Neuro-bone-skin tri-regeneration via a microenvironment-responsive PRP-loaded chitosan hydrogel for traumatic brain injury therapy

Traumatic brain injury (TBI) presents a complex repair challenge, involving not only neural damage but also cranial defects and impaired wound healing. Dysregulated inflammation and inadequate angiogenesis are key obstacles in this process. To address these multifaceted needs, we developed CO@P, a microenvironment-responsive hydrogel loaded with platelet-rich plasma (PRP), designed for the controlled release of growth factors to synchronize neural recovery, skull regeneration, and wound healing. In vitro, CO@P demonstrated excellent stability, sustained release, and biocompatibility. It protected N2a cells from LPS-induced death, reduce M1 polarization in LPS-stimulated HMC3 cells, and enhance the migration of BMSC and HUVEC as well as HUVEC tube formation under oxidative stress. In vivo, when applied to TBI mice, the hydrogel’s microenvironment-responsive design enabled a gradient release of growth factors, preventing the burst release typical of PRP. This precise delivery modulated inflammation, accelerated neurogenesis and angiogenesis, and ultimately drove brain remodeling and functional recovery, evidenced by improved motor function, spatial memory, and reduced anxiety-like behaviors. Transcriptomic sequencing confirmed this reparative shift, showing upregulation of regenerative genes alongside downregulation of apoptotic and pro-inflammatory pathways. Multimodal histo-immunological analyses further demonstrated that CO@P accelerated scalp wound healing by enhancing angiogenesis and suppressing inflammation. Concurrently, micro-CT and histochemistry revealed its potent osteogenic effect in cranial defects, marked by upregulated osteocalcin/osteopontin and improved structural parameters. In summary, the CO@P hydrogel, through its intelligent and microenvironment-controlled release profiles, orchestrates a multi-dimensional repair process that integrates neuroprotection with structural regeneration, offering a novel and integrated therapeutic strategy for the complex sequelae of TBI. • CO@P hydrogel's enzyme-resistant scaffold enables spatiotemporally controlled release of growth factors, which reprogram macrophage polarization to M2 phenotype, suppressing neuroinflammation and synergistically enhancing angiogenesis and osteogenesis. • CO@P hydrogel provides a novel integrated therapeutic strategy for complex tissue injuries following TBI. The hydrogel drives synchronous neurovascular functional recovery, scalp wound healing, and cranial bone regeneration in TBI. • Transcriptomic sequencing confirms the hydrogel upregulates reparative genes while downregulating apoptotic and pro-inflammatory genes.