U polymers and preparation of supramolecular PGS-U film. 1) Schematic of PGS-U polymer synthesis and the supramolecular elastic film preparation by solvent evaporation. 2) Optical images of PGS prepolymer and supramolecular PGS-U film. Left: the viscous morphology of PGS prepolymer. Right: the bending, twisting, and stretching shapes of PGS-U polymer film. Scale bars: 20 mm. Adapted with permission.[98] Copyright 2016, Elsevier.</figcaption></figure>

prepared via hydrogen bonding under physiological conditions, with 1,6-hexamethylenediamine as a bridging unit between the nucleobases and HA. G' could be increased to 100 kPa, and self-healing was visually confirmed after 24 h. These hydrogels exhibited mass losses of ≈40% after 7 d in PBS solution in vitro. Hydrogels with identical healing times were prepared using BSA, with epichlorohydrin as the cross-linker.[92] The mechanical properties could be tuned as a function of the cross-linking density, with G' ranging from 10 Pa to 4 kPa. The degradation was limited in PBS but could reach 70% in a trypsin solution after 72 h at 37 °C. Finally, cell viability assays using cancer cell lines confirmed the absence of hydrogel toxicity despite the use of epichlorohydrin.

For hydrogen bonding in elastomers, a commonly used chemical moiety is 2-ureido-4-[1H]-pyrimidinone (UPy), which is a self-complementary quadruple hydrogen-bonding unit with a high dimerization constant and bonding strength (Figure 6). It is the focus of attention in the literature and used in biomedical applications, in particular as will be detailed in the last part of this review. To ensure degradability, three major degradable synthetic polymers have been used: polylactic acid (PLA), PCL, and poly(polyol-co-sebacate) (PPS). PLA-based elastomers were prepared using supramolecular assemblies of functional α,ω-UPy copolymers, including PLA-poly(ethylene-co-butylene)-PLA[93] or PLA-PEG-PLA.[94] In another strategy, PU with pending UPy units was prepared via the polycondensation of PLA diol, polytetrahydrofuran (PTHF), and a UPy-diol derivative in the presence of IPDI.[95] For the first two elastomers, E ranged

from 4[93] to 900 MPa,[94] and self-healing times from 270 s[94] to 20 min[93] were observed with quantitative recoveries of E. In comparison, 24 h at a temperature of >Tg was required to obtain a quantitative SHE in terms of σmax for the last example.[95]

A dynamic network was obtained by grafting UPy into telechelic PTHF and 4-arm star-shaped PCL.[96] The resulting elastomers exhibited σmax values of 3–8 MPa, and SHE could reach 88% with respect to σmax after 48 h at 40 °C. A PCL-based reactive ink for use in digital light processing was formulated by combining dimethacrylate PCL macromonomers with methacrylates bearing UPy functionalities.[97] The 3D printed materials displayed E and σmax values of 170 and ~11 MPa, respectively. At 80 °C, i.e., above the melting temperature of PCL, self-healing was visually realized after 1 h with a SHE of 80%.

Finally, regarding PPS, Wu et al. synthesized UPy-functionalized poly(glycerol-co-sebacate) (PGS) elastomers.[98] With an increase in the UPy concentration in the chain (from 16 to 33 wt.%), E increased from 0.4 to 33 MPa but the SHE decreased due to decreased chain mobility. Self-healing was realized visually at 55 °C after 60 min and mechanically after 12 h, as confirmed by the SHE with respect to σmax of 85%. The enzymatic degradation of these PGS-based elastomers was studied, confirming a lower degree of degradation at the highest UPy content compared to those of UPy-free elastomers (59% vs 12% remaining mass after 84 h). Similar polymers and similar behaviors were reported by Chen et al. after grafting UPy into poly(sebacoyl diglyceride) (PSeD). The PSeD elastomers induced only a weak inflammation in vivo
<figure><img src="image_8.png" /><figcaption>**Figure 6.** Synthesis of PGS-U polymers and preparation of supramolecular PGS-U film. 1) Schematic of PGS-U polymer synthesis and the supramolecular elastic film preparation by solvent evaporation. 2) Optical images of PGS prepolymer and supramolecular PGS-U film. Left: the viscous morphology of PGS prepolymer. Right: the bending, twisting, and stretching shapes of PGS-U polymer film. Scale bars: 20 mm. Adapted with permission.[98] Copyright 2016, Elsevier.</figcaption></figure>

prepared via hydrogen bonding under physiological conditions, with 1,6-hexamethylenediamine as a bridging unit between the nucleobases and HA. G' could be increased to 100 kPa, and self-healing was visually confirmed after 24 h. These hydrogels exhibited mass losses of ≈40% after 7 d in PBS solution in vitro. Hydrogels with identical healing times were prepared using BSA, with epichlorohydrin as the cross-linker.[92] The mechanical properties could be tuned as a function of the cross-linking density, with G' ranging from 10 Pa to 4 kPa. The degradation was limited in PBS but could reach 70% in a trypsin solution after 72 h at 37 °C. Finally, cell viability assays using cancer cell lines confirmed the absence of hydrogel toxicity despite the use of epichlorohydrin.

For hydrogen bonding in elastomers, a commonly used chemical moiety is 2-ureido-4-[1H]-pyrimidinone (UPy), which is a self-complementary quadruple hydrogen-bonding unit with a high dimerization constant and bonding strength (Figure 6). It is the focus of attention in the literature and used in biomedical applications, in particular as will be detailed in the last part of this review. To ensure degradability, three major degradable synthetic polymers have been used: polylactic acid (PLA), PCL, and poly(polyol-co-sebacate) (PPS). PLA-based elastomers were prepared using supramolecular assemblies of functional α,ω-UPy copolymers, including PLA-poly(ethylene-co-butylene)-PLA[93] or PLA-PEG-PLA.[94] In another strategy, PU with pending UPy units was prepared via the polycondensation of PLA diol, polytetrahydrofuran (PTHF), and a UPy-diol derivative in the presence of IPDI.[95] For the first two elastomers, E ranged

from 4[93] to 900 MPa,[94] and self-healing times from 270 s[94] to 20 min[93] were observed with quantitative recoveries of E. In comparison, 24 h at a temperature of >T_g was required to obtain a quantitative SHE in terms of σ_max for the last example.[95]

A dynamic network was obtained by grafting UPy into telechelic PTHF and 4-arm star-shaped PCL.[96] The resulting elastomers exhibited σ_max values of 3–8 MPa, and SHE could reach 88% with respect to σ_max after 48 h at 40 °C. A PCL-based reactive ink for use in digital light processing was formulated by combining dimethacrylate PCL macromonomers with methacrylates bearing UPy functionalities.[97] The 3D printed materials displayed E and σ_max values of 170 and ~11 MPa, respectively. At 80 °C, i.e., above the melting temperature of PCL, self-healing was visually realized after 1 h with a SHE of 80%.

Finally, regarding PPS, Wu et al. synthesized UPy-functionalized poly(glycerol-co-sebacate) (PGS) elastomers.[98] With an increase in the UPy concentration in the chain (from 16 to 33 wt.%), E increased from 0.4 to 33 MPa but the SHE decreased due to decreased chain mobility. Self-healing was realized visually at 55 °C after 60 min and mechanically after 12 h, as confirmed by the SHE with respect to σ_max of 85%. The enzymatic degradation of these PGS-based elastomers was studied, confirming a lower degree of degradation at the highest UPy content compared to those of UPy-free elastomers (59% vs 12% remaining mass after 84 h). Similar polymers and similar behaviors were reported by Chen et al. after grafting UPy into poly(sebacoyl diglyceride) (PSeD). The PSeD elastomers induced only a weak inflammation in vivo
<table><caption>**Table 6.** Self-healing hydrogels and elastomers based on hydrophobic, host-guest, or electrostatic/ionic interactions (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>Pentablock terpolypeptide</td><td>G' = 200 Pa to 8 kPa</td><td>—</td><td>&lt; 15 s at 37 °C</td><td>100% (G')</td><td>In vitro, with leucine ami- nopeptidase and trypsin</td><td>[100]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>Ferrocene-modified chitosan</td><td>G' = 1 kPa</td><td>Cut</td><td>4 h</td><td>100% (G')</td><td>—</td><td>[102]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>Alginate, micelles of regenerated silk fibroin, and stearyl methacrylate</td><td>G' = 1 to 10kPa</td><td>Surface damage</td><td>12 h</td><td>100% (G')</td><td>In vitro, with protease XIV, no degradation in PBS</td><td>[103]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>4-arm PEG-b-poly(γ-o-nitrobenzyl-L-glutamate)</td><td>G' = 2 kPa</td><td>Cut</td><td>5 min</td><td>100% (G')</td><td>Upon UV stimulation</td><td>[101]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>HA-CD/HA-AD</td><td>G' = 50 to 400 Pa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, proteolytic</td><td>[104]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>β-CD-modified PGA Cholesterol-modified triblock PGA-b-PEG-b-PGA</td><td>G' up to 20 kPa</td><td>Cut</td><td>60 s</td><td>—</td><td>In vitro, 36 d</td><td>[106]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>β-CD-modified alginate/AD-modified graphene oxide</td><td>G' = 100 kPa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, 20 to 40% mass loss in 20 d</td><td>[105]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>Poly(CD) Acrylamide N-vinyl-pyrrolidinone</td><td>E = 815 kPa</td><td>Cut</td><td>24 h, RT</td><td>98% (E)</td><td>In vitro, 28 to 35 h with β-lactamase</td><td>[107]</td></tr><tr><td>Hydrogel</td><td>Electrostatic/ionic interactions</td><td>Chitosan Carboxymethyl cellulose</td><td>G' = 500 Pa</td><td>Cut</td><td>12 h, RT</td><td>100% (G')</td><td>—</td><td>[108]</td></tr><tr><td>Elastomer</td><td>Electrostatic/ionic interactions</td><td>PCL diol modified with IPDI before chain extension with anionic oligo-alginate and cationic N-methyldiethanolamine</td><td>E = 19 to 93 MPa σ<sub>max</sub> = 20 to 48 MPa ε<sub>max</sub> = 800%</td><td>Cut</td><td>—</td><td>87% (toughness)</td><td>—</td><td>[109]</td></tr></tbody></table>

AD, adamantane; CD, cyclodextrin; E, Young's modulus; G', storage modulus; HA, hyaluronic acid; IPDI, isophorone diisocyanate; PCL, polycaprolactone; PGA, poly(L-glutamic acid); RT, room temperature; ε<sub>max</sub>, strain at break; σ<sub>max</sub>, stress at break.

28 d post-implantation in rats, which was comparable to the results observed using the poly(lactic-co-glycolic acid) (PLGA) control.[99]

## 5.2. Hydrophobic Interactions

Hydrophobic interactions are reversible and noncovalent and occur between non-polar hydrophobic groups immersed in aqueous media. Non-polar substances generally aggregate to minimize their contact with water. Numerous classical physically cross-linked hydrogels are based on hydrophobic interactions and by nature, they could be considered self-healable. However, in this review, we only analyze the most recent examples of such hydrogels claiming self-healing properties (Table 6).

These examples rely on interactions between the hydrophobic groups of the (co)polymer chain, such as benzyl,[100] photo-labile o-nitrobenzyl,[101] and ferrocene groups,[102] e.g., Bilalis et al. mixed a poly(lysine)-b-poly(L-histidine-co-γ-benzyl-L-glutamate)-b-poly(lysine)-b-poly(L-histidine-co-γ-benzyl-L-glutamate)-b-poly(lysine) pentablock copolymer with an aqueous solution of gemcitabine to prepare hydrogels with G' values of 200 Pa–8 kPa and very fast self-healing times of 15 s.[100] Another strategy involving hydrophobic interactions with micelles was proposed by Meng et al.[103] They prepared micelles of amphiphilic regenerated silk fibroin containing the hydrophobic monomer stearyl methacrylate in an alginate

network physically cross-linked with calcium ions. Owing to the hydrophobic interactions used as sacrificial bonds, the rupture energy could be efficiently dissipated while ensuring the reversibility of the interactions, a higher modulus (≈ 400 Pa), and self-healing within 12 h after damage.

## 5.3. Host-Guest Interactions

Host-guest interactions occur via mutual molecular recognition of “host” and “guest” moieties. The host moieties are macrocyclic molecules wherein the guest moiety may be inserted to form a unique inclusion complex. One important molecule used to form host-guest interactions in the examples reported in the recent literature is cyclodextrin (CD), as shown in Table 6. Two strategies are used to exploit the CD moieties. First, CD may be used as a functional group on the polymer backbone. This approach is largely used in preparing supra-molecular shear-thinning, self-healing hydrogels based on the host-guest interactions between HA modified with adamantane (AD) and CD,[104] β-CD-modified alginate and AD-modified graphene oxide,[105] or β-CD-modified poly(L-glutamic acid) (PGA) and cholesterol-modified triblock PGA-b-PEG-b-PGA.[106] The second strategy relies on the use of polycyclodextrin. An example was reported by Yu et al. with a host backbone comprising polycarboxymethyl-β-CDs, a β-lactam-sensitive bifunctional AD guest molecule, and to reinforce the network, an
<table><caption>**Table 6.** Self-healing hydrogels and elastomers based on hydrophobic, host-guest, or electrostatic/ionic interactions (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>Pentablock terpolypeptide</td><td>G' = 200 Pa to 8 kPa</td><td>—</td><td>&lt; 15 s at 37 °C</td><td>100% (G')</td><td>In vitro, with leucine ami- nopeptidase and trypsin</td><td>[100]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>Ferrocene-modified chitosan</td><td>G' = 1 kPa</td><td>Cut</td><td>4 h</td><td>100% (G')</td><td>—</td><td>[102]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>Alginate, micelles of regenerated silk fibroin, and stearyl methacrylate</td><td>G' = 1 to 10kPa</td><td>Surface damage</td><td>12 h</td><td>100% (G')</td><td>In vitro, with protease XIV, no degradation in PBS</td><td>[103]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions</td><td>4-arm PEG-b-poly(γ-o-nitrobenzyl-L-glutamate)</td><td>G' = 2 kPa</td><td>Cut</td><td>5 min</td><td>100% (G')</td><td>Upon UV stimulation</td><td>[101]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>HA-CD/HA-AD</td><td>G' = 50 to 400 Pa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, proteolytic</td><td>[104]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>β-CD-modified PGA<br>Cholesterol-modified triblock PGA-b-PEG-b-PGA</td><td>G' up to 20 kPa</td><td>Cut</td><td>60 s</td><td>—</td><td>In vitro, 36 d</td><td>[106]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>β-CD-modified alginate/AD-modified graphene oxide</td><td>G' = 100 kPa</td><td>—</td><td>—</td><td>100% (G')</td><td>In vitro, 20 to 40% mass loss in 20 d</td><td>[105]</td></tr><tr><td>Hydrogel</td><td>Host-guest interactions</td><td>Poly(CD) Acrylamide<br>N-vinyl-pyrrolidinone</td><td>E = 815 kPa</td><td>Cut</td><td>24 h, RT</td><td>98% (E)</td><td>In vitro, 28 to 35 h with β-lactamase</td><td>[107]</td></tr><tr><td>Hydrogel</td><td>Electrostatic/ionic interactions</td><td>Chitosan<br>Carboxymethyl cellulose</td><td>G' = 500 Pa</td><td>Cut</td><td>12 h, RT</td><td>100% (G')</td><td>—</td><td>[108]</td></tr><tr><td>Elastomer</td><td>Electrostatic/ionic interactions</td><td>PCL diol modified with IPDI before chain extension with anionic oligo-alginate and cationic N-methyldiethanolamine</td><td>E = 19 to 93 MPa<br>σ<sub>max</sub> = 20 to 48 MPa<br>ε<sub>max</sub> = 800%</td><td>Cut</td><td>—</td><td>87%<br>(toughness)</td><td>—</td><td>[109]</td></tr></tbody></table>

AD, adamantane; CD, cyclodextrin; E, Young's modulus; G', storage modulus; HA, hyaluronic acid; IPDI, isophorone diisocyanate; PCL, polycaprolactone; PGA, poly(L-glutamic acid); RT, room temperature; ε<sub>max</sub>, strain at break; σ<sub>max</sub>, stress at break.

28 d post-implantation in rats, which was comparable to the results observed using the poly(lactic-co-glycolic acid) (PLGA) control.[99]

## 5.2. Hydrophobic Interactions

Hydrophobic interactions are reversible and noncovalent and occur between non-polar hydrophobic groups immersed in aqueous media. Non-polar substances generally aggregate to minimize their contact with water. Numerous classical physically cross-linked hydrogels are based on hydrophobic interactions and by nature, they could be considered self-healable. However, in this review, we only analyze the most recent examples of such hydrogels claiming self-healing properties (Table 6).

These examples rely on interactions between the hydrophobic groups of the (co)polymer chain, such as benzyl,[100] photo-labile o-nitrobenzyl,[101] and ferrocene groups,[102] e.g., Bilalis et al. mixed a poly(lysine)-b-poly(L-histidine-co-γ-benzyl-L-glutamate)-b-poly(lysine)-b-poly(L-histidine-co-γ-benzyl-L-glutamate)-b-poly(lysine) pentablock copolymer with an aqueous solution of gemcitabine to prepare hydrogels with G' values of 200 Pa–8 kPa and very fast self-healing times of 15 s.[100] Another strategy involving hydrophobic interactions with micelles was proposed by Meng et al.[103] They prepared micelles of amphiphilic regenerated silk fibroin containing the hydrophobic monomer stearyl methacrylate in an alginate

network physically cross-linked with calcium ions. Owing to the hydrophobic interactions used as sacrificial bonds, the rupture energy could be efficiently dissipated while ensuring the reversibility of the interactions, a higher modulus (≈ 400 Pa), and self-healing within 12 h after damage.

## 5.3. Host-Guest Interactions

Host-guest interactions occur via mutual molecular recognition of “host” and “guest” moieties. The host moieties are macrocyclic molecules wherein the guest moiety may be inserted to form a unique inclusion complex. One important molecule used to form host-guest interactions in the examples reported in the recent literature is cyclodextrin (CD), as shown in Table 6. Two strategies are used to exploit the CD moieties. First, CD may be used as a functional group on the polymer backbone. This approach is largely used in preparing supra-molecular shear-thinning, self-healing hydrogels based on the host-guest interactions between HA modified with adamantane (AD) and CD,[104] β-CD-modified alginate and AD-modified graphene oxide,[105] or β-CD-modified poly(L-glutamic acid) (PGA) and cholesterol-modified triblock PGA-b-PEG-b-PGA.[106] The second strategy relies on the use of polycyclodextrin. An example was reported by Yu et al. with a host backbone comprising polycarboxymethyl-β-CDs, a β-lactam-sensitive bifunctional AD guest molecule, and to reinforce the network, an
<table><caption>**Table 7.** Self-healing hydrogels based on metal-coordination (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td rowspan="3">Hydrogel</td><td>PAA</td><td>σ<sub>max</sub> = 0.52 to 0.83 MPa</td><td rowspan="3">Cut</td><td rowspan="3">12 h, 37 °C</td><td rowspan="3">74% (σ<sub>max</sub>)</td><td rowspan="3">—</td><td rowspan="3">[110]</td></tr><tr><td>Polypyrrole</td><td>ε<sub>max</sub> = 180 to 448%</td></tr><tr><td>Fe<sup>3+</sup></td><td></td></tr><tr><td rowspan="2">Hydrogel</td><td>CMC</td><td>G' = 700 to 800 Pa</td><td rowspan="2">Cut</td><td rowspan="2">1min</td><td rowspan="2">—</td><td rowspan="2">—</td><td rowspan="2">[112]</td></tr><tr><td>EDTA:Fe<sup>3+</sup></td><td></td></tr><tr><td rowspan="3">Hydrogel</td><td>Silver nanoparticles</td><td></td><td rowspan="3">Cut</td><td rowspan="3">24 h, 70 °C</td><td>38% (σ<sub>max</sub>)</td><td rowspan="3">—</td><td rowspan="3">[111]</td></tr><tr><td>PAA</td><td>σ<sub>max</sub> = 3.7 MPa</td><td>58% (ε<sub>max</sub>)</td></tr><tr><td>Chitosan</td><td>ε<sub>max</sub> = 1200%</td><td></td></tr><tr><td rowspan="2">Hydrogel</td><td>Fe<sup>3+</sup></td><td></td><td rowspan="2">Cut</td><td rowspan="2">1 min, RT</td><td rowspan="2">100% (G')</td><td rowspan="2">—</td><td rowspan="2">[113]</td></tr><tr><td>CMC</td><td>G' = 2 kPa</td></tr><tr><td rowspan="3">Hydrogel</td><td>Fe<sup>3+</sup>/Al<sup>3+</sup></td><td></td><td rowspan="3">Cut</td><td rowspan="3">12 to 24 h, RT</td><td>92% (σ<sub>max</sub>)</td><td rowspan="3">—</td><td rowspan="3">[114]</td></tr><tr><td>CMC</td><td>E = 3. To 16.8 kPa</td><td>95% (ε<sub>max</sub>)</td></tr><tr><td>PCAD</td><td>σ<sub>max</sub> = 5.1 to 12.9 kPa</td><td></td></tr><tr><td rowspan="2">Hydrogel</td><td>Al<sup>3+</sup></td><td>ε<sub>max</sub> = 90 to 280%</td><td rowspan="2">Cut</td><td rowspan="2">5 h, water</td><td rowspan="2">—</td><td rowspan="2">—</td><td rowspan="2">[115]</td></tr><tr><td>Polyaspartamide/histamine conjugate</td><td>G' up to 10 kPa</td></tr><tr><td rowspan="2">Hydrogel</td><td>Cu<sup>2+</sup></td><td></td><td rowspan="2">Cut</td><td rowspan="2">—</td><td rowspan="2">100% (G')</td><td rowspan="2">—</td><td rowspan="2">[116]</td></tr><tr><td>Thiolated BSA</td><td>G' = 400 Pa</td></tr><tr><td rowspan="2">Hydrogel</td><td>Silver nitrate</td><td></td><td rowspan="2">Cut</td><td rowspan="2">1 h</td><td rowspan="2">100% (G')</td><td rowspan="2">—</td><td rowspan="2">[117]</td></tr><tr><td>Histidine peptide</td><td>E = 15 kPa</td></tr><tr><td></td><td>Zn<sup>2+</sup></td><td>ε<sub>max</sub> = 620%</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

BSA, bovine serum albumin; CMC, carboxymethyl chitosan; G', storage modulus; PAA, poly(acrylic acid); PCAD, photoluminescent citric acid derivatives; ε<sub>max</sub>, strain at break; σ<sub>max</sub>, stress at break.

interpenetrating network polymerized via acrylamide and N-vinylpyrrolidinone.[107] Depending on the system, soft (G' < 500 Pa) [104] or strong (G' > 100 kPa) [105,107] gels are formed, with the stronger gels obtained owing to the hybrid natures of those with embedded particles or the reinforcing effects of the interpenetrating networks. In all cases, they exhibited quantitative SHEs after repair times ranging from a few seconds [106] to one day.[107] Complete degradation of these host-guest hydrogels was ensured via enzymatic degradation by collagenases, matrix metalloproteinases,[104] or β-lactamases,[107] although simple hydrolytic degradation was also reported.[105,106]

## 5.4. Electrostatic/Ionic Interactions

Electrostatic or ionic interactions occur between ions with opposite charges and may be used to produce self-healing hydrogels. However, similar to hydrophobic interactions, although these interactions are commonly used to yield polyelectrolyte-based hydrogels, only a few examples have been reported in the recent literature (Table 6).

Electrostatic interactions between positively charged chitosan and negatively charged carboxymethyl cellulose have been exploited.[108] When cut into two pieces, the samples displayed self-repair times of 12 h at room temperature. Healing was confirmed via SEM and rheological studies, with the healed hydrogels displaying G' values close to the original value (500 Pa). Regarding elastomers, Baharvand et al. focused on biodegradable elastomers engineered via supramolecular ionic interactions. To enhance the strengths of the biodegradable elastomers, they used a PCL diol that was further modified

with IPDI before chain extension with anionic oligo-alginate or cationic N-methyldiethanolamine.[109] This synthetic pathway yielded PU networks with ionic interactions between the PU chains, resulting in elastomers with high elastic contributions. The highest G' values were observed for networks with 1:1 ratios of cationic and anionic segments, with E and σ<sub>max</sub> values of up to 93 and 48 MPa, respectively, and ε<sub>max</sub> values of ≈ 800%. Their degrees of self-healing was estimated by measuring their toughnesses, yielding SHEs of 87%.

## 5.5. Metal Coordination

The use of reversible metal coordination interactions is another method of producing self-healing hydrogels via dynamic physical bonding, and several recent examples are shown in Table 7.

Although different metals may be used, Fe<sup>3+</sup> is the most widely employed. Fe<sup>3+</sup>-coordination interactions enable self-healing, but with discrepancies in terms of SHE and repair time ranging from 1 min to 1 d. For example, slow repair times (>12 h) and limited SHEs were observed for hydrogels composed of polyacrylic acid (PAA) and Fe<sup>3+</sup> ions, with the highest SHE of 74% observed when mixed with polypyrrole,[110] and a SHE of only 38% observed when mixed with chitosan.[111] This limited self-healing may be due to the high mechanical properties of the systems, which exhibit remarkable σ<sub>max</sub> values for hydrogels in the megapascal range, trading the strength of the initial network. In contrast, the use of Fe<sup>3+</sup> with CMC yielded softer hydrogels that displayed faster full repair.[112,113]
<table><caption>**Table 7.** Self-healing hydrogels based on metal-coordination (materials, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td rowspan="3">Hydrogel</td><td>PAA</td><td>σ<sub>max</sub> = 0.52 to 0.83 MPa</td><td rowspan="3">Cut</td><td rowspan="3">12 h, 37 °C</td><td rowspan="3">74% (σ<sub>max</sub>)</td><td rowspan="3">–</td><td rowspan="3">[110]</td></tr><tr><td>Polypyrrole</td><td>ε<sub>max</sub> = 180 to 448%</td></tr><tr><td>Fe<sup>3+</sup></td><td></td></tr><tr><td rowspan="2">Hydrogel</td><td>CMC</td><td>G' = 700 to 800 Pa</td><td rowspan="2">Cut</td><td rowspan="2">1min</td><td rowspan="2">–</td><td rowspan="2">–</td><td rowspan="2">[112]</td></tr><tr><td>EDTA:Fe<sup>3+</sup></td><td></td></tr><tr><td rowspan="3">Hydrogel</td><td>Silver nanoparticles</td><td></td><td rowspan="3">Cut</td><td rowspan="3">24 h, 70 °C</td><td>38% (σ<sub>max</sub>)</td><td rowspan="3">–</td><td rowspan="3">[111]</td></tr><tr><td>PAA</td><td>σ<sub>max</sub> = 3.7 MPa</td><td>58% (ε<sub>max</sub>)</td></tr><tr><td>Chitosan</td><td>ε<sub>max</sub> = 1200%</td><td></td></tr><tr><td rowspan="2">Hydrogel</td><td>Fe<sup>3+</sup></td><td></td><td rowspan="2">Cut</td><td rowspan="2">1 min, RT</td><td rowspan="2">100% (G')</td><td rowspan="2">–</td><td rowspan="2">[113]</td></tr><tr><td>CMC</td><td>G' = 2 kPa</td></tr><tr><td rowspan="3">Hydrogel</td><td>Fe<sup>3+</sup>/Al<sup>3+</sup></td><td></td><td rowspan="3">Cut</td><td rowspan="3">12 to 24 h, RT</td><td>92% (σ<sub>max</sub>)</td><td rowspan="3">–</td><td rowspan="3">[114]</td></tr><tr><td>CMC</td><td>E = 3. To 16.8 kPa</td><td>95% (ε<sub>max</sub>)</td></tr><tr><td>PCAD</td><td>σ<sub>max</sub> = 5.1 to 12.9 kPa</td><td></td></tr><tr><td rowspan="2">Hydrogel</td><td>Al<sup>3+</sup></td><td>ε<sub>max</sub> = 90 to 280%</td><td rowspan="2">Cut</td><td rowspan="2">5 h, water</td><td rowspan="2">–</td><td rowspan="2">–</td><td rowspan="2">[115]</td></tr><tr><td>Polyaspartamide/histamine conjugate</td><td>G' up to 10 kPa</td></tr><tr><td rowspan="2">Hydrogel</td><td>Cu<sup>2+</sup></td><td></td><td rowspan="2">Cut</td><td rowspan="2">–</td><td rowspan="2">100% (G')</td><td rowspan="2">–</td><td rowspan="2">[116]</td></tr><tr><td>Thiolated BSA</td><td>G' = 400 Pa</td></tr><tr><td rowspan="2">Hydrogel</td><td>Silver nitrate</td><td></td><td rowspan="2">Cut</td><td rowspan="2">1 h</td><td rowspan="2">100% (G')</td><td rowspan="2">–</td><td rowspan="2">[117]</td></tr><tr><td>Histidine peptide</td><td>E = 15 kPa</td></tr><tr><td></td><td>Zn<sup>2+</sup></td><td>ε<sub>max</sub> = 620%</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

BSA, bovine serum albumin; CMC, carboxymethyl chitosan; G', storage modulus; PAA, poly(acrylic acid); PCAD, photoluminescent citric acid derivatives; ε<sub>max</sub>, strain at break; σ<sub>max</sub>, stress at break.

interpenetrating network polymerized via acrylamide and N-vinylpyrrolidinone.[107] Depending on the system, soft (G' < 500 Pa) [104] or strong (G' > 100 kPa) [105,107] gels are formed, with the stronger gels obtained owing to the hybrid natures of those with embedded particles or the reinforcing effects of the inter-penetrating networks. In all cases, they exhibited quantitative SHEs after repair times ranging from a few seconds [106] to one day.[107] Complete degradation of these host-guest hydrogels was ensured via enzymatic degradation by collagenases, matrix metalloproteinases,[104] or β-lactamases,[107] although simple hydro-lytic degradation was also reported.[105,106]

## 5.4. Electrostatic/Ionic Interactions

Electrostatic or ionic interactions occur between ions with opposite charges and may be used to produce self-healing hydrogels. However, similar to hydrophobic interactions, although these interactions are commonly used to yield polyelectrolyte-based hydrogels, only a few examples have been reported in the recent literature (Table 6).

Electrostatic interactions between positively charged chitosan and negatively charged carboxymethyl cellulose have been exploited.[108] When cut into two pieces, the samples displayed self-repair times of 12 h at room temperature. Healing was confirmed via SEM and rheological studies, with the healed hydrogels displaying G' values close to the original value (500 Pa). Regarding elastomers, Baharvand et al. focused on biodegradable elastomers engineered via supramolecular ionic interactions. To enhance the strengths of the biodegradable elastomers, they used a PCL diol that was further modified

with IPDI before chain extension with anionic oligo-alginate or cationic N-methyldiethanolamine.[109] This synthetic pathway yielded PU networks with ionic interactions between the PU chains, resulting in elastomers with high elastic contributions. The highest G' values were observed for networks with 1:1 ratios of cationic and anionic segments, with E and σ<sub>max</sub> values of up to 93 and 48 MPa, respectively, and ε<sub>max</sub> values of ≈ 800%. Their degrees of self-healing was estimated by measuring their toughnesses, yielding SHEs of 87%.

## 5.5. Metal Coordination

The use of reversible metal coordination interactions is another method of producing self-healing hydrogels via dynamic physical bonding, and several recent examples are shown in Table 7.

Although different metals may be used, Fe<sup>3+</sup> is the most widely employed. Fe<sup>3+</sup>-coordination interactions enable self-healing, but with discrepancies in terms of SHE and repair time ranging from 1 min to 1 d. For example, slow repair times (>12 h) and limited SHEs were observed for hydrogels composed of polyacrylic acid (PAA) and Fe<sup>3+</sup> ions, with the highest SHE of 74% observed when mixed with polypyrrole,[110] and a SHE of only 38% observed when mixed with chitosan.[111] This limited self-healing may be due to the high mechanical properties of the systems, which exhibit remarkable σ<sub>max</sub> values for hydrogels in the megapascal range, trading the strength of the initial network. In contrast, the use of Fe<sup>3+</sup> with CMC yielded softer hydrogels that displayed faster full repair.[112,113]
<table><caption>**Table 8.** Self-healing hydrogels and elastomers based on combination of dynamic chemical bonds (materials, mechanisms, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Schiff base<br>Acylhydrazone bonds</td><td>Gelatin<br>A-Alg<br>Adipic acid dihydrazide</td><td>G' = 20 kPa</td><td>Cut</td><td>Moisture</td><td>100% (G')</td><td>In vitro, with collagenase, 70% mass loss after 20 d</td><td>[118]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Acylhydrazone bonds</td><td>Gelatin<br>A-Dex<br>Adipic acid dihydrazide<br>bFGF@PLGA<br>Chlorhexidine acetate</td><td>G' = 600 Pa to 1.8 kPa</td><td>Cut, Hole</td><td>1 h</td><td>—</td><td>In vitro, 50 h</td><td>[119]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Boronate ester bonds</td><td>PEG-BA<br>Phenylboronic acid-PEG<br>PVA<br>Glycol chitosan</td><td>G' up to 5.7 kPa</td><td>Syringe injection</td><td>1 h</td><td>98% (G')</td><td>—</td><td>[120]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Boronate ester bonds</td><td>Gelatin/A-Alg<br>Borax</td><td>G' = 1 kPa</td><td>Cut</td><td>7 d</td><td>80% (G')</td><td>—</td><td>[121]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Boronate ester bonds</td><td>Gelatin/Dialdehyde<br>dextrin<br>Dialdehyde<br>carboxymethylcellulose<br>Borax<br>Glutaraldehyde</td><td>—</td><td>Cut</td><td>4 h, pressure</td><td>—</td><td>In vitro, 1 week</td><td>[122]</td></tr><tr><td>Elastomer</td><td>DA<br>Disulfide bonds</td><td>Polyurethane (HDI)<br>with PCL</td><td>E = 0.1 MPa<br>σ<sub>max</sub> up to 33 MPa</td><td>Scratch</td><td>60 °C, then 120 °C, 113% (σ<sub>max</sub>)<br>then RT</td><td>—</td><td>—</td><td>[123]</td></tr></tbody></table>

A-Alg, aldehyde-modified alginate; A-Dex, aldehyde-modified dextran, bFGF@PLGA, PLGA microspheres integrated with a basic fibroblast growth factor; E, Young's modulus; G', storage modulus; HDI, hexamethylene diisocyanate; PCL, polycaprolactone; PEG, poly(ethylene glycol); PEG-BA, benzaldehyde poly(ethylene glycol); PVA, poly(vinyl alcohol); RT, room temperature; σ<sub>max</sub>, stress at break.

In addition to Fe³⁺, other metal ions, including Al³⁺, [114] Cu²⁺, [115] Ag⁺, [116] and Zn²⁺, [117] have been used. For example, Moon et al. [115] reported the syntheses of biodegradable polyaspartamide derivatives conjugated with histamine to prepare a metal-coordinated supramolecular hydrogel with Cu²⁺ metal ions in an aqueous solution that displayed the capacity to heal in 5 h, with a G' of ≈10 kPa. Thiolated BSA and silver nitrate have also been used to produce an injectable, self-healing, antibacterial BSA-based hydrogel for use in bone regeneration. [116] The resulting hydrogel was softer than the previous one, with a G' of ≈400 Pa and shear-thinning behavior, enabling its rapid recovery.

## 6. Degradable Networks with Self-Healing Properties Based on Multi-Mechanisms

The aforementioned examples of degradable self-healing hydrogels and elastomers rely on single self-healing mechanisms. However, self-healing may also be caused by a combination of various dynamic chemical bonds, various physical interactions, or a combination of chemical bonds and physical interactions. Owing to the complexity of designing such materials, this approach has been mainly applied to dual-self-healing mechanisms, although degradable networks with more than two self-healing mechanisms are also described in this section. The selection of mechanisms associated with the optimal properties depends mainly on the desired application. Generally, to increase Young's modulus or elasticity of the material, higher

contents of reversible covalent linkages are preferred, whereas to favor more spontaneous self-healing without depending on external stimuli, physical dynamic bonds should be selected.

### 6.1. Dual Self-Healing via the Combination Of Dynamic Chemical Bonds

Five examples of degradable self-healing hydrogels with combinations of dynamic chemical bonds have recently been reported and are summarized in Table 8. In the first two cases, the networks are based on dynamic Schiff base reactions and acylhydrazone bonds in similar systems, relying on gelatin, adipic acid dihydrazide, and A-Alg [118] or A-Dex [119] (Figure 7.1). To enhance the antibacterial activity and accelerate wound healing, microspheres of PLGA loaded with basic fibroblast growth factor (bFGF@PLGA) and chlorhexidine acetate (CHA) were embedded in soft gels (typical G' values of 600 Pa–1.8 kPa) that self-repaired after 1 h and could be fully degraded in PBS after 50 h.

Notably, these systems, based on dextran or alginate, displayed good biocompatibilities in vitro and in vivo. In another example, self-healing was based on dynamic imine bonds associated with borate ester linkages. [120] The system was composed of multifunctional benzaldehyde- and phenylboronic acid-modified PEG cross-linked with PVA and glycol chitosan. Regarding the self-healing capacity, even the stiffer sample (G' = 5.7 kPa) could recover after 45 min post-injection, with a SHE of 98%.
<table><caption>**Table 8.** Self-healing hydrogels and elastomers based on combination of dynamic chemical bonds (materials, mechanisms, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Schiff base<br>Acylhydrazone bonds</td><td>Gelatin<br>A-Alg<br>Adipic acid dihydrazide</td><td>G' = 20 kPa</td><td>Cut</td><td>Moisture</td><td>100% (G')</td><td>In vitro, with collagenase, 70% mass loss after 20 d</td><td>[118]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Acylhydrazone bonds</td><td>Gelatin<br>A-Dex<br>Adipic acid dihydrazide<br>bFGF@PLGA<br>Chlorhexidine acetate</td><td>G' = 600 Pa to 1.8 kPa</td><td>Cut, Hole</td><td>1 h</td><td>—</td><td>In vitro, 50 h</td><td>[119]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Boronate ester bonds</td><td>PEG-BA<br>Phenylboronic acid-PEG<br>PVA<br>Glycol chitosan</td><td>G' up to 5.7 kPa</td><td>Syringe injection</td><td>1 h</td><td>98% (G')</td><td>—</td><td>[120]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Boronate ester bonds</td><td>Gelatin/A-Alg<br>Borax</td><td>G' = 1 kPa</td><td>Cut</td><td>7 d</td><td>80% (G')</td><td>—</td><td>[121]</td></tr><tr><td>Hydrogel</td><td>Schiff base<br>Boronate ester bonds</td><td>Gelatin/Dialdehyde<br>dextrin<br>Dialdehyde<br>carboxymethylcellulose<br>Borax<br>Glutaraldehyde</td><td>—</td><td>Cut</td><td>4 h, pressure</td><td>—</td><td>In vitro, 1 week</td><td>[122]</td></tr><tr><td>Elastomer</td><td>DA<br>Disulfide bonds</td><td>Polyurethane (HDI)<br>with PCL</td><td>E = 0.1 MPa<br>σ<sub>max</sub> up to 33 MPa</td><td>Scratch</td><td>60 °C, then 120 °C, 113% (σ<sub>max</sub>)<br>then RT</td><td>—</td><td>—</td><td>[123]</td></tr></tbody></table>

A-Alg, aldehyde-modified alginate; A-Dex, aldehyde-modified dextran, bFGF@PLGA, PLGA microspheres integrated with a basic fibroblast growth factor; E, Young's modulus; G', storage modulus; HDI, hexamethylene diisocyanate; PCL, polycaprolactone; PEG, poly(ethylene glycol); PEG-BA, benzaldehyde poly(ethylene glycol); PVA, poly(vinyl alcohol); RT, room temperature; σ<sub>max</sub>, stress at break.

In addition to Fe³⁺, other metal ions, including Al³⁺, [114] Cu²⁺, [115] Ag⁺, [116] and Zn²⁺, [117] have been used. For example, Moon et al. [115] reported the syntheses of biodegradable polyaspartamide derivatives conjugated with histamine to prepare a metal-coordinated supramolecular hydrogel with Cu²⁺ metal ions in an aqueous solution that displayed the capacity to heal in 5 h, with a G' of ≈10 kPa. Thiolated BSA and silver nitrate have also been used to produce an injectable, self-healing, antibacterial BSA-based hydrogel for use in bone regeneration. [116] The resulting hydrogel was softer than the previous one, with a G' of ≈400 Pa and shear-thinning behavior, enabling its rapid recovery.

## 6. Degradable Networks with Self-Healing Properties Based on Multi-Mechanisms

The aforementioned examples of degradable self-healing hydrogels and elastomers rely on single self-healing mechanisms. However, self-healing may also be caused by a combination of various dynamic chemical bonds, various physical interactions, or a combination of chemical bonds and physical interactions. Owing to the complexity of designing such materials, this approach has been mainly applied to dual-self-healing mechanisms, although degradable networks with more than two self-healing mechanisms are also described in this section. The selection of mechanisms associated with the optimal properties depends mainly on the desired application. Generally, to increase Young's modulus or elasticity of the material, higher

contents of reversible covalent linkages are preferred, whereas to favor more spontaneous self-healing without depending on external stimuli, physical dynamic bonds should be selected.

### 6.1. Dual Self-Healing via the Combination Of Dynamic Chemical Bonds

Five examples of degradable self-healing hydrogels with combinations of dynamic chemical bonds have recently been reported and are summarized in Table 8. In the first two cases, the networks are based on dynamic Schiff base reactions and acylhydrazone bonds in similar systems, relying on gelatin, adipic acid dihydrazide, and A-Alg [118] or A-Dex [119] (Figure 7.1). To enhance the antibacterial activity and accelerate wound healing, microspheres of PLGA loaded with basic fibroblast growth factor (bFGF@PLGA) and chlorhexidine acetate (CHA) were embedded in soft gels (typical G' values of 600 Pa–1.8 kPa) that self-repaired after 1 h and could be fully degraded in PBS after 50 h.

Notably, these systems, based on dextran or alginate, displayed good biocompatibilities in vitro and in vivo. In another example, self-healing was based on dynamic imine bonds associated with borate ester linkages. [120] The system was composed of multifunctional benzaldehyde- and phenylboronic acid-modified PEG cross-linked with PVA and glycol chitosan. Regarding the self-healing capacity, even the stiffer sample (G' = 5.7 kPa) could recover after 45 min post-injection, with a SHE of 98%.
<figure><img src="image_9.png" /><figcaption>**Figure 7.** 1) Schematic representation of the self-healing mechanism based on Schiff base and acylhydrazone bonds. 2) Schematic presentations of dual physically cross-linked supramolecular elastomers composed of ionic networks with different strengths. The strong bonds (soft tertiary ammonium-soft sulfate pairs) and weak bonds (soft tertiary ammonium-hard carboxylate groups) act as reversible sacrificial bonds under deformation. Adapted with permission.[119,130] Copyright 2019, Elsevier. Copyright 2021, Elsevier.</figcaption></figure>

Other examples include gelatin that was associated with A-Alg and borax [121] or dialdehyde dextrin and dialdehyde carboxymethyl cellulose with borax and glutaraldehyde,[122] which exhibited slow (7 d) and fast (4 h) self-healing, respectively.

Wang et al. designed a dual self-healing PU elastomer based on DA adducts and disulfide bonds as self-repairing coatings with shape-memory properties.[123] The PU was prepared using diols containing DA bonds, PCL-diol, and HDI. The PU prepolymer was further cross-linked with trimethylolpropane tris(3-mercapto-propionate). $\sigma_{max}$ reached 33 MPa and G' was close to 0.1 MPa, with a SHE of 113%. Self-healing was realized in three phases: heating at 60 °C to enable the melting of PCL and reduce the scratch, heating at 120 °C to activate the retro-DA reaction, and the final DA reaction occurred after cooling to room temperature.

## 6.2. Dual Self-Healing via the Combination of Physical Interactions

Compared with the limited number of examples combining two types of dynamic bonds, numerous self-healing hydrogels are based on multiple physical interactions, and the main combinations are listed in this section and Table 9.

### 6.2.1. Combination of Hydrogen Bonds and Hydrophobic Interactions

The combination of hydrophobic interactions and hydrogen bonding is illustrated here using three recent examples. The first hydrogel relied on polyglycerol sebacate-polyethylene

glycol methyl ether methacrylate copolymers associated with $\alpha$-CD.[124] Another synthetic hydrogel was obtained by polymerizing gelatin methacrylate with 2-(2-methoxyethoxy)ethyl methacrylate to produce a hybrid branched copolymer.[126] Both hydrogels displayed the capacity to recover after shear thinning. However, they differed in terms of degradation, with the first exhibiting stability over 2 months at neutral pH and requiring acidic or basic conditions to degrade. Conversely, the second could be enzymatically degraded in the presence of collagenase after 36 h in vitro and 2–3 months in vivo. In terms of natural polymers, denaturation of BSA via thermal treatment has been proposed.[125] Denaturation leads to changes in the protein conformation and the exposure of hydrophobic groups initially concealed in the protein core to enable hydrophobic interactions in parallel to hydrogen bonding, resulting in a SHE in terms of $\sigma_{max}$ of 100% after 1 h.

### 6.2.2. Combination of Hydrogen Bonds and Electrostatic/Ionic Interactions

Natural polymers are key in preparing degradable networks that combine hydrogen bonding and electrostatic interactions. A gelatin-based electroconductive soft hydrogel was prepared using cross-linked gelatin functionalized with carboxylated multi-walled carbon nanotubes (CNTs) and PEDOT:PSS (mix of poly(3.4-ethylenedioxythiphene) and polystyrene sulfonate).[127] A chitosan-based hydrogel was synthesized via in situ free-radical polymerization of acrylic acid and acrylamide in the presence of chitosan in a dilute aqueous acetic
<figure><img src="image_9.png" /><figcaption>**Figure 7.** 1) Schematic representation of the self-healing mechanism based on Schiff base and acylhydrazone bonds. 2) Schematic presentations of dual physically cross-linked supramolecular elastomers composed of ionic networks with different strengths. The strong bonds (soft tertiary ammonium-soft sulfate pairs) and weak bonds (soft tertiary ammonium-hard carboxylate groups) act as reversible sacrificial bonds under deformation. Adapted with permission.[119,130] Copyright 2019, Elsevier. Copyright 2021, Elsevier.</figcaption></figure>

Other examples include gelatin that was associated with A-Alg and borax [121] or dialdehyde dextrin and dialdehyde carboxymethyl cellulose with borax and glutaraldehyde,[122] which exhibited slow (7 d) and fast (4 h) self-healing, respectively.

Wang et al. designed a dual self-healing PU elastomer based on DA adducts and disulfide bonds as self-repairing coatings with shape-memory properties.[123] The PU was prepared using diols containing DA bonds, PCL-diol, and HDI. The PU prepolymer was further cross-linked with trimethylolpropane tris(3-mercapto-propionate). $\sigma_{max}$ reached 33 MPa and G' was close to 0.1 MPa, with a SHE of 113%. Self-healing was realized in three phases: heating at 60 °C to enable the melting of PCL and reduce the scratch, heating at 120 °C to activate the retro-DA reaction, and the final DA reaction occurred after cooling to room temperature.

## 6.2. Dual Self-Healing via the Combination of Physical Interactions

Compared with the limited number of examples combining two types of dynamic bonds, numerous self-healing hydrogels are based on multiple physical interactions, and the main combinations are listed in this section and Table 9.

### 6.2.1. Combination of Hydrogen Bonds and Hydrophobic Interactions

The combination of hydrophobic interactions and hydrogen bonding is illustrated here using three recent examples. The first hydrogel relied on polyglycerol sebacate-polyethylene

glycol methyl ether methacrylate copolymers associated with α-CD.[124] Another synthetic hydrogel was obtained by polymerizing gelatin methacrylate with 2-(2-methoxyethoxy)ethyl methacrylate to produce a hybrid branched copolymer.[126] Both hydrogels displayed the capacity to recover after shear thinning. However, they differed in terms of degradation, with the first exhibiting stability over 2 months at neutral pH and requiring acidic or basic conditions to degrade. Conversely, the second could be enzymatically degraded in the presence of collagenase after 36 h in vitro and 2–3 months in vivo. In terms of natural polymers, denaturation of BSA via thermal treatment has been proposed.[125] Denaturation leads to changes in the protein conformation and the exposure of hydrophobic groups initially concealed in the protein core to enable hydrophobic interactions in parallel to hydrogen bonding, resulting in a SHE in terms of $\sigma_{max}$ of 100% after 1 h.

### 6.2.2. Combination of Hydrogen Bonds and Electrostatic/Ionic Interactions

Natural polymers are key in preparing degradable networks that combine hydrogen bonding and electrostatic interactions. A gelatin-based electroconductive soft hydrogel was prepared using cross-linked gelatin functionalized with carboxylated multi-walled carbon nanotubes (CNTs) and PEDOT:PSS (mix of poly(3.4-ethylenedioxythiphene) and polystyrene sulfonate).[127] A chitosan-based hydrogel was synthesized via in situ free-radical polymerization of acrylic acid and acrylamide in the presence of chitosan in a dilute aqueous acetic
<table><caption>**Table 9.** Self-healing hydrogels and elastomers based on a combination of physical interactions (materials, mechanism, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Hydrophobic interactions</td><td>Polyglycerol sebacate<br>-PEG methyl ether<br>methacrylate<br>α-CD</td><td>G' = 1 to 100 kPa</td><td>–</td><td>–</td><td>–</td><td>In vitro, in acidic or<br>basic environments</td><td>[124]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Hydrophobic interactions</td><td>Denatured BSA</td><td>σ<sub>max</sub> = 60 kPa</td><td>Cut</td><td>60 min, 80 °C</td><td>100% (σ<sub>max</sub>)</td><td>In vivo</td><td>[125]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Hydrophobic interactions</td><td>Gelatin methacrylate<br>2-(2-methoxyethoxy)<br>ethyl methacrylate</td><td>G' = 1 to 400 Pa</td><td>Scratch</td><td>90 min, 37 °C</td><td>100% (G')</td><td>In vitro, 100% mass<br>loss with collagenase<br>in 36 h<br>In vivo, 100% degrada-<br>tion after 56 to 84 d</td><td>[126]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Gelatin<br>EDC<br>PEDOT:PSS<br>MWCNTs-COOH</td><td>G' = 4 to 11 kPa</td><td>Cut</td><td>10 min</td><td>100% (Visual)</td><td>In vitro, 90 to 100%<br>degradation in 20 d</td><td>[127]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Poly(acrylic<br>acid-co- acrylamide)<br>Chitosan</td><td>G' = 0.2 to 1 kPa</td><td>Cut</td><td>1 d</td><td>88% (σ<sub>max</sub>)</td><td>In vitro, acidic<br>conditions</td><td>[128]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Starch<br>PVA<br>Borax</td><td>ε<sub>max</sub> = 2500%<br>Toughness = 290 kJ m<sup>-3</sup><br>Compression strength =<br>550 kPa</td><td>Cut</td><td>600 s</td><td>69% (σ<sub>max</sub>)<br>81% (ε<sub>max</sub>)</td><td>–</td><td>[129]</td></tr><tr><td>Elastomer</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Polyurethane (PCL/<br>HDI)<br>Sulfated alginate</td><td>E = 0.9 to 7.7 MPa<br>σ<sub>max</sub> = 2 to 8.7 MPa<br>Toughness = 61 MJ m<sup>-3</sup></td><td>Cut</td><td>5 min, RT</td><td>100%</td><td>–</td><td>[130]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Metal-coordination</td><td>Poly(acrylic<br>acid-co- acrylamide)<br>PVA<br>Fe<sup>3+</sup><br>Borax</td><td>G' = 1 to 10 kPa</td><td>Cut</td><td>48 h, 40 °C</td><td>85% (σ<sub>max</sub>)</td><td>In vitro, 3 to 70% mass<br>loss in 10d</td><td>[131]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Metal-coordination</td><td>Poly(glycerol sebacate)-<br>co-poly(ethylene<br>glycol)-g-catechol<br>Fe<sup>3+</sup><br>UPy-functional gelatin</td><td>G' = 2 kPa</td><td>Cut<br>Hole</td><td>&lt; 12 min at 37 °C<br>45 s under NIR<br>irradiation</td><td>–</td><td>In vitro, 7 to 10d</td><td>[132]</td></tr><tr><td>Elastomer</td><td>Hydrogen bonds<br>Metal-coordination</td><td>Poly(δ-valerolactone)-<br>co-poly(lactic acid)<br>containing UPy<br>bpy</td><td>Fracture energy up to<br>80 MJ.m<sup>-3</sup></td><td>Scratch</td><td>30 min, 50 °C</td><td>77% (Visual)</td><td>–</td><td>[133]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions<br>Metal-coordination</td><td>κ-carrageenan<br>PAA<br>Zr<sup>4+</sup><br>α-galactose<br>Micelles of n-octadecyl<br>acrylate dissolved in<br>sodium dodecyl sulfate</td><td>σ<sub>max</sub> = 2.5 Mpa<br>ε<sub>max</sub> = 1382%<br>Toughness = 13.4 MJ m<sup>-3</sup></td><td>Cut</td><td>24 h, 70 °C</td><td>67%<br>(toughness)</td><td>In vitro, 27 to 47%<br>mass loss after 24d</td><td>[134]</td></tr><tr><td>Hydrogel</td><td>Miscellaneous<br>interactions</td><td>Proline-rich peptide-<br>PEG copolymer, recom-<br>binant linear protein,<br>and PNIPAM</td><td>G' = 100 Pa</td><td>–</td><td>–</td><td>100% (G')</td><td>In vitro, 70%<br>degradation after 14d</td><td>[135]</td></tr></tbody></table>

BSA, bovine serum albumin; CD, cyclodextrin; E, Young's modulus; EDC, N-(3-dimethylamino-propyl)-N'-ethylcarbodiimide hydrochloride; G', storage modulus; HDI, hexamethylene diisocyanate; MWCNTs, multi-walled carbon nanotubes; PCL, polycaprolactone; PEG, poly(ethylene glycol); PVA, poly(vinyl alcohol); σ<sub>max</sub>, stress at break.

acid solution.[128] The resulting hydrogel was composed of poly(acrylic acid-co-acrylamide) copolymers grafted onto chitosan chains and a small proportion of nongrafted chains that

could interact via multiple noncovalent interactions. Finally, a stretchable (ε<sub>max</sub> of 2500%), strong (compression strength of 550 kPa) starch/PVA/borax hybrid dual-cross-linked hydrogel
<table><caption>**Table 9.** Self-healing hydrogels and elastomers based on a combination of physical interactions (materials, mechanism, mechanical properties, SH evaluation, SH conditions, SHE, and degradation).</caption><thead><tr><th>Nature</th><th>Mechanism</th><th>Materials</th><th>Mechanical properties</th><th>SH evaluation</th><th>SH conditions</th><th>SHE</th><th>Degradation</th><th>Ref.</th></tr></thead><tbody><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Hydrophobic interactions</td><td>Polyglycerol sebacate<br>-PEG methyl ether<br>methacrylate<br>α-CD</td><td>G' = 1 to 100 kPa</td><td>–</td><td>–</td><td>–</td><td>In vitro, in acidic or<br>basic environments</td><td>[124]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Hydrophobic interactions</td><td>Denatured BSA</td><td>σ<sub>max</sub> = 60 kPa</td><td>Cut</td><td>60 min, 80 °C</td><td>100% (σ<sub>max</sub>)</td><td>In vivo</td><td>[125]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Hydrophobic interactions</td><td>Gelatin methacrylate<br>2-(2-methoxyethoxy)<br>ethyl methacrylate</td><td>G' = 1 to 400 Pa</td><td>Scratch</td><td>90 min, 37 °C</td><td>100% (G')</td><td>In vitro, 100% mass<br>loss with collagenase<br>in 36 h<br>In vivo, 100% degrada-<br>tion after 56 to 84 d</td><td>[126]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Gelatin<br>EDC<br>PEDOT:PSS<br>MWCNTs-COOH</td><td>G' = 4 to 11 kPa</td><td>Cut</td><td>10 min</td><td>100% (Visual)</td><td>In vitro, 90 to 100%<br>degradation in 20 d</td><td>[127]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Poly(acrylic<br>acid-co- acrylamide)<br>Chitosan</td><td>G' = 0.2 to 1 kPa</td><td>Cut</td><td>1 d</td><td>88% (σ<sub>max</sub>)</td><td>In vitro, acidic<br>conditions</td><td>[128]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Starch<br>PVA<br>Borax</td><td>ε<sub>max</sub> = 2500%<br>Toughness = 290 kJ m<sup>-3</sup><br>Compression strength =<br>550 kPa</td><td>Cut</td><td>600 s</td><td>69% (σ<sub>max</sub>)<br>81% (ε<sub>max</sub>)</td><td>–</td><td>[129]</td></tr><tr><td>Elastomer</td><td>Hydrogen bonds<br>Electrostatic/ionic<br>interactions</td><td>Polyurethane (PCL/<br>HDI)<br>Sulfated alginate</td><td>E = 0.9 to 7.7 MPa<br>σ<sub>max</sub> = 2 to 8.7 MPa<br>Toughness = 61 MJ m<sup>-3</sup></td><td>Cut</td><td>5 min, RT</td><td>100%</td><td>–</td><td>[130]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Metal-coordination</td><td>Poly(acrylic<br>acid-co- acrylamide)<br>PVA<br>Fe<sup>3+</sup><br>Borax</td><td>G' = 1 to 10 kPa</td><td>Cut</td><td>48 h, 40 °C</td><td>85% (σ<sub>max</sub>)</td><td>In vitro, 3 to 70% mass<br>loss in 10d</td><td>[131]</td></tr><tr><td>Hydrogel</td><td>Hydrogen bonds<br>Metal-coordination</td><td>Poly(glycerol sebacate)-<br>co-poly(ethylene<br>glycol)-g-catechol<br>Fe<sup>3+</sup><br>UPy-functional gelatin</td><td>G' = 2 kPa</td><td>Cut<br>Hole</td><td>&lt; 12 min at 37 °C<br>45 s under NIR<br>irradiation</td><td>–</td><td>In vitro, 7 to 10d</td><td>[132]</td></tr><tr><td>Elastomer</td><td>Hydrogen bonds<br>Metal-coordination</td><td>Poly(δ-valerolactone)-<br>co-poly(lactic acid)<br>containing UPy<br>bpy</td><td>Fracture energy up to<br>80 MJ.m<sup>-3</sup></td><td>Scratch</td><td>30 min, 50 °C</td><td>77% (Visual)</td><td>–</td><td>[133]</td></tr><tr><td>Hydrogel</td><td>Hydrophobic interactions<br>Metal-coordination</td><td>κ-carrageenan<br>PAA<br>Zr<sup>4+</sup><br>α-galactose<br>Micelles of n-octadecyl<br>acrylate dissolved in<br>sodium dodecyl sulfate</td><td>σ<sub>max</sub> = 2.5 Mpa<br>ε<sub>max</sub> = 1382%<br>Toughness = 13.4 MJ m<sup>-3</sup></td><td>Cut</td><td>24 h, 70 °C</td><td>67%<br>(toughness)</td><td>In vitro, 27 to 47%<br>mass loss after 24d</td><td>[134]</td></tr><tr><td>Hydrogel</td><td>Miscellaneous<br>interactions</td><td>Proline-rich peptide-<br>PEG copolymer, recom-<br>binant linear protein,<br>and PNIPAM</td><td>G' = 100 Pa</td><td>–</td><td>–</td><td>100% (G')</td><td>In vitro, 70%<br>degradation after 14d</td><td>[135]</td></tr></tbody></table>

BSA, bovine serum albumin; CD, cyclodextrin; E, Young's modulus; EDC, N-(3-dimethylamino-propyl)-N'-ethylcarbodiimide hydrochloride; G', storage modulus; HDI, hexamethylene diisocyanate; MWCNTs, multi-walled carbon nanotubes; PCL, polycaprolactone; PEG, poly(ethylene glycol); PVA, poly(vinyl alcohol); σ<sub>max</sub>, stress at break.

acid solution.[128] The resulting hydrogel was composed of poly(acrylic acid-co-acrylamide) copolymers grafted onto chitosan chains and a small proportion of nongrafted chains that

could interact via multiple noncovalent interactions. Finally, a stretchable (ε<sub>max</sub> of 2500%), strong (compression strength of 550 kPa) starch/PVA/borax hybrid dual-cross-linked hydrogel
<figure><img src="image_10.png" /><figcaption>**Figure 8.** 1) Schematic diagram of the dual dynamic cross-linking based on hydrogen bonds and catechol-Fe coordination in the hydrogel network. 2) a) Preparation of bpy-PVL-PLA-UPy b) Schematic illustration of the bpy-UPy and ([M(bpy)ₙ]²⁺-UPy film. Adapted with permission.[132,133] Copyright 2020, Wiley-VCH. Copyright 2019, Royal Society of Chemistry.</figcaption></figure>

was developed.[129] These hydrogels displayed rapid self-healing capacities, with repair times ranging from a few seconds to 1 h.

Only one dual self-healable elastomer with this combination of interactions was reported by Baharvand et al. Based on their previous studies regarding alginate-based supramolecular PU based on PCL,[109] they introduced dual cross-linking via chain-end functionalization using sulfated alginate,[130] enabling strong and weak ionic interactions between tertiary ammonium and sulfate or carboxylate groups, respectively (Figure 7.2). The dual physically cross-linked elastomers exhibited SHEs of 100% after 5 min at room temperature, with high toughnesses and mechanical properties close to those of vascular tissues (E values of 1–8 MPa).

### 6.2.3. Combination of Hydrogen Bonds and Metal-Coordination Interactions

Biodegradable double-network hydrogels composed of biodegradable poly(acrylic acid-*co*-acrylamide)/PVA and involving metal coordination were developed by Jing et al.[131] The ionic coordination between the carboxylate groups and Fe³⁺ and hydrogen bonding between the carboxylic and amide groups formed the first network, whereas the second was based on the complexation between PVA and borax. The resulting hydrogel exhibited a G' of 1–10 kPa, and the SHE in terms of σmax reached 85% after 48 h at 40 °C. After 10 d in PBS and simulated intestinal fluid, a mass loss of up to 70% was measured as a function of the acrylamide content. In another study, Zhao et al.[132] designed an injectable dual-network self-healing

hydrogel combining poly(glycerol sebacate)-*co*-PEG-*g*-catechol to yield catechol-Fe³⁺ coordination cross-links and UPy-functionalized gelatin to yield quadruple hydrogen bonding cross-links (Figure 8.1). G' was ≈ 1 kPa at 37 °C, and the hydrogel could heal at body temperature in 12 min and even 45 s under heating via near-IR irradiation. In PBS, the hydrogels exhibited linear mass losses and were completely degraded after 10 d.

An elastomer with dual self-healing properties and displaying hydrogen-bonding and metal-ligand interactions was developed using a poly(δ-valerolactone)-*co*-PLA copolymer containing UPy, 2,2-bipyridine, and Fe²⁺, Co²⁺ or Zn²⁺ ions (Figure 8.2).[133] With dual-cross-linking, the fracture energy, which reached 80 MJ m⁻³, was a function of the cation in the order Fe²⁺ > Co²⁺ > Zn²⁺. Using the scratch method, visual healing was realized after 30 min at 50 °C with a SHE of 77% for metal-UPy, whereas the SHE of the pure UPy under the same conditions was only 51%.

### 6.2.4. Other Combinations of Physical Interactions

Zhao et al.[134] prepared a κ-carrageenan/PAA double-network hydrogel based on metal coordination and hydrophobic interactions. The first network was composed of κ-carrageenan chains and Zr⁴⁺ cations that interacted with D-galactose. The second interpenetrated network was based on PAA and associated with hydrophobic micelles of n-octadecyl acrylate dissolved in sodium dodecyl sulfate. After cutting, samples placed in contact for 24 h at 70 °C could heal and withstand large deformations (~400%) without breakage, whereas the
<figure><img src="image_10.png" /><figcaption>**Figure 8.** 1) Schematic diagram of the dual dynamic cross-linking based on hydrogen bonds and catechol-Fe coordination in the hydrogel network. 2) a) Preparation of bpy-PVL-PLA-UPy b) Schematic illustration of the bpy-UPy and ([M(bpy)ₙ]²⁺-UPy film. Adapted with permission.[132,133] Copyright 2020, Wiley-VCH. Copyright 2019, Royal Society of Chemistry.</figcaption></figure>

was developed.[129] These hydrogels displayed rapid self-healing capacities, with repair times ranging from a few seconds to 1 h.

Only one dual self-healable elastomer with this combination of interactions was reported by Baharvand et al. Based on their previous studies regarding alginate-based supramolecular PU based on PCL,[109] they introduced dual cross-linking via chain-end functionalization using sulfated alginate,[130] enabling strong and weak ionic interactions between tertiary ammonium and sulfate or carboxylate groups, respectively (Figure 7.2). The dual physically cross-linked elastomers exhibited SHEs of 100% after 5 min at room temperature, with high toughnesses and mechanical properties close to those of vascular tissues (E values of 1–8 MPa).

### 6.2.3. Combination of Hydrogen Bonds and Metal-Coordination Interactions

Biodegradable double-network hydrogels composed of biodegradable poly(acrylic acid-co-acrylamide)/PVA and involving metal coordination were developed by Jing et al.[131] The ionic coordination between the carboxylate groups and Fe³⁺ and hydrogen bonding between the carboxylic and amide groups formed the first network, whereas the second was based on the complexation between PVA and borax. The resulting hydrogel exhibited a G' of 1–10 kPa, and the SHE in terms of σmax reached 85% after 48 h at 40 °C. After 10 d in PBS and simulated intestinal fluid, a mass loss of up to 70% was measured as a function of the acrylamide content. In another study, Zhao et al.[132] designed an injectable dual-network self-healing

hydrogel combining poly(glycerol sebacate)-co-PEG-g-catechol to yield catechol-Fe³⁺ coordination cross-links and UPy-functionalized gelatin to yield quadruple hydrogen bonding cross-links (Figure 8.1). G' was ≈ 1 kPa at 37 °C, and the hydrogel could heal at body temperature in 12 min and even 45 s under heating via near-IR irradiation. In PBS, the hydrogels exhibited linear mass losses and were completely degraded after 10 d.

An elastomer with dual self-healing properties and displaying hydrogen-bonding and metal-ligand interactions was developed using a poly(δ-valerolactone)-co-PLA copolymer containing UPy, 2,2-bipyridine, and Fe²⁺, Co²⁺ or Zn²⁺ ions (Figure 8.2).[133] With dual-cross-linking, the fracture energy, which reached 80 MJ m⁻³, was a function of the cation in the order Fe²⁺ > Co²⁺ > Zn²⁺. Using the scratch method, visual healing was realized after 30 min at 50 °C with a SHE of 77% for metal-UPy, whereas the SHE of the pure UPy under the same conditions was only 51%.

### 6.2.4. Other Combinations of Physical Interactions

Zhao et al.[134] prepared a κ-carrageenan/PAA double-network hydrogel based on metal coordination and hydrophobic interactions. The first network was composed of κ-carrageenan chains and Zr⁴⁺ cations that interacted with D-galactose. The second interpenetrated network was based on PAA and associated with hydrophobic micelles of n-octadecyl acrylate dissolved in sodium dodecyl sulfate. After cutting, samples placed in contact for 24 h at 70 °C could heal and withstand large deformations (~400%) without breakage, whereas the
toughness recovery was 67% after 2 min. The biodegradability was investigated in vitro in PBS and evaluated via the loss of mechanical properties (close to zero after 24 h) and mass (27–47% after 24 d).

Cai et al. [135] designed soft hydrogels with maximum G' values of ≈ 100 Pa with two physical cross-linking mechanisms: weak heterodimeric *ex vivo* molecular recognition and in vivo cross-linking due to the thermo-responsive formation of a reinforcing network. The first network was composed of a star-shaped proline-rich peptide-PEG copolymer assembled with a recombinant linear protein bearing CC43 WW and RGD cell-binding domains connected by hydrophilic spacers. The second was based on PNIPAM chains conjugated to the PEG copolymer, and the erosion of the material was ~70% after 14 d in vitro.

## 6.3. Dual Self-Healing via a Combination Of Dynamic Chemical Bonds and Physical Interactions

### 6.3.1. Combination of Schiff-base and Physical Interactions

Unsurprisingly, due to the numerous self-healing systems relying on Schiff-base reactions, this dynamic bond is the most common one in dual self-healing systems combining dynamic chemical bonds and physical interactions. Several examples of self-healing hydrogels based on the combination of dynamic Schiff-base bonds as the chemical bonds and copolymer micelle cross-linking as the physical interactions have been reported (Table 10). Guo et al. [136] prepared hydrogels by mixing quaternized chitosan with micelles of benzaldehyde-terminated Pluronic F-127 (PF-127) under physiological conditions. Similarly, hydrogels based on CEC and benzaldehyde-terminated PF-127/CNTs were prepared.[137] Self-healing was due to the Schiff-base and physical cross-linking interactions of the PF-127 micelles and CNTs. In both examples, the self-healing times were 2–3 h and the G' values were in the range of 10–30 kPa.

Other dual self-healing hydrogels combine Schiff-base bonds and catechol-Fe coordination. This is the case for catechol-modified poly(l-lysine) and A-Dex [138] or catechol-modified oxidized HA and aminated gelatin,[139] which are associated with Fe³⁺ ions. The first system yielded soft gels with G' values limited to 7.6 kPa compared to the G' of the second system of 535 kPa. The hydrogels rapidly self-healed with SHEs of >91% and could degrade in PBS or in the presence of iron-chelating competitors. The cytocompatibility of the catechol-modified poly(l-lysine)/A-Dex hydrogel was confirmed toward L929 and NIH 3T3 murine cells.

Finally, Schiff-base linkages were also combined with host-guest interactions [140] or hydrogen bonds.[141] This is exemplified by hydrogels composed of the guest polymer, phenolphthalein-grafted CEC, the host molecule, hexamethylenediamine-modified β-CD, and A-Alg,[140] or chitosan hydrogels cross-linked with vanillin.[141] In the latter case, the amino group of chitosan could react with the aldehyde group of vanillin via a Schiff-base reaction, and its hydroxyl groups could form hydrogen bonds with the hydroxyl or amino groups of another chitosan chain. For these two types of hydrogels, repair times of a few hours were required to reach SHEs of ≥80%.

### 6.3.2. Dual-self-healing systems: other combinations

Two recent examples based on hydrogen bonds and boronate esters are reported in the literature (Table 10). The first was composed of PVA, borax, and carboxymethyl cellulose.[142] In this case, $\sigma_{max}$ and E could reach 720 and 340 kPa, respectively, and self-healing was realized after 16 h at 20 °C. In the second example, hydrogels were obtained using dynamic benzoxaborole-sugar interactions and quadruple hydrogen bonds of UPy moieties in poly(DMA-st-META-st-LAEMA) and poly(MPC-st-UPyHEMA-st-MAABO) copolymers.[143] Depending on the compositions of the different gels, G' ranged from 0.3 to 1.1 kPa. Self-healing times were rapid, with shape recoveries in only 20 s for the samples evaluated via the cutting method.

Disulfide bonds have also been used in systems with hydrogen bonds. Wen et al. proposed a degradable PU hydrogel composed of PCL, PEG, and IPDI, containing disulfide bonds and hydrogen bonds.[144] The SHE, as quantified via tensile test reached 97%, and the materials exhibited high mechanical strengths, with $\sigma_{max}$ values of up to 3.3 MPa. At all PU/PCL ratios, the mass loss in PBS was limited to 8% after 30 d.

A combination of DA adducts and electrostatic interactions was proposed by Li et al., using pectin/chitosan hydrogels. Pectin was modified with furfural to form the conjugated diene partner, and 6-maleidocaproic acid was grafted onto chitosan to yield the dienophile partner.[145] The hydrogels healed in 5 h at 37 °C and could bear a mass of 5 N without damage.

Finally, Jiang et al. imparted self-healing properties on elastomers due to oxime-urethane and hydrogen bonds.[146] PU copolymers based on dimethylglyoxime, IPDI, PTHF, and glycerol were prepared. Depending on the glycerol content, $\sigma_{max}$, E, and $\epsilon_{max}$ values of 33 kPa–4.4 MPa, 172 kPa–3.7 MPa, and 500–3300%, respectively, were obtained. The self-healing capacity was also a function of the glycerol content. After healing at room temperature for 5 min, the SHEs in terms of $\sigma_{max}$ were >80% for elastomers but limited to 37% at low and high glycerol contents. Under in vitro enzymatic conditions, the elastomers lost 7.5% of their masses after nine days.

## 6.4. Multi-mechanism self-healing systems

Finally, although uncommon, the self-healing properties may be due to the combination of more than two mechanisms. To the best of our knowledge, only two examples have combined two types of chemical linkages with one physical interaction. In both cases, boronate ester bonds are associated with Schiff-base linkages and hydrogen bonds [147] or electrostatic interactions.[148] In the first system, hydrogels were prepared using PVA and borax as the matrix, which was reinforced with cellulose nanofibers and dopamine-grafted oxidized carboxymethyl cellulose. In the second study, gels were prepared using borax-functionalized oxidized chondroitin sulfate (BOC), gelatin, and BOC-doped polypyrrole. Both hydrogels were cytocompatible in vitro and exhibited similar healing times of ≈ 5 min and G' values in the range of 0.4–10 kPa.

A combination of two physical interactions and one chemical reversible bond is also possible. This is the case in a study by Tran et al. [149] that reported hydrogels based on dynamic