Pathophysiology and prevention of degeneration of heterograft biomaterials due to advanced glycation end products and serum protein infiltration

由于晚期糖基化终产物和血清蛋白浸润导致异种移植生物材料变性的病理生理学和预防

• 批准号: 10679910
• 负责人: Tina Thomas
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679910
• 关键词: Adhesions; Advanced Glycosylation End Products; Affect; Animals; Biocompatible Materials; Biological Models; Bioprosthesis device; Blood; Calcium; Cattle; Cell Adhesion; Cell Culture Techniques; Cell Survival; Cell-Matrix Junction; Cells; Clinical; Collagen; Endothelial Cells; Endothelium; Ethanol; Exclusion; Exposure to; FDA approved; Feasibility Studies; Fellowship; Functional disorder; Generations; Glutaral; Harvest; Heart Valve Diseases; Heart Valves; Human; Immunohistochemistry; Impairment; Implant; In Vitro; Incubated; Individual; Infiltration; Inflammatory; Intervention; Knowledge; Mediating; Methodology; Microscopy; Modeling; Modification; Oral Administration; Pathology; Patients; Persons; Prevention; Proteins; Publications; Publishing; Pyridoxamine; Rattus; Repeat Surgery; Research; Research Design; Research Training; Serum; Serum Albumin; Serum Proteins; Stains; Surface; Time; Vascular Cell Adhesion Molecule-1; Vitamin B6; Work; Xenograft procedure; biomaterial compatibility; calcification; cell growth; efficacy study; in vivo; inhibitor; innovation; insight; intercellular cell adhesion molecule; novel strategies; pericardial sac; pre-doctoral; receptor expression; receptor for advanced glycation endproducts; second harmonic; simulation; subcutaneous; surface coating; uptake

Bioprosthetic heart valves (BHV), fabricated from heterograft biomaterials such as glutaraldehyde-fixed bovine pericardium (BP), are widely used as a replacement for patients who have severe heart valve disease (HVD), which affects millions of people worldwide. Despite being effective, a limitation of BHV fabricated from BP is that they undergo structural valve degeneration (SVD) which limits durability. Although most commonly attributed to calcification, recent research has shown that advanced glycation end products (AGE) and serum protein infiltration also contributes to SVD. AGE mechanisms impair endothelial cell growth and may mechanistically contribute to lack of endothelialization of BHV experimentally and clinically. Many studies to inhibit calcification of BP have been done; however, strategies to mitigate AGE-serum protein accumulation have just begun to be explored. Through our studies we have recently identified, the AGE-inhibitor pyridoxamine (PYR), a vitamin B6 vitamer, to be a leading model compound that is effective in significantly reducing AGE accumulation and serum protein uptake of BP both in vitro and in vivo in rat subdermal implant studies. Furthermore, we have also established an innovative modification of BP with Poly-2-methyl-2- oxazoline (POZ), which significantly reduced serum protein uptake both in vitro and in rat subdermal explants. The central hypothesis of both my dissertation and this proposal is: Pretreatment of BP with PYR and POZ can mitigate AGE and serum protein pathophysiology that contributes to noncalcific SVD mechanisms. Ethanol (EtOH) pretreatment of BP, an FDA approved anti-calcification methodology, will be a mechanistically based experimental intervention in my study design, that will help explore the interactions between calcific and non- calcific SVD mechanisms. Aim 1: Investigate in vitro the mechanism and efficacy of inhibition of AGE and serum protein infiltration to enhance heterograft biocompatibility by studying endothelial cell-BP interactions. Subaim 1a: Evaluate the effects of PYR pretreatment of BP to mitigate AGE and serum protein mechanisms: blood outgrowth endothelial cell (BOEC) culture studies with high shear flow simulation. Subaim 1b: To determine the effect of POZ mediated serum protein exclusion on promotion of BOEC adhesion and reduction of endothelial activation. Aim 2: To investigate the mechanism and efficacy of inhibition of AGE and serum protein SVD pathology, and interactions with calcification using rat subdermal BP implants: PYR and POZ studies. Subaim 2a: To study the efficacy of PYR pretreated BP, with or without ethanol pretreatment, on mitigating AGE-serum protein pathophysiology and calcification using a rat subdermal implant model. Subaim 2b: To study the efficacy of POZ alone, and the combined BP pretreatment with PYR, POZ, and ethanol for mitigating AGE, serum protein uptake and calcification in the rat subdermal implant model. The findings from this proposal will advance my research training and contribute to advances in our knowledge of SVD of BHV.

生物修复心脏瓣膜（BHV），由异源移植生物材料制成，如戊二醛固定牛