Functional tissue engineering and regeneration of the aortic root

功能性组织工程与主动脉根部再生

• 批准号: 9336501
• 负责人: Jeffrey Martin Gimble
• 金额: $ 40.4万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336501
• 关键词: Adult; Affect; Age; Allografting; Animals; Aorta; Area; Autologous Transplantation; Biochemical; Biological; Biology; Biomechanics; Bioreactors; Blood flow; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cell Maturation; Cells; Cellularity; Childhood; Chronic; Clinical; Cues; Detergents; Development; Devices; Disease; Endothelial Cells; Endothelium; Engineering; Ensure; Equilibrium; Exhibits; Exposure to; Extracellular Matrix; Family suidae; Fiber; Fibroblasts; Glutaral; Health; Heart; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valves; Homeostasis; Human; Implant; In Vitro; Injection of therapeutic agent; Label; Lead; Life; Lung; Mechanics; Mediating; Methods; Molecular; Myofibroblast; Natural regeneration; Operative Surgical Procedures; Outcome; Pathology; Patients; Perfusion; Phenotype; Physiological; Pilot Projects; Plant Roots; Polymers; Procedures; Process; Property; Quality of life; Regimen; Seeds; Shapes; Sinus; Skin; Smooth Muscle Myocytes; Stem cells; Stenosis; Stimulus; Stroke Volume; Structure; Surface; Surgical Flaps; System; Techniques; Testing; Time; Tissue Engineering; Tissues; Tunica Adventitia; Valsalva sinus; adult stem cell; animal tissue; aortic valve; aortic valve disorder; aortic valve replacement; base; conditioning; density; digital; drug testing; functional outcomes; heart valve replacement; hemodynamics; human adult stem cell; implantation; innovation; interstitial; interstitial cell; molecular marker; novel; patient population; pre-clinical; preconditioning; pressure; reconstitution; repaired; response; scaffold; shear stress; soft tissue; stem cell biology; stem cell differentiation; tissue regeneration; valve replacement; young adult

 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.

 描述（由申请人提供）：临床对适合所有年龄段患者的优质心脏瓣膜置换术有很大的需求。目前的瓣膜替代品可提供卓越的生活质量，但耐用性有限，主要是因为它们是无生命的植入物。最符合生理性的瓣膜置换被认为是同种瓣膜移植，其具有良好的血流动力学，但缺乏细胞。因此，理想的瓣膜替代品将是一种体外再生的活体结构，它密切模仿主动脉根部独特的生物学和血流动力学特征。主动脉根部包含不同的解剖成分、细胞外基质分子和细胞，维持平衡的基质稳态；终生机械耐力的秘密。我们假设，通过用成体干细胞或预分化的成体干细胞接种异种无细胞根的每个解剖成分，并将细胞接种的根暴露于受控机械信号，诱导干细胞分化和成熟为靶细胞，作为对“利基”生物学和生物力学的反应，体外功能性主动脉根再生是可能的。拟议的目标是通过用细胞完成无细胞根的内部和外部播种，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，系统地测试这一假设。试点研究证明了每种拟议技术的可行性，包括开发基于微阵列的新型播种方法、用于适应的 3D 旋转器和用于调节的先进阀门生物反应器。由各个关键领域的世界知名专家组成的多 PI 团队已组建在一起，以确保研究的成功完成。预计此类手术将产生机械坚固、功能齐全、可行的主动脉瓣根，其中填充有能够进行基质重塑的代谢活跃细胞。这将确保植入后立即具有血流动力学功能，以及由于连续的细胞介导的基质修复而产生的长期机械和生物稳定性。这些替换瓣膜是在技术先进的集成再生平台的帮助下开发的，可用于大型动物的临床前转化测试。

项目成果

A Standardized Dissection Protocol to Generate Aortic Valvular Scaffolds from Porcine Hearts.

从猪心脏生成主动脉瓣支架的标准化解剖方案。

• DOI: 10.1515/amma-2017-0029
• 发表时间: 2017
• 期刊: Acta medica marisiensis
• 作者: Movileanu,Lonela;Harpa,Marius;Branzaniuc,Klara;Suciu,Horatiu;Cotoi,OvidiuS;Olah,Peter;Simionescu,Dan
• 通讯作者: Simionescu,Dan