Promotion of tissue engineering angiogenesis via analysis of cellular decision-making processes in response to mechanical and biomolecular cues

点击翻译按钮获取中文摘要

PI: Masters, KristynProposal Number: 1401584Institution: University of Wisconsin-Madison Title: Promotion of tissue engineering angiogenesis via analysis of cellular decision-making processes in response to mechanical and biomolecular cuesBecause diffusion alone is not sufficient to provide adequate nutrient delivery and waste removal in tissues, a blood vessel supply is considered necessary to maintain the viability and function of most tissues thicker than 0.2 mm. Currently, the inability to promote the formation of such a blood vessel supply in biomaterial scaffolds remains a major obstacle in the creation of healthy engineered tissues. The work proposed in this project will provide both computational and experimental information to help the design of scaffold environments that permit enhanced blood vessel formation (known as angiogenesis). Proposed studies are expected to identify specific scaffold design parameters that best promote angiogenesis, as well as investigate pharmaceutical strategies for switching poorly angiogenic scaffold environments into ones that better support angiogenesis. Overall, this work is intended to yield information that helps overcome the most significant obstacle currently facing the construction of viable engineered tissues. Additionally, this work sets the stage to perform similar investigations with other cell and tissue types; such an expanded library of information with respect to controlling and predicting cellular behaviors would be invaluable in numerous applications. This proposal is co-funded by the Biomedical Engineering Program in the Chemical, Bioengineering, Environmental and Transport Systems Division, and by the Biomaterials Program in the Division of Materials Research.The process of angiogenesis may be guided by numerous extracellular influences, such as soluble growth factors, immobilized growth factors, extracellular matrix (ECM) components, and mechanical forces. While the angiogenic response of endothelial cells (ECs) to these individual stimuli has been characterized, little is known on how cells interpret and respond to combinations of these signals. Moreover, the identification of optimally angiogenic culture conditions alone will not be sufficient for all tissue engineering applications, as the other physical and biological requirements specific to a given target tissue will constrain many elements of the scaffold design. Understanding the manner in which these cues regulate angiogenesis is critical in making advances in applications that require angiogenesis, such as tissue engineering. This proposal is based on the hypothesis that angiogenesis can be promoted in tissue engineering applications via manipulation of cellular decision-making processes that occur in response to the delivery of combinations of microenvironmental cues. This hypothesis will be addressed by an integrated experimental and computational research approach and specifically by 1) analyzing how ECs respond to combinations of growth factor, mechanical, and ECM cues, 2) determining the signaling processes by which ECs sense, interpret, and respond to these cues, 3) building a computational model relating signaling processes and angiogenic outcomes, and 4) applying this model to experimentally manipulate angiogenic responses. Ultimately, the proposed studies will help to better understand and predict cellular decision-making processes that could be used to identify scaffold conditions that support angiogenesis, more broadly inform tissue engineering scaffold design principles, and develop pharmaceutical approaches to promote angiogenesis in scaffolds that restrict angiogenesis.