Biomaterials and stem cells targeting the microenvironment for traumatic brain injury repair: progress and prospects

Traumatic brain injury (TBI) disrupts neural pathways, leading to sensory, motor, and autonomic dysfunctions, with no fully restorative therapies currently available. The pathophysiology of TBI involves two phases: primary injury and secondary injury. These stages are characterized by dynamic alterations in cellular death, glial activation, and inflammatory cytokine profiles, collectively establishing a regeneration-inhibitory microenvironment. Biomaterials, such as hydrogels and nanofiber scaffolds, mimic the extracellular matrix (ECM) to provide structural support, modulate local inflammatory responses, and degrade glial scar components. However, standalone biomaterial applications face limitations in dynamically addressing the multifaceted pathological progression. Combinatorial therapies integrating stem cells overcome these constraints: stem cells promote angiogenesis and synaptic remodeling through paracrine secretion of exosomes and cytokines, while differentiating into functional neural cells. Concurrently, biomaterials shield transplanted stem cells from hypoxia and cytokine toxicity, enhancing their viability and differentiation efficiency. Further combination with targeted strategies, such as functionalized material delivery of anti-inflammatory drugs, gene editing stem cell overexpression of nerve growth factor BDNF, precisely intervenes in the key pathways of secondary injury. This review systematically summarizes synergistic approaches combining biomaterials with cells, pharmaceuticals, and cytokines, emphasizing the critical roles played by spatiotemporal dynamic regulation and personalized design. These integrated strategies provide novel insights into developing multidimensional therapeutic frameworks to address TBI repair challenges.