Mechanisms of Prosthetic Arterial Bypass Graft Failure

人工动脉搭桥术失败的机制

基本信息

批准号：
9235691
负责人：
CHRISTIANE FERRAN
金额：
$ 76.81万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-07-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9235691
关键词：
Achievement Alginates Anastomosis - action Animal Model Anti-Inflammatory Agents Anti-inflammatory Arteries Atherosclerosis Biocompatible Materials Biological Biology Blood Blood Vessels Blood flow Bypass Canis familiaris Cardiovascular Diseases Carotid Arteries Cell Culture Techniques Cell-Matrix Junction Cells Clinical Coagulation Process Collaborations Custom Dependovirus Development Distal Drug Delivery Systems Effectiveness Endothelial Cells Environment External Capsule Future Gel Gene Delivery Gene Expression Gene Silencing Gene Targeting Genes Goals Heparin Hernia Homeostasis Hyaluronic Acid Hyperplasia Implant In Vitro Injury Intervention Invaded Kinetics Knowledge Lesion Longevity MARCKS gene Mediating Microarray Analysis Modeling Molecular Molecular Profiling Muscle Cells Nanotechnology Operating Rooms Operative Surgical Procedures Oryctolagus cuniculus Pathogenesis Pathogenicity Pathologic Pharmaceutical Preparations Phenotype Platelet aggregation Polyethylene Terephthalates Polymers Positioning Attribute Property Prosthesis RGD (sequence)RNA Interference Recombinants Research Role Series Site Smooth Muscle Myocytes Surface System TNF gene Technology Testing Therapeutic Therapeutic Agents Thrombosis Time Tissues Transplanted tissue Ursidae Family Vascular Graft Vascular Smooth Muscle Vascular remodeling Vertebral column Viral Vector Vision Work Wound Healing atheroprotective base biomaterial development clinical translation cohesion controlled release cryogel dacron design drug efficacy ex vivo perfusion gene therapy genetic signature graft failure heart circulation implantation improved improved outcome in vivo in vivo Model innovation knock-down laser capture microdissection macrophage monocyte multidisciplinary overexpression prevent protein expression reconstruction repaired response therapeutic target therapy development thrombospondin 2 tissue repair translational approach uptake wound

项目摘要

This is a proposal to create a biologically active prosthetic arterial graft (PG) incorporating gene silencing and gene overexpression in an antithrombotic and pro-angiogenic surface. The research team is unique in its cohesiveness and breadth of expertise including nanotechnology, polymers, gene therapy, vascular biology, and surgery, all with an established focus on vascular grafts. This project builds on our long-standing work where we have 1) characterized the lesion of anastomotic neointimal hyperplasia (AIH) downstream of the prosthetic graft, 2) established the role of blood flow-surface interaction in AIH pathogenesis, 3) determined the unique gene signature associated with AIH development, including identification of high profile pathogenic and protective targets, 4) documented delivery of siRNA from a prosthetic surface to knockdown pathogenic genes in vascular smooth muscle cells, 5 ) documented adeno associated virus (AAV) mediated delivery of atheroprotective genes to the vascular wall and through the prosthetic surface to endothelial cells and, 6) demonstrated the advantages of a cryogel coating as a delivery system for antithrombotic and pro-angiogenic molecules and gene therapy. Based on this knowledge and achievements, we propose an optimized approach to create a highly functional and adaptable flow surface. We will build a composite PG comprising three components: A) A `backbone' graft composed of standard polyethyleneterephthalate (PET), B) An anti-thrombotic (heparin) gel with improved cell attachment properties (RGD) to be applied to the graft prior to cryogelation, and C) Biologic therapeutic agents to be incorporated in the cryogel-PG prior to surgery, which would create a high capacity multifunctional bioactive flow surface. Using gene therapy technologies, biologics with anti-inflammatory and atheroprotective properties that have been fully validated by our group will be incorporated to synthesize the composite PG. Our goal is to optimize the composite PG for delivery of drugs and biologics from the flow surface into the PG microenvironment. This would target the circulating cells invading the pseudo intima, decreasing contact activation and platelet aggregation. Additionally, this will modulate endothelial and smooth muscle cells of the native artery at the anastomosis site as to prevent their phenotypic switch that fuels AIH. In a rabbit model we will implant the composite PG with the bioactive gel applied intraluminally and/or extraluminally. We will then gauge efficacy of drug delivery, and determine its effect on PG molecular signature and AIH. This is a stepwise study bringing to bear the necessary and broad range of expertise on the effective application of a multifunctional bioactive prosthetic arterial graft to improve outcome. This work will also serve as proof of concept to instill bioactivity and adapt biomaterials for therapeutic purposes such as endografts, hernia repair, and wound coverage.

这是一项创建具有生物活性的人工动脉移植物（PG）的提案，该移植物结合了基因沉默和基因在抗血栓和促血管生成表面过度表达。该研究团队的独特之处在于专业知识的凝聚力和广度，包括纳米技术、聚合物、基因治疗、血管生物学、和手术，所有这些都以血管移植为重点。该项目建立在我们长期工作的基础上，其中我们 1) 描述了吻合口病变的特征假体移植物下游的新内膜增生（AIH），2）建立了血流表面的作用 AIH 发病机制中的相互作用，3) 确定了与 AIH 发展相关的独特基因特征，包括识别高调致病性和保护性靶点，4) 记录的 siRNA 递送敲除血管平滑肌细胞中致病基因的假体表面，5）记录的腺相关病毒（AAV）介导将动脉粥样硬化保护基因传递至血管壁并通过内皮细胞的假体表面，6) 证明了冷冻凝胶涂层作为递送的优势抗血栓和促血管生成分子和基因治疗系统。基于这些知识和成就，我们提出了一种优化方法来创建功能强大的和适应性的流动表面。我们将构建一个由三个组件组成的复合 PG： A) “主干”移植物由标准聚对苯二甲酸乙二醇酯 (PET) 组成，B) 具有改良细胞功能的抗血栓（肝素）凝胶在冷冻凝胶化之前应用于移植物的附着特性 (RGD)，以及 C) 生物治疗剂在手术前将其纳入冷冻凝胶-PG中，这将创造出高容量的多功能生物活性流动表面。使用基因治疗技术，具有抗炎和动脉粥样硬化作用的生物制剂我们小组已经充分验证的特性将被纳入合成复合 PG 中。我们的目标是优化复合 PG，以便将药物和生物制剂从流动表面输送到 PG 中微环境。这将针对侵入假内膜的循环细胞，减少接触活化和血小板聚集。此外，这将调节内皮细胞和平滑肌细胞吻合口处的天然动脉，以防止其表型转换而导致 AIH。在兔子模型中，我们将植入具有管腔内和/或管外施加的生物活性凝胶的复合PG。我们随后将衡量药物递送的功效，并确定其对 PG 分子特征和 AIH 的影响。这是一项逐步的研究，为有效的研究提供了必要和广泛的专业知识。应用多功能生物活性人工动脉移植物来改善预后。这项工作也将服务于作为灌输生物活性和调整生物材料用于治疗目的（例如内移植物）的概念证明，疝气修复和伤口覆盖。