Mechanisms of In-Vivo Remodeling in Tissue Engineered Heart Valves

组织工程心脏瓣膜体内重塑机制

• 批准号: 7673989
• 负责人: Michael S Sacks
• 金额: $ 78.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673989
• 关键词: Accounting; Address; Adolescent; Affect; Age; Animal Model; Animals; Apoptosis; Architecture; Area; Atrial Heart Septal Defects; Autologous; Behavior; Biochemical; Biological; Biological Factors; Biomechanics; Biomedical Engineering; Bioprosthesis device; Blood Vessels; Bone Marrow; Cell physiology; Cells; Characteristics; Chemistry; Childhood; Clinical; Collagen; Data; Deposition; Development; Dimensions; Elastin; Engineering; Engraftment; Event; Evolution; Extracellular Matrix; Fiber; Frequencies; Generations; Goals; Grant; Growth; Heart Valves; Image; Implant; In Vitro; Kinetics; Knowledge; Label; Laboratories; Lead; Lung; Magnetic Resonance Imaging; Matrix Metalloproteinases; Measurement; Measures; Mechanical Stress; Mechanics; Mediating; Mesenchymal Stem Cells; Methodology; Methods; Microscopic; Modeling; Normal tissue morphology; Operative Surgical Procedures; Outcome; Patients; Phenotype; Plant Roots; Population; Procedures; Process; Production; Property; Proteins; Proteoglycan; Public Health; Pulmonary Circulation; Pulmonary artery structure; Pulmonary valve structure; Research; Research Personnel; Role; Simulate; Stimulus; Stress; Structure; Techniques; Testing; Thrombosis; Time; Tissue Engineering; Tissues; Ventricular; Work; base; biodegradable polymer; computerized; conditioning; design; heart valve replacement; implantation; improved; in vivo; inhibitor/antagonist; insight; interstitial cell; light scattering; morphometry; pressure; programs; retroviral transduction; scaffold; shear stress; stressor

DESCRIPTION (provided by applicant): Using autologous cells and biodegradable polymers, tissue engineered pulmonary valves (TEPV) have been fabricated and have functioned in the pulmonary circulation of growing lambs for up to 20 weeks, with tissue evolving into a differentiated layered structure resembling that of native valve. More recent studies have demonstrated that use of bone marrow mesenchymal stem cells (BMSC) and PGA/PLLA scaffolds produce functioning implants for up to 8 months in growing lambs which also demonstrated in-vivo structural evolution. These studies have demonstrated the feasibility of engineering pulmonary valve (PV) leaflets and segments of main pulmonary artery (PA) in-vitro. Both structures have functioned well without thrombosis. Moreover, both the gross and microscopic characteristics of the TEPV structures began to approximate those of normal tissues, strongly suggesting that cell phenotypes evolved in a directed fashion to remodel the valvular and vascular tissue. However, while these intriguing studies have yielded insight into TEPV development, our efforts thus far have been largely empirical. There remain significant bioengineering challenges in determining parameters that lead to optimal ECM development and strength. For example, despite the in-vivo evolution of TEPV valve tissue into a tri-layered structure that resembles native valve tissue, we have only very limited information on the extent to which TEPV truly duplicates native PV biomechanical function, nor the mechanisms that regulate the in-vivo remodeling process. The goal of the current research program is to thus quantify and simulate tissue remodeling events that occur post- implantation, and to understand the factors that influence the remodeling rate and the quality and architecture of the ultimate tissue. Specifically, we hypothesize that TEPV implant remodeling is primarily mediated by the level of in-vivo mechanical stimuli to the interstitial cells and developing ECM. Mechanical stimuli will affect the rate of scaffold degradation and the degree of post-implant cellular ingrowth. Relevance to public health includes the develop of valved pulmonary conduits for the pediatric population that can grow with the patient, minimizing the need for continued re-operations to bring the patient to adulthood.

描述（由申请人提供）：使用自体细胞和可生物降解的聚合物，组织工程肺动脉瓣（TEPV）已被制造出来，并在生长中的羔羊的肺循环中发挥作用长达20周，组织进化成类似于天然瓣膜的分化层状结构。最近的研究表明，使用骨髓间充质干细胞 (BMSC) 和 PGA/PLLA 支架可以在生长中的羔羊中产生长达 8 个月的功能植入物，这也证明了体内结构进化。这些研究证明了在体外设计肺动脉瓣（PV）小叶和主肺动脉（PA）段的可行性。两种结构均功能良好，无血栓形成。此外，TEPV 结构的总体和微观特征开始接近正常组织，强烈表明细胞表型以定向方式进化以重塑瓣膜和血管组织。然而，虽然这些有趣的研究已经深入了解了 TEPV 的发展，但迄今为止我们的努力主要是经验性的。在确定导致最佳 ECM 开发和强度的参数方面，仍然存在重大的生物工程挑战。例如，尽管 TEPV 瓣膜组织在体内进化成类似于天然瓣膜组织的三层结构，但我们对 TEPV 真正复制天然 PV 生物力学功能的程度以及调节体内重塑过程的机制只有非常有限的信息。当前研究计划的目标是量化和模拟植入后发生的组织重塑事件，并了解影响重塑率以及最终组织的质量和结构的因素。具体来说，我们假设 TEPV 植入物重塑主要是由间质细胞的体内机械刺激水平和发育的 ECM 介导的。机械刺激会影响支架降解速率和植入后细胞向内生长的程度。与公共卫生的相关性包括为儿科人群开发带瓣膜的肺导管，该导管可以随着患者的生长而生长，从而最大限度地减少患者成年后持续进行再次手术的需要。