There is a great unmet clinical need to develop small diameter tissue engineered blood vessels (TEBV) with low thrombogenicity and immune response, suitable mechanical properties, and a capacity to remodel to their environment. Our central hypothesis is that axial extension will induce remodeling in collagen-fibrin TEBVs at rates that exceed that of pressure- or flow-induced remodeling and combining these multidirectional mechanical stimuli will increase remodeling rates beyond the additive response of these unidirectional stimuli alone. The goals of this proposal are (I) to develop and test an experimental device to that can precisely and independently control multidirectional mechanical loading and is capable of performing intermittent pressure- diameter (P-d) and axial force-length (f- changes in the biomechanical response and microstructural organization, respectively, at multiple time-points in culture, (ii) to develop a microstructurally-motivate computational model to describe TEBV remodeling to mechanical stimuli, and (iii) to employ these experimental and computational models to characterize remodeling of combined collagen-fibrin gel-derived TEBVs exposed to unidirectional and multidirectional loading. We will test our central hypothesis by characterize remodeling of collagen-fibrin gel-derived TEBVs exposed to gradual increases in (a) axial extension, (b) pulsatile pressure, (c) luminal flow, or (d) simultaneous increases in axial extension, pulsatile pressure, and luminal flow. Successful realization of these aims will establish an innovative new paradigm for evaluating the role of mechanical stimuli on TEBVs that integrates biomechanical stimulation, biomechanical testing, LSM, and computational modeling. One expected outcome will be to characterize, in parallel, the temporal changes in the biaxial stress-strain response and the amount and organization of collagen, elastin, glycosaminoglycans (GAGs), and smooth muscle in TEBVs exposed to gradual increases in unidirectional and multidirectional loading. Another expected outcome will be to demonstrate that axial mechanical stimulation and multidirectional stimulation will improve the rates of remodeling in TEBVs. A third expected outcome will be to develop a multi-scale microstructurally-motivated computational model for mechanically-induced remodeling of collagen-fibrin gel-derived TEBVs; such a model that can be used to motivate subsequent experiments to optimize loading strategies to effectively and efficiently achieve suitable mechanical properties of TEBVs. Overall, we will demonstrate the feasibility of combining theoretical modeling and experiments to optimize strategies to develop TEBVs in a time- and cost-efficient manner. Over half a million coronary by-pass procedures are performed in the United States each year, however many patients lack adequate autologous grafting tissue; there is a great unmet clinical need to develop small diameter tissue engineered blood vessels with low thrombogenicity and immune response, suitable mechanical properties, and a capacity to remodel to their environment that will be suitable for coronary by-pass surgery. The purpose of this work is to optimize the use of biomechanical stimuli, such as gradual pressurization and axial extension, to stimulate remodeling of TEBVs to optimize their mechanical properties for coronary by-pass grafting. ? ? ?
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