Xenogeneic Scaffolds for Heart Valve Tissue Engineering

用于心脏瓣膜组织工程的异种支架

• 批准号: 8704274
• 负责人: Leigh Gareth Griffiths
• 金额: $ 36.95万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704274
• 关键词: Accounting; Allogenic; American Heart Association; Antigens; Biocompatible Materials; Biomaterials Research; Cardiac Surgery procedures; Cattle; Cells; Cessation of life; Chronic; Clinical; Ensure; Excision; Exhibits; Experimental Designs; Extracellular Matrix; Failure; Future; Glutaral; Gold; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valves; Heavy Metals; Heterophile Antigens; Immune; Immune response; Immunocompetent; Implant; In Vitro; Investigation; Laboratories; Left; Life; Lipids; Literature; Longevity; Mechanics; Mediating; Mesenchymal Stem Cells; Methodology; Methods; Modeling; National Heart, Lung, and Blood Institute; Oryctolagus cuniculus; Outcome; Outcome Measure; Patients; Phase; Prevalence; Production; Property; Protein Chemistry; Proteins; Proteomics; Publishing; Recommendation; Reporting; Sodium Dodecyl Sulfate; Solubility; Solutions; Structure; Structure-Activity Relationship; Tissue Engineering; Tissues; United States; Water; Work; Xenograft procedure; biomaterial compatibility; calcification; clinically relevant; combinatorial; design; heart valve replacement; immunoregulation; implantation; improved; in vivo; innovation; lipid solubility; metal chelator; novel; pericardial sac; public health relevance; scaffold; sound; valve replacement; working group

DESCRIPTION (provided by applicant): American Heart Association estimates that valvular heart disease has a US prevalence of 2.5% and accounts for 20,000 deaths annually. Although replacement of the diseased valve with a xenogeneic glutaraldehyde- fixed valve (e.g., bovine pericardium (BP)) dramatically improves short term outcome, long term immune mediated attack results in calcification and ultimately valve failure (~10 yr lifespan). Deficiencies of curent valve replacements led the National Heart Lung and Blood Institute (NHLBI) cardiac surgery working group to recommend support for heart valve prosthesis biomaterial research. A tissue engineered heart valve utilizing un-fixed BP as a scaffold onto which patients' cells are grown (recellularization), has the potential to produce a potentially ideal heart valve. However, as noted by the NHLBI xenotransplantation working group, components which stimulate a recipient immune response (xenoantigens) represent the critical barrier to expanding clinical use of xenogeneic biomaterials. We propose a combinatorial approach (our novel antigen removal methodology combined with mesenchymal stem cell (MSC) mediated immunomodulation) for production of an immunologically-acceptable xenogeneic biomaterial for heart valve tissue engineering. Antigen removal aims to remove biomaterial xenoantigens, while leaving the extracellular matrix (ECM) intact and compatible with recellularization. We hypothesize that solubilization of xenoantigens is critical to facilitate their removal from the biomaterial. We therefore propose stepwise application of protein chemistry principles to solubilize and consequently removal BP xenoantigens. Aim 1: Remove water-soluble xenoantigens from intact BP while maintaining native ECM structure/function relationships and recellularization potential. Aim 1 will be conducted in two phases. Phase 1 will assess the effect of two novel factors on removal of water-soluble antigens from BP. Phase 2 will ensure that the resulting scaffold retains ECM properties compatible with heart valve tissue engineering. Aim 2: Remove lipid-soluble xenoantigens from intact BP in a stepwise manner after initial removal of water-soluble xenoantigens, while maintaining native ECM structure/function relationships and recellularization potential. Aim 2 will be conducted using the same 2 phased approach, with the exception that factors used in aim 2 are designed to remove lipid-soluble antigens. The resulting BP scaffold (with or without MSC recellularization) must be immunologically-acceptable following implantation in an immunocompetent recipient. We therefore propose: Aim 3: Assess the in vivo immune response to BP following stepwise antigen removal of water- and lipid-soluble xenoantigens. Assess effect of allogeneic MSC recellularization of BP following antigen removal (BP-AR) on in vivo immune response towards the biomaterial. Aim 3 utilizes an immunocompetent rabbit model for assessment of immune response to both BP-AR and MSC recellularized BP-AR. Completion of this proposal will result in a structurally integral, mechanically sound, immunologically- acceptable xenogeneic scaffold compatible with recellularization for heart valve tissue engineering.

描述（由申请人提供）：美国心脏协会估计瓣膜性心脏病在美国的患病率为 2.5%，每年导致 20,000 人死亡。虽然用异种戊二醛固定瓣膜（例如牛心包 (BP)）替换患病瓣膜可显着改善短期结果，但长期免疫介导的攻击会导致钙化并最终导致瓣膜衰竭（约 10 年寿命）。由于当前瓣膜置换术的缺陷，国家心肺和血液研究所 (NHLBI) 心脏外科工作组建议支持心脏瓣膜假体生物材料研究。利用未固定的血压作为支架的组织工程心脏瓣膜，患者细胞在其上生长（再细胞化），有可能产生理想的心脏瓣膜。然而，正如 NHLBI 异种移植工作组所指出的，刺激受体免疫反应的成分（异种抗原）是扩大异种生物材料临床应用的关键障碍。我们提出了一种组合方法（我们的新型抗原去除方法与间充质干细胞（MSC）介导的免疫调节相结合）来生产用于心脏瓣膜组织工程的免疫学可接受的异种生物材料。抗原去除的目的是去除生物材料的异种抗原，同时保持细胞外基质 (ECM) 完整并与再细胞化相容。我们假设异种抗原的溶解对于促进它们从生物材料中去除至关重要。因此，我们建议逐步应用蛋白质化学原理来溶解并随后去除 BP 异种抗原。目标 1：从完整的 BP 中去除水溶性异种抗原，同时保持天然 ECM 结构/功能关系和再细胞化潜力。目标1将分两个阶段进行。第一阶段将评估两种新因素对从 BP 中去除水溶性抗原的影响。第二阶段将确保所得支架保留与心脏瓣膜组织工程兼容的 ECM 特性。目标 2：在最初去除水溶性异种抗原后，逐步从完整 BP 中去除脂溶性异种抗原，同时保持天然 ECM 结构/功能关系和再细胞化潜力。目标 2 将使用相同的两阶段方法进行，但目标 2 中使用的因子旨在去除脂溶性抗原。所得的 BP 支架（有或没有 MSC 再细胞化）在植入免疫活性受体后必须是免疫学可接受的。因此，我们建议： 目标 3：逐步去除水溶性和脂溶性异种抗原后，评估对 BP 的体内免疫反应。评估抗原去除后 BP 的同种异体 MSC 再细胞化 (BP-AR) 对生物材料体内免疫反应的影响。目标 3 利用免疫活性兔模型来评估对 BP-AR 和 MSC 再细胞化 BP-AR 的免疫反应。该提案的完成将产生结构完整、机械健全、免疫学可接受的异种支架，与心脏瓣膜组织工程的再细胞化兼容。