Gelatin Methacryloyl Hydrogels as a Multifaceted Platform for Promoting Nerve Regeneration

Abstract

Nerve injuries pose a significant clinical challenge in both the central and peripheral nervous systems, which often lead to permanent functional deficits. Nerve tissue engineering offers a promising path forward, and gelatin methacryloyl (GelMA) hydrogels have emerged as a powerful and versatile platform in this endeavor. Derived from natural collagen, GelMA possesses inherent biocompatibility and cell-adhesive properties, while its photocrosslinkable nature allows for the precise tuning of its mechanical stiffness, degradation rate, and porous architecture to recapitulate the native neural microenvironment. This review comprehensively elucidates the evolution of GelMA from a passive physical support to an active and instructive biomaterial. We explore a wide array of functionalization strategies, including the incorporation of therapeutic cells, the sustained delivery of neurotrophic factors, and the integration of conductive materials to guide regeneration. Furthermore, we discuss the development of advanced stimuli-responsive systems and the application of 3D bioprinting to fabricate anatomically complex nerve guidance conduits. Ultimately, this work establishes GelMA as a pivotal technology for developing the next generation of intelligent and clinically translatable strategies for nerve repair.

Impact Statement

This review highlights the transformative potential of gelatin methacryloyl (GelMA) hydrogels in nerve tissue engineering. By comprehensively analyzing advanced functionalization strategies and “smart” stimuli-responsive systems that adapt to pathological microenvironments, this work underscores the capacity of GelMA to overcome critical barriers in neural repair. We detail how these versatile scaffolds can be engineered for precise drug delivery, electrical conductivity, and gene editing. These insights provide a roadmap for developing next-generation, autonomous biomaterials, paving the way for personalized clinical solutions that significantly enhance functional recovery in patients with severe neuronal injuries.

Keywords

gelatin methacryloyl nerve injuries nerve tissue engineering 3D bioprinting regeneration

Introduction

Traumatic injury to the nervous system inflicts a significant burden on patients, often leading to permanent loss of motor, sensory, and autonomic functions.^1–3 The human nervous system is broadly divided into the central nervous system (CNS), comprising the brain and spinal cord, and the peripheral nervous system (PNS), which includes all other neural tissues. These two systems exhibit different responses to injury.^1,4 The CNS possesses an extremely limited capacity for self-repair. Following an injury, a cascade of pathological events, including the formation of a dense glial scar and the upregulation of potent inhibitory molecules, creates a microenvironment that is inhibitory to axonal regrowth.⁵ This results in the functional deficits associated with spinal cord injury (SCI) and traumatic brain injury being largely irreversible.^6–8 In contrast, the PNS displays a more permissive environment and an innate, albeit limited, potential for regeneration.⁹ This process is orchestrated by Schwann cells, which clear debris and organize into structures known as Bands of Büngner to guide regenerating axons back to their targets. However, this natural repair mechanism is only effective over very short distances.¹⁰ When a significant nerve gap is present, spontaneous regeneration fails, necessitating clinical intervention. The current gold standard for bridging large nerve defects is the autologous nerve graft, where a segment of nerve is harvested from another part of the patient’s body.¹¹ While this approach can be effective, it is fraught with limitations, including the restricted availability of donor nerves, the creation of a secondary injury site with potential for chronic pain or sensory loss, and the frequent mismatch in nerve diameter, which can compromise functional recovery. These substantial shortcomings underscore the urgent need for effective alternative strategies.¹²

Nerve tissue engineering has emerged as a promising alternative to conventional treatments, offering a systematic approach to creating functional substitutes that promote and guide the regenerative process. This strategy is founded upon the synergistic interplay of three core components: a supportive scaffold, therapeutic cells, and bioactive factors.¹³ Within this triad, the biomaterial scaffold holds a critical and indispensable position, as it is the platform that integrates the cellular and molecular components into a cohesive and functional therapeutic construct. Of paramount importance in the design of an ideal nerve scaffold is its degradation kinetic profile.¹⁴ The scaffold is not intended to be a permanent implant but rather a temporary template that facilitates the body’s own regenerative processes. Therefore, the rate at which the scaffold degrades must be carefully synchronized with the timeline of nerve repair.¹⁵ An ideal scaffold must persist long enough to provide crucial mechanical support and directional guidance for migrating cells and extending axons across the nerve gap. Subsequently, it must degrade and be resorbed by the body in a timely manner to create physical space for the newly forming tissue, allowing for complete tissue integration, vascularization, and functional maturation. This temporal harmony between material degradation and biological regeneration is a critical prerequisite of therapeutic success.¹⁶ A mismatch in these rates can lead to significant complications and regenerative failure. If a scaffold degrades prematurely, it results in the loss of structural integrity before the regenerating nerve has successfully bridged the gap. This can lead to infiltration of scar tissue and misdirection of axonal growth. For instance, unmodified metallic materials like magnesium, while promising for their biodegradability, often exhibit a rapid degradation rate that compromises their structural support and can create an unfavorable microenvironment.^17,18 Conversely, a scaffold that degrades too slowly can act as a long-term physical impediment. It can hinder the later stages of nerve maturation, such as myelination and revascularization, and may induce a chronic inflammatory response, leading to fibrosis and potential compression of the newly formed nerve cable. Additionally, a successful scaffold must do more than simply fill a void; it must act as a dynamic and permissive microenvironment that actively supports the complex biological processes of nerve repair.¹⁹ The presence of an interconnected porous network is essential for this role, as it serves as a critical highway for the transport of nutrients, oxygen, and signaling molecules to encapsulated or migrating cells, while simultaneously allowing for the efficient removal of metabolic waste. This constant exchange is a prerequisite for cell viability, proliferation, and function. Without such a structure, cells would be isolated and quickly succumb to nutrient deprivation and the buildup of toxic byproducts. Structurally, the scaffold requires mechanical properties, specifically stiffness, that match the soft neural tissue to prevent compression trauma.^14,20,21 Furthermore, given the electrophysiological nature of nerves, electrical conductivity is a highly desirable feature to restore bioelectrical signal transmission. In the search for an ideal biomaterial, gelatin methacryloyl (GelMA) has emerged as a leading candidate that effectively balances biological functionality with engineering versatility.¹⁵ GelMA is a semisynthetic hydrogel derived from gelatin, which is the denatured form of collagen, the most abundant protein in the native extracellular matrix. As illustrated in Figure 1, the properties of GelMA-based bioinks can be precisely tailored, allowing them to respond to various internal or external stimuli and function within different pathological microenvironments, such as tumors, inflammation, and infection.

FIG. 1.

GelMA-based bioinks: from fundamental properties to smart responses and applications in pathological microenvironments. GelMA, gelatin methacryloyl. Reproduced from Zhu et al., CC BY 4.0.¹⁶

This review provides a comprehensive overview of the multifaceted role of GelMA in promoting nerve regeneration. We will begin by discussing its fundamental properties and preparation methods. We then delve into the diverse strategies used to functionalize GelMA, including biomimetic modifications and the loading of bioactive molecules. Following this, we will explore advanced manufacturing and cell-loading technologies, its preclinical applications in both PNS and CNS repair, and finally conclude with a discussion of the current challenges and future perspectives that will shape the next generation of GelMA-based neural therapies.

Fundamental Properties of GelMA for Nerve Regeneration

GelMA is a semisynthetic biomaterial derived from the chemical modification of gelatin, which is the denatured form of collagen. The synthesis process is a basis of its versatility, as it endows the natural polymer with photocrosslinkable properties while preserving its inherent biological motifs. The most widely adopted method for producing GelMA involves the direct reaction of gelatin, typically sourced from porcine or bovine origins, with methacrylic anhydride (MA).²² This reaction is generally conducted in a buffered aqueous solution, such as phosphate-buffered saline, at a controlled temperature of around 50°C to ensure the gelatin remains in a sol state (Fig. 2). During this process, the methacryloyl groups from MA are covalently grafted onto the primary amine and hydroxyl groups of the amino acid residues within the gelatin backbone, such as lysine.²³ Following the reaction, a critical purification step involving extensive dialysis against deionized water is performed to remove unreacted MA and cytotoxic methacrylic acid byproducts. The final product is then obtained as a white, porous foam through lyophilization, which can be stored long-term and readily dissolved for use.

FIG. 2.

Scheme for preparation of photo-crosslinked GelMA hydrogel. Reproduced from Zhu et al., CC BY 4.0.¹⁶

A key advantage of GelMA is the ability to precisely control its structural and subsequent functional properties by tuning the degree of methacryloylation (DM), also referred to as the degree of substitution. The DM represents the percentage of reactive lysine amino groups that have been functionalized with methacryloyl groups, and it is the critical parameter to control during synthesis as it directly dictates the final characteristics of the hydrogel.²⁴ The most straightforward way to modulate the DM is by adjusting the amount of MA added during the reaction; a higher concentration of MA leads to a higher DM. Furthermore, the reaction pH also plays a significant role, with more alkaline conditions enhancing the reactivity of the amine groups and thus resulting in a greater degree of substitution.²⁵ This tunability is fundamental, as the DM determines the crosslinking density of the resulting hydrogel after photo-polymerization, which in turn governs its key physical properties including mechanical stiffness, swelling ratio, pore size, and degradation rate, all of which are critical for applications in tissue engineering, from bone repair to infection control.²⁶

The structural characterization of GelMA, specifically the quantification of the DM, is most commonly performed using proton nuclear magnetic resonance (¹H NMR) spectroscopy. By analyzing the ¹H NMR spectrum, researchers can compare the signal intensity of the methylene protons of the lysine residues in native gelatin with their reduced intensity in GelMA, thereby calculating the percentage of modification. While the foundational synthesis protocol is well established, ongoing research continues to refine the process for specific advanced applications. For instance, alternative reaction solvents and buffer systems, such as carbonate–bicarbonate buffer, have been explored to achieve higher degrees of substitution or to optimize the resulting material for use as a bioink in 3D bioprinting.¹⁶ This robust and controllable synthesis is what makes GelMA a multifaceted and highly adaptable platform in regenerative medicine.

Critical Assessment: Limitations and Challenges of GelMA Scaffolds

While GelMA scaffolds have demonstrated immense potential as a multifaceted platform for nerve regeneration, a critical evaluation reveals inherent limitations that must be navigated.

First, degradation kinetics can be unpredictable in vivo. GelMA is susceptible to enzymatic degradation by matrix metalloproteinases (MMPs). In the harsh, inflammatory microenvironment of a severe nerve injury, upregulated MMPs may degrade the scaffold too rapidly before the regenerating axons have successfully bridged the gap. Conversely, overly crosslinked networks may linger too long, physically impeding tissue remodeling. To achieve this delicate balance, the degradation rate of GelMA-based hydrogels can be precisely tuned through various material engineering strategies. The inherent degradability of GelMA, which can lose a significant portion of its mass within weeks, is advantageous for creating space for cellular infiltration and new tissue deposition.²⁷ However, for applications requiring more prolonged support, this rate can be modulated. This can be achieved by blending GelMA with more stable polymers or by altering the internal chemistry of the hydrogel network. For example, incorporating a more slowly degrading synthetic polymer like pHEMA into a GelMA network can extend the functional lifetime of the scaffold.²⁷ Similarly, the degradation profile can be controlled by adjusting the concentration of different components within a composite hydrogel, as demonstrated in systems where varying the amount of sodium alginate methacrylate (SAMA) directly influences the overall degradation time.²⁸ This tunability is essential for tailoring the scaffold to the specific needs of different nerve defect sizes and locations.

Second, the mechanical-biological trade-off remains an important problem. Native nerve tissue requires a delicate balance: soft enough to mimic the neural extracellular matrix (ECM) (∼0.1–10 kPa) for axonal growth, yet strong enough to withstand surgical handling and suturing (in the range of MPa for peripheral nerves). Pure GelMA often falls short; low-concentration hydrogels (<5%) offer optimal cell viability and porosity but lack the tensile strength to bridge large gaps or hold sutures, necessitating the use of synthetic reinforcing polymers or conduits, which may compromise the all-natural advantage. The most sophisticated strategies integrate mechanical optimization with other instructive cues. Reinforcing a GelMA/silk fibroin double network hydrogel with a graphene mesh results in a conduit with a Young’s modulus of approximately 528 kPa, closely matching that of native peripheral nerves (∼570 kPa).²⁹ Such composite hydrogels not only possess ideal mechanical strength but also introduce electrical conductivity, a powerful signal for guiding nerve growth. The incorporation of conductive materials like graphene or the polymer PEDOT into the GelMA matrix creates scaffolds that support bioelectrical signal transmission between cells, which is vital for establishing a functional nerve connection.^21,30 Ultimately, by precisely controlling and enhancing its mechanical properties, GelMA scaffolds serve as a multifaceted and highly effective platform for engineering the complex and demanding environments required for successful nerve regeneration in both CNS and PNS.

Third, reproducibility is challenged by batch-to-batch variability. As a derivative of natural collagen (typically from porcine or bovine sources), the molecular weight distribution and impurities in the raw gelatin can vary significantly.^23,31 Consequently, even with a controlled methacryloylation process, the final hydrogel properties, such as swelling, degradation, and stiffness, can fluctuate, complicating the standardization required for clinical regulatory approval.

Finally, the development of bioinks for the 3D bioprinting of GelMA scaffolds is also crucial. Ideal bioinks must exhibit printability, characterized by easy extrusion, clog-free performance, and stable shape fidelity. They also require biocompatibility to support cell viability and proliferation, along with functionality such as the capacity to facilitate tissue repair.³² Nasera et al. developed a novel bioink primarily composed of polyvinyl alcohol, a common water-soluble polymer known for its cytocompatibility, and cerium oxide nanoparticles, an antioxidant nanomaterial capable of scavenging harmful free radicals.³³ Furthermore, a dual crosslinking strategy was employed. The first step utilized citric acid to initially crosslink the components into a printable gel state, while the second step involved a postprinting treatment with sodium hydroxide to reinforce the structure and prevent degradation. Antioxidant assays confirmed that the cerium oxide-loaded ink effectively scavenges free radicals. By optimizing printing parameters such as nozzle diameter and pressure, the team successfully fabricated well-defined 3D scaffolds. Cell experiments demonstrated high postprinting cell viability and sustained proliferation. In conclusion, the scaffolds printed with this novel bioink are particularly suitable for peripheral nerve injury repair due to their dual capability of supporting cell loading and providing antioxidant protection. Thus, this dual crosslinking strategy provides new insights for the future development of bioinks used for GelMA scaffolds.³³

Functionalization Strategies of GelMA for Promoting Nerve Regeneration

To enhance the therapeutic efficacy of GelMA, various functionalization strategies have been developed, ranging from the inclusion of chemical cues to the integration of living components. To provide a clear perspective on the clinical translational potential of these approaches, Table 1 categorizes them into acellular and cell/gene-based strategies, summarizing their respective mechanisms and associated regulatory or manufacturing challenges.

Table 1.

Summary of Functionalization Strategies and Translational Considerations

Strategy category	Specific approach	Classification	Key translational barrier/risk
Bioactive loading	NTF delivery (e.g., NGF, BDNF)	Acellular	Protein stability, half-life, release kinetics (moderate risk).
	Gene delivery (siRNA, pDNA)	Gene-based	Transfection efficiency, off-target effects, vector safety (high risk).
	Cell encapsulation (genetically modified)	Cell + Gene	Immune rejection, tumorigenicity, complex GMP manufacturing (very high risk).
Stimuli-responsive	Glucose/pH responsive (small molecules)	Acellular	Material toxicity, degradation products, reliable triggering in vivo (low–moderate risk).
Stimuli-responsive	Electrical/magnetic (conductive materials)	Acellular	Long-term toxicity of nanomaterials (e.g., CNTs), chronic inflammation (moderate–high risk).
Advanced biofabrication	3D bioprinting with stem cells	Cell-based	Cell viability during printing, batch consistency, cell source ethics (high risk).

BDNF, brain-derived neurotrophic factor; CNTs, carbon nanotubes; GMP, Good Manufacturing Practice; NGF, nerve growth factor; NTF, neurotrophic factor.

Loading and delivery of bioactive molecules

Neurotrophic factors

A cornerstone strategy for promoting neural regeneration is the strategic use of neurotrophic factors (NTFs), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). These signaling proteins are fundamental for ensuring the survival of neurons, stimulating the extension of axons, and guiding their growth.³⁴ However, the clinical application of NTFs is hampered by their inherent instability; they have short biological half-lives and are quickly degraded in the proteolytic environment of an injury site. Direct injection is therefore inefficient, failing to provide the long-term, localized signaling required for the slow process of nerve repair. GelMA hydrogels present a compelling solution to this challenge, serving as protective, implantable reservoirs that enable the sustained and site-specific delivery of these potent but fragile molecules. As an acellular strategy, the hydrogel network can physically entrap NTFs, shielding them from degradation while facilitating their gradual release through diffusion and as the matrix biodegrades, creating a durable and geographically focused gradient of therapeutic support. The principle of using GelMA as a tunable depot for bioactive molecules has been well established, offering a platform for programmable release kinetics essential for long-term therapies.³⁵

The versatility of GelMA as a delivery platform allows for a range of strategies, from the direct encapsulation of NTFs to more sophisticated, indirect approaches that modulate the local cellular environment. An advanced strategy involves creating multicomponent systems where GelMA acts as a key element for programmed molecular release. For instance, a complex “artificial niche” can be designed where a GelMA hydrogel coating releases specific molecules in a controlled sequence to orchestrate the regenerative process, demonstrating its capability for sophisticated, temporal drug delivery.³⁶ This adaptability extends beyond protein-based factors; GelMA has also proven to be an effective vehicle for the sustained delivery of small-molecule drugs that support sciatic nerve function, such as potassium channel blockers, further highlighting its role as a multifaceted therapeutic platform.³⁷

Furthermore, GelMA can be functionalized to create a proregenerative microenvironment that inherently supports the health and function of regenerative cells, thereby enhancing their natural secretome. Peripheral nerve injury is often accompanied by hostile secondary injury cascades, including excessive oxidative stress and local acidosis, which damage key regenerative cells like Schwann cells and suppress their ability to secrete NTFs. By creating a composite GelMA hydrogel with intrinsic antioxidant properties, it is possible to protect Schwann cells from this oxidative damage. This protection restores their functional integrity, enabling them to resume robust secretion of vital factors like BDNF.¹⁹ Similarly, another study showed that a GelMA-based composite hydrogel designed to neutralize the acidic postinjury environment could mitigate mitochondrial dysfunction and cell death, thereby preserving the health of the local cell populations responsible for secreting NTFs and driving spinal cord repair.³⁸

Finally, the most integrated strategies involve designing scaffolds that are not just passive carriers but are themselves intrinsically bioactive. A composite hydrogel combining GelMA with nerve-derived extracellular matrix (NDEM) was shown to inherently promote the neural differentiation of stem cells. This effect is attributed to the endogenous growth factors, such as bFGF, that are naturally present within the NDEM component, creating a scaffold that is itself a source of proregenerative cues.³⁹ These sophisticated approaches highlight a paradigm shift from simply supplying exogenous factors to actively engineering a therapeutic niche that protects local cells, stimulates endogenous NTF production, and provides its own biological signals, empowering the body’s innate regenerative potential of the central nerves.

Gene delivery vector

Capitalizing on its capacity for sustained release and its protective matrix properties, GelMA has emerged as a powerful vehicle for delivering gene therapy vectors. This gene-based strategy enables the localized silencing of specific inhibitory genes within the postinjury microenvironment, offering a highly targeted approach to dismantle molecular barriers to regeneration.⁴⁰ The versatility of GelMA allows it to be combined with various gene carriers, including nanoparticles and extracellular vesicles, to treat complex injuries in both CNS and PNS.

In the context of SCI, where the lesion cavity is often irregular and the cellular environment is profoundly inhibitory, GelMA’s physical properties are particularly advantageous. Its ability to be used as an injectable, photocurable hydrogel allows it to be delivered in a minimally invasive manner and to precisely fill the defect site in situ. This creates a scaffold that can simultaneously deliver multiple types of siRNA to tackle different pathological processes at once. For instance, a dual-siRNA-loaded GelMA system can be engineered to codeliver siRNAs that target both phosphatase and tensin homolog (PTEN) and macrophage migration inhibitory factor (MIF). This dual approach promotes axon regeneration by disinhibiting intrinsic neuronal growth pathways (via PTEN silencing) while concurrently reducing detrimental neuroinflammation (via MIF silencing), leading to a synergistic improvement in functional recovery (Fig. 3).⁴⁰ To further enhance the specificity of this gene delivery, GelMA can be fabricated into microspheres and functionalized with neurotropic peptides. By conjugating rabies glycoprotein-derived peptides to the surface of GelMA microspheres, a platform is created that preferentially binds to and is internalized by neurons. When these neurotropic microspheres are loaded with extracellular vesicles carrying siHDAC3 (an siRNA targeting histone deacetylase 3), the result is a highly specific and sustained knockdown of this epigenetic brake on regeneration exclusively in neuronal cells. This targeted delivery significantly promotes the formation of functional propriospinal detour circuits and enhances locomotor recovery after SCI, showcasing a sophisticated integration of biomaterial engineering with targeted gene silencing.⁴¹

FIG. 3.

Schematic view of the synthesis and therapeutic effect of the siRNAs/PLNG scaffold for the treatment of SCI. SCI, spinal cord injury. Reproduced from Gao et al.⁴⁰ with permission from ACS publications.

GelMA also serves as a critical component in indirect gene therapy strategies, particularly for peripheral nerve regeneration. In this paradigm, the hydrogel is used not to deliver the gene vector itself, but to deliver genetically engineered cells that act as “cellular bioreactors” at the injury site. Schwann cells, for example, can be modified ex vivo using lentiviral vectors to continuously produce and secrete therapeutic proteins, such as the anti-inflammatory cytokine IL-4. These modified cells are then encapsulated within a GelMA-based nerve guidance conduit. The GelMA matrix provides a protective and supportive niche, ensuring the survival and retention of the engineered cells, which in turn provide a long-term, sustained source of IL-4. This localized immunomodulation drives macrophage polarization toward a prohealing M2 phenotype, triggering a regenerative cascade that accelerates angiogenesis and remyelination, ultimately creating a highly favorable microenvironment for peripheral nerve repair.²⁸ While this strategy focuses on immunomodulation, others target the critical need for vascularization in long-gap defects. For instance, Huang et al. recently developed a dual-layer conduit featuring a poly (lactic-co-glycolic acid) (PLGA) shell and a GelMA inner layer encapsulated with Schwann cells genetically engineered to overexpress VEGF-A.⁴² The GelMA matrix maintained the phenotype of these transfected cells, allowing them to serve as a stable source of VEGF-A. This localized delivery significantly accelerated angiogenesis and axonal extension in a rat sciatic nerve defect model, demonstrating that unlike the gene silencing often required in the CNS, PNS strategies frequently benefit from the sustained overexpression of neurotrophic or angiogenic factors. Taken together, the ability to integrate gene-silencing nanoparticles, therapeutic extracellular vesicles, or living, genetically engineered cells demonstrates GelMA’s evolution from a passive delivery vehicle to an active and integral component of advanced regenerative therapies.

Smart stimuli-responsive GelMA systems

Endogenous stimulus

Glucose

Harnessing glucose as an endogenous stimulus provides an effective cell-free strategy for designing intelligent GelMA hydrogels that can respond to their metabolic surroundings. The primary chemical approach to confer glucose sensitivity involves functionalizing the GelMA polymer backbone with phenylboronic acid (PBA) or its derivatives.⁴³ PBA possesses a unique and valuable ability to form dynamic, reversible covalent bonds, known as boronate esters, with molecules that feature a cis-diol configuration. This characteristic enables the hydrogel to act as a responsive reservoir, where therapeutic agents containing cis-diol groups can be temporarily tethered to the scaffold.

This principle has been effectively applied in systems designed for nerve regeneration. For example, a PBA-modified GelMA hydrogel was used to load Sodium Danshensu (DSS), a neuroprotective and anti-inflammatory agent whose catechol structure contains the necessary cis-diol for binding. In this system, the drug remains anchored to the hydrogel matrix until it is exposed to glucose. As a molecule abundant in cis-diols, glucose acts as a competitive binding agent. It displaces the tethered DSS from the PBA sites, triggering a controlled release of the therapeutic payload into the local environment. This release mechanism is not merely an on/off switch; it is highly dependent on the glucose concentration, with higher levels of glucose leading to a faster and more substantial release of the drug.⁴⁴ This strategy effectively leverages the glucose present in standard cell culture medium or physiological fluids to initiate drug delivery. Furthermore, it presents a significant therapeutic potential for treating central nerve damage associated with hyperglycemic conditions, such as diabetic neuropathy, where the pathological glucose levels themselves could become the precise trigger for the on-demand release of regenerative compounds.

pH

The microenvironment of a nerve injury site, particularly within the CNS, undergoes significant and detrimental changes, one of which is a rapid and sustained decrease in pH. This local acidification creates a hostile setting that actively inhibits cell proliferation, promotes apoptosis, and impedes the natural processes of tissue repair.³⁸ Developing GelMA hydrogels that can respond to this pH shift offers two cell-free strategies: one that actively corrects the acidic environment and another that uses the acidity as a precise trigger for drug delivery.

An innovative approach to environmental correction involves designing GelMA hydrogels to act as buffering depots. By incorporating and slowly releasing alkaline molecules, these hydrogels can neutralize the excess acid at the injury site. For instance, a composite hydrogel made of GelMA and lysine-loaded nanoparticles has been shown to gradually release the amino acid lysine. The inherent properties of lysine allow it to buffer the environment, raising the local pH from a pathological, acidic state back toward a more favorable physiological range. This neutralization directly counters the harmful effects of the acidic environment, creating a more permissive niche for cell survival and promoting functional recovery after SCI.³⁸ This strategy focuses on restoring environmental homeostasis to support regeneration.

Alternatively, the acidic pH of the injury site can be exploited as a specific trigger for the on-demand release of therapeutic agents. This is achieved by incorporating acid-labile chemical linkers into the GelMA hydrogel structure. PBA provides an excellent example of this functionality. When PBA is used to form boronate ester bonds that tether a drug to the GelMA backbone, these bonds remain relatively stable at neutral physiological pH. However, upon exposure to the acidic conditions found at a nerve injury site, the boronate ester bonds become unstable and break. This cleavage effectively uncouples the drug from the hydrogel, resulting in its targeted release. A GelMA system functionalized with PBA has demonstrated this principle by releasing the neuroprotective agent Sodium Danshensu more rapidly and in greater quantities as the pH drops.⁴⁴ This approach cleverly transforms a detrimental aspect of the pathology into a highly specific stimulus for localized therapy. According to this, Xu et al. developed an extracellular matrix-mimic hydrogel (GBSH) that was composed of cellulose nanocrystal grafted with sulfated hyperbranched polyglycerols (SHC) and 3-aminophenylboronic acid-modified GelMA (GMPB) for stimuli-responsive release of Sodium Danshensu.⁴⁴ Results showed that DSS-loaded GBSH improved the viability and orientation of fibroblasts and oligodendrocyte precursor cells, myelinating the extensive axons of hippocampal neurons.

Beyond chemical cleavage strategies, pH-responsive release can also be achieved through physical mechanisms, such as modulating electrostatic interactions. This approach is particularly relevant for peripheral nerve regeneration, where sustaining NTF levels is critical. For instance, Zhuang et al. developed a composite system by embedding glial cell line-derived neurotrophic factor (GDNF)-loaded gelatin microspheres within a GelMA hydrogel to treat sciatic nerve defects.⁴⁵ In this design, the release kinetics were governed by the pH-dependent charge of the gelatin microspheres. Under acidic conditions, the protonation of the gelatin matrix weakened the electrostatic attraction to the positively charged GDNF, triggering a rapid release. This smart composite system not only protected the growth factors but also successfully bridged a 10 mm sciatic nerve gap in rats, demonstrating how pH sensitivity can be engineered into GelMA composites to enhance peripheral nerve repair.⁴⁵

External stimulus

Electrical response

Of paramount importance in nerve regeneration is mimicking the native electrical activity of neural tissue. The intrinsic bioelectric signals that govern neuronal communication, growth, and guidance are often disrupted by injury. Consequently, a key strategy in designing advanced GelMA hydrogels is to imbue them with electrical conductivity, thereby creating a platform that is responsive to and can actively participate in electrical signaling. This is typically achieved by incorporating conductive nanomaterials into the GelMA matrix, effectively transforming the insulating hydrogel into an electroactive scaffold. A wide range of materials has been explored for this purpose, including conductive polymers like polypyrrole (PPy) and PEDOT, as well as various carbon-based nanomaterials such as graphene, rGO, and CNTs.^21,46–50 These materials form an interconnected network within the hydrogel, facilitating the transport of electrons and ions (Table 2).

Table 2.

Summary of Novel Electrically Responsive GelMA Hydrogels for Nerve Regeneration

Conductive material/strategy	Fabrication and characterization	ES parameters	In vitro studies and findings	In vivo model and evaluation	Key findings and regenerative mechanism
Pristine GelMA	Standard synthesis of GelMA hydrogel. Characterized for its response to external ES.	External ES applied: Four conditions tested, including 50 Hz and 100 Hz at 200 mV and 400 mV for 2 h/day.	Cell type: PC12 cells. - ES increased neurite length, particularly at 400 mV (ES2 and ES4). - All ES conditions significantly increased the percentage of cells expressing neurites.	Not performed.	Pristine GelMA is inherently, though weakly, responsive to electrical stimulation, showing its potential as a base material for electroconductive scaffolds. The effect is frequency- and voltage-dependent.
GelMA + carbon nanotubes (CNTs) with ice-templating	Ice-templating technology used to create longitudinally oriented porous structures within a GelMA/CNT composite. NGF was also loaded.	Passive conductivity: No external ES applied. The conductivity of the material itself provides electrical cues.	Cell type: PC12 cells. The conductive and oriented scaffold improved cell differentiation and directed neurite outgrowth along the topological structures.	Model: Rat sciatic nerve (10 mm defect). The conductive conduit with NGF (NOGC) showed functional recovery and nerve regeneration (myelination, filament density) comparable with autograft.	A synergistic effect of topographical guidance (from ice-templating), passive electrical cues (from CNTs), and biochemical signals (from loaded NGF) promotes effective nerve regeneration.
GelMA + SWCNTs	DNA-wrapped SWCNTs were incorporated into GelMA hydrogel to improve dispersion and biocompatibility. Electrical conductivity measured via a custom two-point probe.	Passive conductivity platform: Designed as a conductive platform for potential future stimulation; no ES was applied in the study.	Cell types: HUVECs and Schwann cells (SCs). - SWCNTs increased electrical conductivity. - SWCNTs enhanced HUVEC proliferation but negatively impacted protein expression in both HUVECs (CD31, ZO-1) and SCs (S100β, MPZ).	Not performed.	Demonstrates a trade-off: SWCNTs improve electrical properties and initial cell proliferation but may have adverse effects on cell maturation and functionality, highlighting the need for careful optimization.
GelMA + rGO + PCL + EVs	Electrospinning of rGO, GelMA, and PCL to form hybrid nanofibers. The resulting nerve conduit was loaded with BMSC-derived EVs.	Passive conductivity: No external ES applied. The conductivity of rGO provides passive cues.	Cell type: HUVECs. In vitro assays confirmed that BMSC-derived EVs promote angiogenesis (tube formation).	Model: Rat sciatic nerve defect. The EV-loaded conductive conduit significantly improved angiogenesis, myelination, axonal sprouting, and functional recovery compared with the conduit alone.	A multifaceted approach where rGO provides electrical conductivity, the PCL-based conduit offers structural support, and the loaded EVs promote angiogenesis, creating a superior microenvironment for nerve repair.
GelMA + MXene (Ti₃C₂T_x) nanosheets	MXene nanosheets dispersed within a GelMA solution and photocured. Characterized using EIS.	Passive conductivity: No external ES applied.	Cell type: PC12 cells. The GelMA-MX composite hydrogel was biocompatible and supported cell adhesion and proliferation.	Model: Rat peripheral nerve injury (PNI). The GelMA-MX conduit led to significant recovery of sensory and motor function, increased nerve conduction velocity (NCV), and enhanced formation of organized myelinated axons.	The inherent high conductivity of MXene nanosheets provides a favorable electroconductive environment that directly promotes the regeneration and functional recovery of injured peripheral nerves.
GelMA + PPy doped with OCS	Interpenetrating polymer network (IPN) formed from GM, OCS, and OCS-doped PPy conductive nanoparticles.	Passive conductivity: No external ES applied. Designed to interact with endogenous electric fields at the wound site.	Cell types: HUVECs and PC12 cells. Promoted both angiogenesis and neurogenesis. Mechanism involves increasing intracellular Ca²+ concentration.	Model: Diabetic rat wound model. The conductive hydrogel accelerated wound healing by enhancing local neurovascular regeneration.	The conductive hydrogel increases intracellular Ca²+ influx, which activates the PI3K/AKT and MEK/ERK signaling pathways, thereby promoting both angiogenesis and neuroregeneration simultaneously.
GelMA/PEGDA + PEDOT doped with polyphenols	A 3D-bioprinted scaffold using a bioink made of GelMA/PEGDA and PEDOT doped with chondroitin sulfate (CSMA) and TA. NSCs were encapsulated.	Passive conductivity: No external ES applied.	Cell type: NSCs. The polyphenol-doped electroconductive hydrogel (ECH) scaffold provided a benign microenvironment, maintained high NSC viability (>90%) postprinting, and promoted differentiation into neurons rather than astrocytes.	Not performed.	The polyphenol structure in the conductive polymer not only enhances electrical properties but also directly creates a microenvironment that is favorable for neuronal differentiation and inhibits glial scar formation.
GelMA + polyaniline (Pani) (annular electrode)	In situ oxidative polymerization of aniline within a GelMA hydrogel, fabricated into an annular (ring) shape to act as a wireless electrode.	Wireless ES applied: The annular hydrogel acted as a secondary coil, receiving power via electromagnetic induction from an external primary coil (5 kHz, 2 A).	Cell type: Neural stem cells (NSCs). Wireless ES facilitated NSC neuronal differentiation, neurite extension, and the formation of functional neural networks (confirmed by Ca²+ imaging).	Model: Rat ischemic stroke. Implanted annular electrode of the Gel/Pani conductive hydrogel (AECH) with wireless ES significantly ameliorated brain impairment and improved neurological function by activating endogenous neurogenesis.	The novel annular hydrogel design allows for implantable, wireless electrical stimulation. This external control activates endogenous neural repair mechanisms by modulating intracellular Ca²+ signaling, promoting neurogenesis.
GelMA + MWCNTs/cobalt	MWCNTs/cobalt composites were incorporated into a GelMA hydrogel matrix.	External ES applied: Direct current electrical field of 1 V/cm was applied daily for 1 h.	Cell type: Stem cells from apical papilla (SCAP). The conductive scaffold combined with ES significantly enhanced neuronal differentiation and neurite outgrowth.	Not performed.	The synergy between a conductive scaffold (providing the niche) and external electrical stimulation (providing the active signal) greatly enhances the neuronal differentiation of stem cells.
GelMA/Pani annular hydrogel	An annular (ring-shaped) hydrogel was formed by the in situ oxidative polymerization of aniline (Pani) within a GelMA matrix. The final construct is flexible, conductive, and biocompatible.	Wireless ES applied: The annular hydrogel acted as a secondary coil. Wireless ES was achieved via electromagnetic induction from an external primary coil (5 kHz, 2 A), applied for 1 h/day.	Cell type: NSCs. The wireless ES promoted NSC neuronal differentiation, neurite extension, and the formation of functional neural networks, as confirmed by calcium imaging.	Model: Rat ischemic stroke. The implanted annular conductive hydrogel with wireless ES significantly ameliorated brain impairment, improved neurological function, and activated endogenous neurogenesis.	A novel, flexible, and implantable system for wireless ES. The induced current stimulates endogenous neural stem cells, promoting neurogenesis and functional recovery after brain injury.
GelMA/Chitosan/PPy 3D-printed scaffold	A dual-bioink 3D hybrid printing strategy was used. The base bioink (GelMA/chitosan/polypyrrole) creates a stable, conductive support network. A secondary, cell-laden bioink (gel-gelatin) is printed within the base for precise cell deposition.	External ES applied: A stable direct current (DC) electric field of 300 mV cm⁻¹ was applied for 1 h daily for 14 consecutive days.	Cell types: PC-12 and HT-22 cells. The conductive scaffold itself promoted neural differentiation and axon regeneration. ES further enhanced the directional growth of neurites and axons along the scaffold fibers.	Not performed.	The combination of a topographically defined 3D printed structure and external ES provides powerful directional guidance for axonal growth, promoting the formation of aligned, functional neural networks.
GelMA/CNT aligned hydrogel fibers	Aligned hydrogel fibers were created by incorporating CNTs into a GelMA solution via rotating liquid bath electrospinning. This mimics the aligned structure of neural axons.	External ES applied: Direct current stimulation was applied (5 mV for 1 h every 7 days).	Cell types: PC-12 cells and NSCs. The combination of aligned fibers and ES synergistically promoted cell elongation, neurite sprouting, and neuronal differentiation (increased MAP2 and NF expression).	Model: Rat spinal cord injury (T9 transection). The combined treatment (aligned conductive fibers + ES) significantly restored motor function, enhanced remyelination, increased axonal regeneration, and improved tissue conductivity.	Merges regenerative medicine (scaffold) with rehabilitation (ES). The aligned, conductive fibers provide both topographical guidance and an electrical bridge. ES enhances neural regeneration and functional recovery.
GelMA/g-C₃N₄/GO injectable nanofibers	Coaxial electrospinning was used to create core–shell nanofibers with a PLCL core and a GelMA/alginate hydrogel shell. The shell was loaded with photocatalytic g-C₃N₄/GO nanoparticles and NGF. The resulting 2D sheet is injectable.	Wireless optoelectrical stimulation: 450 nm blue light was applied in pulses (1 s ON/1 s OFF) for 30 min every 12 h.	Cell type: PC12 cells. Light stimulation of the photocatalytic nanofibers caused a 36.3% enhancement in neurite extension. - NGF-loaded fibers provided sustained biochemical stimulation for differentiation.	Not performed.	A dual-stimulation system where light activates the g-C₃N₄/GO to generate a local photocurrent, stimulating cells optoelectrically. Simultaneously, sustained NGF release provides biochemical cues for differentiation.
Oriented Chitosan/rGO + GelMA “Artificial Niche”	A multicomponent patch. The core is an oriented chitosan/rGO matrix made by ice-templating. This is coated with a GelMA hydrogel layer that releases chemokines (CXCL12) and antisenescence drugs. The inner matrix is loaded with plant-derived exosomes (L-Exos).	Passive conductivity and ES: The rGO provides inherent conductivity. External electrical stimulation (monophasic cathodic pulses) was used to confirm that the scaffold could induce intracellular Ca²+ flux in PC12 cells.	Cell type: PC12 cells. The oriented, conductive matrix guided directional neurite growth. ES applied to the scaffold successfully triggered an increase in intracellular Ca²+, confirming its electroactive nature.	Model: In situ nerve regeneration in a rat skin wound model. The complete patch successfully recruited endogenous MSCs, promoted their neural differentiation, and accelerated nerve regeneration and sensory function recovery.	A sophisticated “artificial niche” that combines physical cues (oriented structure), electrical cues (rGO conductivity), and a programmed release of multiple biochemical signals to orchestrate in situ nerve regeneration from the body’s own stem cells.

CNT, carbon nanotubes; ES, electrical stimulation; EVs, extracellular vesicles; MSCs, mesenchymal stem cells; MWCNTs, multiwalled carbon nanotubes; NGF, nerve growth factor; NSCs, neural stem cells; PPy, polypyrrole; OCS, oxidized chondroitin sulfate; rGO, reduced graphene oxide; SWCNTs, single-walled carbon nanotubes; TA, tannic acid.

Table 2.

continued

Table 2.

continued

The introduction of conductivity serves as the foundation for applying external ES as a therapeutic modality. Research has shown that even pristine GelMA hydrogels can support peripheral neurite outgrowth under specific ES parameters, suggesting an inherent, albeit weak, responsiveness.³⁴ However, the effect is dramatically amplified in conductive composites. The mechanism by which these conductive scaffolds promote neural regeneration is believed to be rooted in their ability to modulate fundamental cellular processes. These scaffolds can enhance intercellular communication by simulating the native electrophysiological environment, which in turn activates voltage-gated ion channels.⁵¹ This modulation often leads to an increase in intracellular calcium (Ca2+) concentration, a critical secondary messenger that triggers downstream signaling cascades, such as the PI3K/AKT and MEK/ERK pathways, which are instrumental in promoting peripheral neuron survival, differentiation, and axon elongation.

When combined with an external electrical field, these conductive GelMA scaffolds can provide directional guidance for spinal cord axonal growth, encouraging neurites to extend along the path of the electrical current. This synergistic approach has proven highly effective in promoting oriented and accelerated nerve regeneration in vitro and in vivo. The aligned, conductive fibrous scaffolds are particularly noteworthy as they provide both topographical and electrical cues that closely mimic the natural architecture of nerve fascicles.⁵⁰ Moving beyond traditional wired setups, more advanced systems utilize light to trigger a localized electrical response. By incorporating photocatalytic nanoparticles, GelMA hydrogels can be stimulated remotely and noninvasively, representing a significant step toward creating “smart” materials for clinical translation of central nerve regeneration.⁵²

Ultimately, the electrical properties of GelMA hydrogels are not an isolated feature but a foundational component of a multifaceted regenerative strategy. The enhanced conductivity creates a microenvironment that is more conducive to neural growth and synergizes powerfully with other bioactive components. For instance, the electrical cues can work in concert with the neurotrophic and immunomodulatory signals from codelivered biologics like extracellular vesicles or stem cells.^53,54 While conductive GelMA scaffolds alone act as acellular guides, their integration with stem cells (cell-based strategy) creates a synergistic but translationally more complex system. Similarly, modifying conductive polymers with bioactive molecules, such as polyphenols, can concurrently improve electrical properties and the scaffold’s ability to induce neuronal differentiation from neural stem cells.²¹ This integration of electrical responsiveness with physical alignment and biochemical signaling, as seen in oriented artificial niches, is crucial for creating the complex, dynamic microenvironment required for robust and functional nerve regeneration after skin wounds.³⁶

However, the beneficial effects of ES are strictly dose dependent, and defining the optimal safety window is important.^46–48 While appropriate stimulation parameters such as voltage gradient, frequency, and duration enhance regeneration, exceeding the therapeutic threshold can result in adverse effects such as neuronal excitotoxicity, pH fluctuation, Joule heating, or irreversible electrode degradation.^14,55 Thus, future research must focus on establishing standardized stimulation protocols that maximize regenerative outcomes while maintaining the structural integrity of the hydrogel and the viability of the encapsulated cells.

Magnetic field-response

Incorporating responsiveness to magnetic fields represents a highly attractive acellular strategy for developing smart GelMA hydrogels, as magnetic stimulation offers a noninvasive method for remotely controlling the cellular microenvironment with deep tissue penetration. A common approach involves embedding magnetic nanoparticles within the GelMA matrix.²⁵ Once incorporated, these nanoparticles allow for the application of an external magnetic field to create aligned topographical cues that physically guide neural growth. Furthermore, these particles can act as transducers, converting magnetic energy into localized mechanical forces or thermal signals to modulate cell behavior and differentiation.

Beyond creating intrinsically magnetic materials, recent research has explored how external static magnetic fields can directly influence neural and glial cell behavior within nonmagnetic, ionically conductive hydrogels. A significant study demonstrated that applying a static magnetic field could effectively modulate the direction of neurite extension from dorsal root ganglia encapsulated in 3D GelMA scaffolds, without negatively impacting the total amount of neurite outgrowth (Fig. 4A).⁵⁶ This investigation revealed that neurites preferentially organized themselves in a direction perpendicular to the applied magnetic field gradient (Fig. 4B), a finding that contrasts with observations in 2D culture systems where parallel alignment is often reported, thereby highlighting the critical influence of the 3D environment on cellular responses to biophysical stimuli.⁵⁶ The underlying mechanism for this directional guidance is hypothesized to involve the Lorentz force acting on moving ions and charged biomolecules within the hydrogel, creating subtle electrochemical gradients that steer peripheral axonal pathfinding.

FIG. 4.

(A) Comparison of the total neurite outgrowth area across the six different experimental conditions: GelMA control, GelMA + electrical stimulation, GelMA + magnetic stimulation, Gel-Amin control, Gel-Amin + electrical stimulation, Gel-Amin + magnetic stimulation. Four independent trials were conducted (n = 36, 21, 31, 31, 21, 25). Error bars represent the standard deviation. Data were analyzed with a Kruskal–Wallis test with significant differences denoted by ∗ and ∗∗ representing p values of <0.05 and <0.01. (B) GelMA + magnetic stimulation (n = 31). Four independent trials of this experiment were conducted. Significant differences were determined with a Wilcoxon rank-sum test (nonparametric paired t test) and denoted with ∗ representing a p value of <0.05. All error bars represent the standard deviation. Reproduced from Neuman et al., CC BY 4.0.⁵⁶

Conclusion and Future Perspectives

In this review, GelMA hydrogels have been firmly established as a premier platform in both central and peripheral nerve regeneration. Table 3 shows the comparison of GelMA engineering strategies for these two models. Despite recent progress, several challenges must be addressed to translate the promise of GelMA hydrogels from the laboratory to clinical practice. First, there is the challenge of accurately mimicking the in vivo microenvironment. The native process of nerve regeneration is not static; it is a dynamic cascade of cellular and molecular events that evolves over time.¹ Most current GelMA scaffolds provide a fixed set of cues, whereas the ideal scaffold should adapt its physical and biochemical properties in concert with the distinct stages of healing, from the initial inflammatory phase to long-term tissue remodeling.⁴⁶ Second, achieving true synergy among multiple therapeutic strategies remains a complex optimization problem. Integrating features like electrical conductivity with the sustained release of NTFs is a promising concept, but the interactions between these components are not fully understood. For instance, an applied electrical field could alter the release kinetics of charged biomolecules, or the degradation of the scaffold could change its conductive properties over time.⁵⁷ Maximizing the benefit of each component without unintended interference is a significant hurdle. Third, the long-term biological safety and immune response of GelMA implants require deeper investigation. While GelMA is considered highly biocompatible, the complete fate of its degradation products and any incorporated nanomaterials, such as graphene or conductive polymers, within the body over extended periods is not fully known. The potential for chronic inflammation or foreign body responses could compromise regenerative outcomes and must be thoroughly evaluated in relevant long-term animal models. Finally, a substantial gap exists between laboratory research and clinical application. This translational chasm is defined by challenges in scalable manufacturing under Good Manufacturing Practice (GMP) standards, ensuring batch-to-batch consistency, and developing reliable sterilization methods that do not compromise the properties of materials.⁵⁸ Furthermore, the lack of standardized protocols for preclinical evaluation and the complex, costly regulatory pathways for advanced therapeutic products present major barriers to widespread clinical adoption.

Table 3.

Comparison of GelMA Engineering Strategies for CNS Versus PNS Regeneration

Feature	CNS	PNS
Pathological environment	Inhibitory molecules, glial scar, cystic cavities, irregular lesion shapes.	Permissive but limited by gap length, Wallerian degeneration, muscle atrophy.
Primary therapeutic goal	Overcoming inhibition, immunomodulation, filling defects.	Physical guidance (bridging gaps), accelerating growth speed.
Preferred GelMA form	Injectable hydrogels (in situ photocrosslinking) to fill cavities minimally invasively.	NGCs, 3D-bioprinted scaffolds with aligned channels.
Key functionalization	Gene silencing (siRNA), anti-inflammatory agents, pH buffering.	Electrical conductivity, topographical alignment, growth factor gradients.

CNS, central nervous system; NGCs, nerve guidance conduits; PNS, peripheral nervous system.

More importantly, the inherent versatility of GelMA comes with a limitation. The physicochemical properties of the hydrogel are highly sensitive to synthesis and crosslinking parameters.²³ Several factors can result in significant discrepancies in material performance across different studies. These factors include the source of gelatin, such as porcine versus bovine or Type A versus Type B.³¹ Bloom strength serves as a proxy for molecular weight and is also a key variable. Additionally, the precise method used to quantify the degree of methacrylation matters. For instance, variations in proton NMR integration methods can affect the results.²³ Furthermore, the crosslinking process itself introduces variability. Even for GelMA with the same degree of methacrylation, the final stiffness and porosity of the scaffold can change drastically. This depends on the type of photoinitiator, such as Irgacure 2959 or LAP.^31,59 Other critical factors include the concentration, light wavelength, and light intensity.⁶⁰ Thus, this review emphasizes the need for standardized reporting protocols. Future studies should explicitly detail these parameters to improve reproducibility and comparability. The field requires a minimum information standard for GelMA bioinks. This ensures that biological outcomes are accurately interpreted and replicated.

Despite these challenges, the future of GelMA-based nerve regeneration therapies remains promising. Beyond the immediate translational goals, several exciting avenues are poised to overcome current limitations and unlock new therapeutic possibilities. One of the most promising directions is the development of more intelligent, multiresponsive “fourth-generation” biomaterials. Moving beyond simple responses to single stimuli like pH or temperature, these advanced hydrogels could be engineered to sense multiple, subtle cues from the injury microenvironment.⁴³ They could then process this information and execute complex, preprogrammed therapeutic actions, such as releasing different factors sequentially to match the temporal profile of natural healing. This would represent a shift from responsive to truly autonomous biomaterials.

The integration of artificial intelligence (AI) and machine learning offers a valuable tool to manage the immense complexity of scaffold design.¹⁶ Instead of relying on laborious trial-and-error experimentation, AI algorithms can analyze vast datasets to predict how specific combinations of material properties, bioactive factors, and structural designs will influence regenerative outcomes. This approach will enable the rapid in silico optimization of highly sophisticated, multifunctional hydrogels tailored for specific nerve injury types.

To bridge the gap between preclinical models and human biology, GelMA will be increasingly combined with organoid and organ-on-a-chip technologies. By using GelMA to bioprint 3D neural organoids from human induced pluripotent stem cells (iPSCs), researchers can create highly relevant in vitro models. These platforms will allow for high-throughput screening of novel therapeutic agents and mechanistic studies of nerve injury and repair in a human-specific context, accelerating the development of effective therapies.¹⁴ Although technological progress is evident, substantial regulatory barriers persist. A major concern is the prevalence of animal-derived gelatin in current preclinical studies. Reliance on these sources introduces significant risks regarding pathogen transfer, immunogenic reactions, and lot-to-lot inconsistency. To satisfy clinical requirements, it is imperative to transition toward GMP-grade materials, specifically prioritizing recombinant or plant-based alternatives, while ensuring complete supply chain traceability.⁶¹ Furthermore, chemical agents used in synthesis, particularly photoinitiators like Irgacure for GelMA, must undergo rigorous biocompatibility testing to rule out cytotoxicity. From a regulatory standpoint, these hydrogel nerve conduits are expected to be classified as medical devices, or potentially as combination products if they incorporate therapeutic drugs or biologics. Obtaining approval will require comprehensive documentation, including evidence of efficacy in large animal models, alongside data on long-term safety and material degradation. Moreover, prior to initiating human trials, the hydrogels must satisfy strict standards concerning sterility, endotoxin limits, and the retention of mechanical properties following sterilization. Ultimately, accelerating the clinical translation of these technologies depends on fostering strong collaborative networks among material scientists, neurosurgeons, regulatory experts, and industry stakeholders. Consequently, while simple GelMA scaffolds could realistically enter clinical trials within the next 3–5 years, the advanced, multifunctional platforms integrated with AI-driven designs and gene therapy likely represent a long-term horizon of about 10 years, contingent upon the standardization of rigorous quality control measures and the establishment of clearer regulatory guidelines for complex bio-integrative materials.

Ultimately, these advancements will converge toward the goal of personalized and precise regenerative medicine. In the future, it is conceivable that a patient’s specific nerve injury could be detailed using high-resolution imaging. AI could then design a custom-fit, patient-specific scaffold, which would be 3D bioprinted using a GelMA-based bioink containing the patient’s own cells. This personalized construct would provide the ideal structural, cellular, and molecular support needed to orchestrate a robust and functional nerve repair, representing a new era in the treatment of neural injuries.

Authors’ Contributions

S.C. and Y.C. contributed to conception and design, acquisition of data, analysis and interpretation of data, and drafted the article. Y.W. contributed to acquisition of data, analysis, and interpretation of data. C.L. contributed to review critically for important intellectual content and gave final approval of the version to be published. All authors contributed to editorial changes in the article. All authors read and approved the final article.

Footnotes

Acknowledgments

The authors thank all their laboratory members for their helpful and constructive comments on the article.

Consent for Publication

On behalf of all authors, the corresponding author has given the consent for the publication.

Author Disclosure Statement

The authors declare that they have no competing interests.

Funding Information

No funding was received for this article.

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