Traumatic brain injury (TBI) is characterized by neuronal loss, vascular disruption, and limited regenerative capacity, further exacerbated by the absence of a supportive extracellular matrix (ECM) within lesion cavities. Here, an injectable, photo-crosslinkable ECM-based hydrogel (ECMMA/BDNF/SCS) is developed to remodel the post-injury microenvironment and promote neural repair. The hydrogel is derived from decellularized porcine ECM modified with methacrylate groups and incorporated with sulfonated chitosan (SCS) and mesoporous silica nanoparticles for sustained delivery of brain-derived neurotrophic factor (BDNF). The ECMMA/BDNF/SCS hydrogel exhibits tunable mechanical properties matching native brain tissue and enables controlled BDNF release. In vitro, it shows good biocompatibility, promotes endothelial cell migration and tube formation, and directs neural stem cell differentiation toward neuronal lineage, as indicated by increased β-III Tubulin (Tuj1) and decreased GFAP expression. In a rat TBI model, hydrogel implantation reduces lesion volume, enhances vascularization and neurogenesis, and improves sensorimotor and cognitive function. At the molecular level, these effects are associated with reduced neuronal apoptosis and modulation of PI3K/ERK and STAT3 signaling pathways. Overall, this multifunctional ECM-based hydrogel provides structural and biochemical cues to facilitate neurovascular regeneration, highlighting its potential for TBI therapy. Schematic illustration for biomimetic construction of SCS and BDNF-incorporated ECMMA hydrogel, as well as the co-effect on the differentiation of endogenous NSCs and angiogenesis in TBI rats. • Brain-mimetic, photo-crosslinkable ECM hydrogel with tunable mechanics directs coupled neurogenesis and vascularization. • ECM-enabled PI3K/ERK–STAT3 axis establishes a pro-regenerative, astrogliosis-attenuating, anti-apoptotic neurovascular niche. • TBI repair achieved with reduced lesion burden, enhanced vascularization, and improved functional recovery.
Zhang et al. (Fri,) studied this question.