GAGs: Function and Fixation in Bioprosthetic Heart Valves

GAG：生物人工心脏瓣膜的功能和固定

基本信息

批准号：
8099573
负责人：
Michael S Sacks
金额：
$ 44.27万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099573
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 Health Heart Valves Human In Vitro Intervention Life Life Expectancy Light Mediating Modeling 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 sample fixation success tissue processing

项目摘要

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体心脏瓣膜（BHV）每年用于数千例心脏瓣膜置换手术。这些装置经常因变性和病理性钙化而在临床上失败。在没有钙化的情况下，了解 BHV 的退行性衰竭很少得到解决。在之前的资助期间，我们发现瓣膜糖胺聚糖（GAG）在组织固定和植入后会丢失。存在于瓣膜组织中或体内植入后渗透的 GAG 降解酶是 GAG 退化的主要原因。 BHV 中 GAG 的丢失会导致组织弯曲刚度降低、滞后现象消失和胶原蛋白结构恶化。保持加工组织中细胞外基质 (ECM) 的结构完整性对于持久的 BHV 至关重要。我们发现单独的化学固定剂在防止 BHV 中 GAG 损失方面仅部分有效。我们最近的结果表明，在常规戊二醛 (GLUT) 交联之前添加新霉素（一种 GAG 降解酶抑制剂）与通过碳二亚胺交联进行的化学 GAG 固定相结合，可以显着提高瓣膜 GAG 的稳定性。该项目的总体目标是将 BHV 的耐用性延长至 20 年以上。我们建议研究高达 8 亿次循环（25 年阀门功能寿命）的 BHV 耐用性。如此长期的疲劳损伤研究在BHV领域是前所未有的。因此，我们将测试以下假设。1）具有改善的细胞外基质稳定性和乙醇预处理以防止钙化的BHV将在长期弯曲疲劳期间和体内植入后抵抗体外退化。我们新型的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相结合。 a) GAG 稳定性将在储存和高达 8 亿次循环（超过 25 年功能寿命）的循环疲劳期间进行体外测试，b) 在大鼠皮下植入模型中进行体内测试。 2）具有改善的细胞外基质稳定性和乙醇预处理以防止钙化的BHV将具有改善的生物力学功能和增强的长期耐久性。天然 GAG 在保持 GLUT 交联的猪主动脉瓣尖瓣生物力学性能方面的作用将在与瓣膜功能相关的两种主要变形模式中进行研究：存在或不存在 GAG 时的平面双轴拉伸和弯曲。 b) 将研究长达 8 亿次循环（25 年功能寿命）的体外循环疲劳期间的 Cuspal 生物力学功能。 3）具有改善的细胞外基质稳定性和乙醇预处理以防止钙化的BHV将具有改善的生物耐久性。在绵羊二尖瓣置换模型中，将使用 GAG 靶向化学/GLUT/乙醇的 BHV 变性和钙化与临床使用的乙醇预处理的 GLUT 固定 BHV 进行比较。公众健康相关性：大约 175,000 名患者因瓣膜受损或功能失调而需要进行心脏瓣膜置换术。源自化学固定猪心脏瓣膜的生物假体心脏瓣膜经常用于此目的。大多数这些瓣膜在 5-15 年后会因退化和钙化而失效，需要再次更换。该拨款提案正在研究新的化学固定剂，这些固定剂将延长这些瓣膜的功能寿命，从而使瓣膜能够比患者更长寿。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Immersogeometric cardiovascular fluid-structure interaction analysis with divergence-conforming B-splines.

DOI：
10.1016/j.cma.2016.07.028
发表时间：
2017-02-01
期刊：
Computer methods in applied mechanics and engineering
影响因子：
7.2
作者：
Kamensky D;Hsu MC;Yu Y;Evans JA;Sacks MS;Hughes TJ
通讯作者：
Hughes TJ

Neomycin binding preserves extracellular matrix in bioprosthetic heart valves during in vitro cyclic fatigue and storage.

DOI：
10.1016/j.actbio.2008.11.004
发表时间：
2009-05
期刊：
ACTA BIOMATERIALIA
影响因子：
9.7
作者：
Raghavan, Devanathan;Starcher, Barry C.;Vyavahare, Naren R.
通讯作者：
Vyavahare, Naren R.

Nanoparticle targeting to diseased vasculature for imaging and therapy.

DOI：
10.1016/j.nano.2014.02.002
发表时间：
2014-07
期刊：
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
影响因子：
5.4
作者：
Sinha, Aditi;Shaporev, Aleksey;Nosoudi, Nasim;Lei, Yang;Vertegel, Alexey;Lessner, Susan;Vyavahare, Naren
通讯作者：
Vyavahare, Naren

Neomycin fixation followed by ethanol pretreatment leads to reduced buckling and inhibition of calcification in bioprosthetic valves.