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Promoting Wound Healing by Engineering Enzyme-Responsive Delivery of Multiple Proteins and Amphiphilic Injectable Hydrogel

Abstract

The growth of tissues and organs is regulated by orchestrated biological signals such as enzymes and growth factors (GFs). The ability to deliver biologics and small molecule drugs in response to these signals holds great promise for tissue repair and regeneration. This dissertation focuses on two aspects, enhancing angiogenesis and preventing infection, as therapeutic and prophylactic means to promoting wound healing.

Pro-angiogenic factors regulate the formation of new blood vessels and the renewal of vasculature after wounding, which is crucial for ischemic tissue repair. The mode of GF delivery has become increasingly important, as the narrow therapeutic window and threshold of GF dosage for normal angiogenesis is more and more clear. However the majority of delivery vehicles nowadays rely on hydrolysable scaffolds and thin films of protein-containing polymers for constitutive GF release, which cannot be programmed to respond to biological signals. Here, a delivery platform based on enantiomeric protein nanocapsules is demonstrated, which enables controlled delivery of multiple proteins in response to wound proteases. Exemplified by stroke and diabetic wound healing in mice, sequential delivery of vascular endothelial GF (VEGF) and platelet-derived GF greatly enhances tissue revascularization and vessel maturation. Furthermore, the molecular mechanism for sustained released VEGF in enhancing angiogenesis was studied and revealed differential receptor activation and downstream signaling dynamics.

Meanwhile, delivery of hydrophobic drugs to diseased tissue (e.g. antibiotics to an infected wound) is a common therapeutic approach, although little has been done to combine hydrophobic drug release with a scaffold that could provide structural support and additional signals to promote tissue healing. Motivated as such, an injectable amphiphilic synthetic hydrogel is introduced that can effectively solubilize hydrophobic drugs while serving as a scaffold for tissue healing. This self-assembled hydrogel containing solubilized antiobiotics can also be coated as thin films on orthopaedic implants for anti-infectious arthroplasty operations.

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