Tβ4-exosome-loaded hemostatic and antibacterial hydrogel to improve vascular regeneration and modulate macrophage polarization for diabetic wound treatment
Hua Yu, Bin Wang, Zihao Li, Kaibo Liu, Wanying Chen, Songyun Zhao, Yu Zhou, Gaoyi Wang, Yaqin Zhou, Yanming Chen, Housheng Chen, Yunning Lai, Quan Wang, Jingping Wang, Binting Ni, Dupiao Zhang, Chuanmeng Pan, Yucang He, Liqun Li
Abstract
Diabetic wounds often exhibit delayed healing due to compromised vascular function and intensified inflammation. In this study, we overexpressed Thymosin β4 (Tβ4) in Adipose-Derived Stem Cells (ADSCs) to produce Exosomes (Exos) rich in Tβ4. We then utilized a dual photopolymerizable hydrogel composed of Hyaluronic Acid Methacryloyl (HAMA) and Poly-L-lysine Methacryloyl (PLMA) for the sustained release of Tβ4-Exos on diabetic wounds. The results showed that Tβ4-Exos could stimulate angiogenesis and collagen synthesis, and mitigate inflammation in diabetic wounds by promoting the polarization of M1-type macrophages and inhibiting that of M2-type macrophages. Furthermore, Tβ4-Exos was found to activate the PI3K/AKT/mTOR/HIF-1a signaling pathway, thereby enhancing vascular proliferation. In summary, the sustained release of Tβ4-Exos in HAMA-PLMA (HP) hydrogel and the management of inflammation through the upregulation of the HIF-1a pathway and modulation of macrophage polarization in vascular proliferation significantly accelerated the healing process of diabetic wounds. Scheme 1 Schematic illustration of the synthesis method and therapeutic mechanism of Tβ4-Exos and HAMA-PLMA hydrogel. (A) Application of Tβ4-Exos and HAMA-PLMA hydrogel on diabetic mice after synthesis; (B) HAMA-PLMA hydrogel loaded with Tβ4-Exos modulates macrophage M1 polarization towards M2, promotes angiogenesis, and increases collagen deposition; (C) Tβ4-Exos regulate HUVEC through the PI3K/AKT/mTOR/HIF-1a pathway. ADSCs: Adipose-Derived Stem Cells; Tβ4: Thymosinβ4; Exos: Exosomes; HAMA: Hyaluronic Acid Methacryloyl; PLMA: Poly-L-lysine Methacryloyl; HUVEC: Human Umbilical Vein Endothelial Cells. This figure was drawn by Figdraw.