No abstract

Long-term neuroinflammation is a major barrier to neurological recovery after cerebral ischemia−reperfusion injury (CIRI). Here, a thermosensitive injectable supramolecular hybrid hydrogel is developed to sustainably deliver exosomes derived from interleukin-1β-stimulated bone marrow stromal cells (BMSCs) (βExos) with improved exosome production and anti-inflammatory capacity for neuroinflammation inhibition and neurological recovery. The supramolecular hydrogel displays self-healing and injectable features, along with high biocompatibility and tissue-like softness. The βExos effectively reduce the lipopolysaccharide-induced inflammatory responses in the immortalized mouse microglia (BV2) cell line, and the in situ formed hydrogel improves the exosome retention in the ischemic core area. More remarkably, in the middle cerebral artery occlusion in vivo model, glial scar formation and neuronal loss are significantly reduced by regulating neuroinflammation using the released βExos. Therefore, the combination of interleukin-1βstimulated exosomes with injectable supramolecular hydrogel provides an appealing strategy for treating central nervous system diseases.

Cerebral ischemia and the subsequent cerebral ischemia-reperfusion (I/R) injury usually result in neuronal impairment with serious disabilities. Although neural stem cell (NSC) transplantation can help with functional recovery after stroke, due to the improper cellular milieu after brain injury, direct NSC transplantation will result low cell survival rates and differentiation efficiency into neurons. Here a conductive hybrid hydrogel based on gelatin methacryloyl (GelMA) and poly(3,4-ethylenedioxythiophene): poly (styrene sulfonate) (PEDOT:PSS) was created as a NSC niche for the treatment of cerebral I/R injury. GelMA/PEDOT:PSS hybrid hydrogel promoted the development of NSCs into neurons. GelMA/PEDOT:PSS hydrogel along with NSCs could enhance neuronal activity and minimize apoptosis when co-cultured with oxygen-glucose deprivation/reperfusion (OGD/R) neurons. Furthermore, after 7 days of implantation, GelMA/PEDOT:PSS/NSCs on the infarcted brain of rats subjected to reperfusion injury after middle cerebral artery occlusion (MCAO) was verified to attenuate inflammatory responses. These findings show that the conductive GelMA/PEDOT:PSS hybrid hydrogel could regulate NSC development and act as promising cell niches for the treatment of cerebral I/R injury.