Tissue engineering and regenerative medicine is a new interdisciplinary subject integrating life science, material science, engineering technology, and clinical medicine. Through theoretical and technological innovations, novel medical products and technologies are being developed for treating, repairing, and substituting damaged or aging tissues and organs, thereby facilitating the restoration of damaged tissues and organs and the reconstruction of their functions [1]. With the continuous development of science and technology, research on the regulation mechanisms of tissue regeneration and functional reconstruction has deepened, and products have entered the real-world study of clinical human trials [2], [3]. In addition to the three elements of tissue engineering—namely, biomaterials, seed cells, and active factors—the cell matrix and the microenvironment have been recognized as crucial for tissue engineering [4], [5]. Together, these five aspects have been referred to as the five modern elements of the theory of tissue engineering [6]. Progress in tissue engineering and regenerative medicine can facilitate the achievement of perfect tissue regeneration and effective restoration of functions.

Spinal cord injury (SCI) is a severe traumatic condition affecting the central nervous system, and global research on spinal cord regeneration has always been a hot topic. On August 24, 2021, we conducted a literature search in the Web of Science (WOS) Core Collection to identify publications related to SCI regeneration. The search strategy involved three steps. In the first step, publications specifically related to “spinal cord injury regeneration and repair” were included. This search used terms such as “spine OR spinal OR spinal cord* OR “spinal-cord” OR “spinal canal” OR myelon* OR cervical cord* OR “cervical spine” OR “cervical-spine” OR thoracic cord* OR lumbar cord* OR coccygeal cord* OR sacral cord*,” combined with “injur* OR trauma* OR laceration OR contusion OR transection OR avulsion OR stab OR impair* OR concussion” and “traumatic myelopath* OR spinal-cord-injury” in the titles, abstracts, or keywords. Terms related to regeneration and repair, including regenerat*, “tissue engineering,” “tissue engineered,” “tissue-engineered,” and “engineered tissue,” were also included in this search. In the second step, publications specifically related to “spinal cord regeneration” were identified using the terms “spinal cord regeneration” and “spinal cord repair” in the titles, abstracts, or keywords. In the third step, publication years were restricted to 2001–2020. By using this comprehensive search strategy, a broad range of publications on SCI regeneration were identified for further analysis, as presented in Table 1.

The number of people disabled by SCI worldwide each year is relatively large. Clinical symptoms of this condition present as a temporary or permanent loss of sensation and motor function in local or even all limbs below the level of the SCI. SCI frequently results in the death of neurons and axon rupture, accompanied by secondary injuries such as cascading inflammatory reactions, forming an inhibitory pathological microenvironment. The difficulty in its treatment lies in how to improve the immune microenvironment in the affected area and prevent the formation of a dysfunctional pathological microenvironment that inhibits nerve repair around the injury [3], [7]. The use of functional biomaterials at the site of injury shows promise as a potential treatment method, with the ability to effectively modulate the impaired microenvironment, facilitate axon regeneration, promote remyelination at the injured site, and support functional recovery following SCI [8].

The advancement of tissue engineering theory and technology offers novel strategies and methodologies to address the challenge of repairing SCIs and restoring functionality. This paper not only reviews biomaterials, cells, the decellularized extracellular matrix (dECM), and exosomes in the field of tissue engineering of the spinal cord but also covers the bioactive cues related to other active factors, small molecules, and RNA. Moreover, it summarizes methods to promote a regenerative microenvironment for the spinal cord. Finally, we put forward some perspectives in this field.

SCI triggers inflammatory storm, leading to the formation of cystic cavities wrapped in scar tissue, which seriously hinder axon regeneration [9]. Recent research has indicated that biomaterials are crucial in the treatment of SCI, as they can create a new microenvironment at the site of injury, facilitate the regeneration of axons, and contribute to functional recovery. This development offers promising prospects for addressing SCIs. Nevertheless, the biomaterial scaffolds that have been documented thus far often do not match well with spinal cord tissue, resulting in less-than-ideal repair outcomes [10]. Fig. 1 shows many of the biomaterials used for SCI repair, along with their preparation methods, various applications, and ways in which they can be combined with multiple therapeutic strategies to achieve synergies.

In biological contexts, it is crucial to take into account the characteristics of the scaffold. The preferred scaffold for SCI repair should possess the following attributes: ① biocompatibility, ② biodegradability, ③ permeability or porosity, ④ a surface that facilitates cell adhesion and enhances cell proliferation, and ⑤ appropriate biomechanical properties. When considering the use of biodegradable materials for SCI repair, the focus is on how much the restored function of the damaged area can be improved through different approaches. Various natural polymers, including collagen, laminin (LN), fibronectin, fibrin, hyaluronic acid (HA), chitosan, and alginate, have been utilized in various forms, including hydrogels, scaffolds, electrospun nanofibers, and particles [6].

Biodegradable materials are natural or synthetic biomedical substances that undergo degradation, absorption, or excretion by the body upon contact with bodily fluids, acids, or enzymes or upon involvement in metabolic and biochemical processes. Ultimately, biodegradable materials that have been implanted in the body are fully substituted by new tissues [11], [12]. In recent years, the rapid advancement of biological three-dimensional (3D) printing technology has presented a novel approach for addressing SCI. Living cell printing involves the use of bio-ink containing biomaterials, cells, and bioactive factors. By carefully adjusting the ratio of each component in the bio-ink and controlling the printing conditions, it is feasible to accurately replicate the mechanical properties, physiological structure, and biological functions of tissues or organs. This enables rapid and precise fabrication, as well as the repair of damaged tissues or organs [13]. Among various 3D-printed materials, the development of hydrogels has been particularly rapid. The advantages of this material are mainly reflected in its convenient operation, similar structure to natural soft tissues, good absorbability, and biological safety [14], [15].

Recently, Cai et al. [16] fabricated a hydrogel channel featuring a grooved configuration based on a methacryloyl gelatin (GelMA) hydrogel and MXene nanomaterials and explored its role in SCI repair. The research showed that, when used as a functional catheter, the GelMA–MXene composite with a microgroove structure exhibited excellent biocompatibility and electrical conductivity. Its unique micron-scale groove structure facilitated the directional extension of nerve cells and enhanced the connection of nerve stumps. It effectively enhanced the recovery of hind-limb motor function and promoted the regeneration of damaged nerves in rats with SCI. This treatment shows great potential in the management of SCI.

Wang et al. [17] designed an anisotropic Fe₃S₄ ferromagnetic fluid hydrogel (FFH) capable of the sustained release of H₂S. Experimental findings from both in vitro and in vivo studies indicated that the FFH played a crucial part in enhancing the regeneration of axon direction and promoting functional recovery following SCI. The Fe₃S₄ FFH showed excellent compatibility with biological systems, beneficial anti-inflammatory properties, and positive effects on nerve growth. In addition, the directional effect of the magnetic field on the Fe₃S₄ particles promoted the extension of axons in vitro. In vivo experiments showed that the Fe₃S₄ FFH had the potential to attenuate the activation of microglia/macrophages by inhibiting the nuclear factor kappa-B (NF-κB) pathway. Moreover, the directional regeneration of axons and the recovery of motor function in rats with SCI were significantly enhanced by the anisotropic properties of the FFH. The dual effects of immunomodulation and anisotropy make the Fe₃S₄ FFH a promising candidate for the treatment of SCI.

Xu et al. [18] loaded a cell-free fat extract into a hydrogel on an HA methylcellulose substrate to achieve the sustained release of neurotrophic factors. The researchers explained that the fat extract induced microglia/macrophage M2 polarization in the SCI area through the STAT6/Arg-1 pathway, further reducing inflammation and promoting functional recovery after SCI. They explored the role of an HA methylcellulose hydrogel loaded with fat extract in the repair of nervous system injury for the first time and reported its regulation of nerve and vascular regeneration and inflammation after SCI. The regulation mechanism of microglia M2 polarization provides new ideas and directions for the treatment of SCI.

Shen et al. [19] developed a novel multifunctional immune-regulatory hydrogel scaffold that attenuated the acute inflammatory response by eliminating DAMP and facilitated anti-inflammation and tissue remodeling through the continuous release of interleukin-10 (IL-10). Their study revealed that, upon transplantation into mice with complete spinal cord transection injury, the dual-function immune-regulatory hydrogel scaffold alleviated the suppression of pro-inflammatory cytokine secretion, regulated the polarization balance of macrophages/microglia, and inhibited scar formation, thereby enhancing nerve regeneration and axon growth and ultimately boosting the improvement of SCI electrophysiological and motor functions. This study presents a novel strategy for immune-inflammatory treatment of SCI to promote nerve regeneration and motor function recovery.

In addition to the recent research results described above, Liu et al. [20] designed a tough chitosan-based hydrogel (CS-CA-DA) crosslinked by dopamine-modified chitosan and citric acid. The in vitro analysis and experimental results demonstrated that the modification of dopamine significantly enhanced both cell survival and cell adhesion. The CS-CA-DA hydrogel demonstrated good mechanical properties, biocompatibility, and remarkable capacity for cell adhesion. In vivo experiments revealed its potential for mending SCI and enhancing the restoration of hind-limb function in rats. The separate implantation of the CS-CA-DA hydrogel into the injured spinal cord of rats was conducive to improving the cell survival rate, regulating immunity, promoting the polarization of macrophages to the M2 phenotype, facilitating in vivo axon regeneration and cell regeneration in the severely injured area of SCI, and reducing inflammation in that area, thereby providing a favorable regenerative microenvironment and conferring lasting benefits for the recovery of motor function.

Fan et al. [21] developed a novel hydrogel by regulating the concentrations of gelatin and PPy, whose mechanical properties and electrical conductivity are comparable to those of natural spinal cords. To confer biological functions upon the hydrogel, glutathione (GSH) was conjugated to the amino group of gelatin derivatives and the thiol group of GSH derivatives on the hydrogel for the preparation of matrix metalloproteinase (MMP)-responsive hydrogels with recombinant protein glutathione-S-transferase (GST)-MMP-2/9 cleavable peptide PLGLAG (TIMP)-basic fibroblast growth factor (bFGF). The MMP-responsive conductive hydrogel was capable of responding to the SCI microenvironment and releasing bFGF as needed to furnish a favorable biophysical microenvironment with mechanical and electrical properties analogous to those of natural spinal cords. In rats with SCI models, the MMP-responsive biomimetic mechanical and conductive hydrogel were able to inhibit the levels of MMPs, facilitate axon regeneration and angiogenesis, and enhance the recovery of motor function after SCI.

Li et al. [22] developed a composite material called injectable nanofiber-hydrogel (NHC) with interfacial bonding to provide both mechanical strength and porosity. They studied its impact on repairing and regenerating nerve tissue in an adult rat spinal cord contusion model. The findings indicated that NHC offered mechanical support for the injured spinal cord and facilitated pro-regenerative macrophage polarization, axon growth, angiogenesis, and nerve regeneration within the damaged tissue without requiring external factors or cells. These results suggest potential for further refining NHC and optimizing dosing schedules to fully harness its unique properties for treating SCIs.

In addition to significantly promoting axonal regeneration and macrophage polarization, biomaterials can promote synaptic formation and myelin regeneration of various neurotransmitters. Wu et al. [23] designed a biodegradable conductive hydrogel scaffold with capacitive coupled wireless power generation capability and applied it to SCI repair. In a rat model of SCI with complete transection, the implanted conductive hydrogel scaffold combined with the capacitive coupling wireless electrical stimulation function promoted myelin regeneration, accelerated axon regeneration, and facilitated the differentiation of endogenous neural stem cells (NSCs), thereby promoting neural tissue repair and functional recovery. The findings of this study suggest that this capacitive coupling wireless electrical stimulation technology based on a biodegradable conductive hydrogel holds great clinical transformation potential for enhancing neural regeneration and other tissue regeneration.

Xiao et al. [24] designed a kind of bioinspired hydrogel with highly complex features for nerve regeneration after SCI. The hydrogel was composed of chitosan grafted with dihydroxyphenylalanine (DOPA) and a designed polypeptide. It possessed a series of unique properties, including injectability, self-repair ability, and tissue adhesion. In comparison with conventional hydrogels, this particular hydrogel effectively enhanced the regulation of immune response and promoted axon regeneration. It also facilitated the formation of synapses for various neurotransmitters and supported myelin regeneration. Subsequently, there was an improvement in functional recovery, particularly in motor and sensory function, and bladder defect repair. These encouraging results suggest that this hydrogel could be a promising approach for treating SCI.

Fan et al. [25] designed a hydrogel using HA and natural extracellular matrix (ECM) biopolymers, incorporating multiple dynamic covalent bonds. This hydrogel possessed excellent injectability and self-healing properties, allowing for effective injection into injury sites to fill lesion cavities and expedite tissue repair in cases of traumatic SCI. Furthermore, it was compatible with cells and various tissues, exhibiting an appropriate stiffness that matched neural tissue. When implanted at the site of SCI, this HA-based hydrogel promoted the regeneration of axons and the recovery of functions by accelerating myelin regeneration, angiogenesis, and axonal regrowth.

Regarding natural ECM hydrogels, Luo et al. [26] designed a biocompatible conductive ECM-based borax-functionalized oxidized chondroitin sulphate-doped polypyrrole with gelatin (BOCPG) hydrogel that could be injected into the post-traumatic cavity to induce bridging and achieve tissue repair after traumatic SCI. The in vitro experiments demonstrated that the BOCPG-3 hydrogel was able to enhance neuronal and oligodendrocyte differentiation, inhibit astrocyte differentiation, and promote axon growth. Furthermore, the in vivo experimental findings demonstrated that the locally injected conductive hydrogel had the potential to serve as a conduit for facilitating the movement and neural maturation of native NSCs, while impeding the development of glial scars. Finally, the Basso–Beattie–Bresnahan (BBB) score and footprint indicated that the BOCPG-3 hydrogel demonstrated potential for enhancing motor function recovery in rats suffering from SCI. This research offers a hopeful approach for integrating conductive and biocompatible ECM-based hydrogels to develop materials for traumatic spinal cord tissue engineering.

Other cutting-edge studies on biomaterials for repairing SCI were recently published as well. For example, Alvarez et al. [27] reported the promotion of cell regeneration in mice with SCIs, enabling them to regain the ability to walk within four weeks after treatment. In this study, the researchers integrated two types of bioactive polypeptide supramolecular polymers and injected them into the tissues surrounding the spinal cord of paralyzed mice. The polymers were able to self-assemble into nanofiber scaffolds, thereby mimicking the ECM of spinal cord tissue. By binding to the corresponding receptors on cells, different signaling pathways were triggered. The study showed that mutations in the non-bioactive regions on the peptide sequence enhanced the movement of active molecules in the fiber scaffolds, increased the efficiency of binding to receptors, and thereby sent bioactive signals to repair the damaged spinal cord at five key points. This repair included promoting axonal regeneration, forming myelin sheaths to wrap axons and facilitating the transmission of neural signals, forming functional blood vessels, protecting the survival of motor neurons, and reducing the formation of scars by glial cells to avoid physical obstacles to regeneration and repair. Moreover, the supramolecular polymers biodegraded into cellular nutrients and disappeared from the body within 12 weeks after injection, and no obvious side effects were observed in the experiments. This study is expected to provide an effective therapeutic approach for preventing paralysis after major trauma and diseases.

In clinical practice, the majority of patients with spinal cord injuries present with chronic SCI. Scars composed of myelin sheath and cell debris, fibroblasts, astrocytes, microglia, oligodendrocytes, and ECM in the injury area will form physical and chemical barriers, hindering the regeneration of damaged axons [28]. Fig. 2 shows the temporal pathophysiologic changes of different cell types post SCI, including neuron, fibroblast, astrocyte, microglia, oligodendrocyte precursor cell (OPC) and vascular endothelial cell (Figs. 2(a)–(f)), along with some cellular targeted treatment suggested by preclinical studies (Fig. 2(g)). Increased level of Ca²⁺ and ATP release, ischemic, oxidative stress excitotoxicity, and ferroptosis occur in injured neurons firstly (Fig. 2(a)). Most neurons keep ischemic and hypoxic followed by Wallerian degeneration and death eventually, while Vsx²⁺ Hoxa³⁺ Zfhx³⁺ neurons could gradually undergo axonal regeneration. GLAST⁺ perivascular cells and perivascular fibroblasts respectively locate in the gray and white matter of the spinal cord, recruit locally after SCI and region-dependently contribute to fibrotic scarring (Fig. 2(b)). Both types of cells give rise to myofibroblasts and activated fibroblasts, which produce numerous ECM. 90% and 10% of border-forming astrocytes derive from proliferating local astrocytes and OPCs respectively (Fig. 2(c)). SCI induces astrocytes reactive and proliferate to M1 (expressing TNF-α, IL-6, etc.) and M2 (expessing Cdh2, Sox9, etc.) types. Thereafter, astrocytes reprogram into lesion margin astrocytes and involve in repairing wound by interacting with stromal cells and leukocytes. After SCI damage, interferon (IFN)-γ and lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) induce microglias activated and transformed to M1 type, secreting TNF-α, IL-1β, IL-6, and IL-12, while IL-4, IL-13, IL-10, and TLRs induce microglias transforme to M2 type and secret IL-10 and IL-13 (Fig. 2(d)). SCI induce OPCs activate, prolifate and differentiate into Schwann cells, oligodendrocytes expressing NG2, PDGFRα, and GFAP specifically, and reactive astrocytes (Fig. 2(e)). Microvascular rupture causes ECs and pericytes death, increased vascular permeability, and loss of blood–spinal cord barrier (BSCB), followed by secondary cascades including apoptosis, inflammation, and fibrosis. During the recovery phase, endothelial–mesenchymal transition (EndMT) is involved in scar formation, while angiogenesis in the injured area promotes wound healing (Fig. 2(f)).

For an extended period of time, the primary treatment for SCI has been surgical decompression to restore stability and drug therapy, hyperbaric oxygen, and so forth to inhibit or minimize secondary injury. While these approaches have provided some relief of symptoms for patients, they do not result in fundamental changes in neurological function. Consequently, there is an urgent need for an efficient and safe treatment strategy for SCI. Scientists and doctors have high expectations for stem cells in the treatment of SCI, thanks to their strong self-replication ability and paracrine effects [29]. Regarding the underlying mechanisms of SCI repair via stem cells, a growing body of evidence indicates the potential existence of two distinct mechanism types: transplanted cells either facilitate natural repair processes in the originally damaged tissue by providing cytokines for injury repair or prevent further exacerbation of the injury [30]. The transplanted cells serve as replacements for damaged cells, facilitating the formation of a bridge in the cavity area resulting from SCI. They also play a role in guiding nerve regeneration, regulating the immune microenvironment, and repairing non-neural tissues within the spinal cord to promote recovery from nerve injury [31]. At present, within the scope of global clinical trial projects investigating stem cell therapy for SCI, commonly employed cell types include bone-marrow-derived mesenchymal stem cells (MSCs), umbilical-cord-derived MSCs, adipose-derived stem cells (ADSCs), OPCs, neural cells, autologous olfactory ensheathing cells, and autologous Schwann cells.

During clinical trials, MSCs have been widely utilized as the primary cell source for treating SCI. These MSCs are typically obtained from bone marrow, umbilical cord, placenta, adipose tissue, and various other tissues [32], [33]. They can be readily isolated and expanded and possess a wide array of biological functions, such as immune regulation, anti-apoptosis, anti-scarring, angiogenesis, and nutritional support. Clinical data indicates that the application of MSCs in SCI treatment exhibits minimal adverse effects and yields distinct therapeutic efficacy [34], [35], [36]. In 2016, Xiao et al. [37] conducted the world’s first clinical study on nerve regeneration utilizing a collagen scaffold combined with the transplantation of bone marrow mononuclear cells (BMMCs) for the treatment of SCI. Repair surgeries for five cases of SCI were performed in three clinical hospitals, and the results affirmed the safety of this approach. In addition to the pivotal role played by the stem cells, the neural regenerative collagen scaffold demonstrated considerable merit in averting cell dispersion and augmenting the therapeutic efficacy of stem cell treatment.

Bone marrow derived mesenchymal stem cells (BMSCs) are a diverse population of adult stem cells capable of self-renewal and differentiation in multiple directions. They have the potential to be stimulated to develop into adipocytes, chondrocytes, and osteoblasts under in vitro conditions. These particular cells are crucial cellular elements within the bone marrow environment and have an indispensable function in preserving the balance of the hematopoietic microenvironment and bone restructuring. BMSCs are mainly derived from bone marrow, but they can also be extracted from various other sources, including umbilical cord blood, peripheral blood, muscle, bone, cartilage, tendon, adipose tissue, and blood vessels [34], [38]. Wang et al. [39] conducted a study on the advantages of employing a combined tissue engineering approach involving the incorporation of homologous BMSCs and Schwann cells within a 3D scaffold. By leveraging cell gravity and diffusion effects, the researchers strategically positioned BMSCs and rat Schwann cells (RSCs) to facilitate intercellular connections and guide cell differentiation within a specific spatial arrangement. This innovative bioengineering system enabled precise control over various factors such as cell types, cellular positioning, and axon growth orientation within the scaffold. It contributed to motor function recovery by enhancing tissue mimicry and facilitating the reconstruction of myelinated axons. The newly developed 3D fusion printing platform is versatile, capable of simulating bionic tissues using diverse materials and multi-cell scaffolds.

NSCs are a category of multipotent stem cells that possess the capacity to transform into neurons, astrocytes, and oligodendrocytes. However, the inhibitory microenvironment induced by SCI significantly hinders the survival and differentiation of NSCs, thereby severely compromising their therapeutic potential for treating SCI. After SCI, endogenous NSCs located near the site of the injury become activated. However, due to the adverse microenvironment, these activated NSCs encounter challenges in migrating to the injured area and differentiating into neurons. Consequently, facilitating the efficient differentiation of NSCs into neurons within the intricate pathological milieu of SCI poses a significant challenge for nerve regeneration [40]. Liu et al. [41] utilized advanced biological 3D printing technology to fabricate a neural scaffold with a bionic structure resembling the spinal cord. This scaffold created an optimal microenvironment for the survival and differentiation of NSCs into neurons and was employed in the treatment of SCI in Sprague–Dawley (SD) rats. The researchers developed a novel bio-ink, denoted as HBC/HA/MA, comprising hydroxybutyl chitosan (HBC), thiol hyaluronic acid (HA-SH), divinyl sulfone hyaluronic acid (HA-VS), and matrige, with excellent printability and biocompatibility. The results demonstrated that the NSCs implanted within the 3D printing scaffold survived for up to 12 weeks in vivo, underwent transformation into neurons, developed nerve fibers, and facilitated axonal regrowth. This led to an enhancement in the hind-limb motor function of rats with SCI. This study presents an innovative approach for rapidly and accurately constructing neural bionic scaffolds using biological 3D printing technology, with potential applications in regenerative medicine such as SCI repair.

Liu et al. [42] also used supramolecular bio-ink based on methacryloyl gelatin and acryloyl cyclodextrin to construct a neural scaffold with a spinal-cord-like structure by means of 3D printing technology. The scaffold was able to effectively load N-acetylglucosamine (O-GlcNAc) transferase inhibitor OSMI-4, induce neuronal differentiation, and promote SCI repair. This type of neural framework resembling a spinal cord structure can create an optimal growth environment for NSCs and induce the slow release of the small hydrophobic molecule OSMI-4, which significantly improves the efficiency of NSCs in the scaffold differentiating into neurons, thereby forming a rich neural network, realizing the regeneration of nerve fibers and axons in SCI rats, and significantly improving the motor function of hind limbs in rats. This study identified and explored the impact of OSMI-4 on the differentiation of NSCs and its underlying molecular mechanism for the first time. In summary, this work provides a new strategy for the construction of neurofunctional biomimetic scaffolds by means of biological 3D printing and its application in regenerative medicine such as SCI repair.

Li et al. [43] constructed a kind of coaxial hydrogel scaffold with a hierarchical structure by means of coaxial biological 3D printing technology for the on-demand repair of SCI. By encapsulating the double-network hydrogel (composed of HA derivatives and N-cadherin-modified sodium alginate, the core hydrogel scaffold) within a temperature-responsive gelatin/cellulose nanofiber hydrogel (Gel/CNF, the outer hydrogel scaffold), a coaxial hydrogel scaffold with a hierarchical structure was constructed. Not only did the core hydrogel provide mechanical support for NSCs, but its linear topological structure and the loaded N-cadherin were conducive to NSC migration and neuronal differentiation during later stages of SCI treatment. This approach effectively promoted motor function recovery in SCI rats and stimulated nerve fiber regeneration in the damaged area of the spinal cord.

Liu et al. [44] successfully generated human neural stem cells (hNSCs) possessing robust therapeutic potential for the treatment of SCIs. The researchers demonstrated that, by reducing the expression of a gene named SOX9 in human pluripotent stem cell (hPSC)-derived NSCs, they could prioritize the differentiation of the cells within the spinal cord toward motor neurons. When these NSCs were transplanted into a rat model of SCI, the cells generated mature neuronal subtypes capable of integrating and growing axons that projected to distant locations and connected with host neurons. The subjects exhibited a significant reduction in glial scar tissue and remarkable improvements in motor and other functional recoveries. Thus, this approach paves the way for the development of novel therapeutic opportunities.

Some derivatives of NSCs have been verified to facilitate the healing process of spinal cord damage. Recently, Lai et al. [45] revealed that an NSC-derived neural network tissue preconstructed in vitro contained mature functional neurons and had good synaptic formation potential. When transplanted to the spinal cord defect, the neural network tissue established synaptic connections with the nerve fibers that transmit the descending neural information of the brain. Through the relay effect of transplanted neurons on brain-derived neural information, the spinal cord excitatory neurotransmission loop was repaired. As a preclinical study, this work demonstrates the safety of the use of neural network tissue for the repair of SCI. No abnormal pain or self-mutilation was observed in any of the canine models transplanted with neural network tissue. The standardized construction of neural network tissue using clinical seed cells and biological materials through tissue engineering preconstruction is expected to become a valuable approach for the clinical restoration of neural pathways in the spinal cord. Lai et al. [46] also tried to enhance the therapeutic effect of transplanted spinal-cord-like tissue (SCLT) via tail nerve electrical stimulation (TNES). More specifically, they transplanted SCLT into the damaged spinal cord region of rats and used TNES to regulate the number and activity of neurons in the transplanted SCLT. The findings indicated that tail nerve stimulation combined with spinal cord tissue transplantation significantly enhanced the hind-limb function of SCI rats.

Neural progenitor cells (NPCs) are a potential therapeutic approach for the repair and regeneration of neurons after SCI. A review by Fischer et al. [47] has outlined the most recent research advancements in NPC transplantation therapy. NPCs are acquired from diverse tissues or induced and are subsequently transplanted via cell-transplantation technology to attain functional restoration and network connection of the sensory, motor, and autonomic systems. This approach offers an opportunity to formulate effective transplantation strategies for providing new neural cells to facilitate the formation and functional connection of new neuronal networks. Koffler et al. [48] utilized a microscale continuous projection lithography technique to fabricate a sophisticated structure resembling the central nervous system, intended for use in spinal cord regenerative medicine. This method enabled the printing of 3D biomimetic hydrogel scaffolds sized to match that of rodent spinal cords, with potential scalability to human dimensions. The researchers evaluated the scaffold’s capacity to promote axonal regeneration when loaded with NPCs, leading to the formation of new “neural relays” in rodents and the successful bridging of completely injured segments of the spinal cord. Their findings revealed that damaged host axons regenerated within the 3D biomimetic scaffold and established synaptic connections with implanted NPCs, facilitating axon extension from the scaffold into the host spinal cord below the injury site and thereby restoring synaptic transmission. This innovative 3D biomimetic scaffold offers a precision-medicine approach for enhancing central nerve regeneration.

Chen et al. [49] created a specialized decellularized spinal cord fiber (A-DSCF) using electrospinning and tissue decellularization methods, eliminating the need for synthetic polymers or organic solvents. A-DSCF preserved various types of ECM proteins from the spinal cord and formed a parallel-oriented structure. In comparison with well-aligned collagen fibers (A-CF), A-DSCF demonstrated improved mechanical properties, enhanced enzymatic stability, and superior functionality in promoting the adhesion, axon extension, proliferation, and myelination of differentiated NPCs. The promotion of axon extension or myelination in A-DSCF was primarily associated with agrin (AGRN), collagen type IV (COL IV) proteins, or LN. When implanted into rats with complete SCI, A-DSCF loaded with NPCs enhanced the survival, maturation, axon regeneration, and motor function recovery. These results underscore the potential use of biomimetic scaffolds with structural and compositional similarities to promote axon extension and myelin regeneration following SCI.

Kawai et al. [50] investigated how the enhancement of the activity of human induced pluripotent cell-derived neural stem/progenitor cells (hiPSC NS/PCs) transplanted into the host affected both the transplanted cells themselves and the host tissue. Their study revealed that, by selectively stimulating the chemically transplanted NSCs/NPCs within the host, the activity of the transplanted neural cells could be specifically augmented, facilitating their formation of synapses with host neural cells and thereby accelerating the speed and enhancing the extent of recovery of the host’s motor function in the subacute phase. The transplantation of hM3Dq neural cells into a host with SCI and continuous stimulation with clozapine N-oxide (CNO) expedited the recovery of the host’s motor function during the subacute phase, facilitating the formation of synaptic connections between the host neural cells and transplanted neural cells and further promoting the repair and remodeling of neural circuits. This approach provides a fresh perspective for enhancing the efficiency of cell transplantation and improving the therapeutic outcome of SCI repair; it also offers inspiration for cell therapy in other diseases.

In recent years, the utilization of dECM in SCI repair has emerged as a prominent research focus. dECM preserves the structure and bioactive factors of the ECM, thereby offering a conducive environment for nerve regeneration. Sun et al. [51] exploited the developmental dynamics of spinal dECM to augment the regenerative potential of spinal organoids. The researchers discovered that, in contrast to the adult spinal cord, the early developing spinal cord possesses a higher level of dECM proteins associated with neural development and axon growth but a lower amount of inhibitory proteoglycans. The dECM derived from neonatal (DNSCM) and adult (DASCM) rabbit spinal cords retains these disparities. Compared with DASCM, DNSCM is more efficacious in facilitating the proliferation, migration, and neuronal differentiation of NPCs, as well as in promoting axon growth and regeneration in spinal organ tissue. The identified growth factors (PTN) and tendon protein (TNC) within DNSCM are the factors contributing to these capabilities. Furthermore, in an SCI model, DNSCM demonstrates superior performance as a carrier for NPCs and organoids. This finding indicates that early developmental dECM cues might play a substantial role in promoting the remarkable regenerative capacity of the spinal cord.

Xu et al. [52] employed materials science, transcriptomics, and matrix protein analysis to conduct a comparison between a decellularized spinal cord matrix hydrogel (DSCM-gel) and a decellularized nerve matrix hydrogel (DNM-gel). Their findings indicated that both decellularized matrix hydrogels maintained nanofiber structures analogous to the ECM; however, the porosity and fiber diameter of the DSCM-gel were marginally higher than those of the DNM-gel. When NSPCs were encapsulated within the decellularized matrix hydrogels and subjected to 3D culture, it was discovered that the DSCM-gel was more favorable for the survival, proliferation, and migration of the NSPCs and was capable of facilitating their neuronal differentiation. The 3D microenvironment offered by the decellularized matrix and its specific cellular regulation are of critical significance in the design and fabrication of multifunctional biomaterials. This study further increased the current comprehension of the composition, tissue specificity, and biological functions of tissue-derived decellularized matrices, clarified the role of the decellularized spinal cord matrix in influencing the fate of NSCs, and verified the immense potential of DSCM-gels as a transformative biomaterial for the repair of SCIs.

Peng et al. [53] employed microfluidic technology to fabricate water-based gel microspheres composed of LOX-MnO₂ nanocatalysts and dECM, denoted as LMGDNPs, to serve as a stem cell delivery system for intervertebral disc (IVD) degeneration (IDD) treatment. The microspheres possessed uniform sizes, excellent biocompatibility, appropriate microstructures, and favorable resistance to lactate dehydrogenase activity. The LMGDNPs notably mitigated the pro-apoptotic and matrix degradation effects of lactate, as well as activating autophagy by facilitating the formation of TGFB2 overlapping transcript 1 (TGFB2-OT1) autophagosomes and eliminating lactate. Moreover, microspheres consisting of dECM from the natural nucleus pulposus enhanced the tissue-specific differentiation of stem cells for matrix synthesis and IVD regeneration. These glucose-rich dECM microspheres functionalized by LOX-MnO₂ nanocatalysts provided nutrition and eliminated the detrimental effects of glycolysis byproducts, presenting a novel strategy for stem cell delivery to achieve better cell survival and therapeutic effects against IDD.

Liu et al. [54] created a multifunctional ECM derived from decellularized spinal cord (dSECM) and cross-linked it with glial-cell-derived neurotrophic factor (GDNF) using collagenase treatment to promote the differentiation of stem cells into neuron-like cells and to enhance both axon and myelin regeneration. Four weeks after the operation, the dSECM facilitated the transformation of MSCs or NSCs into neuron-like cells, thereby supporting neural repair at the injury site. Additionally, eight weeks after the surgery, the GDNF activated the PI3K/Akt and MEK/Erk signaling pathways to stimulate axonogenesis and myelin regeneration, which in turn strengthened both axonal growth and myelination and improved neural signal transmission, providing a promising therapeutic outcome for enhancing motor function following SCI.

Exosomes are regarded as having therapeutic potential in the clinical practice of SCI treatment and are anticipated to serve as an alternative therapy to cell therapy [33], [55]. The effective therapeutic components in exosomes and their potential repair mechanisms still need to be deeply studied, and biological scaffolds for them also need to be discovered [56], [57]. Zhu et al. [58] developed an HA hydrogel patch with a nanofiber scaffold that was capable of non-invasively releasing exosomes and methylprednisolone into the injured spinal cord. This composite patch demonstrated excellent biocompatibility by maintaining the morphology of the exosomes and minimizing neurocytotoxicity. In vitro studies revealed that the composite patch promoted an increase in M2 macrophage proportion and reduced neuronal apoptosis. Furthermore, in vivo experiments showed that applying this composite patch to cover the hematoma surface significantly enhanced functional and electrophysiological performance in rats with SCI. The study found that this composite patch inhibited the inflammatory response by suppressing the polarization of macrophages from M1 to M2 and inhibited the apoptosis of neurons after SCI to improve the survival of neurons. The findings from the experiment suggest that the therapeutic effect of this composite patch is related to pathways such as TLR4/NF-κB, Akt/mTOR, and MAPK. To sum up, the composite patch developed in this study is a drug-exosome dual-release system, which is expected to provide a new, non-invasive method for the clinical treatment of patients with SCI.

Qin et al. [59] discovered that the local delivery of epidermal growth factor receptor-positive NSC-derived exosomes (EGFR⁺ NSCs-Exos) can promote SCI repair and explored the molecular mechanism of this process. Epidermal growth factor receptor-positive NSCs (EGFR⁺ NSCs) are a subgroup of endogenous NSCs that have been demonstrated to exhibit strong regenerative capacity in central nervous system diseases. In this research, EGFR + NSCs were initially identified, and their exosomes were isolated. Subsequently, the characteristics of EGFR⁺ NSCs and their exosomes were determined through transcriptomics and microRNA sequencing analysis. The study then delved into exploring the mechanism by which EGFR⁺ NSCs-Exos promote axon growth, using in vitro cell models. In addition, a hydrogel-coated exosome patch for treating SCI was designed and implemented through the integration of 3D printing technology and hydrogel scaffolds, demonstrating remarkable efficacy in enhancing nerve regeneration. These findings suggest that EGFR⁺ NSCs-Exos have the ability to transfer miR-34a-5p to neurons, resulting in the downregulation of HDAC6 and subsequently activating neuronal autophagy processes while enhancing microtubule stability. In summary, this investigation introduced a novel type of exosomes derived from EGFR⁺ NSCs that exhibit potential for improving functional recovery following SCI treatment, offering an encouraging cell-free therapeutic approach for SCI treatment.

Because of their capacity for self-renewal and differentiation into multiple lineages, MSCs have been extensively investigated for the treatment of SCI. Studies have demonstrated that the therapeutic effects of MSCs in SCI are predominantly mediated by the exosomes secreted by the MSCs, which exert paracrine activities [33]. Recently, He et al. [60] demonstrated the therapeutic effect of exosome-modified fibrin glue (Gel-Exo) in mouse SCI, discovered neurotrophic factor VGF (nerve growth factor (NGF) inducible) to be an effective therapeutic component of exosomes, and revealed the molecular mechanism by which Gel-Exo promotes oligodendrocyte regeneration. In their work, MSC-derived exosomes were combined with fibrin glue to prepare a Gel-Exo composite scaffold system with good biocompatibility, which was then applied to a mouse complete-transection SCI model. The behavioral score of the mice treated with Gel-Exo increased from 0.6 points to 2.4 points, showing a significant improvement compared with the untreated injury group. Furthermore, transcriptome sequencing results found that VGF is a key regulatory factor in Gel-Exo’s promotion of SCI repair. VGF has a wide range of effects on neurological diseases. Experimental verification revealed that the content of VGF in exosomes was abundant. In mice treated with Gel-Exo, VGF was highly expressed in the injury area, and the number of oligodendrocytes increased. Moreover, the in vivo overexpression of VGF promoted the generation of oligodendrocytes in the injury area, showing an SCI repair effect similar to that of the Gel-Exo treatment group. This finding indicates that the therapeutic effect of Gel-Exo on SCI is mediated by VGF-induced oligodendrocyte regeneration.

Comprehensively regulating the out-of-control local injury microenvironment is the key to treating SCI. Exosomes derived from bone marrow mesenchymal stem cells (MSC-Exo) have displayed promising prospects for treating SCI [61]. Nevertheless, the conventional 2-dimensional (2D) culture approach invariably results in decreased or compromised MSC stemness, significantly constraining the clinical utility of MSC-Exo, whereas 3D-MSC-Exo has higher neural repair efficiency. Han et al. [62] conducted the 3D culture of MSC using a GelMA hydrogel and extracted exosomes, independently constructed a hydrogel microneedle array patch loaded with 3D-MSC-Exo for the in situ treatment of SCI, and achieved good therapeutic effects. Compared with traditional 2D culture, MSCs cultured in 3D with GelMA hydrogel efficiently secreted exosomes with more neuroprotective-related contents, significantly improving the exosomes delivery efficiency. By alleviating neuroinflammatory responses at the injury site, encouraging microglia to adopt the M2 phenotype, reducing glial scarring, and promoting the repair of nerve function damage, this showed itself to be a novel potential approach for treating SCI through biological means. Conductive hydrogels are very attractive candidates for accelerating the repair of SCI because of their capacity to accurately replicate the electrical and mechanical characteristics of neural tissue. Nevertheless, the use of conductive hydrogels in implantation procedures may exacerbate inflammation and impede their repair effects. On the other hand, exosomes derived from bone marrow stem cells (BMSC-exosomes) have demonstrated immunomodulatory and tissue regeneration capabilities. Consequently, nerve-tissue-mimicking conductive hydrogels loaded with BMSC-exosomes have been formulated for a combined approach to treating SCI. These exosome-loaded conductive hydrogels work synergistically to promote neuronal and oligodendrocyte differentiation in NSCs, while inhibiting astrocyte differentiation and enhancing axonal growth through the PTEN/PI3K/AKT/mTOR pathway. Hence, the utilization of conductive hydrogels in conjunction with BMSC-exosomes offers a hopeful therapeutic approach for mending SCI.

Extensive reduction of the inhibitory microenvironment in SCI is necessary for comprehensive relief. Exosomes derived from MSCs serve as endogenous biological carriers of paracrine signaling molecules. Although they can effectively regulate the microenvironment, the effective retention, release, and integration of exosomes have not been well studied. Li et al. [33] used an innovative implantation strategy to immobilize human MSC-derived exosomes in a peptide-modified adhesive hydrogel (Exo-pGel), which differs from the systemic administration of exosomes. Local transplantation resulted in the delivery of a dECM enclosed within exosomes to the damaged nerve tissue, effectively and comprehensively improving the microenvironment of SCI. The implanted exosomes demonstrated efficient retention and ongoing release within the nerve tissue of the host. Exo-pGel reduced inflammation and oxidation and significantly promoted nerve recovery, presenting a hopeful approach for the efficient management of exosome-based implantation in central nervous system diseases.

The combination of dECM and exosomes holds considerable potential for SCI repair. As a component of dECM, exosomes can exert a more potent function when reentering the dECM. For example, in the preparation and application of a biologically active hydrogel, a spinal cord dECM hydrogel—as a biologically active material originating from natural tissues/organs—has extensive applications in the field of tissue engineering and regenerative medicine. Exosomes include various biologically active substances and possess anti-inflammatory and proliferation-stimulating effects. Loading exosomes onto the dECM allows them to gradually and continuously permeate the SCI site and release externally, prolonging their retention at the injury site and facilitating the effective absorption and therapeutic function of the exosome contents. Loading a dECM with exosomes can promote the migration of fibroblasts and significantly accelerate wound healing and collagen fiber deposition in skin tissue. In bone tissue engineering, the combination of exosomes with biological scaffolds can efficaciously address the issues of poor bioavailability and the lack of a regulated release mechanism of exosomes at the site of action. The porosity, moldability, and biocompatibility of the hydrogel can be mutually complementary to exosomes. Moreover, the bioavailability, biocompatibility, and loading/release control of the exosome-loaded scaffold can be enhanced by rationally engineering and functionalizing the hydrogel scaffold, and the effect of the cell-free scaffold on bone repair can be augmented [55], [63].

After SCI, delivering neurotrophic factors to the central nervous system through various methods may facilitate the restoration of both structure and function. The most common neurotrophic factors used for the treatment of SCI include brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), NGF, basic fibroblast growth factor (bFGF), insulin like growth factor (IGF), and glialcellline-derived neurotrophic factor (GDNF). These neurotrophic factors enhance the survival of neurons, modify the characteristics of glial cells, support neural adaptability, and encourage the regrowth of axons [64].

NT3 stands out as a highly potent neurotrophic factor for promoting neuronal regeneration and facilitating functional recovery after SCI [65]. Furthermore, NT3 not only plays a role in the survival of sensory neurons, basal forebrain cholinergic neurons, and motor neurons but also facilitates the development of dopaminergic neurons and encourages the branching out of corticospinal tracts (CSTs) [66], [67]. Increasing the concentration of NT3 significantly improves spinal cord function. When NT3 is used in combination with other neurotrophic factors, such as BDNF, the atrophy and death of rubrospinal tract neurons can be further reduced [65], [68]. Wang et al. [69] systematically identified the neuronal subtypes of newborn neurons (newborn neurons in the lesion area (NNLA)) at the site of injury, established that these neurons had the capacity to form synaptic connections with various brain regions, unveiled the reorganization of local neural circuits in the injured spinal cord, and demonstrated that the neural circuits below the injury plane were still plastic. Using immunohistochemistry, viral tracing, transmission electron microscopy, and electromyography, the researchers systematically revealed that NT3-chitosan promoted the regeneration of neurons at the injured sites and integrated into the host loop to reconstruct the damaged neural network, suggesting that the active biomaterial scaffold could offer a promising new approach for treating patients with complete paraplegia in clinical settings.

Glial scars are physical and chemical barriers that hinder nerve regeneration, and how to deal with glial scarring has become one of the key factors affecting the treatment of old SCI. Zhao et al. [70] performed a 3D reconstruction of glial scars in rats with SCI by means of diffusion tensor imaging. After guiding the surgical release of the scars, different dosage forms of self-developed bioactive materials were implanted, successfully achieving endogenous neurogenesis and stable sensorimotor function recovery after old SCI. In order to effectively repair old SCI, the research team used non-invasive diffusion tensor imaging to monitor the temporal and spatial changes of the lesion area in rats with old SCI. Subsequently, the imaging results were used to guide the removal of cystic tissue in the lesion area and the pruning of solid scar tissue to remove the lesion core. On this basis, rigid tubular bioactive-material scaffolds were implanted, or gel-like bioactive materials were injected. Through imaging, pathology, and behavioral and electrophysiological analysis, the researchers observed that the scar-pruning the animals produced similar effects to the previous acute SCI repair. Both bioactive materials induced axonal growth of the CST and new neurogenesis and stable functional recovery. In contrast, the injection of bioactive materials after the removal of cystic tissue without pruning the scar did not produce effective nerve regeneration. The results of this study indicated the importance of scar pruning in the treatment of old SCI and confirmed the promoting effect of the bioactive materials developed by the researchers on tissue regeneration after old SCI, thus laying a foundation for subsequent clinical trials of this material with subacute and chronic damage to the spinal cord.

Zhu et al. [71] designed a biodegradable layered double hydroxide (LDH) nanomaterial with the ability to modulate immune cell classification at the site of injury and suppress inflammatory responses. This material significantly enhanced NSC migration, neural differentiation, L-Ca²⁺ channel activation, and action potential induction. Following transplantation of the nano-composite system (LDH-NT3) formed by loading LDH with neurotrophic factor NT3 into the injured area of SCI mice, new BrdU⁺ endogenous NSCs and functional neurons were observed, leading to significant improvements in behavioral and electrophysiological evaluations of the mice. The study also revealed that LDH itself promoted nerve regeneration, while LDH-NT3 demonstrated even greater efficacy in repairing SCIs in SCI mice compared with the LDH group. Furthermore, it was found that LDH created an immune microenvironment conducive to SCI repair and was able to carry various neurotrophic factors.

Baloh et al. [72] developed a novel therapeutic approach for amyotrophic lateral sclerosis (ALS) that integrates stem cell therapy and gene therapy. By employing NPCs to express the protein glial cell-line-derived neurotrophic factor (GDNF), which safeguards motor neurons, the issue of the inability of GDNF protein to traverse the blood–brain barrier was addressed. The research team carried out the first human clinical trial using this combined therapy, and the outcomes indicated that this new treatment was safe for ALS patients. Moreover, the NPCs were capable of differentiating into astrocytes and expressing the GDNF protein in the patients’ spinal cords for more than three years (42 months) following a single treatment.

The role of platelet-derived growth factor (PDGF) in the nervous system is complex, encompassing functions such as mitigating neuronal death, participating in neurogenesis and synaptogenesis, facilitating the development of specific neuron types, promoting the differentiation of NSCs into oligodendrocytes and neurons, and contributing to angiogenesis. However, genetically engineered PDGF protein has several limitations, including low stability, a short half-life, poor penetration ability, rapid dispersion after local administration, and the requirement for multiple administrations for in vivo applications [73], [74]. Wu et al. [74] designed PDGF-mimetic peptide hydrogel microspheres (PDGF-MPHMs). After co-transplantation with NSCs in the injured spinal cord of rats, they significantly promoted the survival and neuronal differentiation of NSCs in rats with SCI by reducing apoptosis in the injured area, reducing M1 macrophage infiltration, and stimulating axon regeneration, remyelination, and angiogenesis. Ultimately, they efficiently restored the motor function of the rats, providing a new therapeutic idea for SCI.

Biomaterials can be used as cell carriers to promote nerve regeneration by planting stem cells or neural precursor cells on the surface of materials. The surface morphology of materials has a significant influence on cell adhesion, growth, proliferation, and differentiation. Stem cell transplantation offers a potential therapeutic approach for SCI repair.

Due to the sensitivity and vulnerability of NSCs, there are certain challenges in the field of NSC-based biological 3D printing, including a limited variety of available biological inks, a complex biological printing process, reduced cell survival rates post-printing, and inadequate cell-scaffold interaction. These factors restrict the potential application of NSC-based biological 3D printing in the treatment of SCI. To address this issue, Yuan et al. [75] designed a DNA hydrogel with extremely high permeability that effectively carried homologous NSCs to repair a 2 mm spinal cord gap in SD rats. This approach led to the restoration of fundamental hind-limb function in the rats through the manifestation of detectable motor evoked potentials and established novel neural networks via the implantation, proliferation, and differentiation of endogenous stem cells. The study’s analysis demonstrated that this supramolecular DNA hydrogel satisfied the majority of the criteria for ideal NSC transplantation materials, including excellent permeability, self-healing capacity, and appropriate mechanical support. The DNA hydrogel facilitated the establishment of continuous regenerative neural networks by enabling the unhindered migration, proliferation, and differentiation of implanted and recruited NSCs.

Song et al. [76] fabricated an insulin-like growth factor-1 (IGF-1)-bioactive supramolecular nanofiber hydrogel (IGF-1 gel). The research team discovered that the IGF-1 gel was capable of facilitating the survival, proliferation, and differentiation of NSCs into neurons and oligodendrocytes. The injection of the IGF-1 gel containing NSCs conspicuously stimulated the growth of nerve axons and myelin regeneration at the injured site, thereby ameliorating neural recovery subsequent to SCI. Moreover, the research team affirmed that the IGF-1 gel boosted the enrichment of microRNAs (miRNAs) related to axon and myelin regeneration within the exosomes secreted by NSCs, thereby enhancing the biological functions of the exosomes and promoting intercellular communication between exogenous NSCs and endogenous NSCs.

Drawing upon the intricate anatomical structure and mechanical properties of the spinal cord, Zhou et al. [77] developed 3D hydrogel scaffolds designed to provide structural support for both NSCs and BMSCs. These innovative scaffolds were crosslinked through photopolymerization techniques to facilitate NSC differentiation into neurons while concurrently reducing astrocyte production. The researchers also fabricated various 3D scaffolds with distinct water content and mechanical properties utilizing photo-crosslinked hydrogel technology. In vitro experimental findings demonstrated that this 3D hydrogel scaffold enhanced cell survival, proliferation, and differentiation following co-transplantation. Furthermore, in vivo research revealed that these engineered 3D hydrogel scaffolds carrying co-cultured cells stimulated the generation of neurons and oligodendrocytes while inhibiting astrocytic scar formation and fibrous scarring. Notably, significant enhancements in motor function along with effective mitigation of inflammatory responses and vacuolization were observed within a rat model simulating SCI.

Qiu et al. [78] designed and manufactured a GelMA scaffold with a high specific surface area and self-promoting cell adsorption ability, and loaded a new type of perinatal stem cell with immunomodulatory ability and neural properties—namely, human amniotic epithelial stem cells. The implementation of this cellular technology mitigates the drawbacks associated with traditional stem cells in terms of safety and ethical considerations, while streamlining clinical transformation processes. In vivo experiments, the transplantation of the spinal cord scaffolds caused significant neural circuit reconstruction, inhibited the neuroinflammatory response in the injured area, and facilitated the restoration of movement in the hind-limbs of rats. This approach provides new techniques and ideas for the treatment of SCI and offers a fresh perspective for the potential clinical use of tissue engineering in the future.

Yuan et al. [79] formulated a novel cell-adaptable neurogenic (CaNeu) hydrogel as a carrier for ADSCs, with the goal of facilitating nerve regeneration after SCI. ADSCs are one type of potential stem cell for the treatment of SCI. However, due to the existence of an inflammatory microenvironment after SCI, the therapeutic effect of ADSCs directly transplanted into an SCI is usually limited. This research revealed that the dynamic network of the CaNeu hydrogel created a beneficial microenvironment through yes-associated protein (YAP) signaling to promote the extension of encapsulated ADSCs. At the same time, the ADSCs activated the PI3K/Akt pathway by paracrine to promote the polarization of macrophages to M2. In addition, the up-regulation of Bcl-2 and the down-regulation of Bax inhibited apoptosis. Through the interaction between the ADSCs and the dynamic hydrogel CaNeu, the inflammatory microenvironment after SCI was improved, promoting nerve regeneration and improving the repair effect after SCI. This study demonstrated that the administration of ADSCs via the CaNeu hydrogel significantly attenuated neuroinflammation and apoptosis. Thus, the CaNeu hydrogel is a valuable carrier for stem cell transplantation, and the co-transplantation of CaNeu hydrogel and ADSCs can promote the repair of SCI, providing new ideas and methods for clinical treatment of SCI.

Biomaterials have the potential to be designed for the controlled release of growth factors, including neurotrophic factors and NGFs, in order to facilitate tissue regeneration and enhance functional recovery. Complete SCI leads to cellular demise, disrupted axonal connections, and enduring dysfunction. Extensive research in the field of SCI treatment has focused on investigating the combined approach of cell transplantation and biomaterial-growth factor-based therapy. Recent studies on the addition of active factors, small molecules, and RNA to spinal cord repair materials are listed in Table 2 [19], [24], [80], [81], [82], [83], [84], [85], [86], [87], [88].

Repairing and regenerating SCI involve the utilization of biological components and methods such as biodegradable materials, soluble bioactive molecules, cell matrices, and cell transplantation, alongside engineering techniques such as spinal epidural electrical stimulation, deep brain stimulation, and brain–computer interfaces. This article comprehensively reviewed recent advancements in SCI repair with a focus on biomaterials, cells, dECM and exosomes, and other active factors, small molecules, and RNA. As materials science, tissue engineering, neuroscience, and regenerative medicine advance, the field of repairing tissue-engineered nerves and nerve injuries continues to expand [89]. The repair and functional reconstruction of SCI requires consistent effort and the establishment of new strategies, particularly in the following nine areas: ① regulation of the intrinsic regeneration ability of neurons; ② the effects of immunity on neuronal regeneration; ③ vascular formation and remodeling; ④ function and pattern expression of subpopulations of glial cells after SCI; ⑤ scar formation and tissue fibrosis in the injured region; ⑥ stem cells and growth factors; ⑦ remodeling of the topological architecture of the cell matrix and active regeneration of the microenvironment; ⑧ biodegradable nerve scaffolds and biomimetic materials; and ⑨ epidural electrical stimulation. The novel research advances described herein offer new prospects for the treatment of SCI; however, further research and validation regarding their safety and efficacy are still requisite. This necessitates the coordinated efforts of experts from various disciplines, scholars, and research teams, as well as the integration of diverse laboratory technologies. From the perspective of clinical translation, the quantity of clinical trials in the global SCI repair domain is relatively limited. Moreover, continuous investment in research funding, adherence to standardized guidelines for management, and global collaborative innovation are needed.

This work was supported by grants from the National Natural Science Foundation of China (92368207), the Chinese Academy of Engineering (2023-SBZD-11), and the Natural Science Foundation of Jiangsu Province (BK20232023).

Lai Xu, Songlin Zhou, Xiu Dai, Xiaosong Gu, and Zhaolian Ouyang declare that they have no conflict of interest or financial conflicts to disclose.