Reactive Oxygen Species Degradable Polythioketal Urethane Foam Dressing for Porcine Skin Wound Repair

Abstract

Improving wound healing resolution is a medical priority due to the increasing prevalence of large wounds and skin defects associated with trauma, diabetes, and cardiovascular diseases. Non-healing wounds affect nearly 4.5 million people in the US alone, costing nearly $25B to treat. The current standard of care for non-healing wounds involves the application of advanced wound dressings, designed to provide temporary coverage, and promote wound closure. Biologically derived skin substitutes have achieved moderate success in the clinic, however, high costs have limited their use and added burden to the healthcare system. Alternatively, synthetic biomaterials can be affordably manufactured and designed across a broader range of physiochemical properties. However, currently used polyester-based skin substitutes undergo accelerated hydrolytic degradation resulting in a mismatch between rate of material resorption and neo-tissue formation leading to impaired healing. Furthermore, efforts to develop improved therapies for patients with chronic wounds are hampered by the lack of animal models that accurately recapitulate the clinical manifestations of human chronic skin injuries or allow for high-throughput comprehensive testing. In this dissertation, a series of reactive oxygen species (ROS)-degradable, hydrolytically inert, poly(thioketal) urethane scaffolds with varied isocyanate and diol chemistries were developed as synthetic wound dressings to treat skin wounds. PTK polymers interact with cell-generated ROS and undergo oxidative degradation, tailoring biomaterial resorption to tissue ingrowth. Using a pre-clinical, porcine ischemic skin wound model, the importance of degradable isocyanate chemistries to enhance tissue infiltration and vascularization of skin wounds was demonstrated. Additionally, through structure-function variation of PTK chemistry and incorporation of hydrophilic ethylene glycol (EG) moieties in the polymer backbone, the significance of scaffold hydrophilicity for optimum scaffold-tissue integration and tissue repair was identified. The more hydrophilic PTK-UR scaffolds promoted tissue regeneration of porcine skin wounds while lowering the local inflammatory microenvironment, deemed necessary for successful biomaterial guided tissue regeneration. Overall, ROS-degradable PTK-UR-based dermal substitutes provide an affordable, fully synthetic alternative to more expensive, biologically derived wound dressings.