GAGs: Function & Fixation in Bioprosthetic Heart Valves

GAG：功能

• 批准号: 6686074
• 负责人: Naren R Vyavahare
• 金额: $ 32.63万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686074
• 关键词: acids; bioengineering /biomedical engineering; biotechnology; calcification; calcium disorder; chemical stability; chemical structure function; collagen; crosslink; diamines; extracellular matrix; glutaraldehyde; laboratory rat; mucopolysaccharides; oxidation; physical property; prosthetic heart valve; technology /technique development; tissue /cell preparation; tissue engineering

DESCRIPTION (provided by applicant): Bioprosthetic heart valves (BHVs) derived from glutaraldehyde crosslinked porcine aortic valves are used in thousands of heart valve replacement surgeries. These devices often fail clinically due degeneration and pathologic calcification. In recent years others and we have shown that valvular glycosaminoglycans (GAGs) present in the middle spongiosa layer are lost during tissue fixation and after implantation. Maintaining the structural integrity of the extracellular matrix (ECM) in those processed tissues is the quintessence of a durable BHV. The overall aim of this project is to better understand the role of GAGs in the pathology of BHVs and to increase their retention and stabilization in the valvular ECM. The long-term goal of our research is to improve BHVs function by increasing the retention and stabilization of valvular GAGs so that these devices would function for extended time periods. We hypothesize that the loss of GAGs from the extracellular matrix of glutaraldehyde crosslinked BHVs causes a reduction in bending stiffness and collagen structural deterioration. We further hypothesize that proper GAG stabilization strategies would better preserve the heart valve structure and improve the mechanical properties of the valve, leading to less degeneration during its function. Moreover, based on the GAGs role in physiologic calcification and our preliminary studies, we hypothesize the preservation of these molecules will aid in the prevention of cuspal calcification. We will pursue following aims 1) We will monitor the status of valvular GAGs during tissue harvesting, preparation and glutaraldehyde (GA) fixation and after implantation in an animal model. We will also study the mechanisms by which tissue GAGs are lost from BHVs, focusing on GAG-degrading enzymes as potential candidates. 2) We will chemically manipulate the tissues during the critical stages of preparation to improve retention and stabilization of valvular PGs. We will optimize our novel periodate-based crosslinking procedure for maximum retention and stabilization of valvular GAGs by determining the most advantageous reaction parameters. The crosslinking efficacy of the periodate procedure will be enhanced by including agents such as diamines. 3) We will investigate the mechanical properties of tissues in which GAGs were stabilized with the optimized periodate procedure. Mechanical stability of BHV ECM including GAGs will be monitored by undertaking in vitro cyclic fatigue. Furthermore, we will evaluate the biostability of GAGs and resistance to calcification of BHVs of optimally stabilized valvular tissues by in vivo rat subdermal implantation model.

描述（由申请人提供）： 由戊二醛交联的猪主动脉瓣制成的人工生物心脏瓣膜（BHV）用于数千例心脏瓣膜置换手术。这些装置通常由于变性和病理性钙化而在临床上失效。近年来，其他人和我们已经表明，存在于中间海绵层中的瓣膜糖胺聚糖（GAG）在组织固定期间和植入后丢失。在这些处理过的组织中保持细胞外基质（ECM）的结构完整性是持久BHV的精髓。本项目的总体目标是更好地了解GAG在BHV病理学中的作用，并增加其在瓣膜ECM中的保留和稳定性。我们研究的长期目标是通过增加瓣膜GAG的保留和稳定性来改善BHV功能，以便这些器械能够长时间发挥作用。我们假设，戊二醛交联BHVs细胞外基质中糖胺聚糖的损失会导致抗弯刚度降低和胶原蛋白结构恶化。我们进一步假设，适当的GAG稳定策略将更好地保护心脏瓣膜结构并改善瓣膜的机械性能，从而减少其功能期间的退化。此外，基于GAG在生理性钙化中的作用和我们的初步研究，我们假设保留这些分子将有助于预防瓣尖钙化。我们将追求以下目标：1）我们将在组织采集、准备和戊二醛（GA）固定期间以及在动物模型中植入后监测瓣膜GAG的状态。我们还将研究组织GAG从BHV中丢失的机制，重点是GAG降解酶作为潜在的候选者。2)我们将在准备的关键阶段对组织进行化学处理，以改善瓣膜PG的保留和稳定性。我们将通过确定最有利的反应参数来优化基于高碘酸盐的新型交联程序，以最大限度地保留和稳定瓣膜GAG。高碘酸盐方法的交联功效将通过包括试剂如二胺来增强。3)我们将研究用优化的高碘酸盐程序稳定GAG的组织的机械性能。将通过进行体外循环疲劳来监测BHV ECM（包括GAG）的机械稳定性。此外，我们将通过体内大鼠皮下植入模型评估最佳稳定瓣膜组织的糖皮质激素的生物稳定性和BHVs对钙化的抵抗力。