Chronic wounds such as obesity endemic and diabetic foot ulcers represent a significant socioeconomic and clinical burden given that these wounds fail to follow the normal wound healing program due to the abnormalities in the formation of granulation tissue, a densely vascularized provisional tissue composed of multiple cell types and cell-derived ECM matrix, which acts as a critical foundation for proper wound healing. Failure to form a patent vasculature in granulation tissue is often associated with slow tissue remodeling and healing. Clinically available dermal replacements only perform as a protective barrier to prevent secondary infection, however, are not designed to promote vascular ingrowth, resulting ineffective treatments particularly in large wounds where functional vasculature is required. The goal of this project is to design novel pro-angiogenic biocomposites that can promote rapid host vascularization with defined micro-structures and tunable micromechanics to trigger myofibroblast activation and induce subsequent matrix deposition, two key steps of tissue repair that will likely offer a better treatment for chronic wounds. To develop novel heterogeneous and pro-angiogenic biomaterials as wound dressing replacements, liquid-liquid phase separation (LLPS) strategy will be employed to generate phase-separated, micro-structured hydrogels that feature confined pro-angiogenic component in one phase and tunable size of phase-separated micro-spheres. Orthogonal chemistries will be utilized to increase the rigidity of interfacial micromechanics to induce myofibroblast activation and to enhance provisional matrix deposition and granulation tissue formation. These screened cellular and material compositions and conditions will integrate with a microfluidic organ-on-chip device to establish a physiologically relevant 3D wound/injury model to further investigate pathological conditions associated with chronic wounds. These experiments will provide key insights that allow to test the efficacy using diabetic mouse in vivo model for treating chronic wound healing. The broad research interest and long-term objective is to establish a new approach to generate a class of novel biomaterials for the repair of chronic wounds focusing on restoration of functional vasculature. The material system can be employed to investigate the synergistic effect between biochemical and biophysical cues and to harness mechanistic insights to refine the design of biomaterials for better modulation of cellular behavior, myofibroblast activation and vascularized granulation tissues formation towards functional wound healing.
