Biomechanical Optimization of TE Heart Valves

TE 心脏瓣膜的生物力学优化

• 批准号: 7345448
• 负责人: Michael S Sacks
• 金额: $ 40.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345448
• 关键词: Address; Adhesives; Adolescent; Animals; Anisotropy; Architecture; Autologous; Behavior; Biodegradation; Biomechanics; Biomedical Engineering; Bioreactors; Blood Vessels; Carotid Arteries; Cell physiology; Cell-Matrix Junction; Cells; Cellular Structures; Characteristics; Childhood; Collagen Type I; Complex; Condition; Controlled Study; Coupled; Development; Elements; End Point; Engineering; Esters; Event; Exhibits; Extracellular Matrix; Factor XIII; Family; Family suidae; Feasibility Studies; Fiber; Freedom; Frequencies; Goals; Growth; Heart; Heart Valves; Implant; In Vitro; Individual; Knowledge; Legal patent; Lesion; Liquid substance; Lung; Mechanics; Mediating; Modeling; Modification; Nitric Oxide; Optics; Organ; Patients; Pattern; Penetration; Physiological; Pilot Projects; Property; Prosthesis; Protocols documentation; Pulmonary Circulation; Pulmonary valve structure; Pulsatile Flow; Range; Rate; Relative (related person); Relaxation; Research Personnel; Resistance to infection; Sales; Shapes; Sheep; Simulate; Solutions; Source; Stem cells; Stents; Stimulus; Stress; Stretching; Structure; System; Techniques; Thick; Time; Tissue Engineering; Tissues; Translating; Treatment Protocols; Urea; Urethane; Variant; Week; Work; clinical application; conditioning; cost; day; density; design; elastomeric; hemodynamics; implantation; in vivo; interstitial; novel; peripheral blood; polyurethaneurea; pressure; programs; protocol development; repaired; research study; scaffold; scale up; shear stress; soft tissue; tissue support frame

DESCRIPTION (provided by applicant): Recently, Kaushal et al. isolated endothelial progenitor cells (EPCs) from the peripheral blood of sheep and seeded them onto decellularized porcine iliac vessels. EPC-seeded grafts remained patent for 130 days as a carotid interposition graft in sheep (non-seeded grafts occluded within 15 days), and exhibited contractile activity and nitric-oxide-mediated vascular relaxation similar to native carotid arteries. Sales et al. have demonstrated that EPCs have the potential to provide both valvular interstitial and endothelial cellular functions, demonstrating the potential for EPCs to serve as a single autologous cell source for TEPV. In addition to the identification of clinically feasible cell sources, engineered soft tissues such as the TEPV require scaffolds with anisotropic mechanical properties that undergo large deformations (not possible with current PGA/PLLA non-wovens) coupled with controllable biodegradative and cell-adhesive characteristics. As a next step in fulfilling these design criteria, the Wagner lab has recently synthesized a family of poly (ester-urethane) ureas (PEUUs), including combination with type I collagen at various ratios to enhance cell attachment and increase biodegradation rates. Electrospun PEUU scaffolds have also been produced with biaxial mechanical properties that are remarkably similar to the native pulmonary valve, including the ability to undergo large physiologic strains and pronounced mechanical anisotropy. Moreover, a novel cell micro-integration technique has been developed that allows for successful integration of the cells directly into the scaffolds at the time of fabrication, eliminating cellular penetration problems. These encouraging results suggest that ES-PEUU scaffolds micro-integrated with EPCs can serve as successful TEPV scaffolds. We hypothesize that strategic combinations of individual mechanical factors relevant to heart valves-cyclic flexure, strain, and flow-can be determined that optimize ECM synthesis, organization, and mechanical properties of EPC seeded TEPV. Moreover, we hypothesize that the use of novel elastomeric scaffolds can add a critical degree-of-freedom for TEPV designs by allowing for large strains and highly controllable mechanical anisotropy. These hypotheses will be addressed by the following specific aims: Specific Aim 1 - Optimize ES-PEUU scaffold mechanical anisotropy, layer and pore structures, and cellular integration for EPC-seeded TEPV leaflet applications. Specific Aim 2 - Using optimized PEUU scaffolds of specific aim 1, conduct critical in-vitro "scale-up" studies in intact TEPV under simulated physiological conditions. Specific Aim 3 - Evaluate the EPC-seeded ES-PEUU scaffold's ability to perform in-vivo using a single leaflet model.

描述（由申请人提供）：最近，Kaushal 等人。从绵羊的外周血中分离出内皮祖细胞（EPC）并将其接种到脱细胞的猪髂血管上。 EPC 接种移植物作为绵羊颈动脉中间移植物保留了 130 天（非接种移植物在 15 天内闭塞），并且表现出与天然颈动脉相似的收缩活性和一氧化氮介导的血管松弛。销售等。已经证明 EPCs 有潜力提供瓣膜间质和内皮细胞功能，证明 EPCs 作为 TEPV 单一自体细胞来源的潜力。除了鉴定临床上可行的细胞来源之外，工程软组织（例如 TEPV）还需要具有各向异性机械性能的支架，这些支架可以承受大变形（目前的 PGA/PLLA 无纺布不可能实现），并具有可控的生物降解和细胞粘附特性。作为满足这些设计标准的下一步，瓦格纳实验室最近合成了一系列聚（酯-氨基甲酸酯）脲（PEUU），包括以不同比例与 I 型胶原蛋白组合，以增强细胞附着并提高生物降解率。静电纺丝 PEUU 支架还具有与天然肺动脉瓣非常相似的双轴机械性能，包括承受大的生理应变和明显的机械各向异性的能力。此外，还开发了一种新型细胞微整合技术，可以在制造时将细胞直接成功整合到支架中，从而消除细胞渗透问题。这些令人鼓舞的结果表明，与 EPC 微集成的 ES-PEUU 支架可以作为成功的 TEPV 支架。我们假设可以确定与心脏瓣膜相关的各个机械因素（循环弯曲、应变和流动）的策略组合，从而优化 ECM 合成、组织和 EPC 种子 TEPV 的机械性能。此外，我们假设使用新型弹性支架可以通过允许大应变和高度可控的机械各向异性来增加 TEPV 设计的关键自由度。这些假设将通过以下具体目标来解决：具体目标 1 - 优化 ES-PEUU 支架机械各向异性、层和孔结构以及 EPC 种子 TEPV 小叶应用的细胞整合。具体目标 2 - 使用具体目标 1 的优化 PEUU 支架，在模拟生理条件下在完整的 TEPV 中进行关键的体外“放大”研究。具体目标 3 - 使用单叶模型评估 EPC 种子 ES-PEUU 支架在体内执行的能力。