BME PhD Defense Seminar: Daniel C. Roy

Development of Fibronectin Matrix Mimetics for the Accelerated Healing of Chronic, Cutaneous Wounds

Supervised by Professor Denise Hocking

Abstract:

Cutaneous wound repair is a stepwise process governed by interactions between cells and the surrounding matrix. Fibronectin is an extracellular matrix (ECM) protein that is typically up-regulated following cutaneous injury. Conversely, decreased fibronectin levels are associated with non-healing, chronic wounds. The ECM form of fibronectin specifically stimulates cell and tissue processes critical to wound repair including cell growth, cell migration, and ECM deposition and organization. The bioactivity of ECM fibronectin has been localized, in part, to the matricryptic heparin-binding domain located within the first type III repeat of fibronectin (FNIII1H). A series of fibronectin matrix mimetics were constructed by directly coupling the matricryptic FNIII1H domain to variants of the integrin-binding domain of fibronectin (FNIII8-10).

As adhesive substrates, the fibronectin matrix mimetics GST/III1H,8-10, GST/III1H,8,10 and GST/III1H,8RGD promoted cell growth, cell migration and cell contractility to a similar or greater extent than full-length fibronectin. Fibronectin matrix mimetics also served as integrin-specific adhesive substrates to direct fibronectin matrix assembly. Topical application of fibronectin matrix mimetics to punch biopsy wounds of diabetic mice improved healing by increasing the deposition of collagen-rich granulation tissue. Further, the construct GST/III1H,8-10 accelerated wound closure over GST-treated wounds. These studies suggest that fibronectin matrix mimetics make promising candidates to serve as bioactive coatings for tissue engineered scaffolds and as therapeutic agents to improve healing of chronic wounds.