Mechanisms of the in vivo inhibition of calcification of bioprosthetic porcine aortic valve cusps and aortic wall with triglycidylamine/mercapto bisphosphonate
Mechanisms of the in vivo inhibition of calcification of bioprosthetic porcine aortic valve cusps and aortic wall with triglycidylamine/mercapto bisphosphonate
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DOI：
10.1016/j.biomaterials.2006.09.029
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发表时间：
2007-02-01
期刊：
影响因子：
14
通讯作者：
Levy, Robert J.
中科院分区：
文献类型：
--
作者：
Rapoport, H. Scott;Connolly, Jeanne M.;Levy, Robert J.
由戊二醛（Glut）交联异种移植材料、猪主动脉瓣或牛心包制成的心脏瓣膜置换物已广泛用于心脏手术治疗心脏瓣膜疾病。然而，由于生物瓣叶的病理性钙化，这些生物心脏瓣膜在长期临床植入中经常失败，并且对于无支架猪主动脉瓣生物瓣膜，通常也会发生生物主动脉壁钙化。之前在心脏生物瓣膜材料上使用的环氧基交联剂三缩水甘油胺（TGA）证明了猪主动脉瓣尖（但不是猪主动脉壁）和牛心包上级生物相容性、力学和抗钙化性优于Glu制备的对照品。然而，TGA制备并不能完全防止瓣尖或心包的长期钙化。在本文中，我们报告了对该系统添加的治疗组分2-巯基亚乙基-1，1-双膦酸（MABP）的进一步机制研究，2-巯基亚乙基-1，1-双膦酸是一种定制合成的硫醇双膦酸盐，先前已在初步报告中显示，当与初始TGA交联结合使用7天时，其可防止生物假体异种移植物生物材料钙化。在本研究中，我们进一步研究了MABP在实验中的有效性，这些实验检查：（1）在最佳TGA交联之后使用MABP，以避免交联期间MABP反应与TGA的任何竞争干扰;（2）此外，认识到碱性磷酸酶（ALP）在营养不良性钙化结节形成中的重要性，我们已经研究了MABP主要起作用的机制是通过降低ALP活性的假设。来自无细胞模型系统、细胞培养研究和大鼠皮下植入物的结果表明，TGA交联后用MABP官能化的材料具有降低的ALP活性，并且在体内长期植入物研究中没有显著的钙化。可以得出结论，以这种方式制备的生物心脏瓣膜是Glut制备的生物瓣膜的引人注目的替代品。(c)2006爱思唯尔有限公司保留所有权利。
Heart valve replacements fabricated from glutaraldehyde (Glut)-crosslinked heterograft materials, porcine aortic valves or bovine pericardium, have been widely used in cardiac surgery to treat heart valve disease. However, these bioprosthetic heart valves often fail in long-term clinical implants due to pathologic calcification of the bioprosthetic leaflets, and for stentless porcine aortic valve bioprostheses, bioprosthetic aortic wall calcification also typically occurs. Previous use of the epoxide-based crosslinker, triglycidyl amine (TGA), on cardiac bioprosthetic valve materials demonstrated superior biocompatibility, mechanics, and calcification resistance for porcine aortic valve cusps (but not porcine aortic wall) and bovine pericardium, vs. Glut-prepared controls. However, TGA preparation did not completely prevent long-term calcification of cusps or pericardium. Herein we report further mechanistic investigations of an added therapeutic component to this system, 2-mercaptoethylidene-1,1-bisphosphonic acid (MABP), a custom synthesized thiol bisphosphonate, which has previously been shown in a preliminary report to prevent bioprosthetic heterograft biomaterial calcification when used in combination with initial TGA crosslinking for 7 days. In the present studies, we have further investigated the effectiveness of MABP in experiments that examined: (1) The use of MABP after optimal TGA crosslinking, in order to avoid any competitive interference of MABP-reactions with TGA during crosslinking; (2) Furthermore, recognizing the importance of alkaline phosphatase (ALP) in the formation of dystrophic calcific nodules, we have investigated the hypothesis that the mechanism by which MABP primarily functions is through the reduction of ALP activity. Results from cell-free model systems, cell culture studies, and rat subcutaneous implants, show that materials functionalized with MABP after TGA crosslinking have reduced ALP activity, and in vivo have no significant calcification in long-term implant studies. It is concluded that bioprosthetic heart valves prepared in this fashion are compelling alternatives for Glut-prepared bioprostheses. (c) 2006 Elsevier Ltd. All rights reserved.