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MECHANICALLY-INDUCED REMODELING OF TISSUE ENGINEERED BLOOD VESSELS

组织工程血管的机械诱导重塑

基本信息

批准号：
7500827
负责人：
RUDOLPH L GLEASON
金额：
$ 18.18万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：开发小直径组织工程血管（TEBV）具有巨大的未满足的临床需求，该血管具有低血栓形成性和免疫反应性、合适的机械性能以及重塑其环境的能力。我们的中心假设是，轴向延伸将以超过压力或流动诱导重塑的速率诱导胶原纤维蛋白 TEBV 重塑，并且结合这些多向机械刺激将增加重塑速率，超过这些单向刺激单独的加性反应。该提案的目标是（I）开发和测试一种实验装置，该装置可以精确、独立地控制多向机械载荷，并且能够分别在培养的多个时间点执行间歇压力-直径（P-d）和轴向力-长度（f-生物力学响应和微观结构组织的变化），（ii）开发一种微观结构驱动的计算模型来描述 TEBV 重塑机械刺激，以及（iii）利用这些实验和计算模型来表征暴露于单向和多向负载的组合胶原纤维蛋白凝胶衍生的 TEBV 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，这些 TEBV 暴露于（a）轴向延伸的逐渐增加，（b）脉动压力，(c) 腔内流量，或 (d) 轴向延伸、脉动压力和腔内流量同时增加。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同时描述在单向和多向载荷逐渐增加的情况下，TEBV 中双轴应力-应变响应以及胶原蛋白、弹性蛋白、糖胺聚糖 (GAG) 和平滑肌的数量和组织的时间变化。另一个预期结果是证明轴向机械刺激和多向刺激将提高 TEBV 的重塑率。预计第三个结果将是开发一个多尺度微观结构驱动的计算模型，用于胶原纤维蛋白凝胶衍生的 TEBV 的机械诱导重塑；这样的模型可用于激励后续实验来优化加载策略，以有效且高效地实现 TEBV 合适的机械性能。总的来说，我们将论证结合理论建模和实验来优化的可行性以时间和成本高效的方式开发 TEBV 的策略。美国每年进行超过 50 万例冠状动脉搭桥手术，但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巨大的未满足的临床需求，该血管具有低血栓形成性和免疫反应性、合适的机械性能以及重塑适合冠状动脉搭桥的环境的能力手术。这项工作的目的是优化生物力学刺激的使用，例如逐渐加压和轴向延伸，以刺激 TEBV 重塑，从而优化其用于冠状动脉搭桥术的机械性能。