Hyaluronan-based hydrogel integrating exosomes for traumatic brain injury repair by promoting angiogenesis and neurogenesis

Abstract

With wide clinical demands, therapies for traumatic brain injury (TBI) are far from satisfactory. Combining the merits of stem cells but avoiding the risk of immunologic rejection, bone marrow mesenchymal stem cell-derived exosomes (BME) attract increasing interests and have been proved effective for TBI repair by intravenous or in situ injection. However, difficulties in sustained delivery or aggregation in lesion sites remain obstacle to using BME for TBI. Inspired by that hydrogels are promising to bridge the destroyed neural gap and provide neural niches, we raised a novel strategy of incorporating BME into hyaluronan-collagen hydrogel (DHC-BME) to achieve both mimicking of brain matrix and steady release of exosomes, and thus realizing TBI repair. External characterizations proved that the BME and DHC synergistically promoted neural stem cells (NSCs) differentiation into neurons and oligodendrocytes while inhibited astrocytes differentiation. DHC-BME induced angiogenesis and neurogenesis, from endogenous NSC recruitment to neuronal differentiation and vascularization to synergistically promote axonal regeneration, remyelination, synapse formation and even brain structural remodeling, and lastly, neurological functional recovery of TBI.

Keywords: Biomimetic hydrogels; Bone marrow mesenchymal stem cell; Exosome; Extracellular matrix; Hyaluronan; Traumatic brain injury.