Hydrogels have been recognised for their capacity to provide mechanical support and deliver therapeutic agents, including growth factors, to the SCI site. These materials can mimic the extracellular matrix, offering a conducive environment for cell attachment and proliferation, which is essential for tissue regeneration.^28,29 The structural and functional properties of hydrogels can be fine-tuned to achieve the desired mechanical characteristics and the controlled release of therapeutic substances.^28,30 These materials can fill the lesion cavity and provide a scaffold conducive to tissue repair by promoting axonal regeneration, angiogenesis, and functional recovery.^31,32 Fan et al. illustrated that injectable hyaluronic acid-based hydrogels can fill lesion cavities and promote tissue repair by supporting cell compatibility, matching the stiffness of nervous tissue, and facilitating axonal regeneration, remyelination, and angiogenesis.³¹

Furthermore, alginate (ALG) hydrogels have been recognised for their potential to mimic the mechanical properties of neural tissues, which is essential for providing a conducive environment for neuronal regeneration.³³ Karimi et al. demonstrated that alginate hydrogels incorporating short magnetic nanofibres (M.SNFs) exhibited storage moduli within the range of nerve tissues, suggesting their suitability for neuronal regeneration applications.³⁴ Similarly, Kim et al. described a double-network (DN) hydrogel using alginate and gelatin that exhibited improved mechanical properties such as tensile strength and elastic modulus, which are crucial for fabricating nerve guidance conduits (NGCs) for peripheral nerve repair. Although alginate hydrogels show promise in mimicking neural tissue mechanics, Kim et al. also indicated that single-network (SN) hydrogels may have poor mechanical properties, necessitating the development of more complex hydrogel systems, such as DN hydrogels.³⁵ Ghaderinejad et al. further supported this finding by demonstrating that alginate hydrogels with magnetic short PCL nanofibres can be externally aligned to form an anisotropic network, which is beneficial for nerve injury repair.³⁶

Similarly, fibrin hydrogels have been noted for their biocompatibility and the ability to be modified with cells, ECM proteins, and growth factors to enhance SCI repair.³⁷ These modifications are crucial as they contribute to the repair of damaged nerve tissue by promoting cell function and tissue regeneration. Although fibrin hydrogels offer a promising platform for SCI repair, variations in their sources and modifications can affect their effectiveness. For instance, fibrin hydrogels derived from different sources may exhibit distinct properties, and the internal topographical guidance during polymerisation can be varied to improve outcomes.³⁷ Specifically, hierarchically aligned fibrillar fibrin hydrogels have shown potential in directing stem cells towards the nerve lineage and in spinal cord regeneration, as they provide biomimetic biophysical cues that facilitate the rapid construction of nerve-like microtissues.³⁸ Liu et al. developed an in situ glycidyl-methacrylated silk fibroin/laminin-acrylate (SF-GMA/LM-AC) hydrogel. Activated by ultraviolet (UV) light, this hydrogel quickly forms a network that tightly adheres to the spinal cord and acts as a molecular suture. It provides an optimal environment for neural stem cell growth and enhances neural regeneration when injected into rats with complete SCI.³⁹

Additionally, methacrylate gelatin/ECM-(GelMA)/ECM hydrogel fibrous scaffolds have demonstrated improved mechanical properties and the ability to recruit and differentiate neural stem cells more effectively than traditional scaffolds.⁴⁰ Similarly, the incorporation of oxymatrine (OMT) into spinal cord extracellular matrix hydrogel scaffolds has shown enhanced neural stem cell recruitment and differentiation, as well as improved motor function recovery in rat models.⁴¹

In summary, hydrogels are versatile biomaterials that can be engineered to mimic the mechanical properties of neural tissues and provide localised delivery of therapeutic agents. These properties make these scaffolds ideal for SCI repair, promoting neuronal regeneration, and creating an optimal healing environment. Ongoing research and development to modify and combine these hydrogels continue to advance the field of neural tissue engineering, with the potential to significantly improve functional recovery in patients with SCI.^{28,30,34–38}

Nanofibre scaffolds have garnered attention in the field of SCI treatment because of their extracellular matrix (ECM)-mimicking properties, which are crucial for neural tissue engineering.^9,42,43 These scaffolds provide a conducive environment for cell attachment, proliferation, and differentiation, which are essential for nerve regeneration.⁴³ They also provide topographical cues that guide the growth of new nerve fibres and potentially bridge the gap created by the injury.^9,44

Although nanofibre scaffolds offer a promising approach, their efficacy does not solely depend on their architecture. The incorporation of bioactive cues such as protein binding and cellular adhesion epitopes, can further enhance their therapeutic potential by promoting cell adhesion, viability, and neurite outgrowth, as demonstrated by Sever-Bahcekapili et al., using peptide nanofibres in a rat model of SCI.⁴⁵ Similarly, silk fibroin nanofibres functionalised with laminin have been found to significantly enhance directional axonal extension, providing both physical and bioactive cues for neurite outgrowth.^46,47 Another promising combination therapy involves the integration of electroactive materials, carbon nanotubes, and graphene, to promote functional recovery by restoring the interconnections between neurones.⁴⁸

Moreover, nanofibre scaffolds can function as effective drug carriers, which may influence the biological behaviour of cells on their surfaces, such as differentiation, proliferation, and migration, thereby promoting tissue regeneration and functional recovery. The literature suggests that nanofibres can serve as local drug delivery systems, aiming to prevent secondary damage through neuroprotection and to promote neuroregeneration by re-establishing neuronal connectivity.^49–51 Similarly, lipid nanovesicles have been identified as highly biocompatible carriers that can penetrate the blood-spinal cord barrier (BSCB), offering targeted treatment for SCI.⁵²

In summary, nanofibre scaffolds and nanotechnology- based drug delivery systems are emerging as promising strategies for promoting tissue regeneration and functional recovery in SCI patients. They offer the potential for targeted drug delivery and support for axonal regeneration (Figure 2).^49,52–54

Although biomaterials offer significant potential for SCI treatment, several challenges must be addressed before they can be widely adopted in clinical practice. These challenges include ensuring biocompatibility, avoiding immune responses, achieving targeted delivery, controlling drug release, and standardising production and characterisation.^56–58

Biomaterial scaffolds can be instrumental in addressing the inflammation and immune responses following SCI. They serve not only as structural supports but also actively participate in modulating the inflammatory microenvironment, which is crucial for reducing secondary damage and promoting regeneration.^6,56,59 Biomaterials can inhibit apoptosis, inflammation, and scar formation, while inducing neurogenesis, axonal growth, and angiogenesis.⁶

Although biomaterials alone offer significant benefits, their combination with other therapeutic strategies, such as lentiviral vectors (LVs), may enhance their efficacy. Studies suggest that the synergistic use of LVs and biomaterials can augment the therapeutic effects of each modality in SCI treatment.⁶⁰ Additionally, the use of conductive biomaterials in conjunction with regenerative rehabilitation approaches, such as electrical stimulation, may redefine the potential for functional recovery post-SCI.⁵³

Other studies have focused on developing biomaterials with inherent anti-inflammatory properties or exploring coatings that can minimise immune responses. You et al. used gold nanoparticle-based nanocomposites for hydrogen gas generation to promote neuroprotective effects during the acute phase of SCI.⁶¹ Stigliano et al. presented a study in which nanoparticles (NPs) containing an MK2 inhibitor selectively targeted and modulated activated microglia/macrophages, reducing the pro-inflammatory cytokine IL-6 and increasing the anti-inflammatory cytokine IL-10 in a rat model of SCI.⁶² Similarly, in a study by Gao et al., retinoic acid (RA) and curcumin (Cur) were co-loaded with bovine serum albumin (BSA) to obtain RA@BSA@Cur NPs, which induced polarisation of macrophages towards pro-regenerative phenotypes, reduced the inflammatory response, and promoted functional neurone regeneration after SCI.⁶³ Guo et al. found that melatonin supports polarisation from pro-inflammatory to anti-inflammatory states in microglia, suggesting that biomaterials could be designed to deliver such agents to modulate immune responses after SCI.⁶⁴ This shift could reduce chronic inflammation and support tissue regeneration.

Additionally, surface modifications of biomaterials, such as altering their chemistry or topography, can further reduce the immune response by making the materials less recognisable to the immune system, thereby decreasing the likelihood of a foreign body reaction (FBR). FBR is indeed a significant impediment to the integration of biomaterial scaffolds following SCI, as it can lead to the encapsulation of the implant and its isolation from surrounding tissues, thereby hindering the healing process.⁶⁵ A recent study by Zheng et al. suggested that optimising the mechanical properties of scaffolds, such as stiffness, may alleviate FBR and promote better integration with host tissue.⁶⁶

Additionally, the use of natural biomaterials, such as collagen, hydrogels, or chitosan, can also influence immune responses by affecting immune cell behaviours such as activation and differentiation, and can be engineered to release immunomodulatory factors to promote a tolerogenic immune response.⁶⁷ Wang et al. illustrated that polycitrate-based nanocomposite hydrogel (PMEAC) scaffolds provide biomimetic mechanical and electrical properties that promote locomotion recovery and reduce in vivo inflammation.⁶⁸ In a study by Gao et al., HA hydrogels were shown to possess properties such as damage-associated molecular pattern (DAMP) scavenging and sustained release of anti-inflammatory cytokines, which contribute to the reduction of lymphocyte accumulation and modulation of the immune response, thereby enhancing the survival and function of transplanted tissues after acute SCI.⁶⁹ Although HA-based biomaterials generally support anti-inflammatory responses, they can also be engineered to target specific pathways or cells. For instance, HA-selenium nanoparticles (HA-Se NPs) target the CD44 receptor, which facilitates their internalisation by astrocytes and leads to the suppression of pro-inflammatory cytokines by microglia, thus enhancing functional recovery post-SCI.⁷⁰ Furthermore, Liu et al. reported that a dopamine-modified chitosan hydrogel improved cell survival and modulated immunity by promoting macrophage polarisation to the M2 phenotype, which is associated with anti-inflammatory and tissue repair functions.⁷¹

By incorporating these strategies, biomaterials can create a more conducive environment for healing, reduce the likelihood of chronic inflammation, and ultimately improve the outcomes of treatments for conditions such as spinal cord injuries.^59,72,73