Tannic acid as building block constructing injectable hydrogel and regulating microglial phenotype to enhance neuroplasticity for post-stroke rehabilitation

Background Stroke is the second leading cause of mortality and disability in the world. Post-stroke rehabilitation is still unsatisfactory in clinics, which brings giant pains and economic burdens to stroke patients. In this study, an injectable hydrogel where tannic acid (TA) acts as not only a building block but a therapeutic drug was developed for post-stroke rehabilitation. Methods TA is used as a building block to form an injectable hydrogel (TA-gel) with carboxymethyl chitosan (CMCS) by multivalent hydrogen bonds. The morphology, rheological property, and TA release behavior of the hydrogel were characterized. The abilities of the TA-gel to modulate microglia (BV2 cells) polarization and subsequently enhance the neuroplasticity of neuro cells (N2A cells) were assessed in vitro. The TA-gel was injected into the cavity of the stroke mouse for the evaluation of motor function recovery, microglial polarization, and neuroplasticity in vivo. The investigation of the molecular pathway through which TA modulates microglia polarization was also explored both in vitro and in vivo. Results The TA-gel exhibited a sustainable released behavior of TA. It can suppress the expression of CD16 and IL-1β, and upgrade the expression of CD206 and TGF-β in the oxygen and glucose-deprived (OGD) BV2 cell, indicating the regulation of OGD BV2 cells to anti-inflammatory phenotype in vitro. It further shows the decrease of synaptophysin and PSD95 in the OGD N2a cells is effectively recovered by the anti-inflammatory BV2 cells. Furthermore, it showed the TA-gel can decrease the CD16/iNOS expression, and increase the CD206 expression in the peri-infarct area of stroke mice, implying anti-inflammatory polarization of microglia in vivo. The colocalization of PSD95 and Vglut-1 stains as well as the Golgi stain showed the enhancement of neuroplasticity by the TA-gel. Spontaneously, the TA-gel successfully recovered the motor function of stroke mice. The western blot results in vitro and in vivo suggested TA-gel regulated microglia polarization via the NF-κB pathway. Conclusion The TA gel serves as an effective brain injectable implant to treat stroke and shows promising potential to promote post-stroke rehabilitation in the clinic.