4D printing for minimally invasive biomedical
applications: programmable smart materials for
deployable devices, drug delivery, and tissue
regeneration

Mohammad Amin Yousefi, Davood Rahmatabadi, Mina Ahmadi, Abbas Bayati, Majid Baniassadi, Abdelghani Laachachi, Vadim V Silberschmidt, Daniel George, Mostafa Baghani

► To cite this version:

Mohammad Amin Yousefi, Davood Rahmatabadi, Mina Ahmadi, Abbas Bayati, Majid Baniassadi, et al.. 4D printing for minimally invasive biomedical applications: programmable smart materials for deployable devices, drug delivery, and tissue regeneration. Materials & Design, 2026, 263, pp.115555. 10.1016/j.matdes.2026.115555. hal-05518040

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# 4D printing for minimally invasive biomedical applications: programmable smart materials for deployable devices, drug delivery, and tissue regeneration

Mohammad Amin Yousefi<sup>a, ID</sup>, Davood Rahmatabadi<sup>a, ID</sup>, Mina Ahmadi<sup>b</sup>, Abbas Bayati<sup>a, ID</sup>, Majid Baniassadi<sup>a</sup>, Abdelghani Laachachi<sup>c</sup>, Vadim V. Silberschmidt<sup>d, ID</sup>, Daniel George<sup>e, * ID</sup>, Mostafa Baghani<sup>a, *</sup>

## ARTICLE INFO

### Keywords:

- Additive manufacturing
- Shape-memory materials
- Tissue engineering
- Drug delivery systems
- 4D printing
- Biomedical applications

## ABSTRACT

4D printing extends additive manufacturing beyond static form by enabling structures that change shape or function over time in response to programmed stimuli. This capability is accelerating biomedical innovation in tissue regeneration, on-demand drug delivery, and minimally invasive deployable devices. This review focuses on recent advances in 4D printing for biomedical purposes, emphasizing key developments, challenges, and opportunities that define this emerging field. The review is divided into five main sections. It begins by introducing the concept of 4D printing and its specific relevance to biomedical applications. The second section focuses on applications of 4D printing, categorized into three main areas: drug delivery systems, tissue engineering,

**Abbreviations:** 3D, 3-dimension; 4D, 4-dimension; AAc, acrylic acid; ABS, acrylonitrile butadiene styrene; AI, artificial intelligence; AM, additive manufacturing; ASD, atrial septal defects; AuNR, gold nanorod; BADGE, bisphenol A diglycidyl ether; BJ, binder jetting; C16A, hexadecyl acrylate; CAD, computer aided design; CAL, computed axial lithography; CAM, computer aided manufacturing; CLIP, continuous liquid interface production; CNC, cellulose nanocrystal; CNT, carbon nanotube; CT, computed tomography; DAVP, deep-penetration acoustic volumetric printing; DED, directed energy deposition; DFO, deferoxamine; DIW, direct ink writing; DLP, digital light processing; DMAA, N,N-dimethylacrylamide; DMLS, direct metal laser sintering; DOX, doxorubicin; EBM, electron beam melting; Eth, ethosomes; EVA, ethylene-vinyl acetate; FDM, fused deposition modeling; FEA, finite-element analysis; FFF, fused filament fabrication; FGM, functionally graded material; GelMA, gelatin methacryloyl; GGMA, gellan gum methacrylate; HA, hydroxyapatite; HNT, halloysite nanotube; LAA, left atrial appendage; LCE, liquid crystal elastomer; MAAc, methacrylic acid; ME or MEX, material extrusion; MicroCT, microcomputed tomography; MJ, material jetting; ML, machine learning; MPP, multiphoton polymerization; MSC, mesenchymal stem cell; MWCNT, multi-walled carbon nanotube; NBT, near-body temperature; NdFeB, neodymium-iron-boron; nHAP, nanohydroxyapatite; NIPAm, N-isopropylacrylamide; NIR, near-infrared; NiTi, nickel-titanium; NSC, neural stem cell; OD, occlusion device; OM, optical microscopy; PA, polyamide; PA1212, polyamide 1212; PAAc, poly(acrylic acid); PAAm, poly(acrylamide); PBAE, poly(β-aminoesters); PBAT, poly(butylene adipate terephthalate); PBF, powder bed fusion; PCL, poly(caprolactone); PCL-T, polycaprolactone triol; PDA, polydopamine; PEA, poly(propylene glycol) bis(2-aminopropyl) ether; PEEK, poly(ether ether ketone); PEG, poly(ethylene glycol); PEGDA, poly(ethylene glycol) diacrylate; PEGDM, poly(ethylene glycol) dimethacrylate; PETG, poly(ethylene terephthalate glycol); PGA, poly(glycolic acid); PGDA, poly(glycerol dodecanoate) acrylate; PHA, poly(hydroxyalkanoate); PHB, poly(hydroxybutyrate); PHBV, poly(3-hydroxybutyrate-co-3-hydroxyvalerate); PLA, poly(lactic acid); PLGA, poly(lactic-co-glycolic acid); PLMC, poly(D,L-lactide-co-tri-methylene carbonate); PNIPAm, poly(N-isopropylacrylamide); POMAC, poly(octamethylene maleate (anhydride) citrate); PTX, paclitaxel; PU, polyurethane; PVA, poly(vinyl alcohol); PVP, poly(vinylpyridine); R<sub>f</sub>, shape-fixity ratio; RGD, arginylglycylaspartic acid; R<sub>r</sub>, shape-recovery ratio; SEM, scanning electron microscopy; SH, self-healing; SHL, sheet lamination; SHS, selective heat sintering; SiC, silicon carbide; SLA, stereolithography; SLM, selective laser melting; SLS, selective laser sintering; SM, shape memory; SMA, shape-memory alloys; SMC, shape-memory ceramic; SME, shape-memory elastomers; SMNC, shape-memory nanocomposite; SMP, shape-memory polymer; SMPU, shape-memory polyurethane; SPION, superparamagnetic iron oxide nanoparticle; TBM, tracheobronchomalacia; TCMIP-SL, temperature-controlled mask-image-projection stereolithography; TCP, tricalcium phosphate; T<sub>g</sub>, glass transition temperature; TGME, triethylene glycol methyl ether; T<sub>m</sub>, melting temperature; TPAE, thermoplastic polyamide elastomer; TPC, thermoplastic copolyester; TPGDA, tripropylene glycol diacrylate; TPU, thermoplastic polyurethane; UV, ultraviolet; VP, vat photopolymerization; VSD, ventricular septal defect; ZnO, zinc oxide; βCD, β-cyclodextrin.

<footnote><sup>a</sup> School of Mechanical Engineering, College of Engineering, University of Tehran, Tehran, Iran</footnote>

<footnote><sup>b</sup> School of Automotive Engineering, Iran University of Science and Technology, Tehran, Iran</footnote>

<footnote><sup>c</sup> Luxembourg Institute of Sciences and Technology (LIST), Hautcharage, Luxembourg</footnote>

<footnote><sup>d</sup> Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Leicester LE11 3TU, UK</footnote>

<footnote><sup>e</sup> University of Strasbourg, CNRS, ICube, Strasbourg, France</footnote>

<footnote>* Corresponding authors.</footnote>

<footnote>E-mail addresses: george@unistra.fr (D. George), baghani@ut.ac.ir (M. Baghani).</footnote>
and biomedical devices. Following, the materials used in 4D printing for biomedical purposes, such as shape-memory polymers, hydrogels, shape-memory alloys, shape-memory ceramics, and composites, are discussed in detail. The techniques enabling the fabrication of adaptive structures tailored for medical use are then reviewed. Finally, the challenges associated with 4D printing in biomedical applications are critically analyzed, with a focus on material limitations, scalability in manufacturing, mechanical and functional stability, as well as environmental impact. This integrated perspective provides design guidelines and priority directions to accelerate clinically relevant 4D-printed biomedical systems.

# 1. Introduction

Additive manufacturing refers to advanced methods used to produce intricate shapes and structures from 3D computer models by gradually depositing material in layers [1]. This technology is also known under various names, such as *rapid prototyping*, *on-demand manufacturing*, *digital fabrication*, *desktop manufacturing*, *solid freeform manufacturing*, or *layer manufacturing* [2]. However, the most common name is *3D printing*. The concept of 3D printing originated in 1986 when a patent for the first 3D printer was filed in the USA [3]. Since then, numerous other 3D printing technologies have emerged over the past three decades, such as for example SLM, FDM, DIW SLS, DLP [4]. 3D printing offers several notable benefits, which distinguish it from traditional manufacturing methods [5]. These include the ability to customize the production of intricate three-dimensional objects with exceptional precision [6], reduced material waste during the manufacturing process [7], and faster or shortened product development cycles [8]. These advantages have driven substantial progress in biomedical engineering, enabling patient-specific devices and advanced scaffolds for healthcare applications [9,10]. Still, a key limitation of conventional 3D printing and bio-printing is that printed objects are typically designed to remain static, which restricts functionality in dynamic physiological environments where adaptation to changing conditions is often required [11].

In the last decade, this limitation has been addressed by the emergence of 4D printing, which introduces time as an additional dimension to enable programmed, stimulus-triggered transformations after fabrication [12,13]. For clarity, in this review “4D printing” refers to additionally manufactured structures that undergo time-dependent changes in shape and/or function in response to external stimuli, typically in the absence of living cells, whereas “4D bioprinting” denotes 4D printing of cell-laden constructs. The broader term “4D biofabrication” encompasses biological manufacturing routes that produce dynamically transforming, cell-containing constructs, including approaches beyond bioprinting [14]. Since Tibbits, from the Self-Assembly Lab at Massachusetts Institute of Technology, USA, first introduced the concept in 2014 [15], the definition of 4D printing has expanded from “3D printing plus time” to include controlled changes in shape, properties, and/or functionality under stimuli such as heat, moisture, pH, light, magnetic fields, or electrical inputs. Achieving reliable 4D behavior depends on both smart materials and design-for-transformation strategies, where the architecture and material placement are programmed to produce predictable time-dependent responses [16].

The biomedical relevance of 4D printing is increasing rapidly because many clinical needs are inherently dynamic: tissues remodel, anatomical geometries evolve, and therapeutic demands vary over time. The COVID-19 pandemic further amplified interest in advanced additive manufacturing for healthcare by highlighting the need for rapid, on-demand, and adaptable biomedical solutions. In this context, 4D printing has gained increased attention for creating stimulus-responsive constructs that can deploy, adapt, or deliver therapeutics in dynamic physiological environments [17]. As a result, 4D-printed systems are being explored for adaptive scaffolds, minimally invasive implants that deploy in situ, and stimulus-responsive drug delivery platforms that align with personalized medicine [18]. At the same time, progress is limited by unresolved challenges including biocompatibility and degradation control, repeatability under cyclic actuation, process

reproducibility, and scalable manufacturing pathways compatible with biomedical quality requirements.

Several recent reviews have examined 4D printing from different perspectives, including broad discussions of stimuli-responsive materials and actuation mechanisms, technique-oriented summaries of additive manufacturing routes, and application-driven reports spanning soft robotics and general healthcare use [16,19–22]. However, these contributions frequently treat materials, processing, and biomedical requirements as largely separate topics, with less emphasis on how clinical constraints shape material choice and multi-material architecture, how printing-induced variability influences function, and how practical considerations such as sterilization, standardized performance metrics, and clinically relevant validation govern translation beyond proof-of-concept demonstrations. In parallel, the field is evolving rapidly, with emerging printing approaches, newly engineered responsive material systems, and increasingly sophisticated biomedical device concepts appearing in recent years, creating a moving landscape that benefits from an updated, integrated synthesis. These limitations motivate a more application-grounded overview of biomedical 4D systems.

In the present work, recent progress is consolidated through a biomedical perspective that links material chemistry and transformation mechanisms to device- and scaffold-level requirements, while also reflecting manufacturing realities. Advances in shape-memory polymers, hydrogels, shape-memory alloys, shape-memory ceramics and biocomposites are discussed in relation to the properties most critical for biomedical use. Printing strategies are compared with attention to resolution, multi-material capability, reproducibility, and translation-relevant constraints, and emerging fabrication routes such as volumetric printing, ultrasonic printing, and multi-material or gradient printing are discussed in the context of higher throughput and improved spatial encoding of function. In addition, the key obstacles that repeatedly limit practical deployment, including scalability, degradation control, bio-integration, and stability under cyclic physiological conditions, are critically evaluated to indicate where future efforts are most likely to accelerate translation.

The review is structured as follows: (i) the concept of 4D printing is introduced and major biomedical application areas are surveyed, including adaptive drug delivery, tissue regeneration, and deployable biomedical devices; (ii) the principal material classes used for biomedical 4D printing are reviewed, emphasizing transformation mechanisms and biomedical constraints; (iii) established and emerging 3D/4D printing techniques relevant to biological systems are summarized; and (iv) challenges and opportunities spanning materials, manufacturing, mechanical and functional stability, and environmental considerations are discussed, with focus on factors that influence the transition from laboratory demonstrations to realistic biomedical implementation. Fig. 1 provides an overview of the topics covered in this review.

# 2. 4D printing & Biomedical Applications

## 2.1. 4D Printing Concept

4D printing is a new AM technology with a time dimension added to 3D printing [21]. The behavior of the Venus flytrap plant is an excellent example of the concept of stimulus-responsive behavior [23]. A rapid reaction occurs in this plant: leaves close in about 100 ms to trap insects
[24]. This reaction occurs when a part of the insect's body hits the leaf of this plant (Fig. 2a).

In recent years, the use of smart materials with the AM method has been in the spotlight, and extensive research has been done to overcome various challenges. The time-dependent behavior of smart materials can be observed when they are exposed to external stimuli such as for example stress, temperature, or humidity. Figs. 2b and 2c illustrate complex flower-shaped structures and a cardiovascular stent, respectively, undergoing shape recovery under external stimuli.

Researchers successfully confirmed and used the ability of 4D printing, including smart materials to create physical structures with AM techniques. Such structures exhibit unique features of reacting and changing their shape with time when exposed to certain stimuli [25]. The 4D printing process relies on three key principles (Fig. 2d). The first principle involves the use of smart materials that can respond to stimuli. The second principle focuses on applying a specific stimulus to these materials and observing their unique response. Lastly, the third principle concerns the duration of the response, and the resulting shape change in the structure. These shape changes can involve various phenomena such as folding, bending, twisting, linear or non-linear expansion and contraction, surface twisting, and the creation of surface topographic features [26,27].

The functional performance of 4D-printed structures is highly influenced by 3D printing process parameters, such as printing temperature and speed, which affect how the material responds post-fabrication [27]. By selecting stimuli-responsive materials that activate under triggers, such as heat [31,32], magnetic [33,34] or electrical fields [35,36], light [37], pH changes [38], and biological stimuli [39], 4D printing enables the development of biomedical products that can mimic the behavior of natural tissues [40]. In 4D bioprinting, cell-generated contractile forces have also emerged as an endogenous stimulus that can drive programmed shape transformations in living constructs, enabling self-actuated morphogenesis without external fields [41,42]. Fig. 3 summarizes the main classes of stimuli used to trigger 4D transformations, including biological, physical, and chemical cues.

These smart materials are particularly promising in biomedical applications, as they can be manipulated safely across different length scales to support applications such as targeted drug delivery, dynamic scaffolds, and shape-morphing implants [43]. These capabilities pave the way for the creation of patient-specific implants, scaffolds, and prosthetics that can actively respond to physiological conditions and promote better integration with the surrounding biological

environment. Moreover, 4D printing offers precise control over complex geometries and architectures of biomedical structures. This means that intricate and custom-designed structures can be fabricated with high fidelity and accuracy, allowing their improved functionality and performance. This level of control is particularly crucial for biomedical applications where the design and functionality of the printed structures are closely tied to their intended purpose, such as organ-on-a-chip devices [44] or drug delivery systems [45]. A summary of 4D printing advantages in biomedicine field is depicted in Fig. 4.

Moving on to biomedical devices, 4D printing allows complex structures with dynamic functionalities to be fabricated [46]. In the area of drug delivery, 4D printing offers the potential to create smart drug delivery systems that can release medications in a controlled manner in response to specific triggers or conditions in a body [47]. This innovative approach not only enhances the efficacy of drug therapies but also improves their safety by optimizing dosage and timing. Similarly, 4D printing has a transformative potential in tissue engineering, which involves the creation of functional tissues and organs. Custom-designed scaffolds can be manufactured to fit specific patient requirements, incorporating physical and chemical guidance cues that accelerate and enhance tissue-regeneration processes [48]. Furthermore, as illustrated in Fig. 5, biomedical applications of 4D printing span a wide range of areas, demonstrating their versatility and potential. Beyond drug delivery and tissue engineering, 4D printing enables the development of advanced biomedical devices, such as adaptive implants and prosthetics, designed to conform to changing anatomical conditions or patient-specific needs. This adaptability improves both comfort and performance, offering a significant advancement in personalized healthcare solutions [49–51]. Collectively, these applications highlight the transformative role of 4D printing in addressing complex medical challenges and advancing healthcare technologies.

## 2.2. Drug Delivery

The unique features of 3D printing make it suitable for making personalized drugs for each patient in terms of the shape and dose required and the way the drug is released. As well known, the one-size-fits-all method is not suitable for all groups of patients, particularly in special cases [52]. The use of 3D printing in the production of diverse types of medication forms offers the possibility to design and fabricate customized doses and drug-release profiles, tailored specifically to individual patients, thereby enhancing patient care [53]. Building on this

<figure><img src="image_3.png" /><figcaption>Fig. 1. Overview of 4D printing in biomedical applications.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** (a) Venus flytrap plant [28]. (b) Complex flower shapes created through biomimetic 4D printing [29]. (c) Shape-memory capabilities of a cardiovascular stent 3D-printed using molten macromethacrylate [30]. (d) Overview of 4D printing principles.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Classification of stimuli-responsive materials based on the nature of the triggering stimulus (biological, physical, chemical).</figcaption></figure>

foundation, 4D printing introduces the dimension of time, adding dynamic functionality to printed drug delivery systems and unlocking new possibilities for targeted and controlled medication delivery.

In recent years, the concept of 4D drug products has emerged as an extension of 3D printed formulations, enabling shape transformations in the body under specific stimuli, such as water absorption, pH changes, or UV exposure. Such transformations enhance drug effectiveness and functionality with time. Hydrogels and printable polymers have become

the most widely used materials for the production of 4D drug delivery systems thanks to their responsiveness to external stimuli and biocompatibility [54].

Numerous studies have been conducted to develop such systems that are capable of releasing different types of drugs in response to specific stimuli at desired locations in the body [55]. By combining the capabilities of 3D printing, allowing the customization of drugs, with intelligent materials capable of self-transformation, the field of drug delivery
<figure><img src="image_6.png" /><figcaption>Fig. 4. 4D printing advantages in biomedicine field.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>Fig. 5. Overview of biomedical applications of 4D printing, including smart drug delivery systems, tissue engineering scaffolds, and adaptive biomedical devices such as stents and occlusion devices.</figcaption></figure>

witnessed advancements in achieving targeted and highly effective administration of medication.

In recent years, researchers have been exploring the use of smart materials that can respond to specific stimuli to release drugs in a controlled and targeted manner. This allows for personalized treatment options and improved therapeutic outcomes. In a recent study, Zu et al. [45] developed a novel drug delivery system using a 4D printing technology. They used a plant stomata-inspired smart hydrogel capsule made of UV cross-linked PNIPAm hydrogel as the capsule shell. By exploiting the temperature-responsive properties of PNIPAm hydrogels, the capsules exhibited autonomous control over drug release based on

changes in ambient temperature. The team also demonstrated that adjusting the molecular weight of PEGs in the capsules resulted in improved drug release rates, allowing programmable drug release profiles. In vitro biocompatibility studies indicated that the PNIPAm hydrogel capsules hold promising potential for biomedical applications. These bioinspired 4D printed hydrogel capsules signify a considerable advancement in smart controlled drug release systems. The overview of this work is presented in Fig. 6a.

Zhang et al. [56] explored the application of 4D printing using plant protein gel, specifically zein gel, inspired by the formation mechanism of amyloid fibrils. They developed a specialized layered Carbopol-supporting bath with varying water concentrations in an ethanol-water mixture to modulate hydrophobic and hydrogen-bonding properties, enabling temporal changes in functions. The study demonstrated that 4D printing in different supporting baths led to variations in drug loading, drug release rate, and degradation of printed structures. The researchers printed a tri-segment conduit and a butterfly-shaped structure to evaluate their potential applications as a nerve conduit and a drug delivery system. The 4D-printed conduits also showed effectiveness as drug-eluting urethral stents in a porcine model. The overview of this study is illustrated in Fig. 6b, providing insights into the experimental framework and outcomes. Additionally, Figs. 6c and 6d demonstrate the design of biodegradable photopolymerization inks for 4D printing via DLP, as well as the programming and thermal recovery of an SMP that self-expands at body temperature after oral ingestion.

While these studies span different material systems, they share a common design logic: the stimulus is selected to match the clinical environment (endogenous triggers such as hydration/pH vs exogenous triggers such as light or temperature), and the device geometry is programmed so that a shape change directly modulates diffusion pathways or exposure area. In contrast to deployable implants, most 4D drug platforms prioritize trigger selectivity and predictable release kinetics over high recovery stress, so performance is typically judged by dose control, response reversibility, and stability of the actuation-release coupling rather than force output.

## 2.3. Tissue Regeneration

Tissue loss caused by trauma or disease continues to be a major cause of mortality and disability worldwide [58]. Tissue engineering is a key area of regenerative medicine that uses scaffolds and cell-based strategies to restore, maintain, or replace damaged tissues and organs [58,59]. Scaffolds play a vital role in tissue engineering by providing physical and structural support for cells to grow and differentiate [60]. They also facilitate the transport of nutrients necessary for cell survival and function [61]. To effectively mimic natural extracellular environments, the morphology and chemical composition of the scaffold matrix should resemble those of the extracellular matrix. This encourages strong interaction between the cells and the scaffold material [62]. The pore size and porosity of the scaffold directly affect tissue formation in a three-dimensional structure, making it necessary to customize these factors based on the desired tissue-restoration outcome. These characteristics are crucial to ensure sufficient oxygen supply to promote the formation of new blood vessels [63,64].

In recent years, 3D bioprinting has attracted significant research interest as a method for creating functional biological tissues. Among various techniques, extrusion-based bioprinting has become especially prominent, with hydrogels serving as the primary bioink due to their structural versatility and ability to support cell viability [65].

Because tissues are dynamic and continuously remodel, conventional 3D printed constructs with fixed geometries cannot reproduce time-dependent biological processes. This limitation is addressed by 4D bioprinting, which enables printed structures to undergo programmed changes over time in response to internal or external cues [66]. To better reflect recent morphogenetic cartilage-engineering platforms, a jammed single-component micro-flake hydrogel bioink based on oxidized/
<figure><img src="image_8.png" /><figcaption>**Fig. 6.** (a) Bioinspired 4D printed hydrogel capsule for smart controlled drug release [45]. (b) Water-responsive 4D printing based on self-assembly of hydrophobic zein protein to control degradation rate and drug release [56]. (c) Printing resolution of DLP 3D-printing of drug delivery samples. (d) Programmed configuration of the delivery device compared to its permanent form, followed by incubation in water at 37 °C [57].</figcaption></figure>

methacrylated alginate microgels was developed for 4D living cell bio-
printing [67]. In parallel, scaffold-free and bilayer-based strategies have
also been explored to achieve controlled shape morphing through pro-
grammable material organization and degradation.

Within this framework, Kitana et al. [68] developed 3D-printed
shape-changing layers guided by a mathematical model to achieve
precise shape transformation. Fabricated tubular T-junctions demon-
strated minimal leakage and successfully simulated blood flow with a
maximum velocity of 0.11 m/s. Endothelial cells of a human umbilical
vein were seeded onto the inner surface of the T-junctions, demon-
strating robust growth and viability. The resulting diameters closely
resembled those of original blood vessels, marking a notable advance-
ment in 3D biofabrication. A schematic of the T-junction fabrication
process is shown in Fig. 7a.

In another study, Gugulothu et al. [69] developed a bioink formu-
lation using GelMA and PEGDM combined with a photoinitiator and a
photoabsorber. A DLP-based 3D bioprinting technique operating with
visible light was employed to create constructs capable of shape trans-
formation upon hydration, demonstrating 4D bioprinting behavior.
Structural anisotropy was achieved through differential crosslinking
induced by light attenuation from the photoabsorber. The curvature was
influenced by printed sheet thickness, while angled strands provided
additional control over deformation. The resulting constructs supported
cell viability and proliferation, demonstrating potential for biomedical
applications; Fig. 7b illustrates the structures.

In a more recent advancement, Ding et al. [70] developed a 4D
bioprinting strategy to create shape-changing scaffold-free cell con-
densates with predetermined geometries. The study introduced a bilayer
approach with controllable deformability and microgel degradation,
enabling programmed morphological transformations and controlled
release of deformed cell condensates. As a proof of concept, C- and helix-
shaped cartilage-like tissues were fabricated from human mesenchymal
stem cells. Fig. 7c illustrates the schematic of 4D cell-condensate bio-
printing, tissue maturation, and tissue release. Across tissue-
regeneration examples, the main similarity is that “time” is encoded
through morphogenesis-inspired changes that guide tissue formation,
but the mechanistic source of shape evolution differs. Hydrogel-driven
systems rely on swelling, hydration, and crosslink gradients to create
gentle, cell-compatible morphing, whereas SMP-enabled scaffolds
emphasize programmed recovery for minimally invasive placement
followed by in situ fitting. Accordingly, the dominant evaluation criteria
shift from actuation speed to cytocompatibility, permeability/transport,
and remodeling stability, because successful regeneration depends on
maintaining viable microenvironments while the construct evolves.

2.3.1. *Cell Scaffolds*

Cell scaffolds are designed to mimic the natural tissue architecture,
providing structural and functional support for cell attachment, prolif-
eration, and differentiation [71]. Smart polymers, such as PCL-T and
castor oil crosslinked with multi-isocyanate groups, demonstrated
<figure><img src="image_9.png" /><figcaption>Fig. 7. (a) Sequential self-folding process of the 3D-printed hydrogel structure and development of the T-junction in pure water: (i) Initial state of the dried, UV crosslinked hydrogel immediately after adding water, (ii) Swelling and detachment of the structure from the substrate (t = 160 s), (iii) Emergence and folding of the T-junction structure (t = 674 s), (iv) Final T-junction morphology after water removal and gentle drying, (v) Close-up view of the junction region, (vi) and (vii) Lateral/side perspectives of the folded structure. (b) Perfusion of red aqueous dye solution through the completed T junction structure: (i) Initial dry and empty T-junction at t = 0 s, (ii) Beginning of perfusion, with dye entering and passing through the first arm (t = 30 s), (iii) Dye solution reaching and flowing through the junction area (t = 39 s), (iv) Complete perfusion of the dye throughout the entire structure (t = 47 s), (v) Enlarged view showing the junction region during flow [68]. (c) Light-based 4D-bioprinted tissue scaffold [69]. (d) Schematic of 4D cell-condensate bioprinting, tissue maturation, and tissue release [70].</figcaption></figure>

tunable shape-memory properties that enable recovery at physiological temperatures, making them suitable for scaffold applications. These polymers exhibit adjustable T~g~ ranging from -8 °C to 35 °C, allowing the scaffolds to regain their original shape under physiological conditions. FDM was used to create sacrificial molds with a graded porosity (240-560 µm), enhancing the mechanical properties and cell-proliferation potential of the scaffolds. Notably, a sample formulation with a 40:60 weight ratio of castor oil to PCL-T provided the best balance of mechanical strength and shape-memory behavior, supporting superior cell adhesion and proliferation, particularly with MSCs [72].

The potential of these materials for the development of cell scaffolds was further enhanced by the addition of dual stimuli-sensitive biodegradable PUs into 4D printed scaffolds. These PUs, synthesized via eco-friendly waterborne processes, have both photo- and temperature-sensitive components to enhance structural integrity and shape-memory behavior. Using microextrusion-based 3D printing, PUs such as PUA3, with a T~g~ of -61.25 °C, demonstrated excellent flexibility and biocompatibility for scaffold applications. When embedded with NSCs, the scaffolds exhibited high viability and proliferation of cells,

significantly enhancing their differentiation, as evidenced by the upregulation of key neural markers. This research highlighted the importance of precise material composition and processing parameters for the optimization of scaffold performance for biological functionality [73].

The ability of 4D printing to create anisotropic skeletal muscle scaffolds was investigated by using a distinctive staircase shape inherent for FDM. By controlling the layer height during printing, these scaffolds provided topographical cues that guided the alignment and differentiation of human MSCs, significantly enhancing myogenic gene expression. Additionally, the introduction of SMPs into these scaffolds enabled dynamic shape transformations, facilitating minimally invasive surgical applications and improving scaffold integration with host tissues. The use of PCL in combination with 15% concentration in chloroform resulted in well-defined microgrooves, further enhancing cell alignment and differentiation [74].

Utilizing soy-oil-epoxidized acrylate (Soy) as a unique resin material with SLA for scaffold fabrication is a noteworthy development in 4D printing for cell scaffolds. The Soy resin, with its T~g~ of 20 °C, demonstrated shape-memory properties, allowing scaffolds to undergo
dynamic transformations in response to temperature changes. These scaffolds exhibited excellent biocompatibility, supporting the attachment and proliferation of human MSCs. The precise control of scaffold architecture, achieved through SLA with optimized print speeds and laser frequencies, allowed the manufacture of highly functional scaffolds with a balance between structural integrity and cell compatibility [75].

### 2.3.2. Bone Scaffolds

The emerging field of 4D printing for bone-tissue engineering offers transformative potential for orthopedic applications by reducing infection risks, minimizing surgical invasiveness, and enhancing osseointegration. A significant challenge in this area lies in replicating the biomechanical properties of native bone tissue [76–79]. Current advancements in 4D-printed bone scaffolds can be categorized into four main areas: (i) injectable stimuli-responsive hydrogels; (ii) shape-memory scaffolds; (iii) functional transformation mechanisms; and (iv) neovascularization/neurogenesis to promote bone growth and mineralization [80,81].

Combining PLA with composites, which showed good mechanical, shape-memory, and thermal properties, is one prominent direction [82]. The addition of nanoparticles such as Fe₃O₄ to the PLA matrix enhanced thermal stability, as seen with decomposition temperatures above 300 °C. The mechanical properties of the blends, including storage moduli exceeding 1600 MPa at 40 °C, suggest sufficient stiffness for bone-scaffold applications. These materials also exhibit a rapid shape recovery, either in hot water at 80 °C (within 5-8 s) or under alternating magnetic fields at 27.5 kHz (around 60 s), making them suitable for personalized bone repair. The shape-memory behavior allows their minimally invasive implantation, with in situ expansion to conform to bone defects, offering a tailored solution for regenerative-medicine applications [83].

Porous scaffolds with shape-memory effect were also developed for self-fitting bone implants. PLA with 15 wt% of nano HA was 3D printed into scaffolds with 700 µm pores and 30% porosity, supporting the survival and proliferation of MSC. The addition of HA nanoparticles altered the order of polymer chains and friction between molecular chains during glass transition, increasing the apparent activation energies for shape-memory behavior. These scaffolds displayed favorable mechanical performance, with maximum recovery stresses occurring when shape programming was performed at 64 °C. However, cyclic shape-memory tests revealed a decline in recovery rates with increasing cycles due to defect accumulation. Nonetheless, the shape-memory effect properties of these scaffolds make them promising candidates for bone-replacement applications, particularly for enhancing implant vascularization and the success of bone prostheses [84].

Shape-memory scaffolds were further tailored for specialized applications in bone repair using SMPs as substrates. For instance, magnetoactive SMP-based scaffolds were designed for personalized treatments of bone defects, actuated by external magnetic fields to achieve the desired shape. Temperature-responsive SMP scaffolds were also investigated for their biomechanical compatibility, demonstrating significant potential in fostering osteoblast adhesion, proliferation, and osteogenic gene expression [37,85–88]. Piezoelectric properties of some smart materials were explored for their ability to stimulate osteoblast growth, further advancing scaffold functionality [89].

The combination of PLA and HA in porous scaffolds shows great potential for bone repair thanks to their shape-memory effect, which is activated by direct heating. Scaffolds produced via FFF exhibit 30 vol% porosity and a 700 µm pore size, with HA particles enhancing mechanical properties and shape-memory effect performance. These scaffolds retain 96% of shape recovery after multiple cycles, making them ideal for self-fitting implants for minor bone defects [90]. Additionally, scaffolds with Fe₃O₄@SiO₂ nanoparticles within PLGA/HA matrices exhibit dual responsiveness, achieving shape recovery within approximately 30 s under static magnetic fields or 60 s under NIR stimulation. This rapid and reliable shape recovery enables minimally invasive

implantation and precise adaptation to irregular defect boundaries, offering significant advancements in personalized bone-repair applications [91]. The overview of this work is presented in Fig. 8a; additionally, Figs. 8b and 8c illustrate the basic principles of tissue-engineered scaffolds and conventional preparation techniques, respectively.

Biomaterials such as PCL and HA were highlighted for their ability to enhance osteogenesis, with composite materials demonstrating improved attachment and infiltration of cells. Techniques such as inkjet bioprinting showed success in engineering bone tissues using bioinks composed of PEGDM and bone-marrow-derived mesenchymal stem cells. With these techniques, scaffolds with specific biological and physical characteristics can be created, which has major benefits for bone regeneration [94–98].

Recent studies demonstrated the use of hydrogels, such as GelMA and chitosan blends, in SLA-printed bone scaffolds [99–102]. Such scaffolds exhibited compressive strengths ranging from 30 kPa to 1000 kPa, depending on the formulation, and provided bioactivity suitable for osteoconductivity. The SLA technique also allowed the creation of patient-specific scaffolds with controlled porosity, making it a viable option for guided bone regeneration and alveolar ridge augmentation [103].

Additionally, 4D bioprinting was employed to develop stimuli-responsive scaffolds that can undergo shape transformations in response to external stimuli. Injectable hydrogels made of alginate, PVA, and HA were adjusted for printability and biocompatibility, enabling the encapsulation of living cells during the printing process. This approach provides a favorable environment for osteogenesis and represents a significant advancement over traditional 3D printing methods, enabling the production of personalized bone-tissue substitutes. [104]. Examples of bone scaffolds produced in the above studies are given in Fig. 9. These advancements in 4D printing highlight its potential to develop dynamic, personalized solutions for bone-tissue engineering, offering improved outcomes in orthopedic applications.

### 2.3.3. Vascular, Muscle, Neural, & Tracheal Tissue Regeneration

Beyond cartilage and bone, 4D biofabrication is increasingly being explored for vascular, muscle, neural, and airway regeneration, where the primary functional targets differ substantially and therefore demand distinct design logics [107]. In vascular regeneration, the key requirement is the formation and long-term stability of perfusable lumens; here, time-dependent shape change is mainly used to achieve controlled self-folding/closure into tubular geometries and to introduce anisotropy that guides endothelial organization under physiological flow [108]. For skeletal muscle regeneration, the central challenge is reproducing aligned, contractile architecture; 4D approaches are typically leveraged to create evolving anisotropic cues (topography, stiffness gradients, or programmed deformation) that improve cell alignment and maturation over time rather than only at the time of printing [109]. In neural regeneration, the design emphasis shifts toward directional guidance and supportive electrophysiological microenvironments; accordingly, dynamic constructs are often designed to provide time-dependent guidance features and/or mechanically adaptive interfaces that better match soft neural tissue during healing [110,111]. Finally, tracheal regeneration prioritizes maintaining airway patency while supporting tissue remodeling, which motivates constructs that can undergo controlled maturation-stage shape adjustment while preserving ring-like mechanical support and minimizing long-term mismatch with surrounding tissues [67]. Collectively, these examples share the same principle that “4D” emerges from coupled material-architecture-stimulus design, but the success metrics are tissue-specific (perfusionability, alignment/contractility, neurite guidance, and airway stability).

## 2.4. Deployable Biomedical Devices

Medical devices have extensive applications in monitoring,
<figure><img src="image_10.png" /><figcaption>**Fig. 8.** (a) Schematic of the synthesis process of PLGA/HA/Fe₃O₄@SiO₂ scaffolds, their precise alignment with bone defects guided by NIR stimulation and static magnetic field navigation, with mechanisms promoting osteogenesis and angiogenesis at rat defect site under dual-response stimulation [91]. (b) Fundamental principles of tissue-engineered scaffolds. (c) Traditional methods for scaffold fabrication [92]. (d) Schematic representation of the 4D-printed bilayer membrane designed for bone repair [93].</figcaption></figure>

preventing, diagnosing, prognosing, treating, or mitigating illnesses, injuries, or disabilities [112]. The emergence of 4D printing technology significantly impacted the field of biomedical devices [40]. As a result, there is a growing demand for the development of 4D-bioprinted dynamic implants.

Stents, for example, are widely used in medical treatments to relieve the symptoms of coronary heart disease, a common condition in today's world. These devices help keep blood vessels open and ensure proper blood circulation [113–115]. Traditionally, stents have been made from metals like stainless steel or cobalt-chromium, but these materials have certain drawbacks, such as long-term complications and limited adaptability [116,117]. To address these issues, temporary or bioresorbable scaffolds have gained popularity, as they are designed to remain in the body only during the healing phase of the damaged artery. Polymers are

increasingly used in this context, and more broadly across the medical device industry, in products like sutures, scaffolds, and screws, owing to their favorable mechanical and biological properties and their ability to degrade naturally over time [113,118–121].

With the 4D printing technology, it becomes feasible to create dynamic biomedical implants that can be deployed through minimally invasive surgery thanks to their small sizes. These implants can then be reshaped in situ to fit the specific shape and size of defects at the implantation sites [122].

Beyond internal implants, 4D printing and additive manufacturing are also transforming wearable medical technologies [123]. For example, tremor-suppression orthoses, noninvasive wearable devices used to reduce involuntary hand movements in patients with neurological disorders, have seen performance improvements through AM
<figure><img src="image_11.png" /><figcaption>**Fig. 9.** (a) Illustration of concept for in vivo implantation of injectable, functional cardiac patch. (b) Images of POMAC scaffold before and after injection through 1-mm glass capillary pipette [105]. (c) Near-infrared light-activated shape restoration of the freshly 3D-printed scaffolds implanted in rabbit skull bone defects [106]. (d) Alveolar ridge augmentation using AM bone-tissue scaffold: (i) a bone defect forms in the alveolar ridge; (ii) a bone scaffold is designed and additively manufactured; (iii) the scaffold is placed in the defect area to support regeneration; (iv) new bone grows into the scaffold, which degrades over time; and (v) a dental implant is positioned in the regenerated bone [103]. (e) Simulation of 4D-printed structure used as a bone-repair tool [83]. (f) Demonstration of the deployability of PLMC-PDA scaffolds under NIR irradiation in ex vivo tissues and dental models. (g) Schematic and experimental depiction of a defect in rabbit tibia and NIR-assisted self-fitting of scaffold to conform to the defect in rabbit mandible [106].</figcaption></figure>

and smart materials. Traditional orthoses often suffer from issues such as excessive weight, rigid structures, and poor comfort. However, 4D printing provides a pathway to more lightweight, adaptive, and customizable designs that better conform to the user anatomy and respond to dynamic conditions [124].

In addition to orthoses, customized 3D-printed solutions have shown

potential in enhancing comfort and rehabilitation. One study designed 3D-printed shoe midsoles tailored to body weight and activity level, using lattice structures and FEA to reduce plantar pressure and material use [125]. Similarly, 3D printing and topology optimization have enabled the creation of lightweight, breathable splints for mallet finger injuries, improving both comfort and recovery compared to traditional
options [126].

Building on these advances in personalized medical devices, soft robotics is also gaining attention for its use of 4D printing and smart materials to create flexible, adaptive systems for biomedical use [127]. The combination of 4D printing with soft robotics offers a synergistic effect in this area. Soft robotics focuses on the development of robots using soft materials with inherent elastomeric properties. When combined with 4D printing, it enables the creation of soft robots capable of performing complex functions with minimal manipulation [16]. However, one of the ongoing challenges in this field is accurately modeling and predicting the motion of 4D-printed soft robots, primarily due to the nonlinear behavior of the materials involved [128]. This limitation often reduces the effectiveness of traditional analytical models, but recent approaches using numerical simulations and machine learning techniques have shown promise in improving design efficiency and predictive accuracy [129,130].

4D printing technology shows great potential in the development of advanced biomedical tools [131]. Hu et al. [132] suggested a novel smart hydrogel composed of NIPAM, Laponite nanoclay, and NdFeB magnetic particles for the 4D printing of soft robots. This hydrogel

demonstrated temperature sensation and magnetic actuation, allowing both shape morphing and motion. The material exhibited favorable mechanical properties, machinability, and biocompatibility. Using this hydrogel, the researchers successfully 4D printed soft millirobots with different structures and functions, including a multi-segment magnetic head catheter, a leptasteria-like robot, and a shellfish-like robot. These millirobots could respond to both magnetic and thermal fields. In experiments, the millirobots demonstrated the ability to overcome physical obstacles in a human-stomach model and actively transport cargo. The study concluded that the synergistic responses to magnetic and thermal fields made these 4D-printed soft millirobots adaptable and reduced drug leakage during transportation, thereby opening application prospects in the fields of bioengineering and medical treatment.

In a recent research [133], addressing the challenge of developing NBT-triggered 4D printing materials for manufacturing complex implants, researchers successfully developed shape-memory biocomposites with controllable transition temperatures, allowing the printing of structures that can undergo shape-memory processes at NBT. They utilized this technology to create customized, reconfigurable, biodegradable, and biocompatible 4D-printed biomimetic intestinal stents. These

<figure><img src="image_12.png" /><figcaption>**Fig. 10.** (a) Motion and targeted delivery of a 4D-printed, starfish-inspired (leptasteria-like) microrobot made from NIPAM/NdFeB composite, designed for drug delivery applications, demonstrated within a stomach model [132]. (b) Dynamically reconfigurable shape-memory performance of 4D-printed biomimetic stents (colored blue for enhanced visualization). (c) Simulation demonstrating the feasibility of 4D-printed shape-memory biomimetic stent to open in obstructed swine intestine [133].</figcaption></figure>
stents were designed with wavy biomimetic networks to mimic a nonlinear stress-strain response of biological tissues, providing high flexibility and reduced irritation to the intestinal wall. Additionally, the biodegradability of these stents eliminates the need for secondary endoscope removal required for metallic stents. The research demonstrates an efficient methodology for the fabrication of NBT-triggered 4D printing shape memory biocomposites and highlights the promising application potential of 4D-printed intestinal stents as intelligent implants. The highlights of this study are presented in Fig. 10. Compared with drug delivery and regenerative scaffolds, deployable devices are distinguished by the need for reliable deployment under physiological loads, where the material choice directly sets the attainable recovery stress and fatigue durability. Polymeric SMP systems provide large recoverable strain and easier processing but typically lower recovery force, while SMA-based systems deliver high recovery stress and robust cyclic performance, which is advantageous for mechanically demanding deployment. Thus, device-oriented 4D designs emphasize deployment predictability, fixation/anchoring mechanics, and long-term mechanical stability, in addition to biocompatibility and degradation when bio-resorbable concepts are used.

### 2.4.1. Vascular Stents

The use of cutting-edge material compositions and 4D printing technology greatly revolutionized the development of vascular stents, enabling the production of flexible, self-expanding stents with improved mechanical and shape memory qualities. The introduction of PLMC, with its exceptional shape-changing characteristics close to body temperature, is one of the significant breakthroughs. When printed with DIW, PLMC structures exhibit rapid shape recovery within 35 seconds in water at 45 °C, with $R_f$ of 93.1% and $R_r$ of 97.6%. This behavior, combined with tunable porosity levels ranging from 73.8% to 93.8%, suggests that PLMC stents can promote tissue ingrowth and regeneration while providing the necessary mechanical strength for minimally invasive applications of vascular stents [134].

Another novel ink composed of urethane diacrylate and PCL was developed for 3D printing stretchable, shape-memory, and self-healing elastomers. These elastomers, capable of stretching up to 600%, demonstrate high $R_f$ (over 93%) and $R_r$ (over 95%) levels. The unique semi-interpenetrating polymer network (semi-IPN) structure enables the self-healing of microcracks after heating at 80 °C for 20 min, with the healed material regaining its mechanical properties. These elastomers are attractive prospects for biomedical devices, especially vascular stents, thanks to their combination of SM and SH capabilities, which allow them to repair surface cracks and recover their original shapes [135].

Photocurable star polymers, such as βCD-g-PCL, were explored for the fabrication of peripheral stents, with enhanced mechanical properties and drug-delivery potential. The FDM-printed stents demonstrated tensile strengths of 20.62 MPa and elongations at break of 678%, surpassing the mechanical performance of human great saphenous veins. The integration of βCD into the polymer matrix improved wettability, biocompatibility, and drug-loading capabilities, making these stents suitable for both mechanical support and controlled drug release, particularly for paclitaxel delivery. The ability of the stents to recover their original shape upon thermal stimulation after implantation further enhances their functionality in vascular interventions [136].

The fabrication of vascular stents with FDM and PLA, with an auxetic structure (i.e., with a negative Poisson's ratio), improved the radial compressive properties and self-expansion capabilities of the stents. By optimizing the stent diameter and wall thickness, an enhanced radial force per unit length was achieved, making the design suitable for arterial-wall anchorage. The PLA stents exhibited excellent shape-memory behavior, with a diameter recovery ratio exceeding 95% and maximum recovery reaching 98%. The use of compatibilizers improved the interfacial adhesion and mechanical performance of the stents, highlighting the potential of 4D printing to create highly efficient and

adaptable vascular devices [137].

The introduction of SMNCs into vascular-stent fabrication further enhanced the functionality of these devices. Using PLA modified with UV cross-linking agents and iron-oxide nanoparticles, printed stents demonstrated remarkable shape-memory capabilities, with $R_f$ of 99% for cross-linked PLA (c-PLA) and 95% for c-PLA/Fe₃O₄. The $T_g$ values of 66 °C and 71 °C, respectively, are pivotal to achieve effective shape recovery upon heating. This discovery highlights the possibility to fuse SMPs and SMNCs to create vascular stents with enhanced performance in medical applications and the ability to react to external stimuli [138].

### 2.4.2. Tracheal Stents

Similarly, the use of 4D printing technology in the production of tracheal stents showed considerable promise, as SMPs allow creative solutions to airway management problems [139,140]. SMP-based tracheal stents offer conformable fixation, which traditional scaffolds often lack. These bioinspired scaffolds designed based on the microstructure of glass sponges, exhibit enhanced mechanical strength and stability, making them ideal for support of tracheas during tissue regeneration. Fabrication via FDM, using a composite of PLA and Fe₃O₄ nanoparticles, demonstrated optimal results for a composition with 15 wt% Fe₃O₄. This composition facilitated effective actuation during shape recovery, with scaffolds achieving rapid recovery at around 60 °C, supported by $T_g$ of 65.35 °C. The scaffolds, printed with dimensions suitable for tracheal use, featured a porous design that not only supported the attachment and growth of cells, but also maintained sufficient mechanical support, highlighting the promising role of 4D printing in personalized tracheal repair [66].

The use of Miura-origami structures in PLA-based SMP filaments further advanced the functionality of tracheal stents. These structures, fabricated with FDM, exhibit remarkable shape-recovery ratios, exceeding 94% under optimal conditions. The shape-recovery behavior is influenced by recovery temperatures, with the highest recovery efficiency observed at 90 °C. The addition of 5% by mass compatibilizers significantly enhanced the interfacial adhesion and mechanical performance of these PLA-based SMP stents. This blend not only improved the shape memory behavior but also strengthened the structural integrity of stents under compression, offering a robust solution for tracheal stents [141].

Blends of PLA and PCL also demonstrated considerable promise for the fabrication of 4D-printed tracheal stents via DIW. The shape-memory behavior of these blends is crucial for dynamic tracheal applications, with $T_g$ decreasing from 61.5 °C for pure PLA to 49.1 °C for the PLA30/PCL70 composition. Among all tested formulations, PLA70/PCL30 exhibited the optimal combination of shape-fixity and recovery, achieving $R_f$ of 91% and $R_r$ of 90%. While this composition offers a balanced performance in terms of flexibility and recovery, higher PCL content improves shape retention. Maintaining a PCL content between 30% and 50% was found to ensure the best overall performance, enabling adaptability to physiological conditions and consistent mechanical support for tracheal scaffolds [140].

Fig. 11 illustrates tracheal stents manufactured by PLA/Fe₃O₄ and PCL/Fe₃O₄.

Methacrylated PCL was shown to have superior shape-memory qualities when used in tracheal stents, enabling them to deform temporarily for insertion and then return to their permanent shape upon heating. The stents, printed with SLA, achieved strain fixity rates of 99% and strain recovery rates of 98%, with $T_g$ of 55 °C prior to cross-linking and 47 °C post-cross-linking. This material choice ensures excellent shape-memory behavior, making it highly suitable for airway stenting, where conformable fit and reduced complications such as migration and fracture are important. The inclusion of lower-molecular-weight PCL/dimethacrylate mixtures further tailors the mechanical properties of stents, highlighting the significance of blend composition to improve the stent function [145].

In pediatric applications, 4D-printed tracheal stents were specifically
<figure><img src="image_13.png" /><figcaption>**Fig. 11.** 4D printing of bioinspired tracheal stents with different designs and corresponding shape-recovery process: (a) PLA/Fe₃O₄ [66], (b) PCL/Fe₃O₄ [142], (c) In vivo application of the 4D-printed stent in a mouse aorta, shown immediately after implantation on day 0 (i) and after two weeks on day 14 (ii). For the in vivo evaluation of a shape-memory vascular stent fabricated from PGDA using 4D printing: (iii) Placement of the stent (in its temporary, compressed configuration) into a silicone tube simulating a blood vessel, and (iv) thermal activation leading to its deployment and expansion within the vessel model [143]. (d) Deployable cardiovascular stents and medical devices with different designs and functions, manufactured with PLA using a modified FDM 3D printer [144].</figcaption></figure>

designed to address TBM. PCL-based stents, produced via FDM, offer biocompatibility and bioresorbability, allowing the stents to remain in situ for 2-3 years, accommodating the airway growth in young patients. The shape-memory behavior of these devices enables them to expand in response to airway growth, as confirmed by finite-element analysis predicting a 19% increase in tracheal diameter over three years. This adaptability is critical in pediatric airway management, where traditional stents often fail due to complications such as the formation of granulation tissue [146].

Overall, the combination of SMPs and advanced fabrication techniques such as FDM, SLA, and DIW in the development of tracheal stents offers promising solutions for airway management. These 4D-printed stents provide personalized, adaptable, and biocompatible options that not only support tissue regeneration but also respond to physiological changes, enhancing patient outcomes in treatments of both adult and

pediatric tracheomalacia.

### 2.4.3. Cardiac Stents

One study focused on the application of TPC elastomer in bio-absorbable stents designed through computational modeling and produced via FDM. These stents exhibited shape-memory behavior, allowing them to self-expand after being crimped to a diameter of 12 mm, suitable for transapical delivery in heart-valve implantation. Self-expansion capability is essential for the stent to adapt to the anatomical structure of the cardiac valve once deployed. Measurements of radial forces showed that the TPC-based stents displayed comparable performance to that of nitinol stents, widely used in clinical trials. However, polymer stents experienced some plastic deformation under stress. Crush and crimping tests validated their mechanical properties, with experimental data aligning closely with computational predictions.
Furthermore, degradation studies using tensile tests and gel permeation chromatography revealed that the TPC material underwent gradual hydrolysis, maintaining structural integrity during its initial use but degrading by about 50% with time, indicating its potential for bio-absorption in clinical settings [147].

Custom-made cardiac stents, developed using 4D printing technology with materials such as polyurethane, demonstrated the ability to provide self-expanding properties once deployed inside the body. The use of FDM to fabricate stents from thermoplastic elastomers ensures that they possess sufficient flexibility and mechanical strength. The shape-memory behavior of these polymers allows these stents to conform to the anatomical structure of the cardiac system after deployment, triggered by their $T_g$. The ability of the stents to gain their original form at body temperature is a critical feature to ensure proper function and support within the cardiovascular system. Polyurethane blended with flexible materials was shown to enhance the performance of stents, maintaining both their flexibility and mechanical strength while offering a smooth surface after post-processing. Optimizing the design of stents, including their wall thickness and shape, proved to be essential in order to achieve the best mechanical and functional outcomes, ensuring that the stents could meet the specific anatomical and mechanical demands of the patient's cardiovascular system [148].

Consequently, the use of biodegradable materials such as TPC provides a bioabsorbable option, reducing long-term complications while maintaining mechanical integrity during the initial stage of implantation. On the other hand, blending polymers such as polyurethane with flexible materials ensures the creation of stents that can conform to the cardiac anatomy while offering self-expanding capabilities. These advancements in 4D printing technology have the potential to completely transform the cardiac stent market by offering customized, patient-specific devices with a balance between bioabsorption, durability, and flexibility, making them appropriate for a range of cardiac treatments.

### 2.4.4. Occlusion Devices

A minimally invasive, percutaneous interventional therapy became a standard method to treat congenital heart diseases [149]. However, challenges remain in achieving precision, biodegradability, and remote controllability of conventional occlusion devices. The advent of 4D printing technology offers a transformative solution, enabling the fabrication of highly precise, personalized ODs with improved performance and adaptability [150]. Notably, 4D-printed devices demonstrated significant efficacy in the treatment of atrial septal defects, achieving enhanced accuracy and clinical outcomes [150,151]. Beyond congenital heart and LAA indications, SMP-based endovascular occlusion/embolization concepts are also being actively developed for intracranial aneurysm therapy, where device deliverability, conformal defect filling, and controlled in situ actuation are central design requirements [152–155].

A biomimetic approach was employed in the design of an LAA occlusion device, utilizing 4D printing and SMPs to create a structure inspired by the microstructure of collagen fibers. This design, which features a hexagonal node network, effectively mimics the mechanical properties of the LAA tissue, significantly reducing the risks associated with traditional nitinol-based devices, such as wear and perforation. The device's SMP allows it to transform from a temporary linear shape for interventional delivery back to its original disk shape when exposed to stimuli such as heat, with a shape recovery ratio of 98.31%. The biomimetic design enables the device to withstand mechanical loads exceeding 500 times its weight without damage. Furthermore, its temporary linear configuration fits into a 13-French delivery sheath, underscoring its suitability for minimally invasive procedures. With its improved mechanical characteristics and customizable options, this 4D-printed LAA occlusion device shows great promise as a replacement for conventional atrial fibrillation occlusion devices [156].

More recently, a multifunctional 4D-printed cardiac occlusion device was reported using an extracellular-matrix-like, drug-carrying fiber

platform to simultaneously improve anticoagulation and accelerate endothelialization, addressing two major clinical failure modes of ODs (thrombosis and delayed healing). In addition, radiopaque shape-memory composites enabled in vivo visualization and precise localization during deployment, while biomimetic ligament-inspired structures were designed to better match myocardial mechanics and reduce tissue abrasion [157].

Another significant application of 4D printing is the development of biodegradable ODs for ASDs. Utilizing SMPs based on a PLA matrix with $Fe_3O_4$ magnetic nanoparticles, these devices offer enhanced performance, particularly through improved mechanical properties and controllability. The addition of $Fe_3O_4$ enables magnetic field-induced deployment after implantation, which is essential for minimally invasive procedures. A $Fe_3O_4$ concentration of 5 wt% resulted in the highest tensile strength (~60 MPa), while 10 wt% provided the best overall balance of properties, enabling remote actuation, maintaining high recovery ratios (~95%), and ensuring mechanical robustness. Although further increasing $Fe_3O_4$ content to 15 wt% and 20 wt% improved stiffness, it led to reduced tensile strength due to nanoparticle aggregation. Notably, even these higher concentrations significantly outperformed pure PLA (~14 MPa). Among the tested designs, the 6-arm configuration demonstrated the highest load-bearing capacity, while the 4-arm design using 10 wt% $Fe_3O_4$ was considered optimal for practical use, combining good mechanical performance (~25 N), shape-memory response, and catheter compatibility. The study concludes that 10 wt% $Fe_3O_4$ is the optimal composition considering the trade-offs between mechanical strength, actuation performance, and degradability [150]. Furthermore, these devices often have thin occluding membranes that enhance biodegradability, durability, and biocompatibility, as demonstrated in a 48-week-long in vivo study conducted on mice [158].

In summary, 4D-printed occlusion devices represent a significant advancement in interventional therapy, addressing the limitations of traditional methods by offering precision, adaptability, and improved patient outcomes. Fig. 12 presents an overview of several ODs and orbital stents with their shape-recovery processes.

### 2.4.5. Cancer Therapeutic Devices

Cancer remains a major global health burden, accounting for nearly one in six deaths worldwide. The growing complexity and patient-specific nature of cancer make personalized and targeted treatment strategies increasingly vital. In this context, 4D printing technology has opened new possibilities for improving cancer therapeutics by enabling the development of smart, responsive systems that adapt to tumor-specific environments. 4D-printed platforms in cancer care employ smart materials that respond to specific biological or external stimuli, such as pH, temperature, enzymes, or magnetic fields, to deliver precise, localized treatments. These dynamic constructs have shown great promise in several therapeutic areas including surgical resection, drug delivery, and hyperthermia [160,161].

For instance, shape memory scaffolds incorporating PU and gold nanoparticles were developed to aid post-surgical cancer lesion repair. These scaffolds could be compressed into a temporary shape and then rapidly expanded back to their original form under NIR light irradiation, effectively supporting tissue regeneration at the site of cancer removal [162].

Another application involves self-expanding tracheal stents composed of PCL and $Fe_3O_4$ nanoparticles. These devices release anticancer drugs like PTX when exposed to an alternating magnetic field, combining mechanical support and localized hyperthermia-induced therapy in one system [163].

Additionally, drug delivery systems based on 4D printing allow for on-demand drug release, minimizing side effects while maximizing therapeutic efficacy. Core-shell scaffolds made of gelatin and PDA have demonstrated light-triggered release of DOX, with heat-induced sol-gel transitions providing precise dose control [164]. Other studies introduced magnetically-actuated hydrogel-based robots capable of
<figure><img src="image_14.png" /><figcaption>**Fig. 12.** (a) ASD prototype before and after treatment with OD; (b) designs of three OD frames with various arm structures; (c) 4D-printed ODs featuring frames and membranes; (d) implantation procedure; (e) visual inspection of ODs, (f) programmed shape-recovery process of 10 wt% mPLA 4-arm OD under a magnetic field, (g) in vitro evaluation of the ASD OD's feasibility [150]. (h) Shape-recovery process of the AHP stent in 44 °C water; (i) implantation of the AHP stent between the superior orbital wall and eyeball in rabbits; (j) shape recovery of the AHP stent in the rabbit's orbit stimulated by 44 °C saline solution [159].</figcaption></figure>
navigating the gastrointestinal tract to deliver drugs directly to cancerous sites [132,165].

At smaller length scales, similar design principles are being trans-
lated into untethered micro- and millirobots as emerging cancer-therapy
devices, where stimulus-responsive microstructures combine guided
positioning with site-triggered drug release in confined anatomical
spaces [166]. For example, environmentally adaptive, magnetically
propelled shape-morphing microrobots have been designed to encap-
sulate DOX under physiological conditions (e.g., PBS, pH ≈ 7.4) and
release it under mildly acidic environments (pH < 7), enabling localized
HeLa cell treatment in a vascular-mimicking network [167]. More
recently, pH-responsive hydrogel soft microrobots incorporating mag-
netic nanoparticles have been used to transport and release anti-cancer
drug microbeads (e.g., PCL-docetaxel), demonstrating measurable re-
ductions in cancer-cell viability in vitro [168]. Beyond in vitro concepts,
multifunctional microrobots have also been explored for transcatheter
chemoembolization of liver tumors, leveraging magnetic guidance to
reach tumor-feeding vessels, multimodal visibility (e.g., x-ray/MRI),
and local delivery of chemotherapeutics such as DOX and fluorouracil
(with enhanced release under acidic conditions), thereby sustaining
treatment near the lesion while minimizing systemic exposure [169].
Complementarily, micro-nano 4D printing has enabled tighter integra-
tion of actuation and “smart” feedback: a 4D-printed fish-shaped
microrobot (≈150 µm scale) combined magnetic actuation, pH-
adaptive morphing, and diffractive optical pH sensing (reported pH
window ≈ 5.0-6.5) to modulate DOX release kinetics and support proof-
of-concept gastric cancer cell therapy [170].

Furthermore, 4D-printed microswimmers and sperm-hybrid robots that respond to enzymes like MMP-2 or navigate using external magnetic fields have shown promise in targeted delivery for hard-to-reach tumors, including gynecologic cancers. These biologically driven devices offer new hope for reducing off-target toxicity and enhancing treatment outcomes [171].

In summary, 4D printing represents a transformative shift in cancer
treatment approaches by enabling the fabrication of intelligent, adap-
tive, and minimally invasive therapeutic tools. As the field continues to
evolve, integrating 4D printing with responsive biomaterials and
advanced manufacturing techniques will likely shape the next genera-
tion of personalized cancer care.

2.4.6. Dentistry

The development of temperature-controlled mask-image-projection
stereolithography for (TCMIP-SL) the manufacture of temporary dental
crowns and bridges is an innovation. This method employs the
decreased viscosity of dental composite materials at elevated tempera-
tures, enabling precise and fast printing of dental structures. When the
material is heated to 80 °C, the viscosity drops significantly, allowing
uniform coating and high-resolution printing at 25 µm per pixel. Thanks
to the excellent mechanical properties and accurate fitting of the
resultant temporary crowns, TCMIP-SL is a viable method to create su-
perior, patient-specific dental restorations [172].

Another important application of 4D printing in dentistry involves
the regeneration of oral soft tissues. The use of SMPs in dental scaffolds
allows the development of dynamic structures that can respond to
environmental stimuli, facilitating better integration with surrounding
tissues. FDM and SLA can effectively produce dental models and surgical
guides with biocompatible materials such as PLA. The Tg and shape-
memory behavior of these materials are critical to ensure their adapt-
ability and effectiveness in dental implants and scaffolds. Recent ad-
vancements include the use of hydrogel-based SMPs with superior
biocompatibility, exhibiting self-healing and temperature-responsive
properties. For instance, thermo-responsive SMPs demonstrated a sig-
nificant potential for improvement of the fit and performance of dental
scaffolds by adjusting them to intraoral temperature fluctuations. The
addition of bioactive fillers to these scaffolds further enhances cell
attachment and proliferation, making them more effective in oral tissue

engineering [173]. Additionally, the introduction of compatibilizers,
particularly in blend compositions with 5-10%, significantly improved
the mechanical properties and printability of materials used in dental
tissue engineering. This led to better outcomes in soft-tissue regenera-
tion, demonstrating the potential for 4D printing to revolutionize
personalized dentistry through more effective and adaptive solutions
[174,175].

Furthermore, 4D printing is employed to develop dynamic dental prosthetics and aligners. SMP-based prostheses capable of responding to thermal or hydration triggers allow adaptive solutions that minimize the need for manual adjustments during orthodontic treatments. Such materials were tailored to exhibit high shape-recovery ratios and fast response times, enhancing patient comfort and device precision. Thermoplastic SMPs, for example, showed promising applications in self-fitting aligners and orthodontic devices that adapt to intraoral conditions [173].

Clinical trials demonstrated the efficacy of 3D-printed titanium im-
plants, demonstrating how CAD/CAM and 3D printing can be employed
to create highly accurate and customized dental implants. Additionally,
digital orthodontics advanced significantly with 3D printing, enabling
the production of aligners based on 3D-printed models for more precise
and personalized orthodontic treatments. Research indicates that
interim resin crowns fabricated with photopolymer jetting and milling
in restorative dentistry exhibit superior accuracy in proximal and mar-
ginal areas compared to traditional methods. This highlights the preci-
sion and efficiency of 3D printing in dental restorations [176]. Various
cases of dental applications are shown in Fig. 13. Table 1 also summa-
rizes the most recent literature on biomedical applications of 4D
printing.

3. 4D Printing Materials

Some natural materials demonstrate a kind of intelligence, such as
self-repair, observed in plants and animals when injured. They are
named *shape-memory materials* because they can show dimensional
changes in response to various stimuli such as heat, light, pH, and
magnetic fields. Different types of shape-memory materials were studied
in many works [195]. Among them, SMPs, hydrogels, and composite
systems have emerged as the most versatile and widely used categories
in biomedical applications due to their biocompatibility, tunable me-
chanical behavior, and responsiveness to physiological stimuli. These
materials enable advancements in soft robotics, drug delivery, mini-
mally invasive implants, and tissue engineering scaffolds. While this
review primarily emphasizes polymer-based systems, we recognize the
importance of other smart material classes in the broader context of 4D
bioprinting. SMAs, though well-established, offer high actuation force
and thermal reliability, making them ideal for specific applications such
as vascular stents and orthopedic devices [131,196,197].

3.1. *Shape-memory Polymers*

SMPs are a type of smart materials that can respond to external
triggers such as heat, light, electricity, and magnetism by changing their
properties, such as stiffness and shape [198]. In contrast to shape-
memory alloys, SMPs offer several distinctive advantages, including
lower cost, broader compatibility with various activation mechanisms,
and favorable properties such as biodegradability and biocompatibility,
which make them attractive for biomedical use. One of the key advan-
tages of SMPs is their ability to undergo large, recoverable strains,
recovering their original shape after substantial deformation, which
expands their potential for deployment in minimally invasive medical
devices, self-expanding implants, and tissue scaffolds [199,200].

Despite their promise, conventional SMPs are limited by relatively
low thermal conductivity and reduced stiffness at elevated tempera-
tures, which can restrict their effectiveness in applications that require
high recovery forces [201]. However, their mechanical properties often
<figure><img src="image_15.png" /><figcaption>Fig. 13. CAD model of temporary bridge, second molar, lateral molar shell, and 3D printed specimens [172]. (b) Fixing and positioning 3D-printed guides along with occlusal splint [177]. (c) Framework for removable partial dentures created with SLS, including both the CAD model and the finished framework [178]. (d) Denture base created with 3D printing, with individual denture teeth printed separately and joined to the base [179]. (e) Upper jaw dental model produced via FFF [180].</figcaption></figure>

more closely resemble soft biological tissues compared to metallic systems, which enhances their compatibility for biomedical applications.

Mehrpouya et al. [202] investigated the shape-memory behavior and 4D printing potential of PLA, a biobased and biodegradable polymer. PLA was synthesized via ring-opening polymerization, resulting in variants with different ratios of D-lactide co-monomer. The authors discussed the effects of T~g~ and T~m~ of PLA, about 56 to 63 °C and 125 to 178 °C, respectively, on the fundamental properties determining its shape-memory response. They highlighted that its T~g~ can be tailored by adjusting its molecular weight and stereochemistry. The review also explored the application of PLA to 4D printing, emphasizing the impact of printing parameters on the functionality of final products.

The molecular architecture of SMPs, particularly polymer chain mobility, crystallinity, and crosslinking density, plays a central role in determining their shape-memory behavior. For thermally induced SMPs, the reversible switching segment governs the temporary shape fixation through physical entanglements or crystalline domains, while the permanent network, formed via chemical crosslinks or stereo-complexation, restores the original shape during heating. Tailoring molecular weight and the ratio of soft (amorphous) to hard (crystalline or crosslinked) segments allows precise control over the glass transition or melting temperature, which directly affects recovery speed, strain fixity, and actuation force [203,204]. Table 2 presents the main SMPs and their applications.

In light- and magnetically-triggered SMPs, incorporation of photo-chromic moieties (e.g., azobenzene) or magnetic nanoparticles (e.g., Fe₃O₄) into the polymer matrix enables remote activation by converting absorbed energy into localized heat or molecular rearrangement. These functional fillers can be dispersed uniformly or structured within specific layers using 4D printing, providing spatial control over stimulus response. Such molecular-level design strategies open pathways for multi-functional SMPs with programmable behavior, enabling

sophisticated biomedical devices that respond selectively to in vivo conditions [209].

### 3.1.1. Shape-memory Elastomers

Within the broader category of SMPs, SMEs have emerged as a subclass that combines the flexibility and low modulus of elastomeric materials with the reversible shape-memory effect. SMEs can recover their permanent shape through thermally or light-triggered transitions, offering advantages in applications where gentle mechanical actuation is desired, such as soft tissue engineering, artificial muscles, and deployable cardiovascular devices [210–213].

Recent advancements in 4D printing of SMEs highlight their increasing potential in biomedical soft actuators. Bayati et al. [210] developed highly stretchable artificial muscles through 4D printing of a propylene-based thermoplastic elastomer composite reinforced with 2% carbon black nanoparticles. These printed structures achieved elongations at break of 2665% and tensile strengths up to 5.58 MPa, and demonstrated cyclic shape recovery while lifting loads in biomimetic motion inspired by the chameleon's tongue. In another study, Mahjoubnia et al. [185] introduced a dual-network elastomer comprising a dynamic Diels-Alder reversible network and a UV-crosslinked PEGDA network. This formulation enabled fast recovery within 6 seconds at 60 °C, programmable stiffness ranging from 0.2 to 2.4 MPa, and shape recovery ratios exceeding 96%, all of which are highly desirable for biomedical soft actuators operating under physiological constraints.

### 3.1.2. Self-healing SMPs

Self-healing polymers offer innovative solutions by enabling materials to repair damage autonomously, eliminating the need for external intervention [214]. These polymers are classified into two categories based on their healing mechanisms: intrinsic and extrinsic.

Extrinsic self-healing polymers rely on healing agents encapsulated
<table><caption>**Table 1**
Recent advances in biomedical applications of 4D printing.</caption><thead><tr><th>No.</th><th>Applications</th><th>Material(s)</th><th>3D printing method</th><th>Stimuli</th><th>Highlights</th><th>Ref.</th></tr></thead><tbody><tr><td>1</td><td>Drug delivery, nerve conduit, ureteral stent</td><td>Zein protein gel</td><td>DIW</td><td>Water</td><td>Water-responsive 4D printing using zein enables tunable drug loading, release, and degradation via customized supporting bath; validated in vivo.</td><td>[56]</td></tr><tr><td>2</td><td>Intestinal drug delivery</td><td>PBAE + C18-acrylate</td><td>DLP</td><td>Temperature (37 °C)</td><td>Biodegradable devices with rapid degradation, high fixity/ recovery (~100%), capsule-compatible shape-memory expansion at 37 °C.</td><td>[57]</td></tr><tr><td>3</td><td>Drug delivery</td><td>PNIPAM + PEG hydrogels</td><td>DIW</td><td>Temperature (33 °C)</td><td>Bioinspired hydrogel capsules with pore-size-dependent, temperature-responsive release and excellent biocompatibility.</td><td>[45]</td></tr><tr><td>4</td><td>Soft tissue scaffold</td><td>Methylcellulose/kappa-carrageenan + CNC/CNF</td><td>DIW</td><td>Temperature (15-90 °C)</td><td>4D-printed macroporous scaffold with shape memory and tunable thermo-responsive behavior achieved through high internal phase emulsion templating and cellulose hybrid stabilization.</td><td>[181]</td></tr><tr><td>5</td><td>Bone tissue scaffold</td><td>PLA/Fe<sub>3</sub>O<sub>4</sub> + HA + Alendronate + Col-Dex coating</td><td>FDM</td><td>Magnetic field</td><td>4D-printed PLA-based SMP scaffold with drug-loaded bioactive fillers enables rapid magnetic shape recovery and enhanced osteogenic activity in vivo.</td><td>[85]</td></tr><tr><td>6</td><td>Bone tissue scaffold</td><td>PLGA/HA + Fe<sub>3</sub>O<sub>4</sub>@SiO<sub>2</sub></td><td>DIW</td><td>NIR light (43 °C), Magnetic field</td><td>Dual-responsive scaffold enabling NIR-triggered shape recovery and magnetic navigation; enhances bone regeneration via angiogenesis promotion.</td><td>[91]</td></tr><tr><td>7</td><td>Bone tissue scaffold</td><td>PLA/Fe<sub>3</sub>O<sub>4</sub></td><td>FDM</td><td>Magnetic field, Temperature (~62-67 °C)</td><td>4D-printed porous spinal-bone-like scaffold shows fast shape recovery (~8 s) under a magnetic field, with uniform heating and high recovery ratios (~96%).</td><td>[83]</td></tr><tr><td>8</td><td>Bone tissue scaffold</td><td>PLMC + PDA</td><td>FDM</td><td>NIR light (~42 °C)</td><td>Deployable, NIR-triggered, self-fitting scaffold for complex bone defects showing >99% shape recovery in 30 s and enhanced osteogenic potential in vivo.</td><td>[106]</td></tr><tr><td>9</td><td>Cell scaffold</td><td>PCL (coated with PLA, SOEA, agarose, and thermoset SMP)</td><td>FDM</td><td>Temperature (37 °C)</td><td>Introduced a staircase-effect-based FDM strategy integrated with coating to fabricate anisotropic 4D muscle scaffolds that guide human mesenchymal stem cells alignment and myogenesis.</td><td>[74]</td></tr><tr><td>10</td><td>Cell scaffold</td><td>PEG-based microgels with ester, thioester, amide, and MMP-labile crosslinks</td><td>DIW</td><td>pH</td><td>Logic-gated degradation enables spatiotemporal control of void fraction for tunable cellular colonization and release in 4D cell culture systems.</td><td>[182]</td></tr><tr><td>11</td><td>Cardiac tissue patch</td><td>BADGE + PEA + decylamine</td><td>DLP & DIW</td><td>NIR light, Temperature (~45 °C)</td><td>A curved cardiac patch with aligned microgrooves supports stem cell co-culture and synchronized beating, showing promise for myocardial regeneration.</td><td>[183]</td></tr><tr><td>12</td><td>Cartilage scaffold</td><td>SMPU/nHA composite (HP10)</td><td>DIW</td><td>Temperature (45 °C)</td><td>Inspired by mangroves, this 4D-printed cartilage scaffold demonstrates rapid recovery within 60s and excellent cytocompatibility for minimally invasive repair.</td><td>[184]</td></tr><tr><td>13</td><td>Occlusion device (ASD)</td><td>PLA/Fe<sub>3</sub>O<sub>4</sub></td><td>FDM</td><td>Magnetic field, Temperature (67 °C)</td><td>Biodegradable and remotely controllable shape-memory ODs for atrial septal defects, enabling programmable delivery and rapid endothelialization.</td><td>[150]</td></tr><tr><td>14</td><td>Occlusion device (VSD)</td><td>PLA/PEG + BaSO<sub>4</sub></td><td>FDM</td><td>Temperature (43 °C)</td><td>Customized biodegradable ODs with overall radiop density and shape-memory response; designed for patient-specific VSD types with clinical precision.</td><td>[151]</td></tr><tr><td>15</td><td>Occlusion device (LAA)</td><td>PLA/Fe<sub>3</sub>O<sub>4</sub></td><td>FDM</td><td>Temperature (62.7 °C), Magnetic field</td><td>First bioinspired 4D-printed absorbable LAA OD with tailored mechanical properties and remote-controlled deployment for cardiac therapy.</td><td>[158]</td></tr><tr><td>16</td><td>Occlusion device (LAA)</td><td>PGDA/PAAc</td><td>DLP</td><td>Temperature (39-47 °C)</td><td>4D-printed bioresorbable implants with high stretchability and tunable T<sub>g</sub>; showed successful aortic grafting in vivo and personalized LAA OD's design.</td><td>[185]</td></tr><tr><td>17</td><td>Void-filling scaffold (behave like ODs)</td><td>DTPU (Dynamic thermoset PU: PCL-triol + PEG + DA-diol)</td><td>FDM</td><td>Temperature (37 °C), Water</td><td>Multi-material 4D-printed scaffolds with swelling-stiffening transition, 1D-to-3D morphing, and body-fluid-triggered deformation for minimally invasive implantation.</td><td>[186]</td></tr><tr><td>18</td><td>Esophageal stent</td><td>PLA</td><td>FDM</td><td>Temperature (60 °C)</td><td>Origami-derived stents with programmable crease design enabled compact folding and >94% shrinkage; achieved 97% recovery in warm water bath.</td><td>[187]</td></tr><tr><td>19</td><td>Tracheal stent</td><td>PLA/PCL</td><td>DIW</td><td>Temperature (62 °C)</td><td>Biodegradable PLA/PCL scaffold with tunable shape-memory performance; PLA70/PCL30 blend showed 91% fixity and 90% recovery in tracheal tests.</td><td>[140]</td></tr><tr><td>20</td><td>Tracheal stent</td><td>Silk-MA (methacrylated silk fibroin) hydrogel</td><td>DLP</td><td>Water</td><td>Cell-laden 4D-bioprinted bilayer scaffold mimicked tracheal tissue and achieved shape morphing via osmotic pressure; successfully implanted in rabbits.</td><td>[188]</td></tr><tr><td>21</td><td>Tracheal stent</td><td>PLA/Fe<sub>3</sub>O<sub>4</sub></td><td>FDM</td><td>Magnetic field, Infrared light</td><td>4D-printed biodegradable stents with remote-controlled actuation, >99% recovery in 40 s, and dual deployment modes for minimally invasive treatment.</td><td>[189]</td></tr><tr><td>22</td><td>Vascular stent</td><td>PGDA</td><td>DIW</td><td>Temperature (37 °C)</td><td>Biodegradable 4D-printed scaffolds with excellent shape memory (98% recovery in 0.4 s), geometrical and mechanical adaptability, and successful in vivo grafting.</td><td>[143]</td></tr><tr><td>23</td><td>Vascular stent</td><td>βCD-g-PCL</td><td>DIW</td><td>Temperature (~57 °C)</td><td>4D-printed drug-loaded stents with high radial strength, excellent shape memory, and sustained paclitaxel release via βCD host-guest complexation.</td><td>[136]</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>No.</th><th>Applications</th><th>Material(s)</th><th>3D printing method</th><th>Stimuli</th><th>Highlights</th><th>Ref.</th></tr></thead><tbody><tr><td>24</td><td>Vascular stent</td><td>PLA</td><td>FDM</td><td>Temperature (60 °C)</td><td>4D-printed self-expanding PLA stents showed high recovery (up to 94%), tunable compression force, and controlled degradation under shear flow conditions.</td><td>[190]</td></tr><tr><td>25</td><td>Intestinal stent</td><td>PEG/PLA</td><td>FDM</td><td>Temperature (~42 °C)</td><td>Mass-producible, biodegradable intestinal stents with wavy biomimetic design; reconfigure at NBT to reduce tissue damage and eliminate second surgeries.</td><td>[133]</td></tr><tr><td>26</td><td>Orbital stent</td><td>AHP composite (SMPU + AuNPs + nHA)</td><td>DIW</td><td>Temperature (44 °C)</td><td>Computed Tomography-developable stent with shape recovery in 8 s and >200% volume filling, enabling minimally invasive, personalized treatment of orbital defects.</td><td>[159]</td></tr><tr><td>27</td><td>Arterial stent</td><td>PCL</td><td>FDM</td><td>Temperature</td><td>Bioinspired 4D-printed stents using auxetic architectures; Semi-re-entrant modified structure showed best strength-compressibility tradeoff for catheter deployment simulations.</td><td>[191]</td></tr><tr><td>28</td><td>Cardiac stent</td><td>GelMA + PEGDA hydrogels</td><td>SLA</td><td>Internal stress</td><td>4D cardiac patch with dynamic shape adaptation, triculture system, and long-term in vivo engraftment improving vascularization and structure.</td><td>[192]</td></tr><tr><td>29</td><td>Cardiac stent</td><td>Alginate/PDA + alginate/ GelMA bioinks</td><td>DIW</td><td>Light and temperature (37 °C)</td><td>Deformation is tunable via PDA content, strut pattern, and irradiation; it enables post-print modifications.</td><td>[193]</td></tr><tr><td>30</td><td>Vascular stent</td><td>PLA</td><td>FDM</td><td>Temperature (66 °C)</td><td>Personalized stents with negative Poisson's ratio, optimized via genetic algorithm, with >98% recovery.</td><td>[194]</td></tr></tbody></table>

<caption>**Table 2**</caption>

Summary of shape-memory polymers used in biomedical applications (3D/4D printing).

<table><thead><tr><th>Polymeric material</th><th>3D-printing technology</th><th>Properties</th><th>Application</th><th>Ref.</th></tr></thead><tbody><tr><td>PLA</td><td>FDM/SLA</td><td>Biodegradable, T<sub>g</sub> ~ 55–65 °C, biocompatible, good shape fixity</td><td>Biodegradable stents, sutures, drug delivery systems</td><td>[202]</td></tr><tr><td>PCL</td><td>FDM/SLS</td><td>Flexible, low T<sub>g</sub> ~ 45–55 °C, biodegradable, biocompatible, good shape recovery</td><td>Tissue engineering, bone scaffolds, drug delivery</td><td>[136,205]</td></tr><tr><td>PU</td><td>FDM</td><td>Variable T<sub>g</sub> (40–100 °C), excellent elasticity and recovery</td><td>Wearable devices, actuators, textiles, cell scaffold</td><td>[73,206,207]</td></tr><tr><td>PLMC</td><td>DIW</td><td>Biodegradability, biocompatibility, and tunable mechanical properties, fast shape recovery (4 s for sutures, 3 s for fabrics, 35 s for stents), T<sub>g</sub>:49 °C, R<sub>f</sub> > 99%, R<sub>f</sub> > 99%</td><td>Tissue engineering, scaffolds, nonwoven fabrics</td><td>[134]</td></tr><tr><td>Epoxy-based SMP</td><td>SLA/DLP</td><td>High strength, tunable T<sub>g</sub>, thermal stability</td><td>Self-healing materials, automotive components</td><td>[208]</td></tr></tbody></table>

in microcapsules or vascular networks. Upon damage, these agents are released in the affected area, where they undergo polymerization or other chemical reactions to repair cracks or tears. Although effective, this method is limited by the finite supply of healing agents within the material [215,216].

Intrinsic self-healing polymers have inherent self-healing properties through dynamic chemical bonds, such as disulfide bonds or hydrogen bonding. These reversible bonds allow the material to repeatedly repair itself when triggered by external stimuli such as heat or light [217–219]. For instance, PCL is widely used as a thermoplastic healing phase/agent in heat-activated self-healing systems; when heated above its melting temperature (~ 60 °C), molten PCL can flow/diffuse into damaged

regions and, upon cooling, recrystallize to bridge cracks and partially restore structural integrity [135,220–223].

In SMPs, self-healing is often combined with shape-recovery properties. SMPs can return to a pre-programmed shape when exposed to stimuli, such as heat, which not only repairs the damage but also restores the original shape, further enhancing their mechanical performance [224].

Jiang et al. [225] synthesized shape memory polyurethanes with self-healing properties by integrating disulfide bonds into the polymer network. Using DLP, a vat photopolymerization technique, they fabricated complex structures with high precision. The primary material used was polycaprolactone diol with isophorone diisocyanate. Self-healing efficiency, especially in samples with a higher disulfide bond ratio, reached 78.7% after 12 hours at 80 °C. This self-healing capability was attributed to the reversible nature of disulfide bonds, allowing the polyurethane to repair and extend its functional lifespan without external intervention. Fig. 14(a-j) shows a 3D-printed SMP-hydrogel stent with shape recovery and controlled drug release.

## 3.2. Hydrogels

Smart hydrogels with bi-layered structures, with one or two layers of gels, have been extensively studied for 4D printing. These structures have the ability to fold and unfold thanks to the varying swelling ratio of different layers, achieved through the use of specific solvents, pH levels, or temperature changes [229,230]. Scientists developed the idea of self-evolving structures using hydrophilic materials, particularly hydrogels. These materials have the ability to expand or swell when placed in water, causing shape changes in 3D-printed objects [231,232].

Recent studies demonstrated the versatility of hydrogels in 4D printing for biomedical use [233]. For instance, Abdullah and Okay [234] developed 4D-printed hydrogels based on PAAc with integrated shape-memory and self-healing abilities. These hydrogels were synthesized through the solvent-free copolymerization of AAc and C16A and produced using a stereolithography-based commercial resin printer. The hydrogels exhibited a strong-to-weak gel transition near the human-body temperature thanks to the crystallization and melting of C16A domains. Mechanically, the hydrogels showed tunable properties, with Young's modulus reaching 215 MPa and toughness up to 7 MJ/m3. The shape-memory effect and self-healing were successfully triggered at body temperature, making these materials highly suitable for biomedical applications.

Table 3 presents the main hydrogels used in biomedical applications, while Fig. 15 illustrates their shape-memory behaviors.

In another development, Hao et al. [250] investigated the use of 4D-
<figure><img src="image_16.png" /><figcaption>Fig. 14. 3D-printed SMP stent with drug-release capabilities. (a) Dual function of printed SMP-hydrogel stent, demonstrating blood-vessel expansion and controlled drug release. (b) Overview of structural design of SMP-hydrogel stents. (c) Detailed schematic of the SMP rod encased by drug-loaded hydrogel layer. (d) SMP-hydrogel stent compacted into its programmed shape. (e) DMA analysis with T~g~ = 30°C of SMP material used for the stent. (f-h) Images of printed SMP-hydrogel stent: (f) as-printed state; (g) programmed compacted form; (h) stents fabricated in various sizes. (i) Demonstration of stent's shape-memory and drug-release functions. (j) Evolution of drug release with time [226]. (k) Schematic of Eth-DFO@GelMA/GGMA scaffold fabrication with 3D bioprinting (This scaffold forms a bilayer interpenetrating hydrogel network through photo-crosslinking and ionic crosslinking, enabling a sustained DFO release to enhance the bone-defect repair [227]. Shape recovery (l) and self-healing (m) of sneakers (with cracks marked in red) in response to both simulated and natural sunlight conditions [228].</figcaption></figure>

printed self-assembling microscaffolds for cartilage tissue engineering, employing PEGDA as the base material. Via a customized DLP 3D printer, they fabricated hexagonal microscaffolds optimized for mechanical properties and self-assembly behavior. The scaffolds demonstrated a compressive modulus of 4.4 MPa, closely matching the mechanical characteristics of deep-zone articular cartilage. The addition of 0.2% nanocellulose fibers further improved the modulus to 5.6 MPa. The scaffolds achieved a 73.3% coverage rate in a simulated cartilage lesion, exhibiting their self-assembly capability. Biocompatibility tests confirmed successful cell engraftment and viability for 14 days, highlighting their potential for minimally invasive cartilage repairs.

Narupai et al. [257] further expanded the scope of 4D-printed hydrogels by developing multi-stimuli-responsive protein-based hydrogels for autonomous shape transformations. Utilizing methacrylated bovine serum albumin as the primary material, the researchers created hydrogels that respond to temperature, pH, and enzymatic degradation. The hydrogels were manufactured with DIW 3D printing, incorporating NIPAm and 2-dimethylaminoethyl methacrylate to induce temperature

and pH responsiveness. The study revealed that these hydrogels exhibited reversible shape changes under temperature and pH variations and irreversible degradation in the presence of enzymes.

### 3.2.1. Self-healing Hydrogels

Self-healing hydrogels are increasingly important in biomedical 4D printing because they can recover integrity after damage and, in extrusion-based printing, regain their network structure after shear, improving print fidelity and durability during cyclic actuation. This behavior is typically enabled by reversible crosslinks that break and reform under mild conditions [258–260].

Mechanistically, self-healing hydrogels are commonly designed using supramolecular/physical interactions (hydrogen bonding, ionic interactions, hydrophobic association, host-guest complexation, metal-ligand coordination) and/or dynamic covalent chemistries (e.g., imine/Schiff-base, boronate ester, disulfide exchange), where bond exchange enables repeated recovery. These dynamic networks can be engineered to balance rapid healing with mechanical robustness, often
<table><caption>**Table 3**
Summary of hydrogels used in biomedical applications (3D/4D printing).</caption><thead><tr><th>Hydrogel</th><th>3D-printing technology</th><th>Stimuli</th><th>Properties</th><th>Application</th><th>Ref.</th></tr></thead><tbody><tr><td>AAc</td><td>SLA/DLP</td><td>pH</td><td>pH-responsive swelling, optional self-healing via dynamic bonds, PVP viscosity modifier</td><td>Drug release;<br> Micromanipulation;<br> Actuator</td><td>[234-236]</td></tr><tr><td>Agarose</td><td>DIW</td><td>Thermal</td><td>Thermoreversible gelation, good print fidelity, brittle unless blended</td><td>Actuator;<br> Drug delivery</td><td>[237,238]</td></tr><tr><td>Alginate</td><td>DIW</td><td>Moisture;<br> Chemical (Ca<sup>2+</sup> ion);<br> Magnetic (with Fe<sub>3</sub>O<sub>4</sub>);<br> Light (with PDA)</td><td>Ca<sup>2+</sup>-ionically crosslinked, tunable stiffness, cell-compatible (low adhesion unless modified)</td><td>Actuator;<br> Cell-laden;<br> Hollow self-folding tubes</td><td>[193,239,240]</td></tr><tr><td>PNIPAm</td><td>DIW/SLA/DLP</td><td>Thermal;<br> Moisture (with cellulose);<br> pH (with sodium acrylate or allylamine)</td><td>Lower critical solution temperature thermo-responsive shrink/swell (~32 °C), reversible, tunable by copolymer/porosity</td><td>Actuators;<br> Sensors;<br> Microvalves</td><td>[45,241-246]</td></tr><tr><td>PAAm</td><td>SLA</td><td>Electric field;<br> Thermal</td><td>Hydrophilic elastic network, toughenable (DN designs), electro-response typically via ionic/conductive hybrid formulations</td><td>Soft robotic actuation</td><td>[247,248]</td></tr><tr><td>PEGDA</td><td>DLP</td><td>UV/visible light (photocuring)</td><td>Biocompatibility, improved pull-out force, enhanced tissue adhesion photocrosslinkable, hydrophilic, bioinert unless functionalized</td><td>Medical applications</td><td>[69,249,250]</td></tr><tr><td>PVA</td><td>DIW</td><td>Moisture</td><td>Hydrophilic, physically/chemically crosslinkable, swelling/erosion tunable by crystallinity/crosslinking.</td><td>Intravesical drug delivery devices;<br> endovascular therapy; self-deploying implants</td><td>[251-253]</td></tr><tr><td>GelMA</td><td>DIW/SLA/DLP</td><td>UV light</td><td>Biocompatibility, biodegradability, excellent printability, photocrosslinkable</td><td>Soft robotics;<br> Scaffolds;<br> Wound healing</td><td>[254]</td></tr></tbody></table>

through hybrid or double-network concepts. For example, host-guest interactions integrated within a covalent network have been shown to improve mechanical strength while retaining printability and self-healing [259-264].

Aydin et al. [265] recently demonstrated a solvent-free SLA route to 4D-printed self-healing hydrogels that combine thermoresponsive shape-memory behavior with network recovery, using terpolymerization of C16A, DMAA, and MAAc without added chemical crosslinkers. The hydrogel exhibited a tunable trigger temperature in the 32-40 °C range and showed simultaneous shape recovery and self-healing, highlighting the potential of photopolymerizable dynamic networks for biomedical devices that undergo repeated deformation and handling damage. Fig. 14(k) shows a bioprinted bilayer hydrogel network enabling sustained drug release for bone repair. Also, Fig. 14(l-m) shows sunlight-triggered shape recovery and self-healing.

### 3.3. Shape Memory Alloys

Shape-memory alloys are metal-based smart materials capable of temperature- or field-triggered shape recovery through a reversible martensite-austenite phase transformation [266]. Depending on training and cycling behavior, SMAs are typically discussed as one-way SMAs (recovering a memorized shape upon heating), two-way SMAs (remembering different shapes at low/high temperature after training), and pseudoelastic/superelastic SMAs (recovering large strains upon unloading near body temperature) [267]. NiTi is the archetypal biomedical SMA because its transformation temperatures and recovery stress can be tuned via composition and thermomechanical treatment, enabling self-expanding or force-delivering devices. In contrast to SMPs and hydrogels, SMAs offer high strength, high recovery stress, and excellent fatigue resistance, which is advantageous for load-bearing or mechanically demanding implants; however, their recoverable strain is typically lower than polymers, and processing is more complex and costly [22,266].

Additive manufacturing of SMAs has mainly relied on powder-bed and directed-energy routes (e.g., SLM/LPBF, EBM, DED), with additional reports using binder-based and extrusion-derived approaches

[266,268-273]. These processes provide geometric freedom but can also alter transformation behavior via composition shifts, residual stresses, and microstructural heterogeneity, necessitating careful parameter optimization and post-heat treatments. Clinically and translationally, SMAs have been applied in orthopedic fixation and minimally invasive deployment concepts (e.g., superelastic spinal rods, connectors/screws, and other self-actuating fixation elements) [22,267,274-276].

### 3.4. Shape Memory Ceramics

Shape-memory ceramics represent an emerging class of inorganic smart materials that can exhibit superelasticity and/or shape-memory-like recovery when deformation is coupled to a reversible, martensitic transformation (e.g., in zirconia-based systems) [277-279]. While bulk ceramics are typically brittle, microstructural refinement (e.g., oligocrystalline or micro-/nano-structured architectures) can mitigate transformation-induced mismatch stresses and enable repeated superelastic cycling at appreciable strains, highlighting a pathway for durable ceramic actuation concepts at small scales. In biomedical contexts, ceramic-based shape-morphing is attractive where chemical stability, wear resistance, radiopacity, and high-temperature tolerance are needed, and where post-processing steps (sintering/pyrolysis) can be leveraged as part of the programming or morphing mechanism [22].

From a manufacturing standpoint, complex ceramic architectures can be produced through slurry/ink-based routes (e.g., DIW/robocasting) and photo-curable ceramic suspensions (ceramic stereolithography/DLP), followed by debinding and sintering. Shape change can be encoded via bilayers, spatially varying solid loading, or anisotropic shrinkage during thermal treatment, enabling programmed bending/twisting after firing [277,280,281]. In addition, polymer-derived ceramic strategies can introduce a “programmable precursor” stage: preceramic inks containing reactive polymers and ceramic nanoparticles can be printed, temporarily shaped, and then converted to ceramics during pyrolysis, expanding the design space for lightweight, high-stiffness morphing components [282,283]. Although SMCs are not yet as mature as SMP/hydrogel platforms for biomedical 4D printing, they provide a complementary route when polymer limitations (creep,
<figure><img src="image_17.png" /><figcaption>**Fig. 15.** Wireless hydrogel milli-gripper actuated by magnetic fields, demonstrating a proof-of-concept gripping, transporting, and releasing cargo. (a) Schematic of cargo delivery via rolling motion. (b) Photographs of rolling locomotion of gripper delivering cargo under 25 mT rotating magnetic field. (c) Schematic of sequential actions of grasping, moving, and releasing cargo. (d) The gripper navigates obstructions while transporting cargo, using magnetic-field gradients created by a permanent magnet to complete the tasks. (e) The direction of the gripper's arms' bending is governed by the dipole moment alignment in the 3D profile under a magnetic field. In the absence of the field, the gripper returns to its original shape. Inset: Simulated side-view images of the magnetic profile in the milli-gripper. (f) Relationship between gripper's arms' bending angle and strength of applied magnetic field with inset bending angles of 26° and 45.1° at 8.9 and 14.9 mT, respectively [255]. (g) Mechanisms of shape memory and self-healing of hydrogel blend. (h) Temperature-dependent shape-recovery ratios of printed hydrogel samples during R₀ bending and Rₓ stretching. (i, j) Shape-recovery process in water at 43 °C and printed robotic hand in both its temporary and permanent shapes [234]. (k) Schematic of the fabrication process for the GelMA/β-TCP composite [256].</figcaption></figure>

low modulus, solvent sensitivity) become restrictive.

### 3.5. Composites

Composite materials play a crucial role in the field of 4D printing. These materials are composed of a blend of different materials,

specifically polymeric materials or hydrogels, combined to enhance printed objects' overall properties and functionalities [284,285]. In other words, a composite material is fundamentally defined as a combination of two or more immiscible materials with differing characteristics. The synergy between these distinct components gives rise to properties that surpass those of the individual materials. Typically, a
composite material has one or more discontinuous phases, known as *reinforcements*, embedded within a continuous phase referred to as a *matrix* [286]. Pure polymers typically exhibit a low elastic modulus, but the inclusion of reinforcements, such as fibers or particles, significantly enhances the material's overall performance and properties, thereby broadening its range of practical applications. The reinforcements can take the form of particles [287], short fibers [288,289], long fibers [290], or fabric [291].

Recent advancements in 4D-printed composites focused on tailoring mechanical properties, shape recovery, and microstructural behavior. Huang et al. [292] developed a photocuring-based 4D printing strategy to fabricate multilayer SMPs with adjustable mechanical properties and tunable shape-memory behavior. Using DLP, the researchers integrated MWCNTs into the intermediate layer of the SMPs to control the curing degree and mitigate overexposure, ensuring strong interlayer bonding and optimized structural performance. The resulting SMPs demonstrated high tunability at their mechanical strength, rapid shape recovery, and tailored microstructural properties, making them highly suitable for soft robotics and flexible electronics.

Further advancements were reported by Liu et al. [293], who designed a recyclable and multi-responsive EVA-based hybrid network by integrating Fe₃O₄ nanoparticles into an EVA matrix using a bridging molecule, 3,4-dihydroxyphenylpropionic acid. The resulting EVA-CA@Fe₃O₄ system exhibits dynamic cross-linking via transesterification and metal-ligand coordination, enabling exceptional shape memory effects triggered by heat, NIR light, and alternating magnetic fields. Notably, the EVA-CA@Fe₃O₄ (10%) composite achieved self-healing efficiencies of up to 107% in tensile strength after just 2 minutes of NIR exposure and retained mechanical robustness over three reproducing cycles. This study demonstrates the feasibility of combining photo- and magneto-responsiveness with recyclability in a single shape memory polymer network.

Complementing this, Yang et al. [294] developed a set of PLA-based shape-memory nanocomposites whose actuation can be triggered thermally and further enabled by adding CNTs (photo-to-thermal conversion), carbon black (Joule heating under an electric field), or Fe₃O₄ (inductive heating under alternating magnetic fields). These composites were melt-extruded into filaments compatible with commercial FDM printers and then combined via multi-material 4D printing to fabricate gradient metamaterials with programmable, spatially selective shape change.

The continued development of composite-based 4D printing materials underscores their potential in the fabrication of multifunctional, responsive structures, along with enhancing mechanical strength, bioactivity, or imaging contrast with minimal changes to processing. Table 4 summarizes information about polymeric composites for biomedical applications and their properties.

### 3.6. Review

A comparative evaluation of 4D printing materials reveals a sophisticated interplay between material composition, structural responsiveness, manufacturing constraints, and the specific demands of biomedical applications. Among the key contenders, such as SMPs, hydrogels, SMAs, SMCs, and composites, each class exhibits distinct advantages that make them preferable depending on functional priorities. SMPs, particularly thermally-activated variants such as PLA, PCL, and PU, dominate applications requiring high shape fixity and recovery efficiency, making them ideal for self-expanding implants, sutures, and minimally invasive devices. Their performance is highly dependent on Tg, Rr, and elasticity; for instance, PLMC and epoxy-based SMPs offer fast recovery and tunable mechanical performance, suitable for time-sensitive actuation. Yet, they may fall short where high recovery stress, rapid heat transfer, and mechanical stiffness are required, especially in load-bearing or high-force deployment environments. Elastomeric SMPs address these shortcomings through exceptional

<caption>**Table 4**</caption>

Summary of polymeric composites used in biomedical applications (3D/4D printing).

<table><thead><tr><th>Polymeric composite</th><th>3D-printing technology</th><th>Properties</th><th>Application</th><th>Ref.</th></tr></thead><tbody><tr><td>PLA/Fe₃O₄</td><td>FDM</td><td>Biocompatible, Tg: 62-67 °C, magneto responsive, Rf ~ 97%, Rr ~ 96%, recovery: 8-14 s</td><td>Occlusion devices, bone tissue repair</td><td>[66,83,150]</td></tr><tr><td>PCL/PLGA/TCP</td><td>FDM</td><td>Improved mechanical properties compared to PCL/PLGA, enhanced bioactivity due to TCP</td><td>Bone-tissue engineering scaffolds with improved osteoconductivity</td><td>[295]</td></tr><tr><td>PLA/HA</td><td>FDM</td><td>Higher crack resistance compared to pure PLA, maximum recovery stress at 64°C programming temperature, Rr: 96.3-99.1% with heat</td><td>Bone graft substitutes, Self-fitting implants for bone-defect replacement, platforms for cell colonization prior to implantation</td><td>[84,103]</td></tr><tr><td>PEEK/HA</td><td>SLS</td><td>High mechanical strength, bioactivity</td><td>Dental implants, maxillofacial reconstructions</td><td>[175]</td></tr><tr><td>SiC/C/PLA</td><td>FDM</td><td>Rr: 99-100% with heat</td><td>Hard-tissue engineering</td><td>[296]</td></tr><tr><td>PLMC/CNT</td><td>DIW</td><td>Tg: 69 °C, Rr: >99%, Rr: >96% with electric field</td><td>Neural regeneration, contactless medical devices, drug-delivery systems</td><td>[297]</td></tr><tr><td>SMPU/MWCNT</td><td>FDM/DLP</td><td>Electrically responsive shape-memory effect, enhanced mechanical properties (tensile, flexural, impact strength)</td><td>Soft robotics, flexible electronics, time-delay devices</td><td>[292,298]</td></tr><tr><td>PLA/CB</td><td>FDM</td><td>Tg ≈ 60 °C; storage modulus drops ~10³ from 30-100 °C; stiffness drops ~10× above Tg; electrothermal (Joule) activation</td><td>Self-sensing pneumatic soft actuators; cardiac-mimicking actuator; active therapeutic insoles (plantar pressure sensing/ releasing; assistive medical devices)</td><td>[299]</td></tr></tbody></table>

stretchability and programmable stiffness, as shown by dual-network systems and nanocomposite-reinforced elastomers, which exhibit biomimetic motion capabilities and enhanced recovery dynamics.

Hydrogels, on the other hand, excel in mimicking the hydrated, soft nature of biological tissues and offer reversible shape transformations triggered by moisture, pH, temperature, enzymatic activity, or even magnetic fields. Their bilayer swelling-driven actuation makes them uniquely suitable for constructing autonomous grippers, microscaffolds, and soft robotic components for drug delivery or tissue engineering. Particularly notable are crosslink-gradient designs, PEGDA-based microscaffolds, and multi-stimuli-responsive protein hydrogels that
couple structural integrity with precise, dynamic responsiveness. However, most hydrogel systems exhibit slower response times and relatively lower mechanical robustness, making them less ideal for high-force actuation. The integration of self-healing capabilities, either via dynamic covalent bonds in SMPs or crystallinity-driven healing in hydrogels, further enhances their utility in long-term biomedical deployment by enabling autonomous repair and functionality retention under cyclic deformation.

In contrast to polymeric systems, SMAs provide substantially higher recovery stress, fatigue resistance, and mechanically reliable actuation driven by martensite-austenite transformation, which is advantageous

for force-demanding implants (e.g., fixation elements, self-expanding frames) where polymers may creep or soften. Their limitations for broader 4D biofabrication include lower recoverable strain than many SMPs, higher density and cost, and processing complexity (often requiring post-heat treatments to stabilize transformation behavior). SMCs represent an emerging complement where chemical stability, wear resistance, and radiopacity are prioritized; however, their adoption remains limited by brittleness and the need for sintering/pyrolysis-based processing, making them more suitable for niche, architected components rather than large-strain, soft-tissue actuation.

Composite systems offer a versatile platform that combines the

<figure><img src="image_18.png" /><figcaption>**Fig. 16.** Schematic overview of 3D printing techniques: (a) vat photopolymerization – DLP; (b) vat photopolymerization – SLA; (c) sheet lamination; (d) material jetting; (e) direct energy deposition; (f) material extrusion (1. filament-based; 2. piston-based (pneumatic), 3. screw-based); (g) binder jetting; (h) powder bed fusion (SLS-SLM).</figcaption></figure>
mechanical strength of reinforcement phases with the functional responsiveness of smart matrices. The integration of nano- and micro-fillers, such as CNTs, $Fe_3O_4$, ZnO, or HA, enables tailored responses to thermal, magnetic, pH, or electrical stimuli. Here, “composites” refer to multiphase materials (matrix + reinforcement), whereas “hybrid systems” more broadly include multi-material or multi-network architectures (e.g., SMP-hydrogel bilayers, SMA-polymer constructs, or sequentially functionalized lattices) designed to merge distinct actuation modes or biological functions. Despite these advantages, multi-phase or multi-material designs can introduce challenges in biodegradability, printability, and interface stability, necessitating careful formulation and architecture selection based on the intended application in soft robotics, tissue engineering, or smart biomedical devices.

In conclusion, the selection of a 4D-printing material system must be driven by the intended functional profile: SMPs offer high strain recovery and tunability for implantable devices; hydrogels provide high cytocompatibility and stimulus-responsiveness for dynamic soft systems; composites offer enhanced mechanical performance and multi-functionality; and SMAs/SMCs extend the materials toolbox when high recovery stress, wear resistance, or radiopacity are decisive. The most forward-looking strategies often integrate composites and/or hybrid multi-material architectures to reconcile trade-offs while enabling more intelligent and clinically relevant responsive biofabrication.

## 4. 3D/4D Printing Techniques

ASTM International standards divide polymer AM techniques into seven distinct groups: (i) material extrusion, (ii) powder bed fusion, (iii) vat photopolymerization, (iv) material jetting, (v) binder jetting, (vi) sheet lamination, and (vii) directed energy deposition [300] (See Fig. 16). Every category has many different vendors, solutions, and materials. However, most studies do not use the standard terminology yet and often rely on trade names to describe the specific processes.

In biomedical 4D printing, the printing technique is not only a shape-making tool; it also defines where the responsive material is placed, how gradients/anisotropy are encoded, and whether cells, drugs, and bioactive cues can survive the process. Therefore, technique selection is typically governed by: (i) compatibility with stimuli-responsive inks (SMPs, swelling hydrogels, SMAs, or composite systems), (ii) achievable spatial patterning (bilayers, hinges, graded crosslinking, voxel-wise property control), (iii) post-print “programming” capability (mechanical deformation, hydration/deswelling, thermal cycling, or field exposure), and (iv) biomedical constraints such as cytocompatibility, sterilization/cleanability, residuals/leachables, and reproducibility under cyclic actuation.

### 4.1. Material Extrusion

The most commonly used AM technology is material extrusion [301]. In ME, a material is selectively dispensed through a nozzle onto a platform. Any polymer or polymer-based material that can be heated to an appropriate temperature without degrading can be used in ME. The deposited material has a consistent diameter by keeping the applied pressure and nozzle speed constant [302].

From a 4D perspective, ME is particularly useful because it can intentionally “write” anisotropy (via raster orientation, layer stacking, and multi-material placement), which later converts into time-dependent bending, twisting, or deployment when exposed to a stimulus. In biomedical constructs, this 4D behavior is commonly achieved by (i) printing thermo-responsive SMPs (shape fixity/recovery encoded through post-print programming), (ii) printing swelling/ionic hydrogels (shape change encoded through differential hydration or crosslink density), and/or (iii) printing composites that transduce external fields (e.g., magneto-/photothermal fillers) into localized heating for actuation [245,303].

There are two main approaches to extrusion processes. In the first approach, the material is melted inside a heated nozzle channel and flows out through it. It then bonds with the neighboring material before solidifying [304–306]. This approach, known as FDM, is the most widely used AM technology. It is often employed in inexpensive 3D printers. Different extrusion methods in this approach are shown in Fig. 16f.

In one of our previous works [307], the potential of PLA-PBAT blends for 4D printing was investigated using FDM with a direct granule-based printer (Fig. 16f). Blends with 15%, 30%, and 45% PBAT by weight were successfully printed. The blend with 45% PBAT exhibited 220% elongation and 93% shape recovery within seconds, while the other two blends achieved a full shape recovery in under 8 seconds. The blend with 15% PBAT showed 40 MPa strength and 17% elongation, with a low melting temperature of PBAT enhancing the shape recovery. SEM images confirmed high printability, with the 30% PBAT blend demonstrating optimal interlayer bonding and minimal porosity.

In biomedical 4D printing, FDM/FFF is most often leveraged for deployable implants and self-fitting scaffolds where thermally programmed SMPs recover shape in warm aqueous environments. However, because melt temperatures are high, FDM is generally unsuitable for direct printing of cell-laden inks or temperature-sensitive biologics; instead, biofunctionality is introduced through post-print loading (e.g., drug adsorption/infusion) or by hybrid fabrication with hydrogel printing or coating steps [308]. The second extrusion approach involves the use of flowable slurries as the extrusion material, usually without heating. This method is used, for example, to extrude food substances or print biomaterials loaded with living organisms, including cells. Commercially available biomedical cell printers use this approach and have larger-diameter nozzles to minimize stress on the cells during deposition, improving cell viability compared to FDM printers [309].

DIW is another ink-based extrusion printing method, where a pressurized nozzle dispenses ink and a computer-controlled robotic system moves the dispenser to form geometries layer-by-layer, as illustrated in Figs. 16(f₁-f₃), which show different ME methods [310,311]. DIW is successfully employed to print a wide variety of materials, including metals [312], polymers [313], ceramics [314], and even multi-material systems [315]. One of the key advantages of DIW over other printing techniques is its versatility in material selection, minimal use of raw materials, and open-source nature, making it especially suitable for multi-material printing applications [311,316]. A critical factor in DIW is the ink viscosity, which must meet specific rheological requirements [317,318]. Essential rheological parameters for ink design include apparent viscosity, yield stresses under shear and compression, and viscoelastic properties, such as loss and storage moduli, which must be optimized for the DIW technique [319,320]. For 4D printing with DIW, the ink must have viscoelastic properties, including a shear-thinning behavior and a rapid transition from pseudoplastic to dilatant recovery [320–322].

For biomedical 4D printing, DIW offers a particularly straightforward route to time-dependent function because the “instruction” for morphing can be embedded during fabrication. Shape transformation may be programmed through spatially patterned multi-material deposition (e.g., bilayers with mismatched swelling or modulus), controlled gradients in crosslink density or composition (introduced during/after printing to create anisotropic swelling), and designed filament architectures that convert constrained swelling into bending, twisting, or folding. Because DIW typically operates under mild, near-ambient processing conditions, it is also compatible with cell-laden hydrogel inks, enabling 4D bioprinting in which cell contractility, matrix remodeling, and scaffold degradation can act as internal drivers of gradual shape and function evolution [323–325].

In a study with the DIW method, Ravichandran et al. [326] developed a novel AM technique called Multiphase DIW to fabricate multi-layered polymer/nanoparticle composites. This method, a variant of material extrusion, involves co-extruding two immiscible feedstocks through a specially designed print head to create alternating layers on
the x-y plane. The researchers used PVA and MWNTs as example materials. The resultant 64-layered structures, with layer thicknesses of 32 µm, exhibited significantly improved mechanical properties compared to pure PVA, including a 5-fold increase in Young's modulus and 3-fold improvements in the ultimate tensile strength and energy absorption. These enhancements were attributed to the low layer thickness, which improved interfacial interactions and uniformity of nanoparticle distribution. The multiphase DIW technique achieved high-precision control down to single microns while maintaining printing speeds up to 1200 mm/min. Fig. 17 shows some specimens prepared via DIW and FDM, as well as the related shape-recovery tests.

## 4.2. Powder Bed Fusion

A powder bed fusion process is an AM technology used to create accurate parts based on a 3D solid CAD model. It operates on the principle of adding layers of material to build the desired object. This process utilizes either a laser, or an electron beam to provide the heat energy required to irradiate, fuse, and melt powder particles. Lasers are the most commonly used heat sources in PBF [330]. A schematic of the laser-based PBF process is shown in Fig. 16(h). There are several types of PBF processes:

a. Selective laser sintering (SLS): In this process, a laser beam selectively fuses a powder material to create the desired object [331].

b. Selective laser melting (SLM): SLM involves complete melting of the powder material using a laser to achieve a dense and fully melted finished part [332].

c. Direct metal laser sintering (DMLS): Similar to SLS, DMLS utilizes a laser beam to selectively fuse metal powders to create finished parts [333].

d. Selective heat sintering (SHS): SHS uses a combination of heat and pressure to sinter powder particles and produce solid objects [334].

e. Electron beam melting (EBM): EBM employs an electron beam rather than a laser one to melt and fuse metal powders to fabricate parts [335].

Mei et al. [336] synthesized PA1212-based thermoplastic polyamide elastomer using one-pot melt polycondensation and TPAE powder prepared for SLS by freeze-crushing and sieving. The effects of SLS processing parameters on the properties of sintered parts were investigated, with the tensile strength, elastic modulus, and elongation at break reaching 13.7 MPa, 124 MPa, and 200%, respectively. The PA1212-based TPAEs fabricated with SLS exhibited excellent and stable shape-memory behavior. This work provides a design strategy for 4Dprintable materials and references SLS-processing parameters, broadening the application of polyamide-based elastomer materials to the 4D printing field.

Recently, there has been growing interest in using SLM to fabricate NiTi shape memory alloys, due to their exceptional shape recovery and superelastic behavior in demanding environments [337]. For instance, Li et al. [338] investigated the influence of processing parameters on the mechanical and shape memory properties of NiTi alloys for 4D-printed orthopedic implants. By systematically varying laser power, scanning speed, and hatch spacing, they identified an optimal parameter combination (P = 80 W, v = 600 mm/s, h = 70 µm) that achieved an austenite finish temperature below body temperature, a tensile strength of 612 MPa, and a shape recovery rate of 96.94%. The study demonstrated that scanning speed and hatch spacing had the most significant impact on transformation temperatures, due to their influence on energy density and resulting Ni loss. Fracture surface analysis showed brittle failure with localized ductile dimples, while 3D-CT imaging confirmed that unfused pores from suboptimal parameters were detrimental to mechanical strength. These findings support the application of optimized SLM-NiTi alloys in minimally invasive, patient-specific implants with reliable body-temperature-activated shape memory behavior.

From a 4D-biomedical standpoint, PBF enables “4D by phase transformation” (e.g., SMA-based deployment/superelasticity) and “4D by

<figure><img src="image_19.png" /><figcaption>**Fig. 17.** (a) DIW 3D printing performed with a 500 µm nozzle tip with 20 wt% CNC gel. The first column presents the CAD model; the second column shows the DIW 3D-printed gel structures; and the third column displays the final structures after freeze-drying [327]. (b) Schematic of 4D-printed cellulosic fibrils fabricated via DIW undergoing swelling deformation [328]. (c) Illustration of restricted shape recovery induced by 30 kHz alternating magnetic field and application of 4D scaffold as intravascular stent at deformation temperature of 80 °C [138]. (d) Close-up view of 4D-printed mesostructured orthotic splint [329]. (e) In-vitro feasibility study demonstrating closure of transcatheter LAA [158].</figcaption></figure>
<figure><img src="image_20.png" /><figcaption>**Fig. 18.** Fabrication process of TPAE-based samples with SLS. (a) Schematic of sintering method used for the production of TPAE components. Shape-memory behavior of TPAE sintered structures: (b) sequential shape-memory process for TPAE components, involving deformation at 60 °C under external force for 0.5 hours (I), cooling to -20 °C and force release (II), and recovery upon reheating to 60 °C (III) [336]. (c) β-type titanium-alloy implants with precisely controlled structural units fabricated via powder bed fusion [341]. (d) Complex structures composed of Ti₄₇Cu₃₈Zr₇.₅Fe₂.₅Sn₂Si₁Ag₂ glassy alloy manufactured with SLM [342]. (e) SLM-fabricated glassy Zr₅₂.₅Cu₁₇.₉Ni₁₄.₆Al₁₀Ti₅ scaffolds, produced with unidirectional scanning vectors rotated by 90 ° in adjacent layers to enhance structural integrity [343].</figcaption></figure>

thermo-responsive polymer networks" (SLS of SMP elastomers). The main advantage is mechanical integrity and lattice-level design freedom (porous architectures for fixation, load transfer, and tissue integration), while the main limitation is that high processing temperatures prevent direct incorporation of living cells or many drugs; therefore, biomedical 4D functionality is typically realized through post-processing (heat treatment to tune transformation temperatures, surface functionalization, or secondary hydrogel/drug layers) [339,340]. Fig. 18 presents the fabrication process and shape-memory results, as well as related biomedical devices printed with the PBF method.

### 4.3. Vat Photopolymerization

Vat photopolymerization is an AM process that involves selective and spatial curing of a liquid photopolymer in a vat through light-activated polymerization. This process enables the creation of parts with intricate geometries and exceptionally fine details due to its high resolution. It is particularly suitable for applications requiring smooth surface finishes and tight dimensional tolerances [344]. Several lithography-based AM approaches fall under this category:

a. Stereolithography (SLA): SLA systems use coherent light sources, often lasers emitting in the UV range, to induce polymerization and crosslinking of a liquid resin [345].

b. Digital light processing (DLP): Similar to SLA, it uses light to selectively crosslink a photoresin in a layer-by-layer fashion, resulting in the fabrication of a free-standing object [103,346].

c. Multiphoton polymerization (MPP): it shares similarities with SLA but employs lasers that emit in the near-infrared spectrum. NIR radiation has lower scattering properties compared to UV, enabling deeper penetration through materials such as living tissues without denaturing proteins [347,348].

d. Continuous liquid interface production (CLIP): CLIP relies on an oxygen-permeable film to inhibit polymerization at the surface near the UV sources, creating a persistent liquid interface. This process allows continuous printing of objects rather than building them layer by layer [349].

Chen et al. [350] investigated the manufacture of PEGDA/nHAP biomaterials with SLA 3D printing. They optimized the composition and processing parameters to achieve high compressive strength. The researchers mixed PEGDA, photoinitiator I2959, and nHAP to create a photocurable paste. SLA was used to fabricate the specimens, with the minimum cured width reaching 65 µm in the XY plane. The compressive strength of the printed PEGDA/nHAP specimens reached a maximum of 61.0 ± 3.9 MPa, which was significantly higher than that of pure PEGDA (3.6 ± 0.9 MPa). This study demonstrated that SLA-prepared PEGDA/nHAP biomaterials can meet the compressive-strength requirements for bone-tissue applications (2-80 MPa), showing potential for bone regeneration.
<figure><img src="image_21.png" /><figcaption>**Fig. 19.** Schematic of shape-memory functionality and photothermal therapy using stent as a therapeutic device. (a) A bioresorbable stent with embedded AuNRs fabricated with DLP inserted in tubular organ with a malignant obstruction. Upon NIR irradiation, AuNRs convert light into localized thermal energy inducing heat-mediated death of cancer cells. (b) SMP stent with AuNRs enables thermally activated deployment. (c) Mechanical, photothermal, and shape-memory characteristics of 15k-based 3D-printed composites containing 0.1 wt% AuNRs, compared to a control polymer without AuNRs. Data presented as mean ±standard deviation (n = 4). (d) Temperature profile measured 1 min post-irradiation and three minutes into NIR exposure. (e) $R_f$ and $R_f$ of SMP cuboids (12.5 mm × 2.4 mm × 0.8 mm) over five deformation cycles at -20 °C and room temperature. Deformed shape maintained at -20 °C for 10 min, with $R_f$ determined at -20 °C after force removal and at room temperature after 2 min. (f) Thermal and optical images of mesh stent (11 mm × 10.8 mm × 1.1 mm) made of SMP-AuNRs captured at different time points during 808 nm laser exposure following shape recovery process. (g) 3D-printed stent (12 mm × 16 mm × 1.6 mm) fabricated from composite material with shapes after programming and its ex vivo shape-recovery in a porcine intestinal segment, activated by NIR light irradiation [351].</figcaption></figure>

Paunović et al. [351] developed a multifunctional material system for DLP 3D printing of bioresorbable and NIR-responsive devices. They utilized a composite of AuNRs and a polyester copolymer based on D, L-lactide, and ε-caprolactone. The DLP technique enabled high-resolution manufacturing of complex-shaped objects. The printed composite exhibited robust NIR responsiveness, allowing rapid and stable photothermal effects. Mechanical tests revealed excellent elasticity with

Young's modulus of 4.0 MPa and elongation at a break of 124%. The material demonstrated shape-memory properties, facilitating the insertion and expansion of printed stents ex vivo. Fig. 19 illustrates the test results of this study, highlighting the exceptional properties and performance of the multifunctional material system.

In biomedical 4D printing, vat photopolymerization is frequently used to achieve “4D by spatially programmed network chemistry,”
because crosslink density, resin composition, and inclusion of photo-
thermal/magnetothermal fillers can be varied across layers or regions to
create differential swelling, stiffness gradients, or stimulus-localized
heating. This makes SLA/DLP well-suited for microstructured drug-
delivery devices, fine-featured scaffolds, and minimally invasive
deployable components. However, translation requires careful control
of residual monomers/photoinitiators, extraction/post-curing protocols,
and sterilization compatibility, since leachables can dominate cyto-
compatibility and long-term performance [352,353].

4.4. Material Jetting

According to ISO/ASTM 52900:2015 standard, the material jetting (MJ) technology involves selective deposition of droplets of feedstock material. In MJ, air-excluding tanks are used to store photopolymer materials. These materials are heated in a transmission line and then transmitted from the tank to a nozzle [354]. Once on a build platform, the photopolymer is deposited as droplets to form a very thin layer. UV light is emitted onto the molten material on the build platform to initiate the curing process. The light source, which is of a specific wavelength, cures the monomers or oligomers in the liquid state [355]. Unlike technologies that use specific wavelengths, SLA (355 nm) and DLP (405 nm), MJ has the theoretical flexibility to use various light wavelengths [356]. However, in practice, a wavelength between 190 and 400 nm is typically employed [357]. After each layer is cured, the build platform is lowered by a specific layer thickness, and a new liquid material is jetted onto the previous layer. This process is repeated for each successive layer until a full-scale part is completely built.

He et al. [358] developed a TPGDA-based polymeric support ink for material jetting, an AM technique that selectively deposits droplets of build materials. They added TGME to TPGDA to create a removable support structure. The addition of TGME significantly reduced the modulus of the photocured structure (from 575 to 27 MPa) by forming micro-pores. Thermogravimetric analysis showed that the temperature at which 5% of the sample's weight was lost (T5%) exceeded 150 °C, indicating thermal stability during fabrication. Most decomposition occurred around 400 °C. The researchers successfully fabricated specimens with overhanging structures, such as gate-like and propeller designs, demonstrating the ink's viability as a support material. This study addresses the need for available support materials in MJ, enabling the fabrication of complex 3D objects with overhanging structures.

Further advancements in the MJ technology enabled its application in the AM of ceramics. Willems et al. [359] explored the use of MJ to fabricate 3Y-TZP ceramics, utilizing the XJET Carmel 1400 printer to deposit zirconia ink, followed by drying, binder burnout (debinding), and sintering. This method allowed the precise printing of 10.5 µm layers, achieving a green density of 58% and a sintered density of 99.7%. The researchers examined microstructural properties, mechanical performance, and dimensional accuracy of the printed parts, revealing anisotropic surface roughness with higher bending strength in the XY direction compared to the Z direction. SEM and X-ray computed tomography analyses identified delamination cracks, agglomerates, and spherical pores as primary reasons for fracture. This study provides valuable insights into the mechanical behavior and structural integrity of MJ-fabricated 3Y-TZP ceramics, demonstrating the potential of MJ in high-precision ceramic additive manufacturing.

MJ is particularly relevant to biomedical 4D printing because it of-
fers voxel-/droplet-level multi-material placement, which is a direct
route to encode “time” via spatially varying modulus, swelling, and
hinge-like regions that actuate under thermal/hydration triggers. In
practice, its biomedical 4D adoption is often constrained by the limited
library of truly biocompatible jettable resins and by the need to manage
support-material removal and residuals, which can be critical in
implantable devices [21,360].

4.5. Binder Jetting

Binder jet printing is an AM technology where a liquid binding agent is applied to powder in a specific pattern on each layer. These layers are then stacked on top of each other to create a physical object. The process of binder jetting (BJ) can be used with almost any type of powder and offers high production speeds [361]. Moreover, BJ is successfully used in a wide range of materials, including polymers, metals, and ceramics [362]. The differences between material jetting and binder jetting are presented in Figs. 16d and 16g.

Kunchala and Kappagtantula [363] investigated the effects of nano-
particle densifiers on binder-jeted alumina ceramics. Alumina powder
(40 µm) was used as the main material, with alumina nanoparticles (50
nm) suspended in the printing liquid as densifiers. The researchers
varied nanoparticle concentration from 0 to 15 wt%. Results showed
that adding nanoparticles improved the sample density by about 30%
and increased compressive strength by 743% (from 76 to 641 kPa).
MicroCT imaging revealed decreased interparticle pores with 15 wt%
nanoparticles. The printing liquid's surface tension decreased from 44 to
23 mN/m as the densifier content increased, indicating the reduced
penetration depth in the powder bed.

Further advancements in BJ for biomedical applications were demonstrated by Hong et al. [364], who investigated binder-jet 3D printing of biodegradable Fe-Mn-Ca/Mg alloys for bone-defect treatment. They optimized the alloy composition using computational modeling to enhance their degradation rates and fabricated porous scaffolds via high-energy mechanical alloying and binder-jet 3D printing. The inclusion of Ca and Mg accelerated the degradation of Fe-Mn alloys, and the resulting Fe-Mn-1Ca (referring to 1 wt% calcium addition) scaffolds exhibited improved degradation rates and excellent cytocompatibility with MC3T3 pre-osteoblast cells. The porous architecture (36% open porosity) of scaffolds promoted cell infiltration, demonstrating the potential of binder-jet 3D-printed Fe-Mn-Ca scaffolds as biodegradable bone grafts with customized geometries and controlled degradation behavior. These findings reinforce BJ's potential in structural and biomedical applications, enabling high-precision fabrication of dense ceramics and biodegradable metallic implants.

BJ is less commonly used for classic “actuation-type” 4D (shape
morphing), but it is increasingly relevant to biomedical 4D concepts
when the time-dependent function is dominated by controlled degra-
dation, porosity evolution, or post-infiltration with responsive phases (e.
g., hydrogel infiltration into a porous scaffold to create swelling-driven
actuation or on-demand release). Thus, BJ can serve as a scalable route
to architected substrates that are later functionalized into stimulus-
responsive, translation-oriented systems [365,366]. Fig. 20 presents
3D-printed net-shaped components manufactured with BJ and MJ,
demonstrating various powder processing methods and composite
structures.

4.6. Emerging Techniques for 4D Printing

Beyond the established AM technologies, a new generation of advanced fabrication approaches is being developed to address the specific challenges and opportunities of 4D printing, particularly in biomedical applications. These emerging techniques can be categorized into two groups: (1) novel printing technologies that offer new paradigms for material deposition or structuring, and (2) complementary fabrication strategies that enable the creation of complex, functional, and biologically relevant constructs essential for 4D bioprinting.

These advanced techniques are often integrated with novel printing platforms, such as volumetric, ultrasonic, and high-fidelity multi-material systems, to overcome existing limitations in speed, resolution, and biocompatibility. Concurrently, several advanced biofabrication strategies are increasingly critical for biomedical 4D printing. FRESH (Free-form Reversible Embedding of Suspended Hydrogels) is an embedded-printing method that deposits soft hydrogels within a
<figure><img src="image_22.png" /><figcaption>**Fig. 20.** Post-cured net-shaped components fabricated with 3D printing and various powder processing techniques. (a) Ni-Mn-Ga powders produced through spark erosion in liquid nitrogen. (b) Ni-Mn-Ga products obtained via spark erosion in liquid argon. (c, d) Ball-milled Ni-Mn-Ga products used for material processing. (e-h) Sintered net-shaped components manufactured from ball-milled Ni-Mn-Ga powders [269]. (i-k) BJ-fabricated 3D-printed components demonstrate the potential of this technique for the food industry [367]. (l) Illustration of composite compression samples: The top row shows the printed specimens, and the bottom row displays the parts fabricated with Agilus30 matrix via MJ, embedded with VeroMagentaV particles. The geometries include spherocylindrical, spherical, 45° ellipsoidal, XY ellipsoidal, XYZ ellipsoidal, 90° ellipsoidal, and pure Agilus30 structures [368].</figcaption></figure>

thermoreversible support bath, enabling freeform fabrication of low-modulus, cell-compatible materials (e.g., collagen/alginate/fibrin) that would otherwise collapse during printing [369,370]. Sacrificial (fugitive) printing provides a route to create complex internal voids and perfusable networks by printing a removable template (e.g., carbohydrate-glass lattices) or fugitive inks (e.g., Pluronic F127) that are later evacuated to form channels within hydrogel matrices, which is particularly valuable for vascularized or transport-enabled constructs [371,372]. Finally, scaffold-free (cell-only) bioprinting assembles tissue constructs from cellular aggregates/spheroids (e.g., the Kenzan approach), relying on spheroid fusion and maturation rather than a permanent hydrogel carrier; this “living” fabrication route can complement 4D concepts by enabling time-dependent remodeling and functional evolution of printed tissues [373,374].

Across these emerging methods, the common 4D-enabler is the ability to pattern responsive chemistries (or living components) in 3D while preserving soft-matter fidelity, thereby converting controlled stimuli exposure (thermal, acoustic, optical, chemical, or cellular forces) into predictable morphing or functional change over time.

### 4.6.1. Volumetric Printing

Volumetric printing, exemplified by the CAL technique, is a novel additive manufacturing approach that abandons traditional layer-by-

layer deposition in favor of curing entire 3D geometries simultaneously [375]. This method operates on tomographic principles: a digital projector shines a series of precisely calculated 2D light patterns into a rotating cylinder of photosensitive resin, analogous to a CT scan in reverse [376]. As the resin rotates, each voxel receives a controlled cumulative dose of light, and once the local energy exceeds a polymerization threshold the liquid solidifies at that point, yielding the complete structure concurrently rather than by layered increments [375,376]. Freed from the constraints of layer-by-layer deposition, CAL can dramatically increase fabrication speed and geometric complexity while eliminating the need for support scaffolds and minimizing anisotropy in mechanical properties [377]. Early demonstrations achieved print times on the order of mere minutes for centimeter-scale objects with continuous, smooth surfaces devoid of stair-step artifacts, although the attainable feature resolution (approximately 0.3 mm in the initial study) remains coarser than that of microscale lithography techniques) [375,378].

In their seminal study, Kelly et al. [375] applied CAL to fabricate complex structures in both a conventional acrylate polymer and a biologically relevant hydrogel, underscoring the method's versatility for biomedical 4D printing. Notably, they volumetrically printed GelMA hydrogel constructs – a common tissue-engineering matrix – achieving intricately detailed yet exceptionally smooth architectures without any
<figure><img src="image_23.png" /><figcaption>**Fig. 21.** (a) Schematic of the CAL system used for volumetric printing process in addition to printed samples [375]. Demonstration of DAVP for diverse biomedical 4D printing applications using ultrasonic energy: (b, c) LAA closure in a goat heart showing real-time printing and post-print deformation. (d, e) Bone defect reconstruction beneath 10-mm-thick tissue using nanocomposite fillers, with ultrasound imaging of defect and repair. (f, g) Targeted chemotherapy in porcine liver via sono-ink hydrogels, with visual and fluorescence confirmation of localized drug delivery [379].</figcaption></figure>

layering or support structures. The CAL process produced these soft, centimeter-scale hydrogel objects in just 30–120 s, with minimum feature sizes on the order of a few hundred microns (~300 µm), dramatically outpacing traditional bioprinting in speed while preserving fine structural fidelity. Furthermore, CAL enables unique multi-material capabilities, such as printing new material around pre-existing components – “encasing” an object within the printed volume – in a single fabrication step. Such advances suggest profound potential for 4D biomedicine: volumetric printing can rapidly create complex, functional structures (e.g. patient-specific implants or embedded device-scaffold assemblies) in biofriendly materials, offering unprecedented speed and design freedom for next-generation biomedical applications [376,378]. Fig. 21a shows the volumetric printing process and a printed sample.

### 4.6.2. Ultrasonic Printing

Ultrasonic printing harnesses, focused, high-frequency acoustic waves to pattern and solidify materials in three dimensions without

direct contact. In this technique, a focused ultrasound transducer delivers intense pressure oscillations into a liquid precursor, concentrating energy at a small focal zone (~0.3–0.7 mm) to induce localized polymerization of a specially formulated “sono-ink” via sono-thermal and cavitation effects [379]. A key advantage of ultrasonic printing is its ability to penetrate optically opaque media and print structures at centimeter-scale depths far beyond the reach of light-based methods [380]. This deep, noninvasive volumetric printing approach enables in situ fabrication within biological tissues, eliminating the need for layer-by-layer construction and allowing seamless 3D architectures with smooth surfaces. Moreover, recent developments in sono-ink formulations, such as PEGDA combined with rheology modifiers and acoustic absorbers like PNIPAm, have enabled faster sonothermal gelation (within seconds) and reduced acoustic streaming, thereby enhancing voxel precision and material confinement [380,381]. However, the method requires tailored viscoelastic inks that respond favorably to acoustic exposure to mitigate disruptive streaming, and the achievable
feature resolution is currently limited to the sub-millimeter scale by acoustic diffraction. Additional technical challenges include ROS quenching during cavitation-based crosslinking and managing localized overheating, which has motivated the development of confocal ultrasound systems with intersecting focal zones to improve safety and print fidelity in biological tissues [380].

One landmark study demonstrated the biomedical potential of ultrasonic 4D printing by developing a deep acoustic volumetric printing system with a self-enhancing sono-ink. Kuang et al. [379] designed a phase-transition sono-ink containing acoustic absorbers and thermal radical initiators such that a focused 3.41 MHz ultrasound beam could trigger localized polymerization of acrylate oligomers at the focal point. Using this contactless approach, complex hydrogel and nanocomposite structures were printed at depths up to ~64 mm, with each acoustic voxel on the order of 0.5 mm, even through opaque tissue-mimicking media. The printed GelMA-based hydrogels maintained high cell compatibility, supporting >99% viability of mammalian cells seeded on their surfaces post-fabrication. Notably, the acoustic printing could be performed through excised biological tissue, foreshadowing minimally invasive in-vivo bioprinting; the authors highlighted that centimeter-deep constructs were achieved without a physical scaffold or optics, paving the way for direct printing of implants inside the body. This demonstration of ultrasonic 4D printing underscores its feasibility for

creating patient-specific tissue scaffolds and devices in situ with fine control and minimal collateral damage. Fig. 21(b-g) shows the application of DAVP for 4D bioprinting in complex anatomical environments, including heart closure, subcutaneous bone repair, and targeted drug delivery.

### 4.6.3. *Multi-material Printing*

Multimaterial 4D printing refers to additive fabrication that incorporates two or more distinct inks within a single construct, often using multiple printheads or multi-vat systems to deposit different materials in prescribed regions [382]. The resulting heterogeneous architectures can more closely replicate the complexity of native tissues and integrate diverse functionalities; for example, a 4D-printed implant with a biomimetic multi-material design can provide a time-dependent, programmable dynamic microenvironment that promotes cell activity and tissue regeneration in response to external stimuli [382]. Furthermore, combining materials with distinct stimuli-responsive properties enables programmed multi-phase shape transformations (e.g., one region swelling while another stiffens) that are difficult to achieve with single-material prints [382]. Fig. 22 presents various multimaterial 3D bioprinting mechanisms.

However, this added complexity introduces technical challenges: using a shared nozzle or vat for different inks raises cross-contamination

<figure><img src="image_24.png" /><figcaption>**Fig. 22.** Schematic overview and categorization of various multimaterial 3D bioprinting methods widely employed in creating heterogeneous structures for tissue engineering purposes [382].</figcaption></figure>
risks, interfaces between dissimilar materials may develop defects or weak bonding, and coordinating multiple shape-changing components with different activation triggers is inherently challenging. These limitations necessitate advanced printer designs (e.g., separate or coaxial dispensing systems) and carefully tuned material interfaces, as well as rigorous optimization to ensure that each material cures and functions as intended in the composite 4D construct.

## 4.7. Review

Biomedical 4D printing is more than “printing a shape.” The fabrication route also decides how the responsive behavior is programmed, where active materials go, what gradients or anisotropy are encoded, and whether sensitive cargos such as cells, drugs, and bioactive cues can survive. For this reason, different printing platforms are best compared by what kind of 4D function they can reliably build and activate, not only by resolution or speed.

Material extrusion (FDM/DIW) offers broad material freedom and straightforward routes to encode 4D behavior through print-path anisotropy and multi-material architectures. FDM is most effective for thermo-responsive SMP-based deployable devices and self-fitting scaffolds where post-print programming (deform-fix-recover) is performed before use. DIW is particularly central to biomedical 4D/bioprinting because it can process shear-thinning, cell-compatible hydrogel inks and directly build bilayers/gradients that later morph by swelling, ionic exchange, or degradation-mediated stress relaxation. The trade-offs remain resolution limits (especially for fine vascular features), sensitivity to rheology-driven variability, and the need for robust crosslinking strategies that preserve cell viability while maintaining actuation fidelity.

Powder bed fusion (SLS/SLM/EBM) is strong where mechanical integrity and lattice design dominate, enabling 4D through (i) SMP elastomer powders (thermally activated recovery) and (ii) SMA implants where phase transformation yields deployment/superelasticity. However, high thermal budgets prohibit direct inclusion of cells/drugs, pushing biomedical 4D implementations toward post-processing (heat treatment, surface modification, secondary coatings/hydrogel layers) and rigorous control of porosity-related defects that can degrade fatigue life under physiological cycling.

Vat photopolymerization (SLA/DLP/MPP/CLIP) supports high-resolution, smooth-surface constructs, making it attractive for micro-structured drug-delivery devices and fine-featured scaffolds. Its distinctive 4D advantage is network-level programmability: crosslink gradients, multi-vat chemistries, and photothermal/magnetothermal composites can localize activation and produce controlled morphing or release. The key biomedical constraint is chemistry control, residual monomers/initiators, extraction protocols, and sterilization compatibility often govern cytocompatibility and long-term stability more than geometry does.

Material jetting provides droplet/voxel-level multi-material placement, which can be used to encode hinges, modulus gradients, and differential swelling domains for time-dependent morphing. Its biomedical translation is largely limited by resin availability and support-removal/residual management, but where suitable resin systems exist, MJ can enable highly integrated, multi-functional 4D parts.

Binder jetting excels in scalable fabrication of porous, architected substrates (ceramics/metals/polymers) and becomes “4D-relevant” in biomedicine when time-dependent behavior arises from controlled degradation, porosity evolution, or post-infiltration/functionalization with responsive phases. Thus, BJ is often best viewed as a manufacturing backbone that can be combined with secondary responsive layers to achieve actuation or on-demand release.

Emerging approaches (CAL, ultrasonic printing, embedded/FRESH, sacrificial printing, and cell-only bioprinting) expand biomedical 4D capabilities by preserving soft-matter fidelity, enabling rapid fabrication, supporting complex internal networks, and, in the case of

ultrasonic approaches, opening routes to deep, non-contact or in situ fabrication. Their current barriers are typically material-specific (ink design, initiator chemistry), physics-limited resolution (optical/acoustic constraints), and process control for repeatable actuation.

Overall, no single platform is universally optimal; biomedical 4D printing is most effectively treated as a coupled design-materials-process problem, where the chosen technique must simultaneously support (i) the desired stimulus-response mechanism, (ii) spatial encoding of time-dependent behavior, and (iii) biomedical constraints on viability, safety, and reproducibility. Ultimately, each technique presents a unique balance of capabilities and limitations, and their judicious integration or hybridization will define the trajectory of advanced 4D biofabrication. A comprehensive side-by-side overview is provided in Table 5.

## 5. Conclusion, Challenges, and Opportunities

4D printing emerged as a promising technology for biomedical applications, offering the ability to create dynamic structures that can change their shape, properties, and functionality with time. This technology has the potential to revolutionize such fields as tissue engineering, drug delivery, and biomedical devices. By incorporating time as the fourth dimension, 4D printing enables the development of structures that can mimic the behavior of natural tissues and actively respond to physiological conditions. The application of 4D printing in drug delivery systems holds great promise for personalized medicine. Smart drug delivery systems can be created to release medications in a controlled manner in response to specific triggers or conditions in the body, improving the efficacy and safety of drug therapies. In tissue engineering, 4D printing techniques offer the opportunity to fabricate customized scaffolds and implants that can adapt and conform to changing anatomical conditions or patient-specific needs. This can lead to improved integration with the surrounding biological environment and enhanced tissue regeneration.

Furthermore, the use of 4D printing in biomedical devices allows the fabrication of complex structures with dynamic functionalities. Implants and prosthetics can be designed to actively respond to physiological conditions, providing better comfort and performance for patients. With these advancements come significant challenges that must be addressed for 4D printing to reach its full potential. Fig. 23 provides an overview of challenges in 4D printing for biomedical applications.

### 5.1. Material Limitations

One of the primary challenges in 4D printing is the development of suitable materials that can respond predictably and reliably (and in many cases – repeatedly) to stimuli. Such materials, known as smart materials, must have properties such as shape memory, self-healing, and adaptability to external conditions. However, the current choice of materials is limited, and their behavior under prolonged or repeated stimuli can be unpredictable. For example, hydrogels, such as PEG-based ones, are often used in 4D printing for their ability to swell in response to moisture but can suffer from low response times and instability under multiple cycles. Similarly, while offering robust mechanical properties, SMPs such as PLGA and SMAs such as nitinol can be expensive and challenging to process, especially to achieve reversible transformations. Consequently, among these challenges, biocompatibility, degradation rates, and the limited availability of responsive polymers are particularly critical.

#### 5.1.1. Biocompatibility

Biocompatibility is a cornerstone requirement for materials intended for biomedical applications. Examples of biocompatible materials include gelatin-based hydrogels, PCL, and silk fibroin, which showed promise in scaffolds and implants. The ability of a material to integrate seamlessly with biological systems without eliciting adverse immune responses is essential for applications such as implants, drug delivery
<table><caption>**Table 5**

Overview of 3D/4D printing techniques: principles, materials, printed specimens, advantages, and disadvantages.</caption><thead><tr><th>3D/4D printing technique</th><th>Printing principle</th><th>Typical polymer materials</th><th>Examples of printed specimens</th><th>Typical biomedical Applications</th><th>Advantages</th><th>Disadvantages</th></tr></thead><tbody><tr><td>MEX</td><td>Material is extruded through a heated nozzle and deposited layer by layer</td><td>Thermoplastics (polycarbonates, PETG, PLA, ABS and nylon)</td><td>(a)<br>(b)<br>30 mm</td><td>(a) Tracheal stents [383]. (b) Biocompatible scaffolds [384].</td><td>- Cost-effective<br>- Wide material availability (color printing)<br>- Easy to use</td><td>- Rough surface finish<br>- Limited by nozzle diameter resolution<br>- Nozzle clogging</td></tr><tr><td>PBF</td><td>Powdered material is selectively fused by heat or laser, layer by layer</td><td>Nylon, PA, PEEK, PA12, and polystyrene</td><td>(a)<br>(b)<br>10 mm</td><td>Cranial implant [385]</td><td>- Strong, durable parts<br>- Complex geometries achievable<br>- Support not required</td><td>- High cost<br>- Surface finish requires post-processing</td></tr><tr><td>VP</td><td>UV light selectively cures liquid photopolymer resin layer by layer</td><td>Epoxy, acrylic, photopolymers</td><td>(a)<br>(b)<br>Recovered Shape</td><td>Tracheal stent [221]</td><td>- High precision and detail<br>- Smooth surface finish</td><td>- Limited to photopolymers<br>- Post-processing required</td></tr></tbody></table>

<figure><img src="image_25.png" /></figure>

<figure><img src="image_26.png" /></figure>

<figure><img src="image_27.png" /></figure>

(continued on next page)
<table><caption>**Table 5 (continued)**</caption><thead><tr><th>3D/4D printing technique</th><th>Printing principle</th><th>Typical polymer materials</th><th>Examples of printed specimens</th><th>Typical biomedical Applications</th><th>Advantages</th><th>Disadvantages</th></tr></thead><tbody><tr><td>MJ</td><td>Droplets of photopolymer material are deposited and cured layer by layer</td><td>Acrylate-based photopolymers, poly-jet materials</td><td><img src="image_1.png" alt="Example of 3D printed object: a mesh-like structure with some areas of high detail and some areas of low detail."><br><img src="image_2.png" alt="Example of 3D printed object: a shoe sole with a lattice pattern and some areas of high detail and some areas of low detail."><br><img src="image_3.png" alt="Example of 3D printed object: a pair of shoes with a lattice pattern and some areas of high detail and some areas of low detail."></td><td>(a) Lattice tracheal stent, and (b) shoe sole [386]</td><td>- High accuracy and smooth finish<br>- Multi-material printing</td><td>- Expensive machinery<br>- Limited material range<br>- Support required<br>- Unsuitable for structural use</td></tr><tr><td>BJ</td><td>Liquid binder selectively bonds layers of powder material</td><td>Sand and ceramics + bonding agents</td><td><img src="image_1.png" alt="Example of 3D printed object: a mesh-like structure with some areas of high detail and some areas of low detail."><br><img src="image_2.png" alt="Example of 3D printed object: a pair of shoes with a lattice pattern and some areas of high detail and some areas of low detail."></td><td>(a) Partial denture framework [387].<br>(b) Monetite blocks [388].</td><td>- Low cost<br>- No heat required during printing<br>- High production speed<br>- Support not required</td><td>- Requires post-processing (infiltration or sintering)<br>- Weak mechanical properties<br>- Shrinkage</td></tr><tr><td>Volumetric Printing</td><td>- Projected tomographic light patterns cure resin in a rotating volume<br>- Entire 3D geometry is solidified in a single step</td><td>- PEGDA<br>- Acrylate-based resins<br>- GelMA</td><td><img src="image_1.png" alt="Example of 3D printed object: a mesh-like structure with some areas of high detail and some areas of low detail."><br><img src="image_2.png" alt="Example of 3D printed object: a pair of shoes with a lattice pattern and some areas of high detail and some areas of low detail."><br><img src="image_3.png" alt="Example of 3D printed object: a pair of shoes with a lattice pattern and some areas of high detail and some areas of low detail."></td><td>(a) A highly complex dental model. (b) Complex lattice geometry with fine features as small as 0.3 mm and internal voids [375].</td><td>- Ultra-fast printing (30–120 s)<br>- No layer-by-layer artifacts<br>- Support-free printing<br>- Can encase existing components</td><td>- Limited resolution (~300 µm)<br>- Requires optically transparent, low-viscosity resins<br>- Complex calibration and reconstruction algorithms</td></tr></tbody></table>

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<table><caption>**Table 5 (continued)**</caption><thead><tr><th>3D/4D printing technique</th><th>Printing principle</th><th>Typical polymer materials</th><th>Examples of printed specimens</th><th>Typical biomedical Applications</th><th>Advantages</th><th>Disadvantages</th></tr></thead><tbody><tr><td>Ultrasonic Printing</td><td>- High-frequency ultrasonic vibrations and moderate pressure<br>- Bonding of layered thin foils without melting (solid-state process)</td><td>- Thermoplastic elastomers<br>- TPU<br>- Hybrid elastomer-metal composites</td><td>(a) Tissue<br>(b) Printout</td><td>(i) Tissue phantoms and (ii) 3D-printed models were used for (a) a lattice under porcine liver and (b) a heart-shaped model under porcine kidney [379].</td><td>- Low-temperature processing<br>- Enables metal-polymer integration<br>- Suitable for embedding electronics<br>- High bonding strength without melting</td><td>- Limited to thin foil/laminate feedstocks<br>- Complex equipment alignment<br>- Surface finish may require post-processing<br>- Not suitable for bulk 3D geometries</td></tr><tr><td>Multi-material Printing</td><td>- Simultaneous or sequential deposition of multiple materials<br>- Utilizes inkjet, extrusion, or DLP systems with switching/nozzle control</td><td>- PEGDA-based resins<br>- Hydrogels (e.g., agarose, alginate)<br>- Elastomers with differential swelling/stiffness</td><td>1mm<br>1mm<br>1mm</td><td>Soft tissue mimics and bioinspired motion devices [389].</td><td>- Enables spatial control of function<br>- Combines soft and stiff regions in one print<br>- Ideal for anisotropic actuation<br>- Versatile across printing platforms</td><td>- Requires precise calibration and synchronization<br>- Interface adhesion challenges<br>- Slower print speeds with complex setups<br>- Limited compatible ink/resin combinations</td></tr></tbody></table>

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systems, and tissue scaffolds. As an example, chitosan-based hydrogels are widely studied for their antimicrobial properties and compatibility with cellular growth [390–392]. However, many stimuli-responsive materials currently used in 4D printing, such as SMPs and hydrogels, often lack sufficient biocompatibility. For instance, PNIPAM-based hydrogels showed limited biocompatibility because of their cytotoxic degradation products [393]. Similarly, SMPs such as PLA-based blends face challenges related to protein adsorption and inflammatory reactions [394,395]. Efforts to mitigate these issues include the use of bioactive peptide coatings, such as RGD peptides, which enhance cell adhesion, and plasma-treated surfaces that reduce cytotoxicity and improve protein compatibility. Methods to enhance biocompatibility not only involve the development of inherently non-toxic polymers but also the application of bioactive coatings or surface modifications to promote cellular interactions and tissue integration [396–399]. Tissue scaffolds produced with 4D printing often require materials with high biocompatibility. For example, scaffolds for cartilage repair can cause inflammatory responses due to insufficient biocompatibility of synthetic polymers such as PNIPAM-based hydrogels, hindering their integration with surrounding tissues.

### 5.1.2. Degradation Rates

Controlled degradation is another crucial attribute of materials used in biomedical 4D printing, particularly for applications requiring temporary implants or scaffolds for tissue regeneration. Ideally, materials

should degrade at a rate that aligns with the healing or regeneration process while avoiding premature failure or long-term persistence in the body [400,401]. For instance, PGA was successfully used in sutures thanks to its predictable degradation rates, while PLA is frequently employed in tissue scaffolds [402]. The degradation of PLA in physiological environments is governed by multiple mechanisms, including hydrolysis and biological interactions, making it a complex and sensitive process [403]. Another example is PHB, which offers excellent biodegradability and is explored for drug delivery systems [404]. Furthermore, degradation products must be non-toxic and easily metabolized or excreted by the body. Current research efforts are directed at tailoring polymer chemistry to fine-tune degradation kinetics, often by manipulating crosslinking density or introducing labile bonds that respond to specific stimuli [405]. Hybrid materials, such as PLA-PCL or PLA-PHB blends, are also developed to achieve optimized degradation profiles [406,407]. Drug delivery systems based on 4D printing require precise degradation rates to release therapeutic agents over time. Materials such as PHB sometimes degrade too quickly or slowly, disrupting the intended dosage and timing of drug release [408,409].

### 5.1.3. Limited Availability of Responsive Polymers

The availability of responsive polymers tailored for 4D printing is another significant bottleneck. While advances in polymer science introduced materials capable of responding to stimuli such as temperature, pH, light, or magnetic fields, the choice of such materials remains
<figure><img src="image_36.png" /><figcaption>Fig. 23. Overview of 4D printing challenges, especially in biomedical applications.</figcaption></figure>

limited compared to the diverse demands of biomedical applications. Examples include PNIPAM for temperature sensitivity [410], alginate hydrogels for pH responsiveness [411], and LCEs for light sensitivity [412]. For instance, most temperature-responsive materials operate within ranges unsuitable for human physiological conditions, while pH-sensitive polymers such as PAA often lack the stability required for long-term applications [234,413,414]. Additionally, the mechanical properties of these materials must strike a delicate balance between flexibility, strength, and durability to meet the functional requirements of devices such as stents, sutures, and prosthetics. Multi-responsive materials, such as cellulose-based hydrogels that combine thermal and pH responsiveness, represent an exciting frontier [415]. The synthesis of novel multi-responsive polymers, such as dual-stimuli hydrogels that respond to both pH and temperature, represents a promising avenue for future research [416]. These innovations have the potential to address existing challenges and expand the scope of biomedical applications. Stents fabricated with 4D printing often rely on responsive polymers to adapt to physiological conditions. The limited availability of multi-stimuli polymers can hinder the performance of these devices, reducing their ability to effectively respond to temperature and pH fluctuations.

### 5.1.4. Future Opportunities

One promising direction is the development of next-generation bio-materials that integrate bioactive components, such as growth factors or antimicrobial agents, directly into polymer matrices. These innovations could improve biocompatibility by promoting cellular interactions and reducing inflammatory responses. Advances in nanotechnology may also enable the creation of nanostructured surfaces mimicking natural extracellular matrices, enhancing cellular behavior and integration. Moreover, ML and AI could revolutionize material design by predicting

and optimizing biocompatibility before experimental testing, accelerating discovery and reducing costs. In addition, AI and ML are expected to accelerate progress in 4D printing by enabling data-driven materials discovery and inverse design. In materials development, ML models trained on formulation-property datasets can rapidly screen candidate polymers, hydrogels, and composites for target requirements, reducing experimental trial-and-error. Beyond screening, inverse-design workflows can couple generative design or multi-objective optimization with surrogate (ML) models to identify printing architectures and composition gradients that achieve a prescribed shape-morphing trajectory, actuation window, and mechanical response. Such approaches are particularly valuable for multi-material 4D systems, where the design space (chemistry × geometry × processing) is too large for exhaustive experimental exploration.

To address the degradation challenges, researchers are exploring bio-inspired materials that emulate the dynamic properties of natural tissues. For instance, enzymatically degradable components integrated into polymer networks offer more predictable degradation in specific biological environments. Additionally, materials with adjustable degradation properties, controlled by external stimuli such as light or heat, provide real-time adaptability to varying physiological conditions. Biodegradable nanoparticles, introduced as reinforcement agents, can improve both mechanical stability and controlled degradation of medical devices.

Future advancements in responsive polymers could include multi-stimuli materials capable of adapting to complex biological environments. The use of biohybrid polymers, combining synthetic and natural components, may yield superior mechanical and responsive properties. Collaborative efforts between materials scientists and computational modelers can accelerate the development of such polymers, employing
high-throughput computational tools to simulate and predict material behaviors. Furthermore, sourcing sustainable materials, such as polymers derived from renewable biomass, could address environmental concerns while meeting functional demands.

In addition, the development of hybrid materials by adding nano-particles with additional properties such as magnetism (e.g., Fe₃O₄, γ-Fe₂O₃, or NdFeB) or electrical induction (e.g., carbon-based nano-particles including graphene, carbon nanotubes, and conductive polymers), when combined with degradable matrices, enzymatic sensitivity, and bioactive cues, represents an emerging paradigm. Such synergistic designs aim to create smart materials with adaptive, bio-interactive, and programmable behavior, far beyond the scope of traditional composite systems. This trend is expected to further expand the potential applications of 4D printing in biomedical fields, allowing more precise control over material behavior and enabling advanced therapeutic or diagnostic capabilities.

## 5.2. Scalability & Manufacturing

Another significant challenge lies in the integration of smart materials into existing AM processes. Most 3D printing techniques, such as FDM and SLA, were not originally designed to deal with the complexities of 4D printing. These processes need to be adapted to accommodate the unique requirements of 4D printing, such as precise control over material placement and the ability to apply stimuli during (or after) the printing process. Additionally, the development of multi-material printers capable of printing with various smart materials simultaneously remains a critical hurdle. The lack of commercially available printers that can effectively handle such materials limits the scalability and widespread adoption of 4D printing technologies. Beyond laboratory-scale demonstrations, scalability is also constrained by the limited availability of standardized, cost-effective smart feedstocks and by the added activation/post-processing steps often required to program or trigger 4D behavior.

### 5.2.1. Precision in Complex Shapes

Fabrication of intricate geometries with smart materials requires advanced AM techniques capable of maintaining high resolution and material functionality. For instance, hydrogels used in SLA often suffer from shrinkage or warping during photopolymerization, leading to deviations from the intended shapes [417]. This is particularly problematic for such applications as vascular scaffolds, where precise dimensions are critical for functionality. Similarly, FDM with SMPs can encounter issues with uneven thermal distribution, resulting in weak inter-layer adhesion and compromised structural integrity [418]. Addressing these challenges may involve a precise definition of process parameters, such as optimizing hydrogel curing times or employing controlled cooling systems in FDM. Vascular scaffolds used in 4D printing applications often fail to achieve the necessary resolution and structural integrity due to these limitations, reducing their effectiveness in biomedical use. For vat-based scale-up specifically, maintaining fidelity over larger build areas typically requires improved exposure uniformity/optics and resin chemistries that reduce shrinkage while preserving toughness, including dual-curing strategies that combine photopolymerization with a secondary thermal/chemical cure [419].

### 5.2.2. Reproducibility

Ensuring consistent performance across multiple 4D-printed structures is essential for biomedical applications. However, factors such as variations in raw-material properties, environmental conditions during fabrication, and post-processing inconsistencies often lead to performance variability. For example, batch-to-batch differences in formulations of SMPs can alter their shape-memory behavior [420,421], while fluctuations in humidity during the printing of alginate hydrogels were shown to impact their swelling properties [422–424]. Inconsistent mechanical properties in printed bone scaffolds were also reported as a

result of uneven crosslinking of photopolymerizable resins [425,426]. Real-time monitoring systems equipped with sensors to detect deviations in printing conditions can play a vital role in mitigating these issues. ML algorithms could further enhance reproducibility through prediction and compensation for potential errors during the fabrication process. Bone scaffolds created with 4D printing often exhibit inconsistencies in mechanical properties, limiting their reliability for clinical applications.

### 5.2.3. High Production Costs

The high cost of materials and specialized equipment represents a significant barrier to the widespread adoption of 4D printing. Responsive polymers, such as dual-stimuli hydrogels or LCEs, are often expensive to synthesize, requiring complex chemical processes and high-purity precursors. Additionally, the manufacturing equipment tailored for multi-material and multi-functional 4D printing commands a premium, limiting its accessibility. For instance, the integration of SMPs into multi-material inkjet printers requires precise temperature control systems, which add to operational costs [427]. Efforts to develop cost-effective alternatives, such as hydrogels derived from renewable sources such as alginate or cellulose, offer a promising solution [428]. Furthermore, implementing recycling strategies in the AM workflow could reduce material waste and overall expenses [429]. Drug delivery systems produced with 4D printing are often affected by high material and equipment costs, limiting their scalability and affordability in healthcare applications [430].

### 5.2.4. Future Opportunities

To address these challenges, hybrid AM systems that combine complementary techniques offer significant potential. For example, combining SLA for structural accuracy with inkjet printing for precise material deposition can enhance both precision and material functionality. Another promising direction is the development of digital twins for AM processes, enabling virtual simulations to optimize the printing parameters before actual fabrication. Additionally, breakthroughs in scalable material synthesis, such as enzymatic polymerization methods, could reduce production costs while maintaining high-quality outputs. From an industrialization perspective, expanding material libraries compatible with scalable platforms (e.g., responsive composites and elastomeric systems) and adopting print strategies that shorten cycle time (including continuous/rapid curing approaches) are expected to be key enablers for translating 4D printing toward higher-throughput manufacturing [419].

## 5.3. Mechanical & Functional Stability

The mechanical and functional stability of 4D-printed biomedical structures is crucial to ensure their long-term performance and clinical viability. These structures must maintain their integrity under physiological conditions, which include exposure to dynamic loads, environmental stresses, and prolonged interaction with biological systems. This section explores key challenges, such as long-term mechanical performance, fatigue resistance, and innovative strategies to enhance stability.

Researchers actively explore new material combinations and structural designs to enhance the stability of 4D-printed devices [323,431]. One promising approach involves the use of self-healing polymers, which can autonomously repair microcracks and extend the device's operational lifespan. For instance, SMPs with embedded microcapsules containing healing agents demonstrated their ability to restore functionality after mechanical damage, proving beneficial in high-stress biomedical applications [432,433].

Biomimetic approaches also offer significant potential. Hierarchical structures inspired by natural materials such as bones or nacre provide enhanced mechanical stability and functional adaptability [434–436]. For example, layered composite structures mimicking the bone architecture were developed for load-bearing implants, demonstrating
superior mechanical performance and biological integration [437]. Load-bearing implants, such as orthopedic supports, often fail to meet the required durability without the incorporation of such biomimetic designs, leading to complications in long-term use.

### 5.3.1. Long-term Performance of Printed Structures

4D-printed devices such as implants and tissue scaffolds must withstand extended periods of physiological stress without compromising their functionality. For instance, cardiovascular stents manufactured from SMAs, including nitinol, are exposed to continuous pulsatile blood flow, necessitating exceptional mechanical durability [438]. Research showed that surface treatments, such as electrochemical polishing, can significantly enhance the fatigue life of Nitinol stents, reducing the risk of mechanical degradation [439–441].

Hydrogels used in applications, including soft-tissue engineering, face additional challenges due to their inherent susceptibility to dehydration and structural weakening with time. Strategies such as the inclusion of reinforcing agents such as graphene oxide or the use of double-network hydrogels demonstrated improved mechanical resilience and prolonged functionality. For example, double-network hydrogels were successfully applied in cartilage replacements, offering enhanced compressive strength and resistance to wear [442–444]. Cartilage replacements based on these hydrogels are particularly vulnerable to long-term weakening if structural stability is not optimized, limiting their clinical effectiveness.

### 5.3.2. Fatigue Resistance Under Physiological Conditions

Fatigue resistance is another critical factor, particularly for devices subjected to repetitive loading cycles. Repeated mechanical stresses can induce microcracks or creep, ultimately compromising the structural and functional integrity of printed devices. SMP-based bone scaffolds, for instance, showed susceptibility to fatigue failure under cyclic compressive loads [445]. To address this, researchers developed SMP composites reinforced with CNTs or glass fibers, which improve both fatigue resistance and overall mechanical properties [298,446,447].

Additionally, hydrogels used in joint replacements or load-bearing tissues require exceptional resistance to mechanical fatigue. For example, alginate-based hydrogels combined with calcium phosphate demonstrated enhanced load-bearing capabilities and improved fatigue resistance, making them suitable for applications in osteochondral tissue engineering [448,449]. Joint replacements produced with these hydrogels often experience premature failure if fatigue resistance is not adequately addressed, impacting their longevity and patient outcomes.

### 5.3.3. Future Opportunities

Advances in computational modeling and simulation tools offer transformative opportunities for the prediction of material behavior under diverse physiological conditions. Techniques such as FEA enable the optimization of structural designs for 4D-printed devices, ensuring that they meet specific mechanical and functional requirements. In parallel, in vitro platforms that mimic dynamic physiological environments provide critical insights into the long-term performance and fatigue resistance of these structures before clinical deployment. Further innovation lies in hybrid materials that combine synthetic polymers with bioinspired reinforcements. For instance, the addition of hydroxyapatite nanoparticles into SMP scaffolds enhances their load-bearing capacity while maintaining biocompatibility.

Additionally, self-healing polymers present a novel approach by autonomously repairing microcracks, thus extending the device's lifespan. Biomimetic strategies, such as hierarchical structuring modeled on natural materials such as bones or cartilage, offer another way to improve mechanical stability and functional adaptability in biomedical applications. These advancements collectively drive innovation in 4D printing, expanding its impact on critical healthcare technologies.

Finally, AI/ML-enabled predictive modeling can complement mechanics-based simulations by providing fast surrogates for

computationally expensive analyses (e.g., coupled diffusion-swelling-mechanics, fatigue, and degradation). When integrated with experimental calibration, these models can form digital twins that forecast long-term performance under physiological conditions and guide design updates before fabrication.

## 5.4. Environmental Impacts

The environmental impact of 4D printing, particularly in biomedical applications, warrants comprehensive attention. As technology evolves, addressing issues related to the disposal of non-biodegradable components, sustainable material sourcing, and reduction of the environmental footprint of manufacturing processes is paramount to its long-term viability.

### 5.4.1. Disposal of Non-biodegradable Components

Many materials employed in 4D printing, such as certain synthetic SMPs and hydrogels, are not inherently biodegradable. This limitation poses significant environmental risks, particularly for single-use medical devices or temporary implants. Improper disposal of these materials can contribute to environmental pollution and the accumulation of non-degradable waste [450]. For example, PNPAM-based hydrogels are widely used for their temperature-responsive properties but lack biodegradability [451]. To mitigate this, researchers explore alternatives such as PLA-based SMPs [452] and chitosan-derived hydrogels [453], which decompose naturally under environmental conditions. Recent advances in cellulose-based hydrogels showed promise in temporary biomedical applications, offering a biodegradable and sustainable option that reduces long-term environmental impact [454]. Single-use medical devices, such as temporary implants for drug delivery, often exacerbate environmental pollution due to the use of non-degradable SMPs, highlighting the need for biodegradable alternatives.

### 5.4.2. Sustainable Material Sourcing

The reliance on petroleum-based precursors for many polymers contributes significantly to greenhouse gas emissions and resource depletion. To counteract this, sourcing sustainable materials is a critical focus. Plant-derived polymers, such as PLA, and microbial fermentation products, such as PHA, present renewable alternatives with lower environmental footprints [455]. For instance, lignin-derived SMPs, obtained as a byproduct of paper manufacturing, provide a promising solution for sustainable material production [456]. Additionally, waste-derived materials, such as recycled thermoplastics, are repurposed for the use of 4D printing, reducing the demand for natural resources. For example, waste eggshell-derived CaCO₃ has been used as a filler in PLA filament for material-extrusion AM, supporting circular sourcing of printable feedstocks [457]. Recycling strategies for unused or failed prints, such as re-melting thermoplastics or recovering monomers from degraded polymers, can further minimize material waste and enhance resource efficiency [458]. Tissue scaffolds and prosthetic devices prin ted with 4D techniques often rely on resource-intensive polymers, making the adoption of renewable and recycled materials critical for their sustainability.

### 5.4.3. Future Opportunities

Future advancements in 4D printing could significantly mitigate its environmental impact. One promising approach is the development of closed-loop manufacturing systems, where materials are designed for easy recycling and reuse without substantial loss of functionality. For instance, SMPs with reversible covalent bonds could enable material recovery and reprocessing. Additionally, advances in green chemistry, such as solvent-free polymerization techniques and the use of non-toxic catalysts, could produce high-performance materials with minimal environmental harm.

Incorporating life-cycle assessments into the design and manufacturing processes of 4D printing will be essential for the