Spinal cord injury (SCI) is a complex medical and psychological challenge for which there is no curative therapy currently available. Despite major progress in pharmacological and surgical approaches, clinical trials for SCI patients have been uniformly disappointing thus far as there are many practical and biological issues yet to be resolved. Neuroinflammation is a critical event of the secondary injury phase after SCI, and recent research strategies have focused on modulating the immune response after injury to provide a more favorable recovery environment. Biomaterials can serve this purpose by providing physical and trophic support to the injured spinal cord after SCI. Of all potential biomaterials, functional hydrogels are emerging as a key component in novel treatment strategies for SCI, including controlled and localized delivery of immunomodulatory therapies to drive polarization of immune cells towards a pro-regenerative phenotype. Here, we extensively review recent developments in the use of functional hydrogels as immunomodulatory therapies for SCI. We briefly describe physicochemical properties of hydrogels and demonstrate how advanced fabrication methods lead to the required heterogeneity and hierarchical arrangements that increasingly mimic complex spinal cord tissue. We then summarize potential SCI therapeutic modalities including: (i) hydrogels alone; (ii) hydrogels as cellular or (iii) bioactive molecule delivery vehicles, and; (iv) combinatorial approaches. By linking the structural properties of hydrogels to their functions in treatment with particular focus on immunopharmacological stimuli, this may accelerate further development of functional hydrogels for SCI, and indeed next-generation central nervous system regenerative therapies.

The therapeutic effects of mesenchymal stem cell (MSC) transplantation following spinal cord injury (SCI) to date have been limited. Therefore, we aimed to enhance the immunomodulatory properties of MSCs via continuous secretion of the anti-inflammatory cytokine interleukin-13 (IL-13). By using MSCs as carriers of IL-13 (MSC/IL-13), we investigated their therapeutic potential, compared with non-engineered MSCs, in a mouse model of SCI. We show that transplanted MSC/IL-13 significantly improve functional recovery following SCI, and also decrease lesion size and demyelinated area by more than 40%. Further histological analyses in CX3CR1EGFP/+ CCR2RFP/+ transgenic mice indicated that MSC/IL-13 significantly decrease the number of resident microglia and increase the number of alternatively activated macrophages. In addition, the number of macrophage-axon contacts in MSC/IL-13-treated mice was decreased by 50%, suggesting a reduction in axonal dieback. Our data provide evidence that transplantation of MSC/IL-13 leads to improved functional and histopathological recovery in a mouse model of SCI.

Spinal cord injury (SCI) is a devastating condition with no curative therapy currently available. Immunomodulation can be applied as a therapeutic strategy to drive alternative immune cell activation and promote a proregenerative injury microenvironment. Locally injected hydrogels carrying immunotherapeutic cargo directly to injured tissue offer an encouraging treatment approach from an immunopharmacological perspective. Gelatin methacrylate (GelMA) hydrogels are promising in this regard, however, detailed analysis on the immunogenicity of GelMA in the specific context of the SCI microenvironment is lacking. Here, the immunogenicity of GelMA hydrogels formulated with a translationally relevant photoinitiator is analyzed in vitro and ex vivo. 3% ( w/v ) GelMA, synthesized from gelatin type‐A, is first identified as the optimal hydrogel formulation based on mechanical properties and cytocompatibility. Additionally, 3% GelMA‐A does not alter the expression profile of key polarization markers in BV2 microglia or RAW264.7 macrophages after 48 h. Finally, it is shown for the first time that 3% GelMA‐A can support the ex vivo culture of primary murine organotypic spinal cord slices for 14 days with no direct effect on glial fibrillary acidic protein (GFAP ⁺ ) astrocyte or ionized calcium‐binding adaptor molecule 1 (Iba‐1 ⁺ ) microglia reactivity. This provides evidence that GelMA hydrogels can act as an immunotherapeutic hydrogel‐based platform for preclinical SCI.