Poly-2-methyl-2-oxazoline-modified bioprosthetic heart valve leaflets have enhanced biocompatibility and resist structural degeneration.
Poly-2-methyl-2-oxazoline-modified bioprosthetic heart valve leaflets have enhanced biocompatibility and resist structural degeneration.
复制标题
DOI：
10.1073/pnas.2120694119
复制
发表时间：
2022-02-08
影响因子：
11.1
通讯作者：
Levy RJ
中科院分区：
文献类型：
--
作者：
Zakharchenko A;Xue Y;Keeney S;Rock CA;Alferiev IS;Stachelek SJ;Takano H;Thomas T;Nagaswami C;Krieger AM;Chorny M;Ferrari G;Levy RJ
心脏瓣膜疾病影响着数百万人，由于没有有效的药物治疗，手术修复（更常见的是，切除）是唯一可用的治疗方法。人工生物心脏瓣膜（BHV）是最常用的瓣膜置换术，由异种移植组织组成，通常固定在戊二醛中，并准备用于人体，作为外科植入器械或经导管输送。蛋白质糖化限制了BHV的耐久性，导致器械失效，通常仅在十年或更短的功能后需要再次手术。通过用聚-2-甲基-2-恶唑啉修饰BHV小叶，有效地减轻糖化和血清蛋白浸润并增强生物相容性来解决该问题。由戊二醛固定的异种移植组织（如牛心包（BP））制成的生物人工心脏瓣膜（BHV）广泛用于治疗心脏瓣膜疾病，这是一组影响数百万人的疾病。由于钙化和晚期糖基化终末产物（AGE）与相关血清蛋白的累积，BHV的结构性瓣膜变性（SVD）限制了耐久性。我们假设用聚-2-甲基-2-恶唑啉（POZ）修饰的BP抑制蛋白质进入，将显示AGE和血清蛋白的蓄积减少，从而减轻SVD。POZ修饰BP的体外研究表明，血清白蛋白和AGE的积累减少。尽管AGE孵育，BP-POZ在体外仍维持双光子显微镜下的胶原微结构，并且在细胞培养研究中，暴露于AGE和活化的巨噬细胞后，肿瘤坏死因子-α无变化。在体外比较POZ和聚乙二醇（PEG）修饰的BP，BP-POZ受氧化条件的影响最小，而BP-PEG易受氧化变质。在幼年大鼠皮下植入物中，BP-POZ表现出减少AGE形成和血清白蛋白浸润，而钙化不受抑制。然而，BP-POZ大鼠皮下植入物与乙醇预处理表现出抑制AGE的积累和钙化。用人血进行的离体层流研究表明，BP-POZ增强了抗血栓性，减少了白色血细胞积聚。我们的结论是，SVD与AGE和血清蛋白积累可以减轻通过POZ功能化，既增强生物相容性和促进乙醇预处理抑制BP钙化。
Heart valve disease affects millions, and since there is no effective medical therapy, surgical repair when possible—or more commonly, replacement—are the only treatments available. Bioprosthetic heart valves (BHV), the most frequently used valve replacements, are composed of heterograft tissue, typically fixed in glutaraldehyde, and prepared for human use either as surgically implantable devices or for transcatheter delivery. Protein-glycation limits the durability of BHV, contributing to device failure, often requiring reoperation after only a decade or less of functionality. This problem is addressed by modifying BHV leaflets with poly-2-methyl-2-oxazoline, effectively mitigating glycation and serum protein infiltration and enhancing biocompatibility. Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde-fixed heterograft tissue, such as bovine pericardium (BP), are widely used for treating heart valve disease, a group of disorders that affects millions. Structural valve degeneration (SVD) of BHV due to both calcification and the accumulation of advanced glycation end products (AGE) with associated serum proteins limits durability. We hypothesized that BP modified with poly-2-methyl-2-oxazoline (POZ) to inhibit protein entry would demonstrate reduced accumulation of AGE and serum proteins, mitigating SVD. In vitro studies of POZ-modified BP demonstrated reduced accumulation of serum albumin and AGE. BP-POZ in vitro maintained collagen microarchitecture per two-photon microscopy despite AGE incubation, and in cell culture studies was associated with no change in tumor necrosis factor-α after exposure to AGE and activated macrophages. Comparing POZ and polyethylene glycol (PEG)–modified BP in vitro, BP-POZ was minimally affected by oxidative conditions, whereas BP-PEG was susceptible to oxidative deterioration. In juvenile rat subdermal implants, BP-POZ demonstrated reduced AGE formation and serum albumin infiltration, while calcification was not inhibited. However, BP-POZ rat subdermal implants with ethanol pretreatment demonstrated inhibition of both AGE accumulation and calcification. Ex vivo laminar flow studies with human blood demonstrated BP-POZ enhanced thromboresistance with reduced white blood cell accumulation. We conclude that SVD associated with AGE and serum protein accumulation can be mitigated through POZ functionalization that both enhances biocompatibility and facilitates ethanol pretreatment inhibition of BP calcification.
登录
查看更多内容
影响因子：
3.3
作者：
Reid B;Gibson M;Singh A;Taube J;Furlong C;Murcia M;Elisseeff J
通讯作者：
Elisseeff J
影响因子：
2.9
作者：
REDDY, S;BICHLER, J;BAYNES, JW
通讯作者：
BAYNES, JW
影响因子：
5.4
作者：
Marro M;Kossar AP;Xue Y;Frasca A;Levy RJ;Ferrari G
通讯作者：
Ferrari G
影响因子：
1.6
作者：
Mariscalco, Giovanni;Mariani, Silvia;Beghi, Cesare
通讯作者：
Beghi, Cesare
影响因子：
4.6
作者：
Connolly, Jeanne M.;Bakay, Marina A.;Alferiev, Ivan S.;Gorman, Robert C.;Gorman, Joseph H., III;Kruth, Howard S.;Ashworth, Paul E.;Kutty, Jaishankar K.;Schoen, Frederick J.;Bianco, Richard W.;Levy, Robert J.
通讯作者：
Levy, Robert J.