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.
