MECHANICALLY-INDUCED REMODELING OF TISSUE ENGINEERED BLOOD VESSELS

组织工程血管的机械诱导重塑

• 批准号: 7236882
• 负责人: RUDOLPH L GLEASON
• 金额: $ 20.68万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236882
• 关键词: 3-Dimensional; Autologous; Behavior; Biochemistry; Biomechanics; Blood Vessel Tissue; Blood Vessels; Caliber; Cellular biology; Clinical; Collagen; Computer Simulation; Coronary; Development; Devices; Discipline; Elastin; Environment; Exhibits; Extracellular Matrix; Fibrin; Gel; Glycosaminoglycans; Goals; Heart Valves; Immune response; Laboratories; Laser Scanning Microscopy; Length; Mechanical Stimulation; Mechanics; Modeling; Molecular; Operative Surgical Procedures; Outcome; Patients; Procedures; Production; Property; Purpose; Range; Rate; Reporting; Role; Science; Smooth Muscle; Stimulus; Stress; Stretching; Techniques; Testing; Theoretical model; Time; Tissue Engineering; Tissue Grafts; USA Georgia; United States; Western Asia Georgia; Work; computer framework; cost; improved; innovation; interest; novel; pressure; research study; response; scaffold; self assembly; shear stress

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(申请人提供)：有一个巨大的临床需求尚未得到满足，开发小直径组织工程血管(TEBV)，具有低的血栓形成和免疫反应，合适的机械性能，以及根据其环境进行重塑的能力。我们的中心假设是，轴向伸展将以超过压力或流动诱导的重塑的速度诱导胶原纤维蛋白TEBV的重塑，并且这些多方向机械刺激的组合将增加重建率，而不是这些单向刺激单独的相加反应。该建议的目标是(I)开发和测试一种能够精确和独立地控制多方向机械载荷并能够在培养的多个时间点分别执行间歇性压力-直径(P-d)和轴向力-长度(F)的实验装置，(Ii)开发微结构激励的计算模型来描述机械刺激下的TEBV重塑，以及(Iii)利用这些实验和计算模型来表征单向和多向载荷下胶原-纤维蛋白凝胶衍生的组合型TEBV的重塑。我们将通过表征胶原纤维蛋白凝胶衍生的TEBV的重塑特征来验证我们的中心假设，这些TEBV在(A)轴向伸展、(B)脉动压、(C)腔内血流或(D)轴向伸展、脉动压和管腔流同时增加的情况下逐渐增加。这些目标的成功实现将为评估机械刺激在TEBV上的作用建立一个创新的新范式，它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，平行地描述在单向和多向负荷逐渐增加的TEBV中，双向应力-应变响应以及胶原、弹性蛋白、糖胺聚糖(GAG)和平滑肌的数量和组织的时间变化。另一个预期的结果将是证明轴向机械刺激和多方向刺激将提高TEBV的重建率。第三个预期成果将是开发一个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TEBV的机械诱导重塑；这样的模型可用于激励后续实验，以优化加载策略，以有效和高效地获得合适的TEBV的力学性能。总体而言，我们将论证理论建模和实验相结合的可行性，以优化策略，以节省时间和成本地开发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；开发具有低凝血性和免疫反应性、合适的机械性能和适应其环境的能力的小直径组织工程血管以适应冠状动脉旁路手术的能力，是临床上尚未满足的巨大需求。本工作的目的是优化生物力学刺激的使用，如逐步加压和轴向伸展，以刺激TEBV的重塑，以优化其在冠状动脉旁路移植中的力学性能。