The nervous system is a crucial component of living organisms, composed of the brain, spinal cord, and peripheral nervous tissue, and consists of abundant neurons and supportive glial cells that form neural circuits, regulating life activities and transmitting physiological information (Brodal, 2004; Sanes et al., 2011). In general, nerve damage or injury may result in the death of endogenous nerve cells at the lesion site, making spontaneous regeneration challenging and leading to abnormal or deteriorating organ functions, and even patient death. For instance, spinal cord fractures or dislocations due to accidents such as trauma, traffic accidents, falls, or sports injuries can cause nerve damage, leading to gradual deterioration of organ functions and consciousness below the injury site, and even paralysis in severe cases. Moreover, the high morbidity and mortality rates of nerve damage make it a significant public health issue worldwide, causing enormous psychological pain and economic burden to patients and their families (Karsy et al., 2019). Therefore, nerve injury repair is a topic of great interest, and the induction of nerve cell regeneration in the damaged area to restore the neural circuit and recover patients’ motor function is currently a crucial issue in the field of basic medical research and clinical transformation practice related to nerve damage treatment.

In the meantime, recent advances in tissue engineering and regenerative medicine have highlighted three crucial factors that play a key role in reshaping neural tissue structure and function. These include seed cells, biomaterial scaffolds, and bioactive factors (Schmidt and Leach, 2003; Gu et al., 2014). Usually, neural stem cells are used as seed cells for neural repair, and biomaterial scaffolds act as carriers for both seed cells and bioactive factors during stem cell transplantation. Other than that, an ideal biomaterial scaffold should provide anchoring sites for stem cells to adhere and grow, as well as induce their proliferation and differentiation within the microenvironment, ultimately leading to the formation of functional neural tissue with mechanical stability.

As a scaffold material widely used in neural tissue engineering, hydrogel has the following properties. Hydrogels are highly porous network materials that result from crosslinking hydrophilic polymers through both physical and chemical processes (Ullah et al., 2015). They possess excellent biocompatibility, and as such, are widely used in the diagnosis and treatment of various diseases (Hoffman, 2012; Caló and Khutoryanskiy, 2015). The physicochemical and structural microenvironment of hydrogels resembles that of the extracellular matrix of neural tissue, and their viscoelastic property is highly compatible with biological tissue. Moreover, hydrogels provide attachment sites and a three-dimensional space for the growth, migration, proliferation, and differentiation of transplanted neural cells. Additionally, hydrogels exhibit tissue affinity on their soft and wet surfaces, making them ideal for in vivo cell scaffolding (Nisbet et al., 2008). To clarify, this mini review is structured around various strategies for distinct hydrogel material designs; however, it is important to note that due to differences in cellular microenvironments, cell types, and post-injury repair capabilities between the central and peripheral nervous systems (CNS and PNS, respectively), the responses to biomaterials vary. Consequently, the requirements for material design diverge as well. For instance, when designing biomaterials, the degradability of the material is a crucial factor. Biomaterials designed for CNS repair must degrade within an appropriate time frame to prevent long-term disruption to surrounding tissues, while in PNS repair, the degradation rate of biomaterials should correspond with the rate of nerve regeneration to ensure adequate support for nerve growth. Another example is the variation in biomaterial types for CNS and PNS injuries. CNS injury repair materials may encompass scaffolds, gels, nanoparticles, and other components with the primary aim of providing physical support, promoting cell growth and differentiation, and releasing growth factors. In contrast, PNS injury repair materials typically involve nerve conduits, biofilms, and the like, with the main functions of guiding nerve growth and supplying extracellular matrix support. Furthermore, drug delivery to the CNS can be challenging due to the blood–brain barrier. As a result, when designing biomaterials for CNS repair, it is worth considering the development of materials with drug carrier capabilities to enhance the efficiency of drug delivery to the damaged site. In PNS repair, however, the limitation imposed by the blood–brain barrier is less significant. In summary, the design of biomaterials for CNS and PNS injury repair necessitates a comprehensive understanding of their distinct biological, biomechanical, and biocompatibility aspects. Thus, this article reviews the fundamental research in neural injury repair that utilizes various functionalized hydrogels, explores their potential for clinical practice, and discusses the synthesis strategies and application conditions of different types of hydrogels (Figure 1).

Hydrogels play a crucial role in nerve injury repair by providing physical support, enhancing mechanical and guiding capabilities, and promoting nerve regeneration and repair. The polymer chains within hydrogels can be crosslinked to form a three-dimensional network that enhances their mechanical properties, such as toughness, strength, and elasticity, allowing them to closely mimic physiological tissue structures (Lesný et al., 2002; Ma et al., 2022). Furthermore, the strength and elasticity of hydrogels can be adjusted by controlling their crosslinking density and structure, and subsequent adsorption of water molecules can increase their toughness and durability. The three-dimensional network structure formed by hydrogels at the microscale provides physical support to the surrounding tissues and cells, promoting oriented cell growth, facilitating the generation of new neural tissue and blood vessels, and enhancing the supply of oxygen and nutrients to support neural cell growth and regeneration (Deligkaris et al., 2010; Xia and Chen, 2022). Moreover, hydrogels can effectively fill damaged areas of neural tissue, reducing tissue gaps, forming supportive structures, and aiding in neural tissue repair (Štulík and Syková, 2008). Hydrogels can also be used as a carrier for bioactive molecules, making them a promising biomaterial for promoting neural tissue regeneration and repair (Ma et al., 2022).

Overall, the supportive role of hydrogels in neural injury repair is based on their formation of a three-dimensional network with uniform micro-pores, excellent biocompatibility, and the ability to promote neural regeneration and repair. The combination of these advantageous properties makes hydrogels a crucial and effective material for nerve repair, resulting in the survival and functional recovery of neurons, and providing hope for the millions of people affected by nerve injuries.

The nervous system communicates mainly through electrical signals, and in the CNS, neurons are responsible for signal transduction. The severe inflammatory reaction after nerve injury can lead to the death of neurons and the formation of glial scar, which affects the repair of CNS injury. Therefore, ideal CNS repair materials need to have properties that minimize the occurrence of inflammatory reactions (Raposo and Stahl, 2019). Studies have shown that extracellular vesicles (EVs) contain a diverse array of biological molecules, such as cell factors, proteins, and nucleic acids, and have multiple biological functions, including promoting cell proliferation and reducing inflammation (Raposo and Stahl, 2019). Previous studies have indicated that EVs derived from cells possess robust regenerative and reparative capabilities in various systems, including the musculoskeletal (Alcaraz et al., 2019), cardiovascular (Adamiak et al., 2018), liver injury (Psaraki et al., 2022), kidney injury (Aghajani Nargesi et al., 2017), traumatic brain injury (Mondello et al., 2018) and others. These vesicles have significant potential as a “cell-free” therapeutic approach for regenerative medicine and may serve as a replacement for stem cells. Notably, many cells in the peripheral nervous system, such as small glial cells and astrocytes, are capable of secreting different types of EVs, particularly following nerve injury.

And EVs can participate in protein synthesis in neurons, promote axonal regeneration, and inhibit axonal degeneration through various mechanisms. One such mechanism involves the binding of vesicular membrane proteins with target cell membrane proteins through ligand-receptor interactions (Liu et al., 2021). Another mechanism is that vesicular proteins can activate signaling pathway proteins on the surface of target cells after vesicle degradation, leading to a series of biological responses (Guo et al., 2021; Lee et al., 2022). Loading functionalized hydrogels with EVs is a novel therapeutic approach that can promote neural repair through various pathways such as enhancing the proliferation and migration of neural cells, improving neuronal survival, and restoring function. Studies have shown that EVs derived from skin-derived precursor Schwann cells (SKP-SC-EVs) accelerate the recovery of motor, sensory and electrophysiological functions in rats, promote the growth of regenerative axons and the formation of myelin sheaths, reduce the atrophy of target muscles caused by denervation, and promote the neurite growth of motor neurons (MNs) and sensory neurons, which is helpful for PNI repair (Yu et al., 2021; Jiang et al., 2022; Zhang et al., 2022). This promising approach may hold significant potential for the development of regenerative medicine therapies for neural injury and degenerative disorders.

Various studies have demonstrated the potential of stem cell-derived extracellular vesicles (EVs) and exosomes to reduce inflammation, inhibit cell apoptosis, and mitigate the impact of neural damage on surrounding tissues. For instance, researchers have loaded human mesenchymal stem cell-derived EVs onto chitosan-based functional hydrogels to repair peripheral nerve injury in rats. The results of the study indicated that the EV-loaded functional hydrogels promoted neuronal cells proliferation and migration, while reducing inflammation and cell apoptosis, leading to a significant improvement in neural damage repair (Ju et al., 2023). Another study utilized exosomes derived from mouse neural stem cells loaded onto poly (ε-caprolactone) based functional hydrogels and reported a significant increase in the survival and regeneration of spinal cord neurons, accompanied by a reduction in inflammation and glial scar formation (Xie et al., 2022). Moreover, there have been studies loading exosomes containing miRNA into collagen hydrogels for neural injury repair, demonstrating that they not only promote neuronal growth and regeneration but also improve the structure and function of damaged neural tissue (Lei et al., 2019; Xu et al., 2021; Zhang et al., 2021). In this study, the 3D fiber-hydrogel scaffold delivered axon microRNA (miR) to the injured site and repaired it in a non-viral manner. In the presence of methylprednisolone, the role of axon miRs in promoting mature axon regeneration is not affected, which can reduce the inflammatory response. More importantly, axon miRs in the presence of methylprednisolone reduced cyst formation and provided a tendency to improve functional recovery (Zhang et al., 2021).

Despite the promising therapeutic effects of EVs in regenerative medicine research, such as tissue repair and regeneration, their naturally low quantity and difficulty in controlling them present challenges in terms of extraction efficiency and purification yield, which has limited their research and application (Ingato et al., 2016; Usman et al., 2018). Therefore, it is crucial to improve the quality and yield of EVs, which will be a key focus for future research. Furthermore, before they can be effectively applied in clinical settings, more studies are needed to validate their safety and efficacy. But with the progress of technology, we believe that these issues will be addressed soon, and look forward to further development in this field.

In recent years, research on nano-functionalized hydrogels for neural injury repair has gained significant attention due to the expanding and enhancing of hydrogel functionality by nanomaterials (Rafieian et al., 2019; Kailasa et al., 2022). Nanomaterials can provide more growth factors and cell adhesion molecules, promoting the regeneration and growth of neural cells, while hydrogels provide a supportive and protective environment that facilitates the directional growth of neural cells. Additionally, nanomaterials can serve as drug carriers, enhancing drug loading and release efficiency for neural repair drugs, and even enabling intelligent and precise controlled release. As a result, nanomaterial-based hydrogels offer promising potential for the development of effective neural injury repair strategies. Hydrogels can limit drug diffusion and degradation, thus increasing drug concentration and duration at the treatment site. Furthermore, nanomaterials can enhance the mechanical properties and stability of hydrogels, resulting in improved durability and lifespan of the material (Li and Mooney, 2016). With their large and specific surface area, nanoparticles can increase drug delivery efficiency, and in combination with hydrogels, the use of nanomaterials can minimize immune reactions. Composites of nanoparticle-metal-hydrogel have been found to promote neuronal growth and have the potential to facilitate nerve regeneration and repair.

Nanoparticle biosensors have been combined with hydrogels to promote nerve regeneration and repair by enhancing neuronal proliferation and differentiation. Nanocarbon tube hydrogels have shown promise in nerve regeneration by promoting neuronal proliferation, reducing inflammation, and increasing the rate of neuronal regeneration (Ye et al., 2021). Similarly, nanoparticle proton pump hydrogels have been developed to reduce inflammation during nerve regeneration and promote neuronal regeneration, improving the effectiveness of nerve injury repair (Mendiratta et al., 2019). Graphene oxide nanosheets have also been incorporated into gelatin hydrogels to create a composite material for nerve regeneration, which has been shown to promote the proliferation and differentiation of neural stem cells and achieve nerve regeneration in vivo. The incorporation of micropatterns and bioactive substances into the inner wall of nerve-guide conduits (NGCs) can effectively regulate the behavior of Schwann cells, axon elongation, and macrophage phenotype, ultimately promoting the regeneration of injured nerves. In a recent study, 3/3, 5/5/, 10/10, and 30/30 μm linear micro-ribbons were prepared on poly (D, l-lactic acid-co-caprolactone) (PLCL) films. Surface ammonolysis and electrostatic adsorption of graphene oxide (GO) nanosheets were performed. This material has demonstrated great potential for promoting nerve regeneration (Zhang et al., 2020). Additionally, magnetic nanoparticle (MNPs) and gelatin hydrogel composites have been developed, which exhibit a significant magnetic guiding effect, facilitating the directional differentiation of neural stem cells and promoting nerve regeneration (Pavón et al., 2019). Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) dispersed in hydrogels have shown potential for assisting in the treatment of neurodegenerative diseases such as Alzheimer’s disease (Ribeiro et al., 2022). Additionally, a dual responsive hydrogel based on poly N-isopropylacrylamide (PNIPAM) and polyacrylic acid (PAA) functionalized mesoporous silica nanoparticles (MSNs) has been shown to be effective for killing tumor cells while also promoting tissue regeneration (Chen et al., 2017). Further, studies have demonstrated that the incorporation of lipid nanoparticles into hyaluronic acid-functionalized hydrogels can help create an anti-inflammatory microenvironment and reduce immune response (Pavón et al., 2019). Currently, there is relatively limited research on the combination of hydrogels with nanomagnetic hyperthermia for neural injury repair. However, due to the potential benefits of hyperthermia, there may be significant applications in this area. We have found previous research demonstrating that a novel thermosensitive heparin-poloxamer (HP) hydrogel, delivering basic fibroblast growth factor (bFGF) and nerve growth factor (NGF), can be used for sciatic nerve compression injury in diabetic rats, promoting axonal and myelin sheath regeneration, and improving motor function recovery (Li et al., 2018). We believe that the combination of hydrogels with nanomagnetic hyperthermia has tremendous potential in neural injury repair and look forward to further progress in future studies (Pavón et al., 2019). Nanomaterials have shown promise in inhibiting the activity of inflammatory cells, which can help reduce inflammation, minimize immune reactions, and decrease immune rejection.

Table 3 provides a comprehensive overview of the growing body of research showcasing the effectiveness of using nanomaterials in combination with hydrogels for repairing neural injuries. These applications have been preliminarily validated in laboratory experiments, and some studies have progressed to animal and human trials. The combination of nanomaterials and hydrogels offers multiple advantages and has broad application prospects in neural tissue engineering. With further technological development, these materials are expected to play an even more significant role in the field of neural injury repair. It is excited to witness the potential of these materials and look forward to further advancements in this field.

Although nanomaterials hold great potential for the repair and regeneration of damaged tissues, their use in synthesizing new materials must consider potential immune responses and toxicity to tissues and organs, as well as issues of instability. Therefore, ensuring the biosafety and stability of nanomaterials is a crucial direction for future research in the field (Zheng et al., 2021).

The above paragraph describes different types of functionalized hydrogels, and the following materials have been specifically applied in cases of CNS or peripheral nervous system injuries. For instance, dopamine-modified chitosan hydrogels have been shown to improve cell survival, modulate immunity, and promote axonal regeneration (Liu et al., 2022). Additionally, the construction of injectable silk fibroin/dopamine hydrogels has been found to be helpful in promoting the repair of spinal cord injuries (Ye et al., 2021).

A novel conductive hydrogel made from gelatin methacrylate (GelMA), hyaluronic acid methacrylate (HAMA), and poly (3,4-ethylenedioxythiophene): sulfonated lignin (PEDOT: LS) has shown promise in repairing spinal cord injuries and promoting neuronal differentiation of neural stem cells (Gao et al., 2023). Additionally, bone marrow stem cell-derived exosomes (BMSC-exosomes) have been found to bind to conductive hydrogels, enhancing axonal growth and promoting tissue repair (Fan et al., 2022). The combination of a conductive hydrogel with chitosan to form a multifunctional double-layer hydrogel catheter has been shown to be effective for peripheral nerve injury repair (Deng et al., 2022). Finally, a rubber-like conductive hydrogel composed of gelatin, conductive polypyrrole, and tannic acid (referred to as GPT) has demonstrated the ability to promote peripheral nerve regeneration (Ye et al., 2021).

Injectable thermosensitive hydrogels containing immunoregulatory extracellular vesicles have been found to help alleviate inflammation and promote nerve regeneration in cases of spinal cord injury (Zhang et al., 2022). Additionally, the combination of exosomes derived from mouse neural stem cells with functional hydrogels based on poly (ε-caprolactone) has shown promise in promoting the survival and regeneration of spinal cord neurons, as well as reducing inflammation and glial scar formation (Xie et al., 2022). Another study found that the use of human mesenchymal stem cell-derived extracellular vesicles combined with chitosan-based functional hydrogels is effective in repairing peripheral nerve injuries in rats (Ju et al., 2023).

A composite hydrogel consisting of polyvinyl alcohol (PVA) and molybdenum sulfide/graphene oxide (MoS₂/GO) nanomaterials has been shown to promote the differentiation of neural stem cells into neurons for use in spinal cord injury repair (Chen et al., 2022). Additionally, multifunctional biomimetic hydrogels based on graphene nanoparticles and sodium alginate have demonstrated the ability to simulate the microenvironment of nerve growth, reduce inflammatory factors, and contribute to the repair of peripheral nerve injuries (Ju et al., 2023).

Biomedical materials for neural tissue engineering must possess not only excellent biocompatibility but also specific neural conduction functions that promote cell-to-cell signaling. Hydrogels, which are gel-like polymers containing water, represent the most water-like scaffold materials that closely resemble human soft tissue and are crosslinked by either physical or covalent bonds. However, conventional hydrogels exhibit low strength, weak biological activity, and a single function, limiting their ability to meet the complex demands of neural injury repair. Recent studies have demonstrated that functionalized hydrogels, created through combination with other functional materials, can improve biocompatibility and responsiveness to various stimuli by regulating their composition and structure. These functionalized hydrogels effectively mimic the in vivo neural extracellular matrix microenvironment, facilitating efficient repair, replication, or differentiation of neural cells and achieving high matching of the elastic modulus between the biomaterials and neural tissue. Despite their potential for aiding in the repair of nerve tissue after injury, functionalized hydrogels are still plagued by various deficiencies, such as concerns related to biosafety and stability. Additionally, their practical implementation in clinical applications remains an area of ongoing exploration. However, with continued advancements in technology, I am optimistic that these issues will be successfully resolved, and look forward to the further development and refinement of this exciting field.

Conceptualization was made by JL and FZ. WZ and HT contributed equally to manuscript writing. HL and JW drafted the picture and summary the table. JC organized the material. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (no. 31800836) and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (Project number: 2019PY087).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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