Combatting Retraction in Tissue Engineered Heart Valves

对抗组织工程心脏瓣膜的回缩

• 批准号: 8772755
• 负责人: Kristen L Billiar
• 金额: $ 45.06万
• 依托单位: WORCESTER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772755
• 关键词: Adopted; Biochemical; Bioprosthesis device; Bone Morphogenetic Proteins; Cardiac; Cell Proliferation; Cells; Childhood; Clinical; Clinical Trials; Collagen; Computer Simulation; Coupled; Dermal; Development; Embryo; Embryonic Development; Engineering; Epidermal Growth Factor; Equilibrium; Extracellular Matrix; Extracellular Matrix Proteins; Extravasation; Family suidae; Fibrin; Fibroblasts; Gel; Glycosaminoglycans; Goals; Growth Factor; Heart Valves; Human; Hyaluronic Acid; Individual; Knowledge; Laws; Lead; Mechanics; Methodology; Modeling; Myofibroblast; Operative Surgical Procedures; Patients; Polymers; Production; Property; Proteins; Residual state; Role; Solutions; Stimulus; Stress; System; Testing; Tissue Engineering; Tissue Model; Tissues; Traction; Transforming Growth Factor beta; base; bone morphogenetic protein 2; cell type; cofactor; combat; conditioning; heart valve replacement; hemodynamics; human TGFB1 protein; innovation; interstitial cell; novel; prevent; public health relevance; repaired; scaffold; seal; success; valve replacement

DESCRIPTION (provided by applicant): We propose to emulate and model key mechanical and biochemical conditions of developing heart valves towards the ultimate goal of creating a robust tissue engineered heart valve (TEHV). We hypothesize that growth factors critical to embryonic valve development regulate valve interstitial cell (VIC) extracellular matrix (ECM) synthesis and remodeling in a tension- dependent manner. We propose that a quantitative understanding of growth factor-tension interactions will reveal conditions which stimulate VICs to produce tissues with high glycosaminoglycan (GAG) content that resist shortening. To test our hypothesis, VICs will be cultured in small-scale tissue models made from natural proteins which allow for control over tension generated by the cells and rapid analysis of tissue mechanical and biochemical properties in a high-throughput manner. We will quantitatively assess the effect of tissue tension and combinations of exogenous addition of transforming growth factor-beta1, epidermal growth factor, and bone morphogenetic protein-2 on tissue mechanics and composition and model the balance between ECM secretion and degradation computationally. The results from this systematic study will have a direct impact on tissue engineered heart valve (TEHV) development by determining optimal culture conditions for robust tissue formation with minimal shortening. The findings will also increase our understanding of how growth factors and mechanical stimuli coordinate valve development and repair and lead to pathological remodeling. The approach of creating immature tissue under low tension based on embryonic valve development is an innovative departure from standard TEHV fabrication paradigms.

描述（由申请人提供）：我们建议模拟和建模开发心脏瓣膜的关键机械和生化条件，以实现创建稳健的组织工程心脏瓣膜（TEHV）的最终目标。我们假设胚胎瓣膜发育的关键生长因子以张力依赖的方式调节瓣膜间质细胞（维克）细胞外基质（ECM）的合成和重塑。我们建议，生长因子-张力相互作用的定量理解将揭示刺激VIC产生具有高糖胺聚糖（GAG）含量的组织的条件，该组织抵抗缩短。为了验证我们的假设，VIC将在由天然蛋白质制成的小规模组织模型中培养，该模型允许控制由细胞产生的张力，并以高通量方式快速分析组织机械和生化特性。我们将定量评估组织张力和外源性添加转化生长因子-β 1、表皮生长因子和骨形态发生蛋白-2组合对组织力学和组成的影响，并通过计算模拟ECM分泌和降解之间的平衡。这项系统性研究的结果将通过确定最佳培养条件对组织工程心脏瓣膜（TEHV）的开发产生直接影响，以实现最小缩短的稳健组织形成。这些发现也将增加我们对生长因子和机械刺激如何协调瓣膜发育和修复以及导致病理性重塑的理解。基于胚胎瓣膜发育在低张力下产生未成熟组织的方法是对标准TEHV制造范例的创新偏离。