Chronic wounds affect more than 6.5 million patients and cause a significant social and economic burden, with an overall cost for wound treatment exceeding $25 billion annually in the United States alone. Chronic wounds do not follow the normal wound healing process due to the abnormalities in the formation of a vascularized granulation tissue, a provisional matrix composed of multiple cell types and cell-derived ECM matrices. Failure to form a functional vasculature is often associated with slow matrix remodeling and delayed tissue healing, which is highly linked to many pathological conditions such as ischemia. Although a variety of therapeutic approaches including growth factor delivery, cell delivery, scaffolding materials, or wound dressings have previously been applied to treat chronic wounds, the outcome of granulation tissue formation and wound angiogenesis remains limited.
The overall goal of this proposal is to promote the formation of a vascularized granulation tissue in pro-angiogenic and micro-structured hydrogels that better recapitulate the effective extracellular microenvironment for improved chronic wound healing. To achieve this goal, we aim to employ a simple, one-step liquid-liquid phase separation method to capture the phase separation process via chemical reactions, to formulate micro-structured hydrogels with controlled release of pro-angiogenic factors and tunable micro-domains. Such biomaterial system offers unique opportunities to understand how extra-cellular microenvironmental cues regulate cellular behavior in promoting angiogenesis and chronic wound healing. We will also establish a humanized in vitro system of wound injury and closure model to capture the de novo formation of vascularized granulation tissue and evaluate the effect of microdomains and vascular endothelial growth factors on tissue angiogenesis and wound closure.
The development of injectable micro-structured biomaterials as dermal replacements that enhance wound angiogenesis will expand our understanding of how hydrogel microstructure and tissue vascularization contributes to wound healing. The integration of tunable biomaterials with a novel in vitro 3D wound injury and closure model builds a bottom-up biomimetic system to explore the synergistic effects between biochemical signals and biophysical cues with the minimum components required for enhanced wound angiogenesis. This comprehensive in vitro platform of a 3D multicellular culturing system will identify the key matrix properties for wound healing and can be used for future investigation of pathological conditions associated with chronic wounds.
