Research Progress on Biomaterials for Spinal Cord Repair

The Current State of Spinal Cord Injury

Epidemiology of Spinal Cord Injury

Spinal cord injury (SCI) is a common traumatic disorder. With the development of transportation and construction industries, the number of SCI cases is escalating rapidly. The incidence ratio of SCI ranges from 14.6–60.6 per million, and the average age of onset is 34–55 years old.¹ SCI causes serious dysfunction below the injury site and reduces the life quality of patients, creating a heavy familial and societal economic burden. However, there is no effective treatment for SCI in clinics, and more detailed research is urgently needed in the medical field.

Pathophysiological Mechanism of Spinal Cord Injury

The pathophysiological change of SCI comprises two stages: primary and secondary^2,3 (Figure 1). In clinics, primary SCI is usually caused by vertebral fracture or dislocation from violent injury. The displacement of bone fragments and the tearing of ligaments often causes spinal cord compression³ and bleeding and blood supply interruption which lead to hypoxia and ischemic infarction. Furthermore, the damaged area contains neurons that are physically broken with reduced myelin thickness, and the damaged tissue forms edemas in which macrophages accumulate⁴ to cause irreversible neurological defects. Secondary injury develops from primary injury⁵ with a time progression that can be divided into acute, subacute, and chronic stages.^6,7 The acute phase commences approximately 2 hours after injury with increased cell permeability, ischemia, vascular damage, edema, neurotransmitter accumulation, calcium influx, inflammation, lipid peroxidation, and free radical formation. In addition, severe bleeding resulting from vascular injury exposes the spinal cord to a substantial influx of inflammatory cells, cytokines, and vasoactive peptides. Previous research has demonstrated that pro-inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1β (IL-1β), exhibit marked increases within minutes following SCI. Concurrently, a significant number of immune cells including macrophages, neutrophils, and lymphocytes migrate into the spinal cord via the bloodstream and persist in this region. The extensive inflammatory response that occurs during both acute and subacute phases of injury. Two weeks later, the injury develops to a subacute stage characterized by demyelination, Wallerian degeneration, matrix remodeling, and fibroglial scar formation.³ The chronic phase often begins 6 months after injury and is characterized by cyst formation, axon retraction, and glial scar maturation.^7,8 Thus, after SCI, the activated microglia, astrocytes, and macrophages trigger the secretion of extracellular matrix (ECM) proteins, such as chondroitin sulfate proteoglycans (CSPG), tenascin, and NG2 proteoglycans. These proteins interact with reactive astrocytes to form glial scars. Subsequently, these scar tissue creates an impenetrable barrier to nerve regeneration. Therefore, targeting these inhibitory microenvironments might be the most effective approach to promoting axon regeneration in the injured spinal cord. With advances in tissue engineering, it is feasible to utilize biomaterials to regulate the local microenvironment of the injured spinal cord, which may achieve better functional recovery in spinal cord injury repair.

Figure 1 The pathophysiological mechanism of spinal cord injury: In the acute stage of SCI, severing of axon, hemorrhage of blood vessels, death of neuron and glia, ischemia and swelling of spinal cord, astrocytes are started to be activated. In the intermediate stage, macrophages infiltrate and activated, astrocytes proliferate, and glial scars form. In the chronic stage, continued glial scars formation, development of cyst and Wallerian degeneration. By Figdraw.

Clinical Treatment

The current clinical treatment of SCI is a cooperative multidisciplinary approach aimed at minimizing the symptoms and sequelae after injury and helping patients recover function and improve life quality. At present, the clinical treatment methods for SCI mainly include:

First Aid and Initial Care

For patients with acute SCI, first aid is critical. This includes stabilizing the spine and protecting the spinal cord to prevent further injury. Timely emergency management can reduce the extent of injury and reduce the risk of complications.⁹

Surgery

Surgical decompression can effectively reduce bone fragment compression on the spinal cord and prevent further expansion of the injury. Timely surgical operations after severe SCI also can improve patient prognosis.¹⁰

Pharmacologic Therapy

Pharmacologic therapies include the use of anti-inflammatory drugs, antispasmodic drugs, and analgesics to reduce inflammation and pain. Glucocorticoid hormone shock therapy is used extensively,⁹ and neuroprotectants or other drugs may also be used to promote nerve regeneration.¹¹

Physical Therapy and Rehabilitation Training

Physical therapy and rehabilitation training are the core of SCI patients to recover muscle strength, balance, and motor function, and further improve patients’ self-care abilities.^12–14

Moral Support

SCI can impact patients and their families psychologically and spiritually, and psychological support and counseling is also important for rehabilitation and the reconstruction of an adapted life.¹⁵

Neuroprosthetics

The neuroprosthetic technology directly acts on the muscular system or an external device by analyzing electroencephalogram signals to obtain motor commands from brain signals, thereby compensating the brain-spinal⁃muscle fundamental efferent pathway and restoring the motor function of SCI patients. Recently, artificial intelligence technology and brain-computer interface (BCIs) have emerged as an alternative to drug therapy, opening a new era of SCI rehabilitation treatment.¹⁶ There are two main therapeutic strategies based on BCIs technology applied to SCI treatments, one is BCI-controlled rehabilitation robot, and the other is BCI-controlled functional electrical stimulation of neuromuscular system. It is worth mentioning that most patients with upper limb motor dysfunction caused by cervical SCI can recover and compensate the upper limb motor function through neuroprosthetic approach in clinic. With the improvement of technologies, it is believed that using the functional electrical stimulation of BSI to control the denervated muscles in SCI patients, so that they can restore motor function will be achieved.

However, these strategies cannot fully repair SCIs but can improve symptoms and reduce some complications. Some pharmacological interventions may play a crucial role in mitigating secondary injury when administered promptly, whereas rehabilitation therapies are likely to be effective during the later stages of recovery to facilitate functional improvement.

The Current State of SCI Research

SCI treatment research is currently very active; neuroscientists and medical experts are actively exploring new treatment methods to improve functional recovery and life quality in SCI patients. Current animal studies for SCI include genetic manipulations, biomaterial transplantation, pharmacological interventions, and stem cell therapies (Figure 2).

Figure 2 Current major strategies for SCI treatment research. It mainly includes surgical treatment, biomaterial transplantation, pharmacological interventions, and stem cell therapies. By Figdraw.

Traditional pharmacological therapy for SCI is still being improved, and includes the use of glucocorticoid hormone therapy, nerve growth factor, ganglioside, and traditional Chinese medicine. Glucocorticoids are very common in clinical SCI treatment. The administration of methylprednisolone to patients within 8 hours of acute SCI can inhibit local inflammatory responses and lipid peroxidation.¹⁷ However, glucocorticoid hormone therapy is controversial for acute SCI regarding dosage regimens, as large doses of glucocorticoid hormones have many systemic side effects.¹⁸ Many neurotrophic factors regulate neuronal survival and synaptic function in the adult central and peripheral nervous systems.¹¹ Rosich et al found that glial cell line-derived neurotrophic factor (GDNF) is more effective for SCI when used in combination with other neurotrophic factors than when used alone. Other neurotrophic factors such as brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3), neurotrophic factor-4/5 (NT-4/5), and neuro-proliferative acid (NAP) also substantially improve SCI functional recovery.¹⁹ However, neurotrophic factors are unstable in vivo and cannot penetrate the blood-brain barrier to achieve the desired therapeutic effects. Therefore, ideal carriers are needed to load them and increase their local effects.

Stem cell transplantation is another promising treatment method for SCI. Stem cells can be replenished to differentiate into neurons and restore neurological function. Curtis et al’s Phase I clinical trial showed that chronic SCI patients can recover motor function with reduced spasticity after NSI-566 cell transplantation, without side effects for at least 27 months after transplantation.²⁰ Despite the many potential advantages of stem cell therapy for SCI, there are still some shortcomings and challenges, including its safety, cost, and a lack of long-term follow-up data. Nevertheless, the approach remains cutting-edge and highly anticipated, and these challenges will be overcome with advances in science and technology and more clinical trial data.

In addition to the above methods, new therapeutics are being studied and explored, including biomaterial scaffold^21,22 that are expected to bring new breakthroughs in SCI treatment. Early diagnosis and timely treatment can improve therapeutic effects and recovery potential. Though SCI treatment has made great progress in recent years, neurological functions still cannot be restored to patients, and each treatment has strict restrictions with limited functional recovery. Due to the complex pathological process of SCI, using a single target or a single strategy alone is not sufficient to promote spinal cord repair in clinic. Therefore, the future research on SCI should shift towards multi-target, multi-phase treatment strategies.

Application of Biomaterials for SCI Treatment

With advances in tissue engineering, biomaterials have become very attractive for repairing damaged nerve tissues. Biomaterial scaffolds can be used for drug delivery, cell load, and tissue engineering to facilitate the repair of SCIs, while acting as a scaffold and microenvironment for tissue growth with reduced inflammatory responses (Figure 3). In this review, we discuss the properties of various biomaterials and their applications in SCI to guide future research direction.

Figure 3 The main strategies of SCI treatment using biomaterials. (1) Inhibit inflammatory responses.(2) Reduces oxidative stress. (3) Stem cell filling. (4) Mechanical support. (5) guide axon growth. (6) Controlled drug release. By Figdraw.

Natural Biomaterial Scaffold

Natural biological materials are easily obtained and have good biocompatibility and degradability, with strong biological activity in vivo and minimal immune responses. Most natural biomaterials are soft and easily prepared as hydrogels that effectively fill the SCI lesion cavity. In addition, they mostly have good adhesion properties and are ideal carriers for seed cells. These materials include collagen, gelatin, acellular matrix, and polysaccharide (Table 1).

Table 1 Application of Natural Biomaterials in Spinal Cord Injury

Collagen

Collagen is a mechanically strong triple-helical structure comprising three alpha-chain polypeptides.⁴⁶ There are several subtypes; the primary types in the human body are types I, II, and III;^47,48 type I is the most widely used in biomedicine. Collagen is a major component of the extracellular matrix (ECM) of connective tissue and a highly dynamic material that can be constantly reshaped to maintain original physiological functions.⁴⁹ Although collagen scaffolds are limited by rapid degradation rate and poor mechanical strength, mammalian cells have cell-surface integrins with a high affinity for specific collagen sequences,⁴⁶ making collagen superior for promoting cell adhesion and growth. Therefore, collagen-based three-dimensional (3D) porous scaffolds are advantageous and can be made into hydrogels, sponges, and microspheres¹⁶ that can guide axon regeneration, deliver drugs, and promote tissue healing in SCI repair. Yeh et al inserted collagen scaffold into the T8 spinal cord defect area of rats and observed that collagen scaffolds were effective in maintaining astrocyte production and inhibiting glial scarring.⁵⁰ Breen et al injected NT-3-loaded collagen hydrogel into the SCI lesion site and found enhanced nerve regeneration.⁵¹

Neural stem cells (NSC) are the most ideal seed cells for SCI repair, but the harmful microenvironment of SCI promotes their differentiation into astrocytes.⁵² However, collagen scaffolds can create a favorable microenvironment for NSCs and enhance their differentiation into neurons. A collagen scaffold loaded with paclitaxel liposomes can activate the Wnt/β-catenin signaling pathway and promote NSC differentiation into neurons.⁵³ A collagen sponge with basic fibroblast growth factor (bFGF) can enhance NSCs to proliferate efficiently.⁵⁴ In addition, collagen hydrogels are well-suited for the delivery of immunosuppressive drugs; a tacrolimus-coated collagen hydrogel implanted into the spinal cord provides sustained drug release with reduced immune rejection and promotes nerve regeneration.⁵⁵

Gelatin

Gelatin is a water-soluble protein obtained from the partial hydrolysis of collagen and like to collagen, is renewable, biodegradable, and hydrophilic, with good biocompatibility and low antigenicity^56,57 and a 3D gelatin sponge (3D-GS) scaffold can induce strong axon growth.⁵⁸ Typically, a GFAP-positive glial scar barrier forms around the SCI lesion site and inhibits axon growth. However, after 3D-GS scaffold transplantation, the GFAP⁺ astrocytes become axon conductive, and numerous regenerated axon fibers are detected behind the lesion site. In addition, 3D-GS scaffolds can destroy the GFAP⁺/αSMA⁺ cell interface and promote the migration of astrocytes and stromal cells. Those migrating cells can secrete ECM components, such as collagen, to improve the local microenvironment of the SCI.⁵⁹ Furthermore, a gelatin microsphere scaffold made by 3D-printing technology can support the survival of severed axons and promote its regeneration.²⁶ Although gelatin have many advantages, however, its biomedical applications is still limited because of poor mechanical strength and rapid degradation.⁶⁰

GelMA gel is a photosensitive hydrogel obtained by the reaction of methacrylate anhydride with natural gelatin.⁶¹ Because of its good histocompatibility, biodegradability, and controllable mechanical properties, GelMA gel widely used in tissue engineering field.⁶² Furthermore, its good mechanical properties are well suited for combining with seed cells for SCI treatment. Fan et al implanted 3D GelMA hydrogel loaded with IPSC-derived NSCs into a spinal cord transection model and found that the astrocyte scar was significantly reduced and showed better motor recovery.²⁸ 3D GelMA hydrogel scaffolds loaded with BMSCs also promote cell survival and differentiation into neurons.⁶³ Therefore, a 3D composite scaffold of GelMA hydrogel can provide a more favorable microenvironment for the cell adhesion, proliferation, and differentiation of NSCs into neurons, and promotes axon regeneration.^64,65

Acellular Scaffolds

Acellular scaffolds (ASCs) have no cellular structure and retain ECM components including collagen IV, fibronectin, and laminin that are conducive to neuron attachment and axon growth.^66,67 ASCs are non-toxic and soft texture with low immunogenicity and good biocompatibility.^32,68,69 ASCs have a 3D network structure with abundant spaces that is conducive to cell proliferation.³¹ Zhu et al implanted ASCs into the spinal cord lesion site in rats and observed many GAP-43 and NF200-positive axon fibers in the scaffold, and the expression of Nestin and GAP-43 was maintained for 12 weeks after injury, showing that ASCs can promote long-term nerve regeneration.²⁹ It has been reported that BMSCs can adhere, proliferate, and migrate well on ASCs surface, and maintain its stemness to continuously express stem cell markers CD44 and CD90.³¹ A composite scaffold crosslinked with a NT-3 and ASCs can promote the differentiation of BMSCs into neuron-like cells. In addition, ASCs can be implanted with adipose-derived stem cells in SCI lesion site that promote axon regeneration and reduce reactive glial cell formation.⁷⁰ However, it has been reported that ASCs are mechanically weak, but it can be improved by modifying the many free amino acid residues.

Polysaccharose

Hyaluronic acid (HA), one of the main polysaccharide components of ECM, is a biopolymer composed of D-glucuronic acid and n-acetylglucosamine disaccharide units that form a biocompatible network structure.^71,72 HA is highly expressed in perineural networks; therefore, HA-based hydrogels are widely used as biocompatible scaffolds. HA can interact with surface receptors of CD44-positive cells to down-regulate inflammatory signaling pathways, thereby indirectly inhibiting astrocyte proliferation and migration. Moreover, HA can reduce the density of GAFP⁺ cells and inhibit glial scar formation.³⁴ However, the non-adhesion of HA hydrogels limits cell penetration and inflammatory cell migration. Khaing et al implanted high-molecular-weight HA hydrogels into an SCI model and found that the number of immune cells decreased in the acute stage of injury, while CSPG deposition was significantly reduced 10 days after injury and astrocyte proliferation was inhibited 9 weeks after injury.⁷³ HA scaffolds can also preserve intact axons at the injured site and are neuroprotective.^74,75 Chitosan is a linear polysaccharide, which has been found to reduce fiber scarring, promote axon regeneration and myelin formation in SCI treatment.^36,76 Agarose is another water-soluble linear polysaccharide extracted from seaweed, it has been reported that agarose-loaded scaffolds containing multiple linear channels can promote axon regeneration at the injured site and reestablish motor circuits.⁷⁷ Agarose scaffolds can also serve as vectors for BMSCs, supporting secretion of BDNF and guiding regenerating axon grow over the lesion site.⁴² Alginate is a natural biopolymer extracted from brown algae, and alginate-based hydrogels are also widely used in SCI treatment.^78,79 Huang et al constructed an alginate gel containing anisotropic capillaries and found that the scaffold supported regeneration of descending motor axons and ascending sensory axons without neurotrophic factors.⁴⁴ Furthermore, sodium alginate/gelatin scaffolds loaded with NSCs, can promote re-myelination, axon regeneration, and motor function recovery.⁸⁰

Synthetic Biomaterial Scaffolds

Compared with natural biomaterials, synthetic biomaterials are more easily available and have adjustable strength and degradation rates. As biomaterials for tissue regeneration, synthetic scaffolds should be histocompatible and provide a favorable microenvironment for stem cell differentiation and proliferation (Table 2).

Table 2 Application of Various Synthetic Materials in Spinal Cord Injury

Synthetic Peptides

Synthetic peptides are composed of small natural amino acids and can be safely metabolized in the human body. In recent years, synthetic peptide scaffolds have been widely used as drug delivery systems to promote neural tissue regeneration. Alvarez et al constructed a scaffold that integrates the laminin IKVAV and fibroblast growth factor 2 (FGF-2) with the diphilic polypeptide (PA). This scaffold improve axon regeneration and functional recovery after transplantation into SCI by enhances the supramolecular motion within the scaffold fibers.⁹⁹ Zahra et al also found that IKVAV-PA hydrogel scaffold carrying BDNF could continuously release BDNF for more than three weeks and reduce the astrocytes proliferation.¹⁰⁰

Synthetic Polymer Scaffolds

Synthetic polymer scaffolds are mainly divided into polycaprolactones (PCL), polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), and polyethylene glycol (PEG). Among them, PCL is a degradable polymer that has recently emerged as a tissue engineering scaffold material for 3D printing because of its low melting point and ductility. In addition, PCL is a partially crystalline hydrophobic polymer, complete degradation takes 2 to 4 years, thus, it also used as a drug delivery system.⁸⁸ PCL is also suitable for electrospinning, which can generate parallel or randomly oriented nanofibers,^101–103 and this PCL nanofiber scaffolds are biocompatible and mechanically strong to support the adhesion and proliferation of BMSCs.¹⁰⁴ The polysialic acid (PSA)-based polyPCL hybrid nanofiber scaffold can inhibit the release of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). This scaffold can promote SCI repair by enhancing axon growth and inhibiting the GFAP and apoptosis-related Caspase-3 protein expression.¹⁰⁵

Polyethylene glycol (PEG) is an attractive and structurally flexible, biocompatible, diphilic molecule with no steric hindrance and good hydration and loading capacity.¹⁰⁶ PEG is a good cell membrane sealant and inhibits apoptosis and oxidative stress while reducing cell membrane permeability.¹⁰⁷ After SCI, cell membrane rupture and uncontrolled ion exchange lead to progressive cell death, and PEG can be applied for SCI treatment by sealing these cell membrane ruptures.¹⁰⁸ In addition, PEG scaffolds promote the migration of glia cells into the lesion area, where they promote remyelination and axon growth. Therefore, PEG scaffolds may be ideal biomaterial for the repair of large nerve defects.¹⁰⁹ However, Cole et al found that prolonged exposure to PEG may inhibit nerve conduction velocity. In general, PEG is widely used in the biomedical field as a sealant for cell membrane fusion and repair in short-term. The therapeutic effects of PEG for SCI treatment can be enhanced with auxiliary materials. Cheng et al explored the effect of combined treatment with electric stimulation and PEG and found that the combined treatment can inhibit cation inflow and promote SCI repair.¹¹⁰

Polylactic acid (PLA) is a biodegradable thermoplastic polymer formed by the lactic acid (LA) molecules polymerization. Since LA is a chiral molecule, three forms of polylactic acid can be formed that differ in their characteristics: poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), and poly-D, L-lactic acid-lactic acid (PDLLA). PDLLA biodegrades more quickly degrades than PDLA and PLLA. This makes PDLLA more suited for medical applications requiring rapid degradation, while PLLA is suited for applications requiring long-term support.¹¹¹ PLA is very hydrophobic, making it unsuitable for drug delivery. Fasolino et al investigated the possibility of an electrospun PLA fiber scaffold coated with eumelanin for SCI repair. The melanin in the scaffold can reduce ROS and regulate the inflammatory response of SCI.¹¹² Raynald et al used polypyrrole (PPy) and PLA composite nanofiber scaffolds combined with BMSCs to promote functional recovery of SCI in rats. Both electrophysiological and behavioral evaluation showed that the Ppy/PLA/BMSCs treatment showed the significant functional recovery.¹¹³ Overall, PLA and its degradation products are biocompatible with spinal cord tissue and have the potential to become scaffolds and drug carriers for SCI repair.

Polylactic acid-glycolic acid copolymer (PLGA) forms a blocky structure or random aggregate with good pore structure, hydrophilicity, and rapid biodegradation.^114,115 During the hydrolysis of PLGA, two monomers are produced: lactic acid and glycolic acid, both of which are common non-toxic cell metabolites. Schwann cells proliferated well on the PLGA scaffold surface and promoted axonal regeneration in the lesioned spinal cord. However, motor function recovery is limited.^116,117 Furthermore, PLGA nanoparticle-based drug delivery systems enable the controlled release of drugs when applied locally. FTY720 was incorporated into PLGA nanoparticles, transplanted with NSCs into an acute SCI model, and significantly promoted nerve function recovery and stem cell differentiation into oligodendrocytes.¹¹⁸ PLGA nanoparticle-loaded chondroitin enzyme ABC (ChABC) can markedly promote motor function and digest local scar tissue.¹¹⁹ Therefore, PLGA can provide a favorable microenvironment for local cells, and can act as a controlled drug delivery system in SCI treatment.

Its degradability and mechanical strength are critical factors that significantly influence the clinical applicability of biomaterials. The advantages of using natural biomaterials for SCI repair are its good biocompatibility, biodegradability, and facilitation of cell adhesion and growth. However, some natural materials may cause inflammatory reactions. Synthetic biomaterials have controlled physical and chemical properties and degradation rate, which can meet different application needs. The major disadvantage of synthetic biomaterials is the potential cell toxicity of their degradation products. Due to the complex biological mechanisms of SCI and nerve regeneration process, a single-function scaffold may not be able to meet the needs. By combining two or more biological materials of different properties, a scaffold with complementary properties can be designed to meet the needs of SCI.

Nanomaterials

Nanomaterials are novel materials ranging in size from 1–100 nm that are lightweight and pH sensitive with diverse compositions including metals (eg, gold, silver, iron oxide, cadmium, zinc, and cerium) and ceramics, carbon-based nanomaterials, and other organic, inorganic, and composite materials. Furthermore, nanomaterials can be combined with each other to achieve new synergetic effects.

After SCI, neuroinflammation is a prominent characteristic of its acute phase. The rupture and bleeding of small blood vessels often triggers the infiltration of inflammatory cells into the injured area of SCI. In addition, a few hours later, relevant inflammatory factors, such as interleukin and Tumor necrosis factor (TNF) began to be released successively. Thus, these inflammatory factors enhance the inflammatory response of neurons, and oxidative stress caused by reactive oxygen species (ROS) often leads to prolonged neuroinflammation response, which in turn triggers furthermore serious spinal tissue damage. In addition, because of the generation and accumulation of ROS in SCI, the efficacy of stem cell transplantation in SCI is seriously reduced by severe inflammation and ROS accumulation that cause a good deal of cell death.¹²⁰ However, antioxidants based on nano-metal oxides can inhibit ROS accumulation. Thus, Liming et al employ HA-peptide-modified MnO2 nanoparticles to mitigate the oxidative environment by regulating reactive oxygen species (ROS) during the acute phase of SCI. In addition, significant motor function recovery was observed in the rat SCI model after implantation of HA-peptide-modified MnO₂ nanoparticles.¹²¹ Dezun et al constructed a ROS-responsive mesoporous silica nanoparticle (rMSN) loaded with an interferon regulatory factor (IRF5)-targeted siRNA. This nanomaterial-mediated delivery of siRNA-IRF5 transforms M1 macrophages into an M2 phenotype that reduced pro-inflammatory cytokines production¹²² and cleavage the ROS to inhibit the inflammatory response.¹²³

At the subacute phase of SCI, the fibroglial scar formation is a major problem of spinal cord repair. For solve this problem, Chen et al developed a composite hydrogel based on polyvinyl alcohol (PVA) and molybdenum sulfide/graphene oxide (MoS₂/GO) nanomaterials for SCI treatment. As in the mouse SCI model, the implantation of MoS₂/GO/PVA hydrogel scaffold promotes the motor function via inhibits glial cell activation and scar tissue formation. In addition, this kind of composite hydrogel also promoted the differentiation of NSCs into neurons and inhibiting the astrocytes proliferation.¹²⁰

In the chronic phase, promoting neuronal regeneration might be the focus of treatment. Thus, multiple strategies may be used to achieve ideal results. The microstructure and high surface area of nanomaterials also can be used for the loading and delivery of drugs during tissue engineering applications. The drug delivery system based on nanomaterials has good drug loading ability and can significantly improve the pharmacokinetic characteristics of the loaded drugs, which effectively increase the local concentration of drugs at the lesion site (Figure 3). It has been found that MnO₂ nanoparticles, cerium oxide nanoparticles, and selenium-doped carbon quantum dots, can effectively alleviate oxidative stress after traumatic SCI, thereby promoting neuronal survival and regeneration.^124,125

Problems and Challenges

Although biomaterials have made significant progress toward clinical applications for SCI treatment, many challenges remain to be solved. First, the detailed molecular mechanisms of SCI treatment by different biomaterials must be elucidated. Second, treatments method must be optimized regarding duration and implantation method, timing, and location, while also considering biocompatibility, degradability, mechanical strength, and toxicity. For example, although natural biomaterials are biocompatible, they have inherent shortcomings. Synthetic materials have high scaffold strength but lack inherent biological activities, thus requiring combination with other biomaterials to trigger the expected biological reaction in vivo. Thus, further investigation is needed to understand their safety and efficacy, and additional clinical studies should be undertaken to promote biomaterials in the SCI treatment. In addition, future research should prioritize enhancing the degradation resistance of biomaterials and their ability to positively interact with the host biological environment. A comprehensive exploration of the physicochemical properties of the scaffold, not only to ensure structural integrity but also to improve the delivery efficiency of bioactive molecules, thereby achieving a synergistic effect between mechanical properties and therapeutic functionality.

Summary

This review summarizes the current research status of the application of biomaterials to the SCI treatment, in recent years, to provide some comprehensive information and reference value for future exploration of new SCI repair strategies. Although biomaterials have great potential for SCI treatment, we should also be aware of the complexity of SCI pathological changes. The complex mechanism of SCI injury cascade and the limitations of translation from animal experiments to clinical trials need to be solved. A single treatment method may be difficult to achieve ideal results. To promote the neural circuits remodeling to achieve functional recovery is the goal of SCI treatment. Thus, the ideal biomaterials should have properties to include activating the intrinsic growth capacity of neurons, creating a favorable local environment conducive to nerve regeneration and axon growth.