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的内皮祖细胞（EPC），并将其播种到脱细胞化的猪乳囊上。 EPC种子的移植物在绵羊（15天内被闭塞的非种子移植物）中保留130天，并表现出收缩活性和一氧化氧化物介导的血管松弛，与本地颈动脉相似。销售等。已经证明EPC具有提供瓣膜间质和内皮细胞功能的潜力，这表明EPC作为TEPV的单个自体细胞源具有潜力。除了鉴定临床上可行的细胞源外，工程软组织（例如TEPV）还需要具有各向异性机械性能的脚手架，这些特性经历了大变形（无法使用当前的PGA/PLLA非织造），并与可控制的生物降解和细胞粘附特性相连。作为符合这些设计标准的下一步，瓦格纳实验室最近合成了一个聚（酯 - 尿素）尿素（PEUUS）家族，包括以各种比例与I型胶原蛋白的组合，以增强细胞附着并提高生物降解速率。电纺PEUU支架也具有双轴机械性能，这些特性与天然肺动脉瓣非常相似，包括经历大型生理菌株和明显的机械各向异性的能力。此外，已经开发了一种新型的细胞微积分技术，该技术允许在制造时成功地将细胞直接整合到脚手架中，从而消除了细胞渗透问题。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。我们假设确定与心脏瓣膜弯曲，应变和流动式相关的单个机械因素的战略组合，以优化ECM综合，组织和机械性能的EPC种子TEPV。此外，我们假设使用新型弹性脚手架可以通过允许大型菌株和高度可控制的机械各向异性来为TEPV设计增加关键的自由度。这些假设将通过以下特定目的来解决：特定目的1-优化ES-PEUU机械各向异性，层和孔结构以及EPC种子TEPV传单应用的细胞整合。特定目标2-使用特定目标1的优化PEUU支架，在模拟生理条件下对完整TEPV进行关键的体外“扩展”研究。特定目标3-评估EPC种子的ES-PEUU支架使用单个传单模型执行体内的能力。