Emerging 4D Fabrication of Tubular Structures and Clinical Challenges: Critical Perspective

Abstract

The burgeoning field of 4D fabrication holds transformative potential in fabricating dynamic, tubular structures such as artificial vascular grafts, stents, and nerve conduits. These are critical for cardiovascular, respiratory, and neurological applications. Traditional 3D printing, despite its advances, remains constrained by the static nature of its structures, often resulting in challenges such as improper vascular integration, restricted endothelialisation in small-diameter grafts, and complex surgical deployment requirements. This perspective delves into the novel integration of stimuli-responsive smart materials that imbue printed structures with the ability to morph, repair, and adapt to specific environmental stimuli, facilitating a more biocompatible and physiologically relevant interface. Highlighting recent breakthroughs in vascular graft fabrication, we discuss the strategic use of multimaterial printing to achieve endothelial compatibility and structural fidelity. Moreover, advancements in bifurcated stents and multichannel nerve conduits underscore the role of self-assembling and self-folding mechanisms in addressing anatomical and biomechanical complexities inherent in regenerative medicine. However, the translational trajectory of 4D bioprinting is impeded by persistent issues like material scalability, stimulus precision control, mechanical stability, and stringent biocompatibility standards. Future research should prioritize the refinement of multifunctional biomaterials and the development of composite, stimuli-responsive scaffolds equipped with biosensor functionalities to better mimic the dynamic biomechanics of native tissues. This review provides an in-depth analysis of these challenges and explores pathways toward the clinical adoption of 4D-printed, biomimetic tubular structures, aiming to bridge the gap between experimental innovation and clinical application.

1. Introduction

Human anatomy comprises complex tissue architectures, each defined by highly complex structural, mechanical, and kinetic properties, responsible for orchestrating distinct physiological functions and maintaining overall systemic homeostasis. To comprehend the intricate complexity of the diverse tissues and organs, Atala et al.’s classification includes: (i) flat tissues such as skin and cornea, (ii) tubular tissues like blood vessels and ureters, (iii) hollow organs such as the bladder, and (iv) complex solid organs like liver and kidney, each posing unique structural and fabrication demands. Tubular structures are fundamental to the functionality of essential organ systems, including the gastrointestinal, respiratory, excretory, cardiovascular, and urinary systems. Constructs such as blood vessels, stents, and nerve conduits are indispensable for sustaining physiological homeostasis by facilitating the regulated transport of fluids and gases throughout the body. Due to the rise in life expectancy and other diseases, people are falling sick and need replacement surgeries, due to which there is a serious need to develop tools and techniques that can manufacture such artificial/synthetic organs. Various advanced fabrication technologies, such as stretch molding, electrospinning, thermal phase separation, weaving techniques, and cross-linking of diverse material classes, have been employed in the development of such tubular structures to enhance their mechanical robustness, optimize structural fidelity, and improve both product stability and reproducibility across applications However, these methods cannot often precisely mimic complex biological architectures to achieve homogeneous cell distribution or facilitate long-term cellular integration. The emergence of tissue engineering has revolutionized the fabrication of these tubular structures by offering unprecedented design accuracy, customization, and complexity.

First, introduced by Charles Hull in 1980, 3D printing technology breathed new life into the tissue engineering sector, allowing to design and printing of structures layer-by-layer with extraordinary precision while lowering material waste and time. Several 3D printing techniques include Fused Deposition Modeling (FDM), which involves extruding thermoplastic materials in layers to form different shapes. Stereolithography (SLA) is a technique that utilizes a laser to cure liquid resin, providing high-resolution printing and accuracy. Direct ink Wwiting (DIW) is an extrusion-based method that uses bioinks composed of hydrogels and polymers. Despite the advantage of achieving advanced constructs with precise geometry, 3D-printed constructs are unable to closely mimic human tissues due to their rigid and fixed configurations. This implies that tubular structures, such as stents, nerve conduits, vascular blood vessel grafts, and airway scaffolds, often encounter issues related to improper fit and rigidity. For instance, 3D fabricated stents cause damage to blood vessels due to their rigid nature in vessel diameter or lack the ability to accommodate movement within the vasculature. Improper fit can lead to complications such as restenosis and inflammation. To overcome such issues, 4D printing techniques utilizing shape memory alloys (SMAs) and other smart materials have been developed to create precisely engineered, space-time-responsive products that can alter their properties when exposed to external stimuli such as pH, temperature, humidity, electrical signals, or ionic conditions. In 2013, Tibbits at MIT introduced the concept of “4D printing” through the shape-altering behaviors of 3D printed structures, with time being the fourth dimension added to the previous spatial dimensions.

The fundamental components of 4D printing include the 3D printing system, stimulus, stimulus-responsive materials, and mathematical modeling. , In general, the preparation of 4D materials typically involves key strategies such as utilizing stimuli-responsive smart materials employing multicomponent systems for improved functionality, and designing intricate infill patterns to achieve controlled, programmable shape transformations. Momeni and Ni outlined three core principles that regulate the shape-shifting mechanisms of all 4D-printed constructs. Smart polymers exhibit the unique capability to undergo shape deformations in response to specific stimuli, subsequently reverting to their original configuration upon activation in a precisely controlled manner. 4D printed tubular structures can show self-folding, self-repair, and programmed self-disassembly properties that remain unattainable with conventional 3D fabrication techniques. While several reviews have addressed 4D printing in general, including different smart materials, stimuli, and their properties or within specific biomedical domains, this perspective uniquely focuses on the fabrication, design strategies, and translational clinical challenges of 4D printed tubular structures, such as vascular grafts, stents, and nerve conduits. Emphasis is placed on the clinical translation roadmap, biomaterial selection intricacies, and recent fabrication strategies, offering a differentiated and application-driven viewpoint not previously consolidated in existing literature. Table provides a summary of smart materials, stimuli, fabrication methods, and characteristics of the structures discussed in this perspective.

1. Summary of Smart Materials, Stimuli, Fabrication Methods, and Characteristics of the 3D/4D Printed Constructs.

S. No	choice of materials	fabrication method	mechanism of 4D effects	properties & characteristic features	refs no.
1	gelatin methacrylamide (GelMA) and methacrylated hyaluronic acid.	3D self-forming, drying-driven shape morphing of hydrogel bilayers	differential swelling and drying induced residual stresses	•tunable diameters (50–500 μm),
				•adjustable wall thickness.
				•Y-shaped, biomimetic microvascular bifurcations
2	alginate and methylcellulose	extrusion-based 3D bioprinting, dual-component system	differential swelling and spatial patterning	•tunable mechanical strength,
				•T-shaped, perfusable bifurcated scaffold
3	polylactide-co-trimethylene carbonate (PLMC)	extrusion-based 3D printing, design-guided infill patterns	thermal (more than ∼37 °C)	•Young’s modulus ∼2 MPa,
				•self-rolled tubes of ∼6–10 mm diameter and 40 mm length
4	sodium alginate, collagen peptide, and endothelial progenitor cells	coaxial extrusion-based 4D printing in CaCl2 support	ionic cross-linking	•biomechanics matched to saphenous vein; 3–3.5 mm lumen.
				•achieved human-scale, perfusable, small-diameter grafts
5	alginate dialdehyde (ADA) and gelatin	extrusion-based 3D printing; with post UV curing	thermal activation near physiological temperature	•diameter of tubular structures: 2 to 15 mm
				•maximum flow velocity of 0.11 m/s, comparable to native blood vessels.
				•T-shaped, perfusable vascular bifurcation scaffold; customizable branching angles.
6	methacrylated polycaprolactone (PCL)	digital light processing (DLP)	thermally triggered shape recovery (T g ≈ 62 °C)	•high resolution (50 μm), fast recovery (<10 s) at body temp,
				•good recovery ratio (∼95%),
				•tunable stiffness via cross-linking density.
				•patient-specific tracheal stent with precise lumen conformity
7	β-cyclodextrin-grafted polycaprolactone (βCD-g-PCL) loaded with paclitaxel	extrusion-based 3D printing with UV light-assisted curing	thermal activation (transition temperature T m = 56.8 °C). To trigger drug release via diffusion	•initial drug release ≈29% in first 3 days then slow release for >30 days
				•small-diameter vascular stent with combined shape memory function and
				•localized antiproliferative drug delivery
8	polyurethrane	FDM 3D printing with kirigami-inspired folding geometry	thermal activation (≈50–60 °C),	•compact shape for delivery, expands to bifurcated form in <8 s
				•bifurcated stent for branched vessels, adaptable lumen geometry.
9	alginate (Alg) and methylcellulose (MC).	extrusion-based 3D printing	differential swelling upon immersion in aqueous medium at 37 °C	•eliminates need for surgical sutures; rapid folding (<10 s); minimizes intraoperative complexity
				•self-closing tubular nerve conduit enabling sutureless neurorrhaphy around severed nerves
10	poly(lactide-co-trimethylene carbonate) (PLATMC)	electrospinning to produce aligned and random by thermal programming	thermal activation at 37–40 °C	•tube diameters: small tubes (0.6 mm) and large tubes (2 mm)
				•shape recovery time: 12 s for small tubes, 25 s for large tubes at 37 °C
				•multichannel conduit mimicking nerve fascicle architecture, promotes oriented axonal regeneration, delivers electrical cues for enhanced repair

2. 4D Fabrication of Tubular Structures

2.1. Vascular Grafts

Conventional vascular grafts, spanning autografts, allografts, xenografts, and synthetic constructs, are employed in the treatment of prevalent cardiovascular diseases such as myocardial infarction, which is associated with stenosis and embolism of blood vessels. However, Various drawbacks of the conventional grafts include difficulty in the cell deposition, lack of production of intricate perfusable bifurcated vascular constructs, static nature, and lack of interaction with the surrounding tissue. , Although widely available, synthetic vascular grafts exhibit low patency rates after implantation and limited clinical effectiveness for small-diameter (<6 mm) blood vessels, primarily due to intimal hyperplasia at the anastomotic site. The desired characteristics of the artificial vascular graft must be histocompatibility to prevent immunogenic rejection, should exhibit adequate mechanical properties to maintain its structural integrity and withstand physiological pressures. Furthermore, the graft’s microarchitecture should facilitate nutrient exchange, removal of metabolic waste, and support cellular growth, allowing endothelial cells to adhere, proliferate, and form a tightly connected endothelial layer capable of resisting thrombosis. In recent years, many researchers have utilized SMPs (Shape Memory Polymers) because they retain memory and can transform into different shapes based on their glass transition temperature (T _g). For example, Choudary et al. developed an acellularized vascular graft using polylactide-co-trimethylene carbonate for its more favorable T _g, which is close to physiological temperature. The tubular grafts were deformed into flat sheets, seeded with endothelial cells (at T _g), and thereafter triggered at 37 °C back into tubes ranging from 6 mm to 10 mm, with cellularized lumens for potential use as medium diameter femur or carotid artery. However, its clinical translation is constrained by the need for high-temperature triggering during initial forming, limited multimaterial and bioactive integration, and a lack of in vivo validation. The constructs were produced at medium vessel scales without comprehensive testing of long-term mechanical durability or graft patency under physiological flow. Moreover, in small-diameter vascular grafts, prolonged endothelialization is a crucial problem. Biological limitations arise from inadequate endothelial-specific adhesion cues, insufficient progenitor cell recruitment, and pro-inflammatory graft interfaces, which collectively impede rapid, stable endothelialization and exacerbate dysfunction under disturbed hemodynamics, precipitating intimal hyperplasia. Whereas technical limitations stem from material and architectural deficiencies such as suboptimal pore geometry, compliance mismatch, and fabrication constraint. To enhance endothelialization, Ding et al. used arginine-glutamic acid-aspartic acid-valine peptide to modify the polyurethane (PU) coating surface to improve endothelial adhesion. Although the endothelialization rate by using PU is faster, the patency rate of PU was proven to be lower, which is insufficient for commercialization. But later PU was used along with Silk by Fathi-Karkan et al., to fabricate vascular grafts with a long patency rate. Biofabrication of small-diameter vascular structures, notably bifurcations like T- or Y-shaped junctions, still poses a significant challenge. Complex bifurcated geometries, such as T- and Y-shaped grafts, pose significantly greater fabrication and functional challenges as they closely replicate native vascular branching, where intricate hemodynamic conditions, including disturbed laminar flow, vortex formation, and branch-specific shear stress gradients, govern endothelial cell behavior and long-term graft patency. , Achieving accurate replication of junction integrity in such bifurcated constructs is critical, as any mismatch in geometry or compliance can precipitate turbulence, intimal hyperplasia, or thrombus formation. Major concern in 4D printing of bifurcated structures is the space between perpendicularly joined tubes, which comes from rolling different sheets and rolling single sheets, hindering the connection of tubular structures to form bifurcations. In a study by Zhang et al., the development of self-forming Y-shaped bifurcated microvascular scaffolds using Gelatin Methacryloyl demonstrated promising potential for bifurcated vascular graft structures. Upon subcutaneous implantation of the microvascular hydrogel tubular constructs beneath the skin flap in a rat model, the authors observed enhanced microcirculation and a significant improvement in skin flap survival, with no evidence of systemic toxicity. Furthermore, histological analyses revealed seamless vascular integration with minimal inflammatory response. However, the presence of leaky cracks in the tube walls compromised the mechanical stability of the scaffolds. Kitana et al. took a similar approach to design a T-shaped vascular bifurcation by using Alginate and Gelatin. Perfusion through the tubular T-junction mimics blood flow in a simulated aqueous medium, demonstrating minimal leakage with a flow velocity of 0.11 m/s. Additionally, the inner surface of the T-junction, which was seeded with human umbilical vein endothelial cells, exhibited good proliferation and high cell viability. Another T-shaped vascular graft with antithrombotic and anti-inflammatory properties using Alginate and methylcellulose was designed by our group previously (Figure A). The dual-component hydrogel system exhibited gradient swelling characteristics that induced self-rolling upon immersion in Calcium Chloride (Cacl₂). In vitro experiments with human umbilical vein endothelial cells (HUVECs) and NIH3T3 cells also demonstrated excellent cell viability. Further evaluations, including in vivo experiments in animal models and mechanical stability comparisons with natural blood vessels, are crucial for their utilization as vascular grafts. However, most of these methods lacked the essential bioartificial integrity and a clear pathway for clinical translation, with their focus primarily on in vitro disease modeling. Recently, Von Witzleben et al. integrated high-resolution melt electrowriting with coaxial 4D bioprinting to fabricate small-diameter vascular grafts exhibiting patient-specific geometrical fidelity, hierarchical microfibrous reinforcement, and tunable compliance matching that closely approximates native arterial mechanics. The engineered luminal microarchitecture promoted rapid endothelial cell adhesion and monolayer formation, addressing both the structural and hemocompatibility deficits typically observed in conventional graft fabrication for complex branched and small-diameter vascular applications. Pfarr et al. introduced a novel personalized approach utilizing coaxial 4D printing with sodium alginate and collagen peptide to fabricate small-diameter, human-scale vascular grafts aimed at potential clinical translation. The fabricated vessels had luminal diameters of 3–3.5 mm, a total length of 30–40 cm, and were embedded with endothelial progenitor cells or HUVECs, offering biomechanical properties similar to human saphenous veins. Coagulation analysis demonstrated low thrombogenicity and high functional integrity. The surgical cardiovascular graft implantation by parachute anastomotic technique in a perfused cadaver model was performed without any technical complications. (Figure B). However, 4D printing of hierarchical tubular structures encompassing varied diameters, from large arteries down to capillaries and arterioles, to authentically recapitulate native vascular complexities and hemodynamics is still unexplored.

1.

Typical representation of 4D fabrication of Vascular Grafts. (A) A 3D printing of dual-component hydrogel systems and their shape deformations in the presence of Ca²⁺. Reproduced with permission from ref . Copyright [2024] [Royal Society of Chemistry]. (B-a). Manufacturing of the vascular grafts and design of the 4D bioprinting process. (a) Endothelial progenitor cells from blood samples and HUVEC from umbilical cords. (B-b) Cross-linking of SA-COP is by CaCl₂ (B-c) extrusion-based printing via a customized nozzle. (B-d) Bioprinting into a support medium (CaCl₂) for curing the printed structure, (B-e) Grafts cultured in the bioreactor with a vessel lumen between 3 and 3.5 mm, and (B-g) graft length of 30–40 cm. (B-h) 3D life imaging via fluorometric visualization with Calcein (B-i) implantation of the vascular grafts in a perfused cadaver model. Reproduced with permission from ref . Copyright [2024] [John Wiley and Sons].

2.2. Stents

Stents are small, tubular devices that widen narrowed blood arteries, bronchi, and esophagal. The high rate of restenosis, which typically occurs 6 months after implantation, requiring stent replacement, is a major drawback of the currently available stents. Various complications include increased morbidity, dangerous stent migration, and stent fracture. Stent failure occurs due to thrombus development and cell regeneration. Numerous researchers have investigated smart material-based stents, and in addition to the shape memory effects, biocompatibility and biodegradability, other important factors to consider include minimizing adverse reactions, such as inflammation, that foreign materials can trigger. , Unlike traditional inert stents, smart materials impart self-fitting capabilities where stimuli-responsive biomaterials with multifunctional properties dynamically adapt to physiological conditions such as pH, oxidative stress, and temperature fluctuations, enabling controlled drug elution and real-time shape adjustments that reduce vascular injury and facilitate endothelial regeneration. Computationally optimized designs incorporating negative Poisson’s ratio geometries further enhance adaptability to dynamic vascular loads without compromising radial strength , and the integration of programmable drug release kinetics within polymer metal hybrid systems ensures sustained, localized delivery of antiproliferative agents essential for restenosis prevention. For example, using stereolithography, Zarek et al. fabricated a tracheal stent made of methacrylate polycaprolactone, which was able to expand and change its shape in response to body temperature changes without causing any damage, ensuring an ideal fit of the trachea (Figure B). Zhou et al. designed a small-diameter vascular stent made from βCD-grafted polycaprolactone to treat limb ischemia. The stent was loaded with paclitaxel for sustained drug release. Initial results indicated a rapid release of ∼29% in the first 3 days, followed by a slower release over the next month, demonstrating the stent’s potential for long-term drug delivery. Another study used SMP fibers for stent fabrication, but lacks studies to test biocompatibility and mechanical stability. Implanting a bifurcated stent at a target site in a branched vessel that is either narrowed or occluded is surgically challenging. To mitigate this, Kim’s research group introduced a kirigami-inspired 4D-printed bifurcated stents, aiming to reduce the need for surgical implantation. Although the kirigami-inspired stents demonstrated improved mechanical properties compared to conventional stents, they were thick, lacked biocompatibility testing, and a clinically impractical shape-changing temperature. (Figure A).

2.

Representation of 4D fabrication of stents. (A) Bifurcated vascular stent design and deployment. Reprinted with permission under a Creative Commons [CC-BY 4.0] license from ref . Copyright [2018] [Springer Nature]. (B) Thermally actuated tracheal stent expands and fits well upon being deployed into the body in 14 s. Reproduced with permission from ref . Copyright [2016] [Wiley].

2.3. Nerve Conduits

Peripheral nerve injuries frequently lead to substantial functional deficits, resulting in muscle atrophy and sensory and motor dysfunction, leading to reduced quality of life. Traditional nerve repair strategies, particularly autografts, are currently considered the gold standard, but are often constrained by several limitations, including limited space for suturing, disruption of nerve grafts, loss of vascularity, and the need for a connecting material at the nerve gaps exceeding 20 mm. To overcome these challenges, tissue-engineered tubular constructs, composed of natural and synthetic biopolymers, have been developed as nerve-guiding conduits (NGCs) to provide mechanical and biochemical cues for neural regeneration. Ideal NGCs should incorporate bioactive cues, such as neurotrophic factors (e.g., NGF, BDNF) to stimulate Schwann cell proliferation and axonal outgrowth, alongside electrical conductivity provided by materials like polypyrene or reduced graphene oxide to enhance neural signaling. NGCs should have a porous structure to facilitate nutrient exchange and neovascularization, along with biocompatibility and mechanical properties. Three-dimensional printing of NGC offers design freedom and the possibility of replicating complicated neural architecture in monolithic devices without any assembly requirements. For example, Miao et al. have developed NGCs by stereolithography-based 4D printing using soybean oil epoxidized acrylate. The conduits exhibited dynamic self-wrapping due to internal stresses induced by gradient light penetration during the curing process, allowing tightly scrolled tubular structures to form. The authors demonstrated a proof-of-concept smart nerve guidance using graphene, highlighting its multifunctional properties for nerve grafting, including dynamic adaptive tubulation, biochemical signaling, physical guidance, and seamless integration. However, there was no in vivo demonstration of the shape change or the regeneration of NGCs. Furthermore, Joshi and colleagues presented an innovative approach to nerve repair using 4D-printed hydrogels that can self-fold into nerve conduits, eliminating the need for sutures. The study utilized a dual-component hydrogel system composed of alginate and methylcellulose, which demonstrated programmable shape deformations upon swelling. In vivo tests on a rat model with 2 mm sciatic nerve defects showed enhanced nerve regeneration, increased axon density with no observation of inflammation. They also validated sutureless nerve repair with programmable 4D morphing conduits, showing excellent functional outcomes and biodegradability. However, the relatively short duration of the follow-up period of 6 weeks may not fully capture the long-term efficacy of the conduits. (Figure B) Occupying the luminal space would restrict the number and size of the axons growing through the conduit. Hence, a multichannel guidance nerve conduit using degradable shape memory poly­(lactide-co-trimethylene carbonate) polymer was designed with four small channels wrapped by a larger tube and featured aligned nanofibers to provide topographical cues for axon regeneration. The self-forming nature of the polymer allowed the conduit to be flattened for cell loading and then restored to its original tubular shape at 37 °C. Results showed improved Schwann cell proliferation, axon alignment, and neural regeneration in a rat sciatic nerve defect model (10 mm gap) compared to single-channel conduits. Furthermore, the NGC promoted angiogenesis during the 12 week follow-up period and showed potential for enhanced neural repair and functional recovery. (Figure A).

3.

4D Fabrication of nerve guiding conduit (A-a) schematic illustration of construction and self-assembly process of four-channel nerve conduit using PLATMC nanofibrous mat. (A-b) In vivo implantation site of the multichannel nerve group (A-c) hematoxylin and eosin-stained cross-sectional images of regenerated nerves. Reproduced with permission from ref . Copyright [2020] American Chemical Society. (B-a) Schematic representation of 3D printed flat hydrogel sheets deforming into a nerve conduit. (B-b) Implantation site recorded postsurgery. (B-c) HE-stained cross-sectional images of nerve regeneration. Reproduced with permission from ref . Copyright [2023] [John Wiley and Sons].

3. Clinical Challenges in 4D Printing of Tubular Structures

Despite groundbreaking progress in the development of 4D-printed tubular structures for biomedical applications, numerous barriers must be surmounted to enable their seamless integration into clinical practice. The inherent complexities of designing stimuli-responsive biomaterials that can reliably replicate dynamic tissue behaviors, coupled with challenges in achieving precise spatiotemporal actuation under physiological conditions, impede widespread clinical adoption.

3.1. Material Consideration

The performance of the 4D-printed tubular structures solely relies on the materials utilized. Smart biomaterials such as SMPs, SMAs, and hydrogels must have a combination of mechanical strength and flexibility to mimic the natural microenvironment, strong enough to withstand physiological pressures while maintaining the elasticity for the movement and expansion in dynamic environments such as blood vessels or nerve pathways without compromising the surface characteristics, including topological smoothness, wettability, hydrophilic–hydrophobic character which is critical to prevent an immune response. − Adsorption of protein on the material interaction plays a vital part in coordinating the adhesion of cells. The constructs must retain their tubular architecture within clinically acceptable deformation thresholds to preserve functionality and ensure vascular patency postimplantation. Resisting degradation, wear, and fatigue over time in a biologically active environment is crucial. In vascular applications, the tubes must be nonthrombogenic, whereas in nerve conduits, they must support neural regeneration without causing additional tissue damage. These aspects could limit the range of materials suitable for the biofabrication of tubular structures.

3.2. Biocompatibility and Degradability

One important consideration in 4D printing of biomedical applications is that the biomaterials utilized should be nontoxic and nonimmunogenic to ensure safety. Beyond cellular toxicity, unwanted residual secretions or particles that cause adverse reactions pose another challenge. Tubular structures produced from synthetic to natural polymers such as collagen, gelatin, and chitosan mimic the native ECM, which can elevate the growth of tissues. Polymer amorphous–crystalline ratio directly impacts immunological response, material degradation, cell viability, cell adhesion, and proliferation. Degradability is a key factor when designing bioartificial implants, as the materials should degrade at an appropriate rate, allowing the structure to perform its intended function without causing harm. For instance, polycaprolactone, another commonly used biodegradable polymer, has a slower degradation rate, which can be advantageous for long-term scaffolding, but prolonged presence can lead to chronic inflammation and fibrosis. A rapid degradation rate may compromise mechanical integrity, while overly slow degradation can lead to fibrotic encapsulation. Optimizing polymer crystallinity and blending with bioactive agents enables tunable degradation conducive to cell adhesion, ECM deposition, and vascular integration. Thus, combining it with other faster-degrading polymers or bioactive materials to tailor its properties for clinical needs is important. Therefore, selecting the appropriate material for a medical device should be based on key factors, including the intended application, biomechanical needs, and the device’s anticipated durability.

3.3. Shape Morphing Difficulties

Precise Actuation and long-term functionality within the body are substantial challenges in fabricating shape-morphing tubular structures. SMPs and Hydrogels used for desired morphing behavior rely on external stimuli (temperature, pH, moisture, etc.). However, controlling these stimuli in vivo could be challenging in various aspects, such as differences in the consistency of batch-to-batch raw biomaterials and difficulty in achieving uniform shape transformation, as stents relying on thermal activation must have the ability to morph precisely at body temperature without external heating. If the environmental conditions fluctuate, it causes partial deformation, compromising the intended support function. Moreover, Actuation speed and timing are crucial for such tubular-shaped devices. In Nerve conduits, the SMPs are employed to aid in aligning and supporting nerve regeneration. Hydrogel-based conduits designed to swell and conform to the surrounding tissue may overshoot their target size when exposed to an uncontrollable, excessive moisture tissue environment, leading to impaired neural regeneration.

3.4. Regulatory and Ethical Compliance

Any new Medical Technology, including 4D printing, must undergo testing and receive approval from regulatory bodies such as the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) and Asian regulatory standards. , The approval process involves several stages, such as preclinical testing, clinical trials, and postmarket monitoring. While best practices such as documenting cell origin, assessing cell viability and functionality, and maintaining high sterility standards can be implemented throughout the bioprinting process, significant bottlenecks remain, particularly regarding logistics and the unknown long-term safety of human hosts. Other Important regulatory considerations include sterility and mechanical properties. The choice of sterilization depends on the specific material properties, sensitivity of the bioinks, and cells to heat radiation or chemicals. A few methods include chemical sterilization with H2O2, UV sterilization, and CO2 sterilization. Upon completion of the postprocessing and sterilization steps, the final fabricated structure is subjected to mechanical testing (Tensile, compression, bend, etc.).

3.5. Scalability and Commercialization

Scalability remains a key challenge in 4D printing technologies, especially when translating laboratory-scale precision to industrial-scale production, where the fabrication of structures must meet both diverse patient needs and stringent industrial standards. While it allows for meticulous control over material deposition and the application of stimulus-responsive coatings, replicating this level of precision and functionality at scale presents significant obstacles. Complex shapes and precise stimulus-responsive behavior are often difficult to reproduce consistently in mass production due to differences in batch-to-batch raw material consistency concerning variability and product quality. Moreover, the clinical application of 4D-printed devices, such as tubular structures, demands specialized training for healthcare providers. Physicians and surgeons must gain a comprehensive understanding of the in vivo behavior of these materials, particularly their shape-morphing dynamics and degradation profiles, to ensure optimal implantation and patient outcomes. Integration of such novel materials into clinical practice also raises issues related to patient acceptance, as long-term clinical outcomes are not well documented. Despite better alternatives, familiarity and the lower cost of traditional materials often outweigh the potential advantages of adopting 4D-printed alternatives.

4. Conclusion

This review has discussed the advancements and clinical challenges in the 4D fabrication of tubular structures for biomedical applications, emphasizing the dynamic potential of shape memory materials such as SMPs and SMAs. While conventional 3D printing techniques have demonstrated substantial progress in the development of tubular constructs like stents, vascular grafts, and nerve conduits, they remain inherently limited by their static nature and inability to adapt to complex, time-dependent physiological environments. 4D printing, by incorporating stimuli-responsive materials that evolve in response to external factors, presents a paradigm shift toward creating more adaptable and functional biomimetic constructs. Nevertheless, there remain significant hurdles in material selection, precise actuation control, and scalability that must be addressed for clinical translation. The need for robust, biocompatible, and mechanically resilient materials that can precisely mimic the dynamic behavior of native tissues, while simultaneously integrating cellular and biochemical cues, is paramount. Future research should focus on developing advanced, multifunctional, Multisimuli-responsive materials integrating biosensors and hybrid fabrication technologies that not only replicate the complexity of biological systems at the micro and macro scale but also address the limitations of current stimuli-responsive materials. Self-healing materials are another potential research area. The emerging 5D printing, where the print head prints and the print part moves, enabling printing of curved layers and twisted surfaces, may further expand this horizon, enabling a new generation of patient-specific, bioactive, and dynamically responsive medical devices for cardiovascular, neurological, and other tissue-engineering applications. This technology synergizes additive and subtractive processes and allows intricate objects to be printed with curved layers rather than flat ones, resulting in parts that are often 3 to 5 times stronger than conventional 3D-printed ones with reduced material usage and lower waste. 4D printing demonstrates considerable potential in the fabrication of complex, patient-specific curved implants and surgical instruments such as orthopedic and dental devices where both superior mechanical strength and precise anatomical conformity are imperative, while simultaneously enabling the creation of anatomically accurate surgical planning models, advanced prosthetics, and tissue engineering scaffolds with spatially controlled, multifunctional architectures. − However, 5D printing faces several challenges, including high costs associated with multiaxis machinery and complex print beds; limited user expertise and support infrastructure; the need for advanced computational design and sophisticated slicing software to manage additional axes; and scarcity of skilled personnel to operate and maintain 5D systems. These factors currently restrict its adoption largely to industrial or specialized medical uses. Moreover, the integration of smart materials that respond over time (as in 4D printing) with the geometric and mechanical benefits of 5D printing is still in early development, suggesting future research must focus on combining these advances for truly dynamic, strong, and adaptive biomedical implants.

CRediT: Krithika Kumar writing - original draft.

The authors declare no competing financial interest.

Published as part of ACS Materials Au special issue “2025 Rising Stars in Materials Science”.