Dual-phase SilMA hydrogel: a dynamic scaffold for sequential drug release and enhanced spinal cord repair via neural differentiation and immunomodulation.

Introduction: Spinal cord injury (SCI) is a severe central nervous system disorder that results in significant sensory, motor, and autonomic dysfunctions. Current surgical techniques and high-dose hormone therapies have not achieved satisfactory clinical outcomes, highlighting the need for innovative therapeutic strategies. Methods: In this study, we developed a Dual-Phase Silk Fibroin Methacryloyl (SilMA) hydrogel scaffold (DPSH) that incorporates PLGA microspheres encapsulating neurotrophin-3 (NT-3) and angiotensin (1-7) (Ang-(1-7)). The DPSH is designed for temporally controlled release of therapeutic agents to reduce inflammation during the acute phase of SCI and to promote neuronal differentiation and axonal regeneration in later stages. Results: Comprehensive characterization of the DPSH revealed a highly porous architecture, suitable mechanical properties for spinal cord tissue, and stability unaffected by the incorporation of microspheres and drugs. In vitro studies demonstrated that Ang-(1-7) significantly induced M2 microglia polarization by 1.8-fold (p < 0.0001), effectively reducing inflammation. Additionally, NT-3 enhanced neural stem cell differentiation into neurons by 3.6-fold (p < 0.0001). In vivo experiments showed that the DPSH group exhibited significantly higher Basso Mouse Scale (BMS) scores (p < 0.0001), enhanced motor function, reduced astrocyte scarring by 54% (p < 0.05), and improved neuronal survival and regeneration. Discussion: These findings underscore the therapeutic potential of the DPSH scaffold for SCI repair, presenting a novel strategy to enhance neural recovery through a combination of immunomodulation and neuroprotection.