Counteracting immunodepression by extracellular matrix hydrogel to promote brain tissue remodeling and neurological function recovery after traumatic brain injury

Traumatic brain injury (TBI), an intractable disorder of the central nervous system (CNS), is a leading cause of long-term disability and mortality in humans worldwide. However, there is still no effective therapy for TBI, and an important reason for this is TBI-induced immunodepression, which renders TBI patients with low resistance to infections and aggravated brain damage. In this study, a multifunctional extracellular matrix hydrogel was constructed for the treatment of TBI in terms of both counteracting the immunodepression and enhancing neurogenesis. The stromal cell-derived factor-1α (SDF-1α)-loaded hyaluronic acid (HA)/decellularized brain extracellular matrix (BM) hydrogel (SDF@HA/BM) not only mimicked the composition and the biological cues of brain extracellular matrix, but also exhibited the injectability, self-healing, and mechanical properties close to those of brain tissue. The SDF@HA/BM hydrogel protected activated immune cells from dysfunction during the acute phase of TBI for normal levels of inflammatory cytokines, thereby creating a favorable immune microenvironment for subsequent neurogenesis. The SDF-1α and the BM synergistically promoted neurogenesis after TBI by recruiting endogenous neural stem/progenitor cells and inducing their differentiation into neurons. In vivo results demonstrated that the SDF@HA/BM hydrogel exhibited desirable therapeutic effects in severe TBI mice through facilitating brain tissue remodeling and neurological function recovery, including limb balance, autonomous locomotion, and spatial learning and memory abilities, and relieving depression and anxiety. Our work provides a novel strategy for TBI treatment in terms of restoring immune homeostasis and enhancing neurogenesis using advanced biomaterials.