Bioinspired sodium alginate/silk fibroin dual-crosslinked conductive injectable hydrogel for neural stem cell therapy in cerebral palsy

Abstract

Cerebral palsy (CP), the leading cause of lifelong motor disability in children, lacks effective neural regeneration therapies. Current treatments only alleviate symptoms, and while neural stem cell (NSC) transplantation shows promise, its efficacy is hindered by poor post-transplant cell survival and differentiation. To overcome this, we developed an injectable, conductive hydrogel (MS-gel) mimicking the brain's electroactive extracellular matrix. The MS-gel integrates oxidized alginate and silk fibroin (MOA/TOA/SF) through dual-crosslinking (Schiff-base and photopolymerization), enabling rapid in situ gelation (<60 s) and stable conductivity (1.19 ± 0.02 mS cm⁻¹) matching neural tissue properties. In vitro, the MS-gel maintained >90% NSC viability and enhanced neuronal differentiation (1.67-fold increase in β-III tubulin). In CP rat models, NSC-loaded MS-gel implantation improved motor function (88% longer rotarod latency) and cognition (80% shorter Morris water maze escape time). Proteomics revealed that NSCs@MS-gel promotes neural circuit repair via enhanced cellular clearance, ion homeostasis, cytoskeletal reorganization, synaptic restoration, and myelin integrity. This study presents the first integrated platform combining light-controlled gelation, tissue-matched electroactivity, and cytoprotection, offering significant potential for CP and other neurological disorder therapies.