Combatting Retraction in Tissue Engineered Heart Valves

描述(由申请人提供)：我们建议模拟和模拟心脏瓣膜发育的关键机械和生化条件，最终目标是创造一个强大的组织工程心脏瓣膜(TEHV)。我们假设，对胚胎瓣膜发育至关重要的生长因子以张力依赖的方式调节瓣膜间质细胞(VIC)的合成和细胞外基质(ECM)的重塑。我们认为，对生长因子-张力相互作用的定量理解将揭示刺激VIC产生抵抗缩短的高糖胺聚糖(GAG)含量的组织的条件。为了验证我们的假设，VICS将在由天然蛋白质制成的小规模组织模型中培养，这种模型允许控制细胞产生的张力，并以高通量的方式快速分析组织的机械和生化特性。我们将定量评估组织张力和外源性添加转化生长因子-β1、表皮生长因子和骨形态发生蛋白-2的组合对组织力学和成分的影响，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对组织工程心脏瓣膜(TEHV)的发展产生直接影响，因为它确定了以最小的缩短实现健壮组织形成的最佳培养条件。这些发现还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并导致病理重构的理解。基于胚胎瓣膜发育的低张力下创造未成熟组织的方法是对标准的TEHV制造范例的创新。

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.