MECHANICALLY-INDUCED REMODELING OF TISSUE ENGINEERED BLOOD VESSELS

描述（由申请人提供）：开发具有低促凝性和免疫反应、合适的机械性能以及根据其环境重塑能力的小直径组织工程血管（TEBV）存在巨大的未满足的临床需求。我们的中心假设是，轴向伸展将诱导重塑胶原纤维蛋白TEBV的速率超过压力或流量诱导的重塑，并结合这些多方向的机械刺激将增加重塑速率超过这些单向刺激单独的附加反应。本课题的主要目的是：（1）研制和测试一种能够精确独立控制多方向机械加载的实验装置，并能够进行间歇压力-直径（P-d）和轴向力-长度（L-D）的试验（f）分别在培养的多个时间点的生物力学响应和显微结构组织的变化，（ii）开发一个微观结构激励的计算模型来描述TEBV重塑机械刺激，和（iii）采用这些实验和计算模型来表征组合的胶原蛋白-纤维蛋白凝胶衍生的TEBV暴露于单向和多向负荷的重塑。我们将通过表征胶原-纤维蛋白凝胶衍生的TEBV的重塑来测试我们的中心假设，所述TEBV暴露于（a）轴向伸展、（B）脉动压力、（c）管腔流量或（d）轴向伸展、脉动压力和管腔流量的同时增加的逐渐增加。这些目标的成功实现将建立一个创新的新范式，用于评估机械刺激对TEBV的作用，该范式集成了生物力学刺激，生物力学测试，LSM和计算建模。一个预期的结果将是表征，在平行的时间变化的双轴应力-应变响应和胶原蛋白，弹性蛋白，糖胺聚糖（GAG），和平滑肌的TEBV暴露于单向和多向负荷逐渐增加的量和组织。另一个预期的结果将是证明轴向机械刺激和多向刺激将改善TEBV的重塑率。第三个预期的结果将是开发一个多尺度的微观结构驱动的计算模型，用于机械诱导的胶原蛋白-纤维蛋白凝胶衍生的TEBV的重塑;这样的模型，可以用来激励后续的实验，以优化加载策略，有效地和高效地实现合适的机械性能的TEBV。总的来说，我们将展示理论建模和实验相结合的可行性，以优化策略，开发TEBV的时间和成本效益的方式。在美国每年进行超过50万例冠状动脉旁路手术，然而许多患者缺乏足够的自体移植组织;存在开发具有低促凝性和免疫应答、合适的机械性能以及改造成适合于冠状动脉旁路手术的环境的能力的小直径组织工程血管的巨大未满足的临床需求。这项工作的目的是优化生物力学刺激的使用，如逐渐加压和轴向伸展，以刺激TEBV的重塑，以优化其机械性能的冠状动脉旁路移植术。

DESCRIPTION (provided by applicant): 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.