GAGs: Function and Fixation in Bioprosthetic Heart Valves

GAG：生物人工心脏瓣膜的功能和固定

• 批准号: 7683027
• 负责人: Michael S Sacks
• 金额: $ 36.71万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683027
• 关键词: Address; Alcohol consumption; Animals; Applications Grants; Biological; Biomechanics; Bioprosthesis device; Calcinosis; Carbodiimides; Cardiac Surgery procedures; Cattle; Chemicals; Chemistry; Clinical; Collagen; Coronary; Coupled; Crosslinker; Deterioration; Devices; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Ethanol; Exhibits; Extracellular Matrix; Failure; Family suidae; Fatigue; Fixatives; Generations; Glutaral; Glycosaminoglycans; Grant; Heart Valves; Human; In Vitro; Intervention; Life; Life Expectancy; Light; Living Wills; Mediating; Modeling; Muscle Rigidity; Neomycin; Operative Surgical Procedures; Patients; Performance; Play; Predisposition; Procedures; Property; Rattus; Role; Sheep; Technology; Testing; Time; Tissue Fixation; Tissues; aortic valve; base; calcification; crosslink; heart valve replacement; implantable device; implantation; improved; in vitro testing; in vivo; inhibitor/antagonist; innovation; meetings; mitral valve replacement; novel; pericardial sac; prevent; public health relevance; sample fixation; success; tissue processing

DESCRIPTION (provided by applicant): Bioprosthetic heart valves (BHVs) derived from glutaraldehyde-crosslinked porcine aortic valves are used annually in thousands of heart valve replacement surgeries. These devices often fail clinically due degeneration and pathologic calcification. Understanding degenerative failure of BHVs in the absence of calcification is rarely addressed. In the previous grant period, we showed that valvular glycosaminoglycans (GAGs) are lost during tissue fixation and after implantation. GAG-degrading enzymes either present in the valve tissue or infiltrated after in vivo implantation are a major cause of GAG degeneration. Loss of GAGs from BHVs leads to decreased tissue flexural rigidity, loss of hysteresis, and collagen structural deterioration. Maintaining the structural integrity of the extracellular matrix (ECM) in the processed tissues is essential for a durable BHV. We found that chemical fixatives alone are only partially effective in preventing GAG loss from BHVs. Our recent results show that addition of neomycin, an inhibitor of GAG-degrading enzymes, in combination with chemical GAG fixation by carbodiimide crosslinking prior to routine glutaraldehyde (GLUT) crosslinking leads to significantly better stabilization of valvular GAGs. The overall aim of this project is extend the durability of BHVs well beyond 20 years. We are proposing to study BHV durability for up to 800 million cycles (25 years of valve functional life). Such long-term fatigue damage study is unprecedented in the BHV field. Thus, we will test the following hypotheses.1) BHVs with improved extracellular matrix stabilization and ethanol pretreatment to prevent calcification will resist degeneration in vitro during extended flexural fatigue and after in vivo implantation. Our novel neomycin-based crosslinking procedure will be combined with clinically used ethanol anti-calcification pretreatment. a) GAG stability will be tested in vitro during storage and cyclic fatigue up to 800 million cycles (more than 25 years of functional life) and b) in vivo in a rat subdermal-implantation model. 2) BHVs with improved extracellular matrix stabilization and ethanol pretreatment for preventing calcification will have improved biomechanical function and enhanced long-term durability. The role of native GAGs in preserving the biomechanical performance of GLUT-crosslinked porcine aortic valve cusps will be studied in two major deformation modes associated with valve function: planar biaxial tension and flexure in presence or absence of GAGs. b) Cuspal biomechanical function during in vitro cyclic fatigue up to 800 million cycles (25 years of functional life) will be studied. 3) BHVs with improved extracellular matrix stabilization and ethanol pretreatment for preventing calcification will be endowed with improved biological durability. Degeneration and calcification of BHVs with GAG-targeted chemistry/GLUT/Ethanol will be compared with clinically used ethanol pretreated GLUT-fixed BHVs in a sheep mitral valve-replacement model. PUBLIC HEALTH RELEVANCE: About 175,000 patients need heart valve replacements due to damaged or dysfunctional valves. Bioprosthetic heart valves derived from chemically fixed pig heart valves are used frequently for this purpose. The majority of these valves fail after 5-15 years due to degeneration and calcification and need replacements again. This grant proposal is investigating new chemical fixatives that would improve functional life-time of these valves so that the valve could outlast the patient.

描述（由申请人提供）：源自戊二醛 - 交联猪主动脉瓣的生物假发心瓣（BHV）每年在数千个心脏瓣膜替代手术中使用。这些设备通常在临床上发生应有的变性和病理钙化失败。在没有钙化的情况下了解BHV的退化失败很少得到解决。在上一个赠款期间，我们表明瓣膜糖胺聚糖（GAG）在组织固定期间和植入后丢失。瓣膜组织中存在的插科打酶或体内植入后浸润的酶是导致GAG变性的主要原因。 BHV的插科打s的损失导致组织弯曲刚度降低，滞后丧失和胶原蛋白结构恶化。在处理后的组织中维持细胞外基质（ECM）的结构完整性对于耐用的BHV至关重要。我们发现，单独的化学固定剂仅在防止BHV的堵塞损失方面有效。我们最近的结果表明，新霉素是一种GAG降解酶的抑制剂，再加上碳二酰亚胺在常规的戊二醛（GLUT）交联之前通过碳二二酰亚胺交联的固定，从而导致瓣膜堵嘴的稳定性更好地稳定。该项目的总体目的是扩大了BHV的耐用性，远远超过20年。我们建议研究BHV耐久性多达8亿个周期（25年的阀门功能寿命）。在BHV领域，这种长期疲劳损伤研究是前所未有的。因此，我们将测试以下假设。1）BHV具有改善的细胞外基质稳定和乙醇预处理以防止钙化的BHV，将在扩展弯曲疲劳期间和体内植入后在体外抵抗退化。我们的新型基于新霉素的交联程序将与临床使用的乙醇抗钙化预处理结合使用。 a）在存储期间，将在体外测试插科打的稳定性，并且在大鼠亚dermal植入模型中的循环疲劳最多可循环疲劳（超过25年的功能寿命）和b）体内。 2）具有改善细胞外基质稳定和预防钙化乙醇预处理的BHV将提高生物力学功能并增强长期耐用性。将以与瓣膜功能相关的两种主要变形模式研究：在存在或不存在GAG的情况下，将研究与GLUT交联猪主动脉瓣膜的生物力学性能：在存在的两种主要变形模式下，研究了天然GAG的作用。 b）将研究在体外循环疲劳期间的尖尖生物力学功能，最高为8亿个周期（功能寿命25年）。 3）具有改善细胞外基质稳定和预防钙化乙醇预处理的BHV将具有改善的生物耐用性。在绵羊二尖瓣替代模型中，将用靶向性化学/乙醇的BHV的退化和钙化将与临床使用的乙醇预处理的乙醇固定BHV进行比较。公共卫生相关性：大约有175,000名患者需要因损坏或功能失调而导致心脏瓣膜更换。源自化学固定的猪心脏瓣膜的生物假发瓣膜经常用于此目的。由于变性和钙化，这些阀中的大多数在5 - 15年后失败，并且需要再次替换。该赠款提案正在调查新的化学固定剂，以改善这些瓣膜的功能寿命，以使阀门可以超过患者。