Fibronectin Mimetics and Synergistic Ultrasound Therapy for Wound Healing in Aging

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Chronic wounds have become a `silent epidemic', affecting 20 million people worldwide, including 5-7 million Americans. Non-healing wounds cause pain and discomfort for the patient, with health complications ranging from serious infections to limb amputations to death. In the U.S. alone, health care costs for treating chronic wounds are estimated to be $25 billion annually, with the majority of those costs directed at adults over the age of 65. Specific interactions between cells and the extracellular matrix (ECM) form of fibronectin (FN) control a broad range of functions essential to wound repair. ECM FN fibrils also serve as mechanosensory elements in tissue, facilitating endothelial cytoskeletal reorganization and vasodilation. As such, restoring the functional and structural properties of ECM FN within non-healing wounds holds immense promise as an effective therapeutic approach to stimulate and facilitate tissue repair in older adults. To deliver ECM FN signals directly to cells in chronic wounds, we developed a series of soluble FN fragments engineered to mimic the ECM form of FN. These recombinant “FN matrix mimetics” stimulate cell and tissue functions to a similar or greater extent than ECM FN. Moreover, topical application of FN matrix mimetics to full-thickness wounds in young diabetic mice accelerates wound closure and promotes granulation tissue deposition, tissue remodeling, and revascularization. The goals of this project are three-fold: (i) to advance our pre-clinical FN matrix mimetics to the treatment of chronic wounds associated with aging, (ii) to use information obtained from these studies to identify mechanisms of ECM remodeling that become dysregulated with age, and (iii) to identify synergistic actions of FN matrix mimetics with adjuvant wound mechanotherapies, specifically therapeutic ultrasound. If successful, our ECM FN-based therapies will help to fill a critical need for new and innovative approaches to treat ulcerative wounds in aging, and will provide new information regarding ECM deficiencies in aging that will inform the design of new treatment approaches. !