Engineering Bacteria-Activated Multifunctionalized Hydrogel for Promoting Diabetic Wound Healing

Engineering therapeutic angiogenesis in impaired tissues is critical for chronic wound healing. Materials can be engineered to deliver specific biological cues that enhance angiogenesis. However, currently available materials have limitations for use in angiogenesis engineering since the complex inflammation environment of wounds requires spatiotemporal control. Immune cells are the central component of wound microenvironment and orchestrate immune responses to wound healing. This study presents a novel approach of using a delivery system comprising living Lactococcus, incorporated in a heparin-poloxamer thermoresponsive hydrogel, designed to bioengineer the wound microenvironment and enhance the angiogenesis in a highly dynamic-temporal manner. The living system can produce and protect vascular endothelial growth factor (VEGF) to increase proliferation, migration, and tube formation of endothelial cells, as well as secrete lactic acid to shift macrophages toward an anti-inflammatory phenotype, resulting in successful angiogenesis in diabetic wounds. Further, the delivery system confines the bacterial population to wounds, thereby minimizing the risk of systemic toxicities. Therefore, this living hydrogel system can be harnessed for safe and efficient delivery of therapeutics that drive the wound microenvironment toward rapid healing and may serve as a promising scaffold in regenerative medicine.