We have developed a novel approach to engineer constructs of organ-level complexity by using pre-existing, explanted microcirculatory beds as a vascular scaffold to provide the starting point for complex organ fabrication, which will occur in a modifiable hydrogel delivery system. We have demonstrated the ability to sustain explanted vascular beds for extended periods ex vivo in a bioreactor, to genetically modify their growth milieu, and to efficiently seed them with progenitor cells creating functional neo-organ units for re-implantation. We believe that isolation and suspension of native pre-formed vascular beds will form the foundation from which to build vascularized organ-level constructs capable of effective reintegration.
Diabetes-induced impairments in new blood vessel growth greatly increase the severity of the sequelae caused by various ischemic processes, including coronary artery disease, cerebrovascular disease, peripheral vascular disease and impaired wound healing. Diabetes affects recovery from ischemic insult by blunting the neovascular response. Ischemic neovascularization occurs via two fundamentally different pathways: the sprouting of new blood vessels from existing vessels (angiogenesis), and the recruitment, proliferation, and assembly of bone marrow-derived progenitor cells into new vessels (vasculogenesis). Our work has shown that diabetes impairs new blood vessel formation in response to hypoxia by causing abnormal ischemia-induced signaling as well as impaired progenitor cell proliferation, function, and trafficking.
Novel biomechanical systems to study the mechanotransduction processes underlying skin fibrosis and hypertrophic scar formation
Mechanical forces are known to significantly modulate cell, tissue, and organ behavior and have long been associated with inflammation and fibrosis, but their molecular relationships remain poorly defined. To investigate this problem, we have developed novel in vivo and in vitro biomechanical systems to study the mechanotransduction processes underlying skin fibrosis. Our preliminary data and current mechanotransduction research suggest that hypertrophic scar formation is regulated by focal adhesion kinase (FAK) pathways, which will be thoroughly investigated to develop novel anti-fibrotic-releasing dermal bioscaffolds to effectively mitigate skin fibrosis.
Aging is a known risk factor for impaired wound healing and poor tissue recovery following an ischemic insult. Effective neovascularization, or new blood vessel formation, is critical for both wound healing and tissue survival following ischemia. Through complex signaling mechanisms, ischemic tissue actively recruits circulating progenitor cells out of the bone marrow and into the area of ischemia to initiate proliferation and differentiation of these cells into new blood vessels. We have shown that aging significantly impairs this communication between ischemic tissue and circulating progenitor cells and leads to dysfunctional vasculogenesis. A more thorough understanding of the mechanisms underlying these impairments will facilitate the development of novel strategies to mitigate these effects.
We have developed various hydrogel and micelle-base transdermal delivery systems for the targeted administration of small molecule therapeutic agents?
The ability to evaluate the therapeutic potential of stem cell therapies is hindered by a lack of precision in defining the cells that are being administered to patients. The standardization of cell-based therapies requires methods that can fingerprint cell populations at the single cell level in a high throughput manner. We have developed technology that is capable of generating gene expression profiles from all the individual cells in a sorted population. This makes it possible to comprehensively characterize cell populations prior to clinical application and ensure uniformity in trials of cell-based therapies.