Carboxymethyl chitosan hydrogel synergistically regulates neural stem cells with ultrasound for the treatment of traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of chronic neurological deficits, with few effective therapies available. Although neural stem cells (NSCs) show promise for neural regeneration, they face limited survival and differentiation in the pathological TBI microenvironment. To address this issue, we developed a synergistic approach combining hydrogel encapsulation with ultrasound (US) stimulation to improve the viability and targeted differentiation of NSCs. We synthesized a biocompatible Schiff base hydrogel by conjugating carboxymethyl chitosan and phenylaldehyde polyethylene glycol phenylaldehyde. This hydrogel was then used to encapsulate NSCs derived from C57BL/6J mice. In vitro, US stimulation was found to significantly promote the differentiation of hydrogel-encapsulated NSCs into neural lineages and increase neurotrophic factor secretion. In vivo, the NSCs + hydrogel + US treatment exhibited improved behavioral performance, facilitated neural tissue regeneration, and increased growth factors expression in mice with TBI. These results suggest that the combination of hydrogel and US synergistically improves the survival rate of transplanted NSCs and promotes better neurological recovery by mitigating the negative effects of the microenvironment associated with TBI. This combination treatment strategy is a promising approach to enhancing the efficacy of NSCs-based interventions for TBI. • Schiff base hydrogel supports delivery and growth of neural stem cells. • Ultrasound helps stem cells become nerve cells and release protective factors. • Hydrogel plus ultrasound improves brain repair in injured mice. • Method reduces brain inflammation and helps transplanted cells survive. • Combined approach may restore brain function after traumatic injury. A novel strategy combining a biocompatible hydrogel with ultrasound stimulation enhances the survival and neural differentiation of transplanted stem cells in traumatic brain injury. This synergistic approach promotes neural regeneration, growth factor expression, and behavioral recovery in vivo, offering a promising platform to boost the effectiveness of stem cell therapies for brain repair.