ABSTRACT

Chronic wounds are skin injuries that recur or fail to heal by 6 weeks. These wounds affect 6.5 million patients in the US and this number is growing rapidly due to a drastic increase in the number of diabetics, the obese, and the elderly--all populations in which wound healing is impaired. Mesenchymal stem cells (commonly known as adult stem cells) and insulin applied to wound surfaces have each shown promise in healing otherwise unhealable wounds. Mesenchymal stem cells assist wound healing by secreting factors that promote actions critical to wound healing, such as new blood vessel formation, increases in the production of skin components, and recruitment of cells that clean wounds and form scar tissue. Insulin assists wound healing by recruiting mesenchymal stem cells and skin cells to the wound area. Motivated by the recent observation that wounds treated with a combination of mesenchymal stem cells and insulin-producing cells healed faster than normal and without scarring, the objective of this project is to identify the type of insulin needed to achieve the observed accelerated healing and reduced scarring and to uncover the wound healing pathways that are recruited. Research results have the potential to transform wound care by enabling rapid healing that would avert the morbidity and mortality associated with chronic wounds and to enhance reconstructive and plastic surgery outcomes by reducing or eliminating scar formation. The project's long-term educational goal is to present future engineers with tissue engineering research in unfamiliar contexts, like aviation, to inspire innovative thinking for future careers in biomedical engineering. In pursuit of this goal, this project's educational objective is to apply research principles to teaching and to develop tissue engineering research modules that integrate research, teaching, mentorship, and learning for use in biomedical engineering course-based undergraduate research experiences (CUREs). The educational and outreach approach is to recruit female students, group them in teams and provide hands-on research activities with wound healing models that will enable them to formulate hypotheses and models, and to propose, conduct, and present experiments that will further their understanding of research. The women will be required to present their research in scientific meetings and to K-12 graders in an aviation science club.

The project's research focus is on investigating the impact of mesynchymal stem cells (MSCs) and insulin producing cells (IPCs), both individually and coencapsulated, on wound healing and its pathways, and on identifying how cell-cell vs. cell-wound interactions govern the secretome of encapsulated cells. The project is motivated by recent studies from the PI's lab that achieved dramatically accelerated (14 vs 40 days), scar-free wound healing after combining these cells. The research plan has four specific aims. Aim 1 is to dissect, via in vitro studies, the role of IPCs vs insulin in survival and function of the coencapsulated cells, i.e., whether it is insulin itself, the presence of the IPCs or the hormone release that improves survival and function. Aim 2 is to dissect, via in vivo studies in mice, the role of IPCs vs insulin in the accelerated wound healing, i. e, whether insulin-producing fibroblasts have the same effect as commercially available IPCs (RIN-5F and RIN-14B) that secrete additional products. Aim 3 is to determine the extent, via in vitro studies, that coencapsulation promotes MSC factor release in comparison to MSC factor release elicited by wound environments, i.e., whether the Akt signaling pathway, which is critical to MSC survival, is activated more strongly in MSCs coencapsulated with IPCs or in MSCs delivered singly to wounds. Aim 4 is to determine the extent that IPCs+MSCs reduce scar formation, i.e., to extend the work to a limited study in pigs, which have an epidermis and dermis similar to human skin and heal at a comparable rate. In summary, this project will examine the metabolic pathways involved in IPC+MSC wound healing, the interplay between the two cells and the wound environment, and whether lessons learned can be applied to other cell therapies.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

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