Neuro-Instructive Hydrogels - A Key to Sensory Innervation in Oral Tissues: A Comprehensive Review

Abstract

Current treatments for oral tissue defects restore structure but rarely restore sensory nerves. Tissues without innervation lose protective reflexes and long-term stability. This review examines neuro-instructive hydrogels designed to guide nerve regeneration in oral tissues. We discuss four design mechanisms: physical cues that direct axon growth, spatiotemporal release of neurotrophic signals, regulation of oral stem cells and Schwann cells, and immunomodulation that supports a pro-regenerative niche. We then map these mechanisms onto three clinical scenarios: regeneration of the dentin-pulp complex, reconstruction of innervated jawbone, and repair of oral mucosal nerves. The oral environment imposes specific constraints (saliva, chewing forces, and a rich microbiome) that call for wet-adhesive, antibacterial, and mechanically adaptable designs. Bioprinting offers a route to patient-specific constructs with controlled architecture, and emerging tools such as stimuli-responsive release and machine learning guided formulation may further improve precision. Key next steps include scalable production under Good Manufacturing Practice, large-animal validation, and objective clinical endpoints for sensory recovery. The central goal is to move oral tissue repair from structural filling toward restoration of sensation.

Graphical Abstract

Introduction

About 2 billion people have untreated caries in permanent teeth worldwide, and oral conditions in total affect almost half of the global population.¹ Among patients receiving chemotherapy or radiotherapy for head and neck cancer, about 40% to 80% develop oral mucositis, often with neuropathic pain.² Current treatments can repair the structure of damaged oral tissues, but they rarely restore sensory nerves.^3,4 Root canal treatment, for example, removes infection but leaves the tooth non-vital and without sensation. Such teeth become brittle and lose their defense mechanisms, so their long-term survival is reduced.^5,6 Bone grafts and synthetic materials used to repair jaw defects can achieve bony union, but they do not rebuild the nerve-bone network needed for bone metabolism and sensory feedback.^7,8 Grafted bone without sensory and sympathetic nerves often shows poor metabolism and low long-term stability. This is one reason why grafts placed in infected sites often fail.⁹ Alveolar bone repair faces the same problem: current methods fill the defect but rarely rebuild a functional nerve-bone network, which is needed to maintain bone health under chewing forces.¹⁰ For oral mucositis, most treatments only relieve pain and do not repair the damaged nerves.^11,12 These examples point to one shared problem. Most current biomaterials are passive. They provide space for tissue growth but cannot actively guide nerve regeneration.^13,14

Peripheral nerve regeneration follows a conserved biological program, and any biomaterial strategy must work with it. After nerve injury, the distal part of the nerve undergoes Wallerian degeneration. Schwann cells then change into a repair phenotype and align inside the basal lamina tubes of the degenerating nerve. There they form longitudinal cords called the bands of Büngner, which guide regenerating axons back to their targets.^14,15 Successful regeneration therefore needs physical guidance, sustained trophic support, and a permissive immune environment. Hydrogels are a diverse material family suited to this task. Natural hydrogels such as collagen, fibrin, hyaluronic acid, alginate, and chitosan offer inherent bioactivity; synthetic hydrogels such as polyethylene glycol and polyacrylamide offer defined and reproducible properties; and hybrid systems combine both. Physically crosslinked gels allow injectable, minimally invasive delivery, whereas covalently crosslinked gels provide greater mechanical stability.^16–18

Oral tissues have a developmental feature that favors nerve regeneration. Dental pulp, dentin, periodontal ligament, and much of the jawbone all derive from the cranial neural crest.¹⁹ Because of this origin, these tissues and their stem cells retain a natural potential to form neural cells.^3,20 Dental pulp stem cells (DPSCs), for example, express neural crest markers and tend to differentiate into neuronal and glial cells even under normal culture conditions.²¹ This property has practical value. It means that oral stem cells might serve as a local source of Schwann-like support cells. DPSCs differentiated toward Schwann-like phenotypes have been used to build aligned tissue-engineered constructs that guide neurite outgrowth in vitro,²² and tooth-derived stem cells have improved nerve repair in animal models of facial and sciatic nerve injury.^23,24 Nerves are not only sensors. In dental pulp, the dense nerve network also controls dentin formation, blood flow, and inflammation.^3,25 In bone, the neurotransmitters CGRP and substance P regulate osteoblast and osteoclast activity,^25–27 and animal studies showed that bone maintenance declines after denervation.^25,26 However, most of this evidence came from denervation models and cell studies. Direct evidence that restoring neuropeptide signaling can repair human bone defects is still limited. This is exactly the gap that innervated hydrogels aim to fill.^26,28 True functional regeneration, as opposed to structural infill, therefore depends on the reconstruction of neural networks.^23,26

Hydrogels have become leading candidates for this task because of their high water content, tunable softness, and three-dimensional porous structure.^16,17 The first hydrogel systems used in oral regeneration, such as the fibrin-based blood clot in regenerative endodontics, acted mainly as passive scaffolds.^5,29–31 The blood clot showed that a three-dimensional matrix can recruit host cells,^5,29 but its composition is uncontrolled and its bioactivity is weak. Later engineered hydrogels were more stable, but they still could not actively direct complex processes such as nerve regeneration.^30,31 The field has therefore moved toward neuro-instructive hydrogels, which are designed to act as active guides rather than passive carriers.³² Two cornerstone studies support this concept. A cell-free and growth factor-free hydrogel induced both blood vessel and nerve ingrowth after subcutaneous implantation, showing that material properties alone can recruit host neural elements.³³ An injectable bioceramic-containing composite hydrogel promoted innervation during pulp-dentin repair, confirming the concept in a dental setting.³⁴ By acting as slow-release depots for neurotrophic factors, as topographical templates for axon guidance, or as carriers for therapeutic cells, neuro-instructive hydrogels now offer a promising route to functional nerve regeneration in oral tissues.^35–37 Bioprinting can further improve these systems by producing hydrogel constructs with biomimetic architecture and defined spatial distribution of cells and factors.^6,13,38–40

A careful reading of the literature reveals a common limitation of previous reviews. They usually treat innervation as a secondary outcome rather than a central design target. This review therefore proposes a specific hypothesis: the decisive step toward functional oral regeneration is the transition from passive scaffolds to bioinstructive hydrogel systems, and the value of any individual system should be judged by the strength of its neural evidence, not merely by positive marker expression. Following this hypothesis, we first explain the four core design principles that give hydrogels their neuro-guiding function: topographical guidance, molecular signal control, cellular orchestration, and immunomodulation. We then apply these principles to three clinical scenarios: pulp-dentin complex regeneration, innervated jawbone reconstruction, and oral mucosal nerve repair. Throughout the review, we compare stronger with weaker evidence and state the limitations of representative systems. Finally, we discuss the translational pathway, including manufacturing, regulation, and the key role of bioprinting, with attention to what makes the oral environment different from other regenerative settings.

What Do We Understand About Neuro-Instructive Hydrogels?

The performance of neuro-instructive hydrogels comes from their ability to mimic key features of the natural neural microenvironment. By combining physical, chemical, biological, and immunomodulatory cues, these materials can guide the complex process of nerve regeneration. We group these design principles into four connected mechanisms (Figure 1). For each mechanism, we first summarize the main evidence and then discuss its strengths and limitations.

Figure 1.

Schematic overview of the four core mechanistic pillars of neuro-instructive hydrogels for oral nerve regeneration. Created in BioRender. c, Y. (2026) https://BioRender.com/5ufil0o.

Physical Cues for Axonal Guidance and Neural Differentiation

The microstructure, porosity, stiffness, and surface pattern of a hydrogel are the most basic physical cues that affect cell behavior. These cues are especially important for nerve regeneration. An ideal three-dimensional scaffold must support the tissue mechanically, allow the exchange of nutrients and waste, and give physical guidance for cell migration and axon growth.⁴¹

Directional nerve growth depends strongly on topographical guidance. During natural peripheral nerve repair, a fibrin cable forms and guides Schwann cells and axons across the injury site. Inspired by this structure, Du et al built a fibrin nanofiber hydrogel with hierarchically aligned fibers that copies the anisotropic structure of native nerve bundles.³⁶ The aligned fibers gave clear physical guidance and markedly accelerated Schwann cell migration and axon regeneration compared with random scaffolds.^18,36 The same principle works in other systems. Aligned collagen I hydrogels can organize DPSC-derived Schwann-like cells into longitudinal columns, which form physical channels for axon growth.²² A nano-hyaluronic acid hydrogel with an anisotropic structure induced neural differentiation of mesenchymal stem cells from the wisdom tooth follicle.⁴² Together, these studies show that nanoscale surface patterns can direct neural differentiation even without added biochemical factors. Their shared limitation is that aligned structures have so far been tested mainly in vitro or in simple defect shapes. Producing such aligned structures inside irregular oral defects remains technically difficult.

The softness of the hydrogel is another key parameter. Neural tissues are very soft, and soft hydrogels tend to promote neural differentiation more effectively. Ansari et al encapsulated human periodontal ligament stem cells and gingival mesenchymal stem cells in soft, RGD-coupled alginate/hyaluronic acid hydrogels. The soft microenvironment increased the expression of the neural markers βIII-tubulin and GFAP.³⁷ However, higher marker expression in vitro does not prove that functional neurons have formed. In vivo confirmation of this mechanical effect is still limited.

A newer strategy goes beyond passive physical support and uses the electrical nature of neural tissue. Conductive hydrogels mimic the natural electrical microenvironment and can enhance nerve repair. For example, an injectable, self-healing conductive hydrogel made from carboxymethyl chitosan grafted with polyaniline promoted Schwann cell migration and axon remyelination. The effect was attributed to the restoration of bioelectrical signal transmission.⁴³ At the molecular level, such hydrogels raise intracellular Ca²⁺ levels and activate the PI3K/AKT and MEK/ERK pathways, which support neuronal survival and differentiation.⁴⁴ Another self-healing conductive hydrogel (HASPy) acts on the IL-17RA receptor and activates IL-17 signaling, which increases the expression of myelin-related genes in Schwann cells.⁴⁵ A related injectable, self-healing, conductive hydrogel based on extracellular matrix components improved tissue repair after spinal cord injury, confirming the broader potential of electroactive scaffolds.⁴⁶ To our knowledge, few studies have evaluated conductive hydrogels in oral models, where the wet and bacteria-rich environment may compromise their performance. Their long-term electrical stability and degradation safety in vivo also remain unclear. Whether these systems can promote sensory nerve regeneration in the pulp, jawbone, and oral mucosa therefore remains an open question.

Spatiotemporal Molecular Signaling for Neural Differentiation

Physical cues set the stage, while the spatiotemporal presentation of biochemical signals directs the cellular script of nerve regeneration. Hydrogels can work as local, slow-release depots for neurotrophic factors. This approach avoids the short half-life and systemic side effects of conventional drug delivery.^18,47

The simplest strategy is to load one growth factor into the hydrogel. Chitosan-based hydrogels are biocompatible and adhere well to mucosa, and they have been used to deliver basic fibroblast growth factor (bFGF). DPSCs grown in bFGF-loaded chitosan hydrogels showed much higher expression of the neural markers GFAP, S100β, and β-tubulin III within 7 days.⁴⁸ Similar systems delivering nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) also promoted neural differentiation of several oral stem cell types.^21,49 In a related example, NGF-loaded formulations promoted corneal nerve repair, showing that local NGF delivery can restore sensory nerves in different tissues.⁵⁰ A general weakness of single-factor delivery is that nerve regeneration needs signals in a changing sequence, not at a constant level. Most current systems cannot yet provide such time-dependent release.

More advanced systems aim for synergy through co-delivery. Lei et al designed an injectable thermosensitive hydrogel containing mesoporous silica nanoparticles for the slow co-release of microRNA-222 and aspirin.³⁵ The system worked through two mechanisms at once: microRNA-222 promoted the neural differentiation of human bone marrow mesenchymal stem cells through the Wnt/β-catenin pathway, while aspirin supported bone formation and reduced inflammation. In a rat mandibular defect model, this combination produced what the authors called innervated bone regeneration.³⁵ Other examples include hydrogels loaded with human platelet lysate⁵¹ and, more recently, silk fibroin/alginate hydrogels carrying angiogenic apoptotic vesicles.⁵² Both systems enhanced vascularization together with the neurogenic potential of DPSCs. A CGRP-loaded, ROS-responsive hydrogel restored neuro-angiogenic signaling and promoted bone regeneration in diabetic periodontitis, showing the therapeutic potential of neuropeptide delivery for innervated bone repair.²⁸ However, co-delivery increases formulation complexity. In most studies, the release kinetics of each agent were not optimized separately or tested over long periods.

The most biomimetic strategy uses decellularized extracellular matrix (dECM) hydrogels. These materials come from native tissues and naturally contain a tissue-specific mixture of structural proteins and bioactive factors. Liang et al directly compared a porcine dental pulp matrix hydrogel with a peripheral nerve matrix hydrogel.⁵³ The dental pulp matrix performed at least as well as the nerve matrix in promoting the neural differentiation of DPSCs in vitro and nerve regeneration in vivo. This suggests that dental pulp dECM carries a signaling environment that is well suited to oral tissue regeneration.⁵³ Several other studies support this conclusion. An injectable xenogeneic dental pulp dECM hydrogel promoted functional pulp regeneration by supporting both odontogenic and neurogenic differentiation of DPSCs.⁵⁴ A human dental pulp dECM hydrogel promoted DPSC proliferation, migration, and differentiation toward several lineages, including neural lineages.⁵⁵ Primary research has also confirmed that DPSCs have an inherent ability to support reinnervation when seeded in suitable scaffolds.^22,56 The main weaknesses of dECM strategies are batch-to-batch variation between donor tissues, incomplete knowledge of the active components, and the regulatory difficulty of animal- or human-derived materials. These issues must be solved before clinical use.

Orchestrating Cellular Behavior for Nerve Repair

Hydrogels can do more than provide structure and signals. They can also carry therapeutic cells to the injury site or recruit and guide the body’s own cells, thereby supplying the cellular building blocks of nerve repair directly. Much attention has focused on Schwann cells, which support, guide, and myelinate axons in the peripheral nervous system. Transplanting Schwann cells within hydrogels can markedly improve nerve repair.^24,57 Other cell types also matter, including neuronal progenitors, glial cells, and oral-derived stem cells. These cells often work together with Schwann cells inside the hydrogel matrix.

Early key work showed the plasticity of oral-derived stem cells. Human DPSCs differentiated into functional Schwann-like cells inside a 3D collagen hydrogel. These cells expressed typical Schwann cell markers, secreted neurotrophic factors, and, most importantly, guided neurite growth from dorsal root ganglion neurons. The resulting structures resembled the bands of Büngner, the longitudinal Schwann cell cords that form inside the basal lamina tubes of degenerating nerves and steer regenerating axons.^22,58 The ability of DPSCs to adopt a Schwann-like phenotype and support nerve regeneration has been reported repeatedly.^21,23 In detail, DPSCs can generate Schwann-like cells (positive for S100β and GFAP), oligodendrocyte-like cells, and neuronal-like cells (positive for Tuj1 and MAP2).²¹ These lineages have been incorporated into engineered nerve conduits and cell-hydrogel constructs, but their evaluation so far is limited to animal models, such as facial nerve and sciatic nerve defect models. To date, no human trial of DPSC-based nerve repair has been reported.^23,24

Hydrogels can also improve the therapeutic value of other oral stem cells. Alginate/hyaluronic acid systems help periodontal ligament stem cells release NGF and undergo neural differentiation.³⁷ Primary research has shown that 3D collagen I hydrogels can organize DPSC-derived Schwann-like cells into longitudinal columns that form physical channels for directed axon growth.²² Cell-free strategies are developing in parallel. Extracellular vesicles from Schwann cells carry bioactive cargo that can activate pro-regenerative pathways in nerve, blood vessel, and bone tissue, and they can be delivered by hydrogel carriers.⁵⁸ Cell-free therapies reduce, but do not abolish, immunogenicity concerns. Allogeneic extracellular vesicles can still be recognized by the host immune system. Their cargo also varies with the state of the donor cells and the isolation method, and dosing standards are not yet established.⁵⁸ Readers should keep these points in mind when comparing cell-based and cell-free approaches.

Recent Schwann cell research outside the hydrogel field also deserves attention, because it defines both the benchmark and the boundary for material-based strategies. At the RNA level, the protein isoforms QKI-6 and QKI-7 control the lineage progression of human Schwann cells and enhance peripheral nerve regeneration.⁵⁹

Epigenetic control matters too: delaying the histone deacetylase response after injury speeds up the conversion of Schwann cells into the repair phenotype and accelerates regeneration, identifying HDAC inhibitors as possible drug partners.¹⁵ These regulatory tools act upstream of what scaffold structure alone can achieve. They are not, however, out of reach for material platforms. Hydrogels can serve as local depots for nucleic acids and small-molecule drugs, so these regulators could in principle be delivered together with a neuro-instructive scaffold. Physical stimulation is another material-free route. Low-intensity pulsed ultrasound promoted peripheral nerve regeneration by reducing Schwann cell pyroptosis.⁶⁰ On the other hand, hydrogel strategies keep one clear advantage. Schwann cells encapsulated in a chitosan-collagen hydrogel nerve conduit performed better than cell-free conduits and silicone tubes in rat sciatic nerve defects.⁵⁷ This shows that a biomaterial carrier is needed to keep transplanted cells in place and functional. Overall, non-material approaches and neuro-instructive hydrogels are complementary rather than competing. The unique value of the hydrogel paradigm is that it can combine Schwann cell support with structural, molecular, and immunomodulatory cues in one spatially organized platform. This combination is the most likely to succeed in the confined and contaminated environment of the oral cavity.

Two further qualifications apply to the cell-based literature. First, most evidence for dental-derived cells in nerve regeneration comes from in vitro studies and small-animal models. Neural outcomes are usually measured by marker expression, while functional tests such as electrophysiology or behavioral analysis are rare.⁶¹ The distance to clinical use should not be understated. Second, many dental stem cells, such as stem cells from human exfoliated deciduous teeth and stem cells from the apical papilla, come from young donors. Their research and future therapeutic use require informed consent from donors or guardians and ethical approval of tissue sourcing. This point is rarely stated in the hydrogel literature, but it is essential for responsible translation.

Immunomodulation to Foster a Pro-Regenerative Niche

After tissue injury, the immune response has two faces. Short-term inflammation is needed to clear debris. But long-lasting or excessive inflammation, often driven by M1-type macrophages, creates a hostile microenvironment that blocks nerve regeneration and increases pain.¹⁸ A key function of advanced neuro-instructive hydrogels is therefore to shift this balance toward a pro-regenerative, anti-inflammatory state linked to M2-type macrophages.⁶² Table 1 compares the roles of M1 and M2 macrophages in health and disease and their relevance to nerve regeneration.

Table 1.

Comparison of M1 and M2 Macrophages and Their Roles in Health, Oral Disease, and Neural Regeneration

Feature	M1 Macrophages (Classically Activated)	M2 Macrophages (Alternatively Activated)
Activation signals	IFN-γ, lipopolysaccharide, TNF-α	IL-4, IL-10, IL-13
Characteristic markers	CD86, CD80, iNOS, MHC-II	CD206, CD163, Arg1
Secretory profile	TNF-α, IL-1β, IL-6, IL-12, reactive oxygen species, nitric oxide	IL-10, TGF-β, VEGF, PDGF, neurotrophic factors
Role in tissue health	Host defense, pathogen killing, clearance of debris in the acute phase after injury	Resolution of inflammation, tissue remodeling, angiogenesis, matrix deposition
Role in oral disease states	Sustained M1 activity drives pulpitis, periodontitis, and mucositis progression; promotes tissue destruction and pain sensitization	M2 activity accompanies the repair phase; insufficient or delayed M2 switching is associated with chronic oral inflammation
Effect on nerve regeneration	Inhibitory: persistent inflammatory cytokines impair axonal growth and Schwann cell function and amplify neuropathic pain18	Supportive: secretion of neurotrophic factors and matrix components supports Schwann cell activity and axonal regeneration18
Hydrogel-based modulation strategies	ROS-scavenging and anti-inflammatory release systems to limit excessive M1 responses62	M2-polarizing designs, including surface-engineered hydrophobic hydrogels62 and dental pulp-derived dECM hydrogels63

Several hydrogel systems can actively promote M2 polarization and thereby build a favorable niche for nerve repair. The surface-engineered hydrophobic hydrogel developed by Zhang et al provides ROS-responsive pain relief, promotes M2 polarization, lowers inflammatory cytokine levels, and enhances the regeneration of epithelial, vascular, and neural structures, shown by increased expression of the neural marker NF200.⁶² However, this study has limitations. It used a small-animal model with only 7 days of observation. NF200 is a structural marker and does not prove functional sensory recovery. The useful release window of ROS-responsive systems in chronically inflamed oral tissue is unknown, and long-term degradation and safety were not tested.⁶² An injectable hydrogel made from decellularized dental pulp matrix was also reported to shift macrophages toward an M2 phenotype, indirectly creating a neuro-regenerative niche during dentin repair.⁶³ This evidence is indirect, because the study did not separate the effect of immunomodulation from the inherent bioactivity of the matrix.⁶³ Together, these examples support M1/M2 balance modulation as an increasingly used design principle. At the same time, they show that the causal link between immunomodulation and neural outcomes still needs stronger proof.

Other immunomodulatory pathways have also been used to reduce pain and support repair. The sprayable NAHAO^® hydrogel, designed for chemotherapy-induced oral mucositis, reduced pain-related behaviors by blocking the COX-2/PGE2 pathway, a key driver of inflammation and pain sensitization.¹¹ The IL-17/MAPK signaling axis, which is central to chronic inflammation, has also been targeted by advanced hydrogel systems to reduce inflammatory cytokines and promote mucosal nerve regeneration.⁶² These examples show that immune modulation can work through several molecular pathways that do not directly involve M1/M2 polarization but still create a more permissive environment for nerve repair. Other emerging ideas include hydrogel delivery of anti-inflammatory cytokines, macrophage-recruiting peptides, and reactive oxygen species scavengers, although their use in oral nerve regeneration is still at an early stage. Overall, immunomodulatory design is a critical frontier for durable sensory reinnervation in oral tissues, but its mechanistic claims need more rigorous testing.

Applications of Neuro-Instructive Hydrogels in Oral Tissue Regeneration

The design strategies described above become clinically meaningful only when they are applied to specific oral tissue defects. Different oral tissues have different regenerative needs. Dental pulp needs simultaneous rebuilding of nerve and blood vessel networks to restore sensation. Jawbone needs nerve-bone synergy to form metabolically active, innervated bone. Oral mucosa needs a shift from passive pain relief to active nerve regeneration.

Two caveats apply to all the evidence discussed below. First, almost all published studies in this field report positive results. Negative or failed results are rarely published, so this publication bias should be kept in mind when judging any single claim. Second, the strength of evidence varies widely, from marker-level in vitro findings to functional recovery in vivo. To make these differences clear, Table 2 shows representative studies by model type, neural outcome measure, and key limitations. In this section, we therefore pair each hydrogel system with a short appraisal of its evidence rather than treating all findings as equal. Three applications are examined: dentin-pulp complex regeneration through neuro-vascular coupling, innervated jawbone reconstruction through bone-nerve synergy, and oral mucosal nerve repair from analgesia to active neurogenesis.

Table 2.

Representative Neuro-Instructive Hydrogel Systems for Sensory Reinnervation in Oral Tissues

Hydrogel System	Composition/Carrier	Mechanism	Application	Model Type	Neural Outcome	Limitation	Refs
SLan self-assembling peptide + iPSC-derived CNCLCs	VEGF-mimetic peptide hydrogel	Recapitulation of developmental cues; neuro-vascular coupling	Pulp regeneration	Immunodeficient mouse, in vivo	Vascularized pulp-like tissue with Tuj1-positive neural-like structures	No functional neural testing; tumorigenicity not assessed; immunodeficient host	[19]
Fibrin hydrogel + SCAPs	Fibrin	Natural matrix niche supporting neurogenic differentiation	Pulp regeneration	In vitro	Upregulation of GDNF and NT-3	In vitro only; no in vivo validation	[29]
Dental pulp dECM hydrogel	Porcine dental pulp matrix	Tissue-specific signaling (TGF-β, Wnt, Notch)	Pulp regeneration	In vitro and in vivo	Increased MAP2 and S100 expression	Active matrix components undefined; batch variability	[53]
Xenogeneic dental pulp dECM hydrogel	Injectable dECM	Odontogenic and neurogenic differentiation support	Functional pulp regeneration	In vivo	Functional pulp-like tissue regeneration	Not orthotopic root canal model; immunogenicity and batch consistency	[54]
dECM-functionalized hydrogel microspheres	Dental pulp matrix microspheres	3D pulp-specific microenvironment	Pulp-dentin complex	Small animal, in vivo	Neurogenic differentiation of DPSCs	Small-animal models; neural outcomes remain marker-based.	[64]
Carbon dot-based photo-cross-linked GelMA	GelMA + carbon dots	Enhanced angiogenic and neural differentiation	Pulp regeneration	Ectopic, in vivo	Vascular-rich pulp-like tissue; neural marker expression	Ectopic model; short observation period; marker-level evidence	[65]
Silk fibroin/alginate + apoptotic vesicles	ApoV-laden composite hydrogel	Focal adhesion signaling; neuro-angiogenic induction	Pulp regeneration	In vivo	Vascularized pulp tissue with neuronal extensions	Vesicle cargo reproducibility and long-term safety unknown	[52]
miR-222/MSN/ASP thermosensitive hydrogel	Colloidal hydrogel + mesoporous silica	Co-delivery; Wnt/β-catenin-mediated neurogenesis	Mandibular bone regeneration	Rat mandibular defect	New bone with high Tuj1 and S100 expression	Single study; not independently replicated	[35]
CGRP-loaded ROS-responsive hydrogel	ROS-responsive hydrogel	Neuropeptide delivery; neuro-angiogenic signaling	Bone regeneration in diabetic periodontitis	Rodent, in vivo	Restored neuro-angiogenic signaling and bone formation	Replication in large animals pending	[28]
Surface-engineered hydrophobic hydrogel	Cholesterol micelle-rearranged hydrogel	ROS-responsive analgesia; IL-17/MAPK modulation; M2 polarization	Oral mucositis	Mouse, in vivo	Regeneration of NF200-positive nerve fibers	No functional sensory testing; short-term evaluation	[62]
NAHAO® sprayable hydrogel	Sprayable hydrogel	COX-2/PGE2 pathway inhibition	Chemotherapy-induced oral mucositis	Rat and preliminary clinical study	Reduced pain behaviors; clinical analgesic efficacy and safety	Neural regeneration not directly assessed in humans	[11,66]
RGD-coupled alginate/hyaluronic acid + PDLSCs/GMSCs	Low-modulus composite hydrogel	Mechanical softness plus cell delivery	Mucosal and nerve regeneration	In vitro	Upregulation of βIII-tubulin, GFAP, and NGF release	In vitro only	[37]

Tissue-Specific Regenerative Demands and Hydrogel Design Responses

Dentin-Pulp Complex Regeneration Through Neurovascular Coupling

Dental pulp is a highly innervated tissue. Its functional regeneration needs not only a dentin bridge but also the simultaneous rebuilding of nerve and blood vessel networks. This neuro-vascular coupling need has pushed hydrogel design from passive scaffolding toward active instruction. Because dental pulp derives from the cranial neural crest, Kobayashi et al combined a self-assembling peptide hydrogel (SLan), which contains a VEGF-mimetic domain, with iPSC-derived cranial neural crest-like cells. In vivo, this combination regenerated pulp-like tissue with rich vascularization and Tuj1-positive neural-like structures, showing the close link between angiogenesis and neurogenesis.^19,20 This work shows that copying developmental signals, rather than simply providing structural support, can enhance neuro-vascular regeneration. However, several limitations should be noted. The study used immunodeficient mice, which limits extrapolation to normal patients. Deriving cranial neural crest-like cells from iPSCs is time-consuming and carries a residual tumor risk. The Tuj1-positive structures were identified by morphology only, without functional tests of neural transmission. The long-term stability of the new blood vessels was also not evaluated¹⁹ (As shown in Figure 2).

Figure 2.

Integrated overview of the components required for dentin-pulp complex regeneration with neuro-instructive hydrogels. Created in BioRender. c, Y. (2026) https://BioRender.com/of0qxrm.

By mimicking the extracellular matrix, hydrogels provide a 3D environment that supports the neural differentiation of dental-derived stem cells. Fibrin hydrogel supports the survival, proliferation, and neural differentiation of stem cells from the apical papilla and increases the expression of the neurotrophic factors GDNF and NT-3.²⁹ This shows the value of early, natural matrix-inspired hydrogels in building a pro-neurogenic niche.²⁹ Beyond generic matrix mimics, tissue-specific matrix hydrogels show unique advantages. Decellularized dental pulp matrix hydrogel strongly promotes the neural differentiation of DPSCs, at levels comparable to nerve-derived matrix hydrogel. In vivo, the dECM group showed higher expression of the neural markers MAP2 and S100.⁵³ The mechanism involves the activation of TGF-β, Wnt, and Notch signaling, pathways linked to neural development.⁵³ This tissue specificity is a better design principle than generic biomaterials, although the exact active components remain unknown.^14,24 Injectable microspheres functionalized with decellularized dental pulp matrix regenerated the pulp-dentin complex by providing a 3D pulp-specific microenvironment that supports neural differentiation.⁶⁴ However, this system is still at the small-animal stage, and the batch consistency of decellularized matrix products is an unsolved manufacturing problem. An injectable tissue-specific hydrogel system has also been developed to guide DPSC differentiation toward several lineages, including neural lineages, for pulp-dentin regeneration.⁶⁷ Hyaluronic acid hydrogels containing platelet lysate, a mixture of growth factors that includes neurotrophins, increase the proliferation and differentiation of human pulp cells and act as a pro-neurogenic growth factor depot.⁵¹ Injectable double-network hydrogel systems for 3D cell culture have also been adapted for pulp regeneration, with stiffness and degradation rates matched to pulp-like tissue.⁶⁸

Angiogenesis and neurogenesis are tightly linked during pulp development and regeneration, and several hydrogel systems exploit this link. Gelatin methacryloyl (GelMA) hydrogel combined with DPSCs can regenerate pulp-like tissue rich in both blood vessels and nerves. Its tunable physical and biological properties make it a versatile platform for neuro-vascularized regeneration.³¹ A recent extension of this platform used a carbon dot-based, photo-cross-linked GelMA hydrogel. In the original study by Cao et al, this material increased the angiogenic and neural differentiation capacity of hDPSCs and produced vascular-rich pulp-like tissue.⁶⁵ However, that preliminary study was limited to ectopic models and short observation periods, and neural differentiation was measured at the marker level only.⁶⁵ The versatility of GelMA for neuro-regenerative endodontics has been reviewed elsewhere.⁶⁹ Beyond GelMA, a silk fibroin/sodium alginate hydrogel loaded with angiogenic apoptotic vesicles enhanced angiogenesis through focal adhesion signaling and created a microenvironment that induced both odontogenic and neurogenic differentiation. After in vivo transplantation, this system formed fully vascularized pulp tissue with aligned odontoblast-like cells and neuronal extensions.⁵² Vesicle-functionalized hydrogels are a potent but young strategy, and cargo reproducibility and long-term safety are not yet established.

A more direct strategy uses hydrogels as local depots for neurotrophic factors. Controlled release of bFGF from gelatin hydrogels induced dentin-like particles and dentinal bridges in dentin defects, providing the structural base on which reinnervation can occur.^70,71 bFGF-loaded chitosan hydrogels increase the expression of GFAP, S100β, and β-tubulin III in DPSCs,⁴⁸ and hydrogels are recognized as promising carriers for bioactive molecules such as NGF in pulp regeneration.⁵ Across these strategies, the inherent neurogenic potential of DPSCs is used repeatedly. Combining DPSCs with 3D hydrogel systems such as GelMA is now a core strategy for building neuro-vascularized pulp tissue, because DPSCs differentiate toward neuronal and glial lineages and secrete neurotrophic factors.^69,72 Early work showed that hDPSCs can differentiate into functional Schwann-like cells in 3D collagen hydrogels, where they guide and myelinate neurites.²² Combining iPSC-derived cranial neural crest-like cells with SLan hydrogel further shows how cells and hydrogels can work together to build complex neuro-vascularized tissue.¹⁹ Pre-vascularized hydrogels co-encapsulating stem cells from human exfoliated deciduous teeth and human umbilical vein endothelial cells form mature microvascular networks, which are needed to support neural survival.⁷³ Hydrogel composites containing deferoxamine-loaded microspheres increase the angiogenic capacity of DPSCs.⁷⁴ Hydrogel-mediated slow delivery of tissue-specific developmental signals, such as dentin matrix proteins, also provides a biomimetic microenvironment for pulp regeneration.⁷⁵ An injectable human amniotic membrane hydrogel has also been made for dentin-pulp complex regeneration, supporting stem cell viability and vascularized tissue formation.⁷⁶ In summary, four complementary design strategies have emerged for neuro-instructive pulp regeneration: copying cranial neural crest developmental cues, using tissue-specific matrix signals, promoting neuro-vascular coupling, and controlled release of neurotrophic factors. Despite encouraging preclinical progress, key gaps remain, especially the functional validation of sensory recovery and the long-term stability of regenerated nerve networks.

Enamel itself contains no cells and no nerves. Even so, progress in enamel regeneration defines the outer boundary of full tooth regeneration and is therefore relevant context for this field. Basic studies of amelogenesis defined the role of matrix metalloproteinase-20 in processing amelogenin and in regulating cadherin expression during enamel development,^77,78 and biomimetic strategies for enamel have been reviewed systematically.⁷⁹ More recently, a single-cell census of human tooth development enabled the generation of human enamel organoids and guided the in vitro differentiation of odontoblasts from human induced pluripotent stem cells.^80,81 A soluble Notch agonist was also shown to drive human ameloblast maturation and the formation of enamel-like tissue.⁸² Whether these epithelial mineralization strategies can be integrated with neuro-instructive hydrogels to rebuild a tooth that is both innervated and mineralized remains a long-term research question.

Innervated Jawbone Regeneration Through Bone-Nerve Synergy

Bone is richly innervated, and innervation is essential for bone metabolism and repair. Sensory nerves are not passive bystanders in craniofacial bone biology. Meyers et al showed that a neurotrophic mechanism directs the transit of sensory nerves in cranial bone during development and repair, establishing innervation as an organizing principle rather than a secondary event.⁸³ Against this background, the injectable miR-222/MSN/ASP hydrogel developed by Lei et al is a paradigm in this field.³⁵ Through slow co-release of miR-222, which drives neural differentiation of hBMSCs through the Wnt/β-catenin/NLK pathway, and aspirin, which supports bone formation and reduces inflammation, the system produced new bone together with high expression of the neural markers Tuj1 and S100 in a rat mandibular defect model. This is a prominent example of innervated bone regeneration.³⁵ The co-delivery design is a sophisticated form of molecular signal control aimed at nerve-bone synergy. However, the evidence comes from a single rodent study and has not yet been independently repeated.^26,52

Oral stem cells naturally carry both osteogenic and neurogenic potential. Early research emphasized the strong angiogenic and neurogenic capacity of DPSCs.³ A 2023 review systematically summarized the use of DPSCs for bone and nerve regeneration in the oral and maxillofacial region, including their combination with GelMA-bFGF hydrogel for peripheral nerve regeneration.²³ A 2024 review described how innervation enhances bone regeneration through neurotransmitters such as CGRP, providing the theoretical basis for this approach.²⁶ Direct evidence for neuropeptide delivery comes from the CGRP-loaded ROS-responsive hydrogel discussed above. It restored neuro-angiogenic signaling and promoted bone regeneration even under the chronic inflammation and metabolic disturbance of diabetic periodontitis.²⁸ This finding is directly relevant to the design of innervated hydrogel therapies for periodontitis and other inflammatory bone defects in the oral cavity, where native innervation is often damaged. Replication in large-animal models is the necessary next step.

Oral stem cell-hydrogel composite systems are also central to this application. DPSCs can differentiate into Schwann-like and oligodendrocyte-like cells and secrete neurotrophic factors with neuroprotective and immunomodulatory effects.²¹ This makes them a promising cell source for peripheral nerve repair, including oral nerves. Peptide-functionalized GelMA hydrogels with 3D cultures of DPSCs enhanced bone formation at multiple sites.⁸⁴ Although the primary endpoint of that study was bone formation, the inherent neurogenic potential of DPSCs in such constructs creates opportunities for simultaneous nerve regeneration.

Oral Mucosal Nerve Repair from Analgesia to Active Neurogenesis

The integrity of the oral mucosa is inseparable from its sophisticated sensory innervation. In diseases such as chemotherapy-induced oral mucositis, nerve damage is not only the source of intense pain but also a major barrier to functional healing. The core mission of neuro-instructive hydrogels here is to actively guide and accelerate nerve regeneration and thereby restore mucosal sensation. Pain relief and anti-inflammatory effects serve as supporting strategies for this primary goal.

For active neurogenesis, the surface-engineered hydrophobic hydrogel represents an advanced design.⁶² It provides on-demand pain relief through ROS-responsive lidocaine release. More importantly, it actively promotes the regeneration of NF200-positive nerve fibers in the healed mucosa by modulating the IL-17/MAPK signaling pathway. This marks a shift from passive wound coverage to active induction of neural repair.⁶² As noted in Immunomodulation to Foster a Pro-Regenerative Niche, however, structural marker expression does not equal restored sensation, and functional validation is still pending.⁶² (As shown in Figure 3) In a related approach, alginate/hyaluronic acid composite hydrogels carrying human periodontal ligament-derived and gingiva-derived mesenchymal stem cells promoted neural-like differentiation and neurotrophic factor release.³⁷ This provides a potential cell source and a supportive microenvironment for regenerating sensory nerve endings in the mucosa. An RGD-modified alginate-GelMA hydrogel sheet containing gingival mesenchymal stem cells was developed for wound healing and soft tissue regeneration.⁸⁵ Given the documented neural differentiation potential of these cells, this platform holds promise for mucosal nerve regeneration, although neural endpoints were not directly tested.

Figure 3.

Schematic diagram of hydrogel with wet adhesion through self-hydrophobicity. (A) Schematic illustration of the fabrication strategy of wet-adhesive EPBA@PC-HD hydrogel by integration of biocompatible cholesterol-micelles into the catechol-modified polyelectrolyte network. (B) The application of the wet-adhesive EPBA@PC-HD hydrogel as protective patch that locally releases anesthetic LD to promote wound repair in mucositis. Reproduced from Elsevier by Zhang et al.

Analgesic strategies create a favorable microenvironment for nerve regeneration. The sprayable NAHAO^® hydrogel reduced pain-related behaviors in preclinical models by blocking the COX-2/PGE2 pathway.¹¹ A later preliminary clinical study confirmed its analgesic efficacy and safety in patients.⁶⁶ This is the only human evidence currently available in this field and therefore the key reference point for translational discussions. A hyaluronic acid-based composite hydrogel with core-shell microgels co-delivers lidocaine for immediate pain relief and epidermal growth factor to support the coordinated repair of the epithelium and its underlying nerve network.⁸⁶ A one-pot, tannic acid-reinforced gelatin hydrogel containing cannabidiol was designed to meet the antioxidant, anti-inflammatory, and analgesic needs of oral wound care, creating a permissive environment for later neural repair.⁸⁷

Self-assembling peptide hydrogels further illustrate the principles of functional hydrogel design for mucosal repair. Their inherent biocompatibility, biodegradability, and matrix-mimicking character make them a versatile platform for building a pro-regenerative niche that supports reinnervation of damaged oral mucosa.⁸⁸ Their ligand-receptor recognition and stimulus-responsive self-assembly allow time- and space-controlled presentation of neurotrophic signals. This is critical for guiding sensory nerve endings into the regenerating epithelial layer. It represents a shift from simple wound coverage toward active rebuilding of a functional neuro-epithelial unit.

In summary, neuro-instructive hydrogels for oral mucosal repair have moved beyond passive wound coverage. By combining physical support, controlled molecular release, cell delivery, and immunomodulation, these materials now aim to restore mucosal structure and sensory function together. The main weaknesses of the field remain the lack of functional sensory endpoints and, except for one preliminary clinical study, the lack of human data.

Hydrogel-Based Combination Strategies

Beyond individual hydrogel design, combining hydrogels with external physical cues, bioactive molecules, or living cells has emerged as a powerful way to improve neuro-regenerative outcomes. These combinations use the tunable delivery capacity and matrix-mimicking character of hydrogels while adding further dimensions of control. Three complementary paradigms are discussed: combination with physical techniques for topographical and external guidance, combination with bioactive factors for precise signal control, and combination with cell therapy to deliver active regenerative units directly to the injury site (Figure 4).

Figure 4.

Synergistic therapeutic strategies combining hydrogels with physical cues, cell therapy, and bioactive factors for enhanced neural regeneration. Created in BioRender. c, Y. (2026) https://BioRender.com/a245fa3.

Combination with Physical Cues

Physical cues can further improve regenerative outcomes. The contact guidance effect of collagen hydrogels aligns differentiated hDPSCs and physically directs neurite extension.²² Three-dimensional printing can produce hydrogel nerve conduits with biomimetic microstructures. Such conduits provide physical pathways for directional regeneration in complex oral regions and can form sandwich architectures that resemble natural periodontal tissue.^30,31 Magnetic field stimulation combined with hydrogels containing magnetic nanoparticles allows remote control of the neural differentiation of DPSCs, offering a non-invasive physical method.³⁰ Among these techniques, bioprinting stands out because it can build hydrogel scaffolds with biomimetic topography, controlled porosity, and defined spatial distribution of cells and factors.^38,39,89 Two limitations should be noted. Evidence for magnetic and printed guidance in oral neural applications is largely extrapolated from non-oral models, and direct oral validation is needed. In a related example, 3D-bioprinted piezoelectric hydrogels combined with low-intensity pulsed ultrasound promoted bone regeneration, showing how printed materials can work together with external physical stimulation.⁹⁰

Combination with Cell Therapy

Hydrogels provide a three-dimensional living environment for stem cells, maintaining their function and promoting directed differentiation. Combining Schwann-like differentiated hDPSCs with type I collagen hydrogels builds engineered neural tissue that can guide directional neurite growth and secrete BDNF, GDNF, and NGF.²² Encapsulating periodontal ligament and gingival stem cells in alginate/hyaluronic acid scaffolds promotes their neural differentiation and neurotrophic factor release.³⁷ Combining iPSC-derived cranial neural crest-like cells with SLan hydrogel shows how cells and hydrogels can cooperate in building complex neurovascularized tissue.¹⁹ The envisioned use of hydrogels as carriers for stem cells and growth factors in oral nerve repair²¹ is now being realized through such combination strategies.^24,37

Dental-derived stem cells show clear potential for nerve repair. Combining DPSCs with a heparin-poloxamer hydrogel and bFGF significantly influenced the nerve repair process.²⁴ DPSCs differentiated toward Schwann cells, combined with nerve conduits, enhanced facial nerve regeneration in preclinical models.²³ Inside 3D collagen hydrogels, DPSCs form longitudinal cell columns that create a favorable environment for axon regeneration.²² The documented neural differentiation potential of DPSCs and stem cells from human exfoliated deciduous teeth provides the basis for combined strategies in nervous system diseases.⁹¹ In vitro studies also support the use of chitosan nerve conduits together with hDPSCs and their conditioned medium for sciatic nerve regeneration, a necessary step toward future in vivo work.⁶¹ More broadly, hydrogel-loaded dental stem cells have gained substantial momentum in tissue regeneration, with particular promise for nerve repair given the neurogenic capacity of these cells.³⁰ Oral stem cell-hydrogel platforms developed for periodontal regeneration can likewise be extended to neuro-regenerative applications.⁹² As noted in Orchestrating Cellular Behavior for Nerve Repair, however, most of this evidence comes from in vitro or small-animal studies, and neural outcomes are usually marker-based. Functional recovery data remain the exception rather than the rule.

Combination with Bioactive Factors

Hydrogels can carry factors such as NGF, BDNF, and bFGF, allowing slow release and direct induction of neural differentiation.^5,22 The miR-222/MSN/ASP hydrogel co-delivers miR-222 and aspirin to achieve neurogenic bone regeneration.³⁵ Hydrogel scaffolds loaded with platelet lysate or apoptotic vesicles not only promote vascularization but also enhance the neurogenic potential of DPSCs.^51,52 Apoptotic vesicles represent an emerging, cell-free way to enrich hydrogel bioactivity.^52,58

A key advantage of hydrogels is their role as intelligent delivery systems. Functional hydrogels can be designed for on-demand release of neuroprotective agents and growth factors, allowing precise temporal control of the repair process.⁶² Hydrogels loaded with agents such as recombinant human β-nerve growth factor can build a favorable regenerative microenvironment indirectly, through anti-inflammatory and pro-regenerative effects.³¹ Neurotization in dentin-pulp complex regeneration likewise involves the combined action of NGF and other hydrogel-released molecules.⁵ Three-dimensional porous hydrogels carrying DPSCs together with macromolecules such as bFGF and NGF promote nerve regeneration through sustained neurotrophic support.²¹ A recurring limitation of these systems is that release profiles are rarely matched to the changing temporal needs of regenerating nerve. Stimuli-responsive design, discussed in Future Prospective, may offer solutions.

Adaptive Design for the Unique Oral Environment

Success in the oral cavity requires careful adaptation to a unique and challenging microenvironment. Unlike most other tissues, the oral cavity is constantly wet with saliva, undergoes dynamic mechanical forces from chewing, and hosts a complex microbiome that tends to form biofilms. These factors create significant barriers to hydrogel retention, stability, and function. They help explain why hydrogel strategies validated elsewhere cannot be transferred to the mouth without adaptation. Three design considerations are essential for oral applications: wet adhesion and long-term retention, antibacterial and anti-biofilm function, and mechanical adaptability under cyclic loading (Figure 5).

Figure 5.

Adaptive design of neuro-instructive hydrogels for the unique oral environment. Created with BioGDP.com.

Wet Adhesion and Long-Term Retention

The wet and dynamic oral environment requires strong adhesion, and several strategies exist. Surface-engineered hydrophobic hydrogels achieve strong wet adhesion, with a lap shear strength of up to 12 kPa, through interfacial interactions between catechol groups and mucins combined with a surface hydrophobic layer. They withstand the dynamic oral environment and self-heal within 5 minutes.⁶² Injectable dECM hydrogels are shear-thinning and thermosensitive. They adapt closely to irregular pulp cavity shapes and remain stable in physiological buffer, which favors long-term retention.⁵⁴ Hyaluronic acid-based composite hydrogels with core-shell microgels adhere rapidly and firmly to mucosa through hydrogen bonding between hydroxyl and carboxyl groups and mucins. They resist saliva erosion and prolong the local action of neurotrophic drugs.⁸⁶ An injectable, tannic acid-containing hydroxypropyl chitin hydrogel is liquid at 4 °C and gels at 37°C, so it adapts closely to irregular pulp chamber walls. Its slow degradation makes it a long-term stable scaffold for neurogenic pulp regeneration.⁹³ The SLan hydrogel is also shear-thinning and can re-gel in situ, which helps its retention inside the pulp after injection.¹⁹

Dopamine chemistry is a particularly powerful adhesion strategy. An alginate-dopamine hydrogel reaches a shear strength of 120 kPa on wet tissue, providing a strong anchor in moist environments.⁹⁴ Dopamine-based, photocrosslinked bioadhesive hydrogels resist salivary washout through chemical bonding. Polyacrylic acid improves wet adhesion by forming ionic bonds between its carboxyl groups and calcium ions in tooth structure.³⁰ Strong wet adhesion matters directly for nerve regeneration. Stable retention of neurotrophic factors and therapeutic cells is a precondition for effective repair, because neuro-regenerative cues must stay at the target site long enough to support axon sprouting and reinnervation, despite saliva flow, bleeding, and mechanical disturbance. To further improve the retention and function of neurogenic stem cells, RGD-conjugated alginate hydrogels use RGD motifs to enhance cell adhesion inside the scaffold.³⁷ A general limitation is that adhesion is usually measured ex vivo on flat surfaces. Performance on blood-contaminated, irregular clinical surfaces may differ considerably.

Antibacterial and Anti-Biofilm Function

Control of infection is essential for nerve regeneration. Chitosan-based hydrogels are naturally antibacterial.^5,48 Other hydrogels carrying clindamycin, metronidazole, chlorhexidine, or silver-doped bioactive glass effectively inhibit oral pathogens such as Streptococcus mutans and Enterococcus faecalis, preventing infection in root canals and mucosal wounds.^30,48 Advanced systems now go beyond passive drug release. Injectable, thermosensitive, antibiotic-loaded chitosan hydrogels developed for regenerative endodontics provide both a scaffold for cell homing and controlled antibiotic release against Enterococcus faecalis biofilms, a common cause of persistent root canal infection.⁹⁵ By reducing the bacterial burden in the root canal space, these hydrogels create conditions that allow regenerating nerve fibers to survive. Antimicrobial components such as tannic acid in hydroxypropyl chitin hydrogels provide long-lasting antibacterial effects without traditional antibiotics, reducing the risk of resistance.⁹³ Some wet-adhesive hydrogels based on hyaluronic acid or polyethylenimine also inhibit common oral pathogens by themselves.⁶² Functional hydrogels can further be combined with antimicrobial peptides or silver nanoparticles, such as Gel-DA/GG@Ag NP systems, to gain broad-spectrum and photothermal antibacterial activity.^31,49 Several antibacterial hydrogels have been reported, including silver-doped bioactive glass/chitosan hydrogels, metronidazole-loaded mesoporous silica composites, and clindamycin-loaded fibrin hydrogels. All of them can protect the neurogenic regeneration process by controlling infection.^5,31 One caveat is that antibacterial potency must be balanced against cytocompatibility. Agents that kill bacteria, especially silver-based components, can also damage neural cells at similar concentrations.

Mechanical Adaptability for Dynamic Loading and Spatial Maintenance

Mechanical adaptability is essential in the dynamic oral environment. One strategy is to build in self-healing and anti-fatigue properties. Surface-modified hydrophobic hydrogels use dynamic crosslinked networks to recover from deformation and resist fracture under cyclic chewing stress. This preserves barrier integrity and local microenvironmental stability.⁶² Performance can be improved further through reversible interactions, such as supramolecular assemblies held by multiple hydrogen bonds or dual-crosslinked systems with dynamic covalent bonds. These designs combine strength, self-repair, and shear-thinning behavior suitable for load-bearing applications.^30,62

Long-term mechanical performance also depends on stable viscoelasticity and controlled degradation. Decellularized matrix hydrogels show solid-like elastic behavior, with stable storage and loss moduli across frequencies, and strong resistance to enzymatic breakdown. They can therefore keep structural support over long periods inside sites such as the pulp chamber.^53,55 Multidomain peptide hydrogels offer tunable viscoelastic profiles. They can be injected as fluids and regain stiffness in situ, adapting to chewing forces.⁵

Matching the mechanical properties of the target tissue also guides cell behavior. Alginate-hyaluronic acid composite hydrogels tuned to low elastic moduli, close to the softness of neural tissue, promote the neural differentiation of periodontal ligament and gingival stem cells more effectively.³⁷ For periodontal regeneration, this principle extends to hydrogels with graded stiffness that meet the distinct mechanical needs of periodontal ligament and alveolar bone.³¹

Finally, structural tunability allows site-specific customization. Three-dimensional printing gives precise control over pore architecture and scaffold geometry, tailoring the mechanical environment to different oral tissues.³⁰ Blending natural and synthetic polymers, or modifying hydrogel chemistry, can further refine mechanical performance and stability for complex applications such as pulp regeneration scaffolds.⁴⁹

How Transformative Is Bioprinting Technology for Innervated Hydrogels?

Bioprinting is a transformative manufacturing approach that enables the precise fabrication of innervated hydrogel scaffolds with customized architectures. Bioinks, which contain hydrogel precursors, cells, and bioactive factors, are deposited layer by layer according to digital models. In this way, bioprinting can build complex three-dimensional structures that mimic native tissue organization.^38,89

Its application to innervated hydrogels covers four areas. The first is biomimetic topography. Extrusion-based and light-based bioprinting can create scaffolds with defined microarchitectures, such as longitudinal channels or aligned fiber networks. These features provide the physical guidance cues needed for directional axon growth and Schwann cell migration.³⁶ The second is spatial patterning of bioactive components. Bioprinting can control the distribution of several cell types, such as Schwann cells, neural stem cells, and endothelial cells, and of neurotrophic factors such as NGF and BDNF within one construct. This enables multicellular niches, concentration gradients, and co-culture systems that copy the regenerative microenvironment.^35,52 The third is patient-specific design. Using clinical imaging data, bioprinting can produce scaffolds tailored to the exact shape of an individual pulp chamber, jawbone defect, or mucosal wound, ensuring optimal fit and integration.³¹ The fourth is dynamic and responsive scaffolds, also called 4D bioprinting.³⁸ Here, printed structures undergo planned changes in shape or function over time in response to physiological stimuli. This concept holds promise for implants that adapt to the dynamic oral environment or to the changing needs of nerve regeneration.

Recent work by Cao et al shows this direction clearly.⁴⁰ A bottom-up strategy assembled microtissues of mesenchymal stem cells, endothelial progenitor cells, and Schwann cells into tissue-engineered bone with both prevascularization and innervation. This demonstrates that neural and vascular compartments can be built together in one construct instead of regenerating one after another.⁴⁰ Despite this potential, significant challenges remain for the clinical use of bioprinted innervated hydrogels. Bioinks must combine printability, biocompatibility, and neuroinductive activity, which is difficult. Cell viability must be kept high throughout printing. Printing resolution must become fine enough to copy the architecture of neural tissue.^38,89 Meeting these requirements needs continued collaboration between materials science, biology, and clinical dentistry.

Future Prospective

Building on current progress, future development of innervated hydrogels will focus on three directions: higher fabrication precision, smarter responsive materials, and deeper integration of data science with biological principles. The shared goal is to overcome the core challenges of translation.

Future breakthroughs rely first on better manufacturing. High-precision bioprinting methods such as digital light processing have reached resolutions of about 50 μm, laying the foundation for biomimetic neural scaffolds.⁸⁹ The next step is systems that can print cells, growth factors, and materials at the same time to create more complex tissue architectures.³⁸ Portable 4D bioprinting is a significant trend, enabling scaffolds to adapt to the dynamic oral environment after implantation. New materials, such as magnesium nanocomposite hydrogels that gel quickly even under bleeding conditions, offer fresh ideas for robust adhesion and repair in complex oral wounds.³⁹ Combining bioprinting with microfluidics and electrospinning may produce multi-scale, multi-material innervated scaffolds with higher biomimetic complexity.

Next-generation hydrogels will evolve from passive scaffolds into intelligent systems that can sense and respond to pathological signals. Hydrogels responsive to enzymes, pH, or reactive oxygen species can release therapeutic agents on demand, and the general field of stimuli-responsive biomaterials for drug delivery is advancing quickly.⁹⁶ The ROS-responsive release concept demonstrated for analgesics can be adapted for on-demand release of neurotrophic factors in the inflamed oral environment.^16,62,97 Microbiome-oriented strategies are also emerging. Ozonized hydrogels have shown clinical utility in managing peri-implant mucositis, suggesting that hydrogel carriers can be used to modulate the oral microbial balance during mucosal repair.⁹⁸ Thermosensitive chitosan hydrogels loaded with antibiotics show how smart responsive systems can support tissue regeneration under controlled infection.⁹⁵ Future smart hydrogels may combine several response mechanisms and adjust their behavior dynamically based on real-time feedback, enabling truly adaptive regenerative processes.

Machine learning offers an efficient way to handle the complexity of hydrogel formulations and processing parameters. Algorithms such as Bayesian optimization and random forest can rapidly optimize hydrogel composition to improve several properties at once, greatly reducing the cost and time of trial-and-error experiments.⁹⁹ Combined with Design of Experiment methods and image processing, machine learning can build predictive models that link printing parameters such as speed, pressure, and bioink viscosity to critical quality attributes of the scaffold, including resolution, porosity, and mechanical integrity.¹⁰⁰ Such predictive capability is valuable for the standardized, large-scale production of patient-specific neuro-instructive hydrogels. In the long run, combining AI-driven design with high-throughput in vitro models, including dental pulp stem cell-based 3D organoid systems,¹⁰¹ could reveal new material-factor combinations that synergistically promote nerve regeneration and accelerate the path from bench to clinic.

Future material design will also rely more on biological principles. Because key oral tissues derive from the cranial neural crest, copying its developmental microenvironment is important for efficient regeneration.¹⁹ New bioactive ingredients are broadening design thinking. Apoptotic vesicles, which are stable under hypoxia and easy to produce in large amounts, have been loaded into silk fibroin/sodium alginate hydrogels to promote angiogenesis and pulp-dentin complex formation.⁵² Extracellular vesicles from Schwann cells are acellular therapeutics whose loading and controlled release will be a new frontier in smart hydrogel design.⁵⁸ A deeper understanding of extracellular matrix components and intercellular signals will provide a blueprint for the next generation of biomimetic hydrogels. Immunomodulatory design is another exciting direction. Future hydrogels will likely carry cues that actively polarize macrophages toward the pro-regenerative M2 phenotype. This not only resolves inflammation but also creates a permissive niche for axon growth, because M2 macrophages secrete neurotrophic factors and matrix components that support Schwann cell activity.¹⁸ The convergence of bioprinting with microfluidics and electrospinning will further enable scaffolds that copy the hierarchical organization of native nerve, from nanoscale topography to millimeter-scale anatomy.³⁸

Moving innervated hydrogels toward the clinic requires solving the core challenges of the translational pathway. The first task is standardized and scalable production. This includes workflows compliant with Good Manufacturing Practice, testing of how sterilization methods such as gamma irradiation affect material properties, and control of batch-to-batch variation of natural polymers.^16,30 Careful preclinical validation in large animal models such as pigs is essential to evaluate efficacy in promoting sensory functional recovery and long-term safety.^6,25,30 Objective, quantitative clinical endpoints for sensory recovery in oral tissues must be established, and rigorous randomized controlled trials must be designed to confirm superiority over existing care. Terminology should also be disciplined. With only one preliminary human study reported so far,⁶⁶ most claims of clinical translation are in fact projections of translational potential. The field will mature faster if this distinction is kept explicit.

In summary, this review has examined four mechanistic pillars of neuro-instructive hydrogel design: topographical guidance, molecular signaling, cellular orchestration, and immunomodulation. We mapped these pillars onto three oral regenerative scenarios and evaluated the strength of the supporting evidence, which currently rests almost entirely on in vitro and small-animal studies, with a single preliminary human trial. What distinguishes this field from general nerve regeneration research is the oral context. Saliva, chewing forces, and a rich microbiome impose design constraints found nowhere else in the body, while the cranial neural crest origin of oral tissues offers a unique neurogenic starting advantage. Neuro-instructive hydrogels represent a shift in oral regenerative medicine, moving biomaterials from passive scaffolds to active, neuro-guiding systems. By combining multiple cues to guide nerve regeneration, they address the critical need to restore sensory function together with structure. Realizing this potential will require interdisciplinary efforts toward adaptive, patient-specific hydrogel systems and, critically, functional evidence that sensation is restored in regenerated oral tissues.

Funding Statement

This work was supported by the University-Industry Collaborative Education Program (Grant No. 230805309315401), Science and Technology Planning Projects of Guangzhou City, China (No. 202201020203), the Undergraduate Teaching Quality and Teaching Reform Engineering Projects of Guangzhou Medical University (No. 2023ZLGC080, 2022-124-1) and the Key Medical Disciplines and Specialities Program of Guangzhou (2025-2027).

Disclosure

The authors report no conflicts of interest in this work.