Completely biological tissue-engineered pulmonic valve grown in vitro from human

描述（由申请人提供）：本研究计划的目标是将先前NIH资助的进展转化为完全生物组织工程肺动脉瓣置换术，由成纤维细胞重塑纤维蛋白体外生长的组织制成。这将通过以下方式实现：（1）心脏瓣膜生物反应器设计和操作的进步，以加强根段和根-瓣叶附着线，以及（2）使用间充质干细胞的新的脱细胞化和可选的再细胞化策略，以抑制植入后由于移植成纤维细胞而发生的瓣叶收缩，所述成纤维细胞用于体外生长组织瓣膜。这种组织工程心脏瓣膜（TEHV），脱细胞化（依赖于宿主细胞入侵）和再细胞化（植入前使用间充质干细胞）将在羔羊模型中进行验证，以证明工程瓣膜的生长能力和持续功能。如果该TEHV随后能够得到改进以承受与主动脉瓣位置相关的力，则成功将最终使美国每年约10，000名儿科患者受益，并最终使美国每年100，000名患者受益。与其他心血管组织工程应用相关的使能技术将作为本研究的副产品产生。 公共卫生相关性：根据AHA的数据，仅在美国，每年就有超过95，000例瓣膜置换手术。虽然机械和生物人工心脏瓣膜自20世纪60年代引入以来已经产生了巨大的影响，但置换后的10年死亡率仍为30- 55%。儿科患者的需求特别大，因为这些瓣膜没有生长的能力。因此，人们对开发新一代组织工程心脏瓣膜有很大的兴趣，本研究旨在设计和测试完全生物活性的瓣膜置换术。

DESCRIPTION (provided by applicant): The goal of this research plan is to translate the progress made with prior NIH funding into a completely biological tissue-engineered pulmonary valve replacement, made of tissue grown in vitro from fibroblast remodeled fibrin. This will be accomplished using (1) advances in heart valve bioreactor design and operation to strengthen the root segment and the root-leaflet attachment line, and (2) a new decellularization and optional recellularization strategy using mesenchymal stem cells to obviate the leaflet contraction that occurred post-implantation due to the transplanted fibroblasts, which are used to grow the tissue valve in vitro. This tissue-engineered heart valve (TEHV), both decellularized (relying on host cell invasion) and recellularized (with mesenchymal stem cells pre-implantation) will be validated in a lamb model to demonstrate growth capacity and sustained function of the engineered valve. Success will ultimately benefit approximately 10,000 pediatric patients in the U.S. annually and ultimately 100,000 patients in the U.S. annually if this TEHV can subsequently be improved to withstand forces associated with the aortic valve position. Enabling technologies relevant to other cardiovascular tissue engineering applications will be generated as a by-product of this research. PUBLIC HEALTH RELEVANCE: In the United States alone, over 95,000 valve replacement surgeries are now performed annually according to the AHA. While mechanical and bioprosthetic heart valves have made a dramatic impact since their introduction in the 1960's, the 10-year mortality after replacement is still 30-55%. The need is particularly great for pediatric patients, since these valves do not have the capacity to grow. Thus, there is great interest in developing a new generation of tissue-engineered heart valves and this research is aimed at the design and testing of a completely biological living valve replacement.