MECHANICALLY-INDUCED REMODELING OF TISSUE ENGINEERED BLOOD VESSELS

描述（由申请人提供）：开发小直径组织工程血管（TEBV）有很大的未满足的临床需求，具有低血栓性和免疫反应，合适的机械性能，以及适应环境的重塑能力。我们的中心假设是，轴向拉伸将诱导胶原-纤维蛋白tebv的重塑，其速度超过压力或血流诱导的重塑，并且结合这些多向机械刺激将增加重塑速度，而不仅仅是这些单向刺激的叠加反应。本课题的目标是：(I)开发和测试一种实验装置，该装置可以精确和独立地控制多向机械载荷，并能够在培养的多个时间点分别执行生物力学响应和微观结构组织的间歇性压力-直径（P-d）和轴向力-长度(f)变化；（ii）开发一个微观结构激励计算模型来描述TEBV在机械刺激下的重塑。（iii）利用这些实验和计算模型来表征胶原-纤维蛋白凝胶衍生的复合tebv在单向和多向负荷下的重塑。我们将通过表征胶原纤维蛋白凝胶衍生的tebv在(a)轴向延伸、(b)脉冲压力、(c)管腔流量或(d)轴向延伸、脉冲压力和管腔流量同时增加的情况下的重塑来验证我们的中心假设。这些目标的成功实现将为评估机械刺激对tebv的作用建立一个创新的新范式，该范式集成了生物力学刺激、生物力学测试、LSM和计算模型。一个预期的结果将是同时表征双向应力应变响应的时间变化，以及暴露于单向和多向负荷逐渐增加的tebv中胶原蛋白、弹性蛋白、糖胺聚糖（GAGs）和平滑肌的数量和组织。另一个预期结果将是证明轴向机械刺激和多向刺激将提高tebv的重塑率。第三个预期结果将是开发一种多尺度微结构驱动的计算模型，用于胶原纤维蛋白凝胶衍生的TEBVs的机械诱导重塑；该模型可用于激励后续实验以优化加载策略，从而有效且高效地获得合适的tebv力学性能。总体而言，我们将论证理论建模与实验相结合的可行性，以优化策略，以时间和成本效益的方式开发tebv。在美国，每年有超过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；开发小直径组织工程血管，具有低血栓形成性和免疫反应，合适的机械性能和适应环境的能力，适合冠状动脉旁路手术，这是一个巨大的未满足的临床需求。这项工作的目的是优化生物力学刺激的使用，如逐渐加压和轴向延伸，刺激tebv重塑，以优化其冠状动脉旁路移植术的机械性能。

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.