PROJECT SUMMARY/ABSTRACT Nonhealing skin wounds are a major source of morbidity worldwide and becoming more of a burden due to an increase in health care costs, an aging population, and growing incidence of diabetes. Non-healing skin wounds occur in nearly 25% of diabetic patients, and ~6% are admitted to the hospital for wound-related treatment, which if not successful, can lead to limb amputation or death. More advanced treatments such as synthetic, resorbable dressings that are placed into the wound to provide a scaffolding for cell infiltration and new tissue formation have started to gain clinical impact. However, currently available polymeric biomaterial wound dressings degrade by hydrolysis, releasing acidic byproducts, creating an autocatalytic degradation process. This can lead to inconsistent degradation rate over time and poor matching between the timeline of cell infiltration / new tissue formation and the timeline of polymeric scaffold resorption. The overall goal of the current project is to develop and apply a next generation cellular reactive oxygen species (ROS) degradable, fully synthetic foam wound dressing. These scaffolds are formed by the reaction of ROS-degradable polythioketal (PTK) diols with isocyanate-containing compounds in the presence of a small quantity of water. This generates a crosslinked polyurethane (resultant bond from reaction of isocyanate and hydroxyl) network that is highly porous in nature due to CO2 generation via the blowing reaction between isocyanates and water. The properties of the resultant polythioketal urethane (PTK-UR) foams can be tuned based on the composition of the PTK diol crosslinker which makes up the bulk of the foam. We propose to develop a library of PTK diols with controlled variation in degree of hydrophilicity, consistent density of thioketal bonds in the backbone, and low potential for immunogenicity. This plan is based on highly- promising preliminary data that PTK-UR scaffold hydrophilicity is a critical factor in the wound healing response to the PTK-UR biomaterials. The proposed polymer series will fill previous gaps in our previous work by yielding a well-controlled, highly-scalable chemistry for better fine tuning of PTK-UR hydrophobic/hydrophilic balance across a broad range with diol chemistries that are not based on potentially immunogenic PEG. The aims of the project will involve synthesis and screening of this new class of thioketal diols, benchmarking of the leading PTK- UR formulations against clinical products for wound healing efficacy, and application of lead PTK-UR formulations for cargo delivery to promote healing in the context of pathological (infected and diabetic) wounds. Our multidisciplinary team includes bioengineers, polymer and polyurethane material chemists, preclinical wound healing model and histopathology expertise, expertise in immunology of wound healing / skin wound infection, and clinical wound care. This group is poised to achieve the proposed goals toward establishing a new clinically impactful, cell-resorbable, synthetic polymer-based foam wound dressing.

PROJECT NARRATIVE Chronic skin wounds are a significant clinical problem, particularly in the context of diabetes. The goal of the proposed work is to develop a fully synthetic, cell-degradable wound dressing that promotes repair of nonhealing skin wounds.