Functional tissue engineering and regeneration of the aortic root

 描述（由申请人提供）：所有年龄段的患者都需要上级心脏瓣膜置换术。目前的瓣膜替代品提供了良好的生活质量，但耐久性有限，主要是因为这些是无生命的植入物。生理性瓣膜置换大多采用同种瓣，其血流动力学良好，但缺乏细胞。因此，理想的瓣膜替代物是一种体外再生的活结构，它可以密切模仿主动脉根部的独特生物学和血流动力学特征。主动脉根包括不同的解剖成分，细胞外基质分子和细胞，它们保持平衡的基质稳态;终身机械耐力的秘密。我们假设，在体外的功能性主动脉根再生是可能的，通过接种每个解剖组件的异种无细胞根与成人干细胞或预分化的成人干细胞，并暴露细胞接种的根控制机械线索，以诱导干细胞分化和成熟为靶细胞作为响应的“生态位”的生物学和生物力学。提出的目标系统的方法来测试这一假设，完成内部和外部接种的无细胞根细胞，然后逐步暴露于机械刺激适应和动态调节，达到主动脉瓣血流动力学条件。试点研究证明了每种技术的可行性，包括开发新的基于微阵列的接种方法，用于适应的3D旋转器和用于调节的先进阀门生物反应器。由每个关键领域的世界知名专家组成的多PI团队已经聚集在一起，以确保成功完成研究。预期这样的程序将导致机械上稳健的、功能齐全的、存活的主动脉瓣根部，其填充有能够基质重塑的代谢活性细胞。这将确保植入后即刻的血液动力学功能以及由于连续的细胞介导的基质修复而导致的长期机械和生物稳定性。这些在技术先进的集成再生平台的帮助下开发的替代瓣膜将准备在大型动物中进行临床前转化测试。

 DESCRIPTION (provided by applicant): There is a great clinical need for superior heart valve replacements for patients of all ages. Current valve substitutes provide excellent quality of life but have limited durability, mostly because these are non-living implants. The most physiologic valve replacements are considered the valve homografts, which have excellent hemodynamics, but lack cells. Therefore, the ideal valve substitute would be an in vitro regenerated, living construct which closely mimics the unique biological and hemodynamic features of the aortic root. The aortic root comprises distinct anatomical components, extracellular matrix molecules and cells, which maintain a balanced matrix homeostasis; the secret to life-long mechanical endurance. We hypothesized that functional aortic root regeneration in vitro is possible by seeding each anatomical component of xenogenic acellular roots with adult stem cells or pre-differentiated adult stem cells, and exposing cell-seeded roots to controlled mechanical cues to induce stem cell differentiation and maturation into target cells as a response to the "niche" biology and biomechanics. Proposed aims systematically approach testing this hypothesis by accomplishing internal and external seeding of acellular roots with cells, followed by progressive exposure to mechanical stimuli adaptation and dynamic conditioning, reaching aortic valve hemodynamic conditions. Pilot studies demonstrate feasibility of each proposed technique, including development of novel microarray-based seeding approaches, 3D rotators for adaptation and advanced valve bioreactors for conditioning. A multi-PI team of world renowned experts in each of the critical fields has been put together to ensure successful completion of the study. It is expected that such procedures will lead to mechanically robust, fully functional, viable aortic valve roots populated with metabolically active cells capable of matrix remodeling. This would ensure hemodynamic functionality immediately after implantation as well as long- term mechanical and biological stability due to continuous cell-mediated matrix repair. These replacement valves, developed with the aid of technologically advanced, integrated regeneration platforms would be ready for preclinical translational testing in large animals.