Cell Instructive Materials For Engineering Vascular Grafts

用于工程血管移植物的细胞指导材料

• 批准号: 8439601
• 负责人: Robert E Akins
• 金额: $ 35.02万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-17 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439601
• 关键词: Anatomy; Angioplasty; Animal Model; Arteries; Attenuated; Autologous; Biocompatible Materials; Biological; Blood Circulation; Blood Vessels; Bypass; Cadherins; Cardiovascular Surgical Procedures; Cardiovascular system; Catheters; Cause of Death; Cell Proliferation; Cell physiology; Cells; Characteristics; Clinical; Congenital Abnormality; Coronary; Coronary Artery Bypass; Coronary heart disease; Data; Dialysis procedure; Drug Formulations; Encapsulated; Engineering; FGF2 gene; Failure; Fibroblast Growth Factor; Fibroblasts; Fibrosis; Gel; Gene Expression; Goals; Growth; Growth Factor; Harvest; Healed; Heparin; Hydrogels; Hyperplasia; Implant; In Situ; Injectable; Injury; Intervention; Mechanics; Medial; Mediator of activation protein; Metabolic; Molecular Profiling; Morbidity - disease rate; Myofibroblast; Operative Surgical Procedures; Outcome; Pathogenesis; Pericytes; Peripheral; Peripheral arterial disease; Phenotype; Procedures; Property; Psyche structure; Risk; Series; Signal Transduction; Signaling Molecule; Stenosis; Stress; Structure; Surface; TGFBR1 gene; Tars; Time; Tissues; Transplantation; Vascular Diseases; Vascular Graft; Vascularization; Veins; Venous; Work; base; cell behavior; cell growth; healing; hemodynamics; improved; in vivo; malformation; meetings; molecular phenotype; mortality; notch protein; public health relevance; repaired; research study; response; rho; scaffold; vasa vasorum

DESCRIPTION (provided by applicant): Coronary and peripheral arterial diseases are leading causes of morbidity and mortality in the US and worldwide. Principal treatments include bypass graft surgery and catheter-based procedures to open blockages (angioplasty). Angioplasty and cardiovascular surgery are also widely employed to maintain venous access for dialysis and to repair congenital cardiovascular malformations. In all cases, stenosis, fibrosis, and vessel failur are significant post-procedure problems with nearly 50% of autologous vein grafts used in peripheral or coronary artery bypass surgery failing over time due to maladaptive vessel remodeling. Vessel failures are driven to a large extent by cellular responses elicited by tissue injury during manipulation and by altered hemodynamic stresses after the re-establishment of circulation. Of principal concern, maladaptive cascades initiated by adventitial fibroblasts (AFs) residing in the exterior portion of at-risk vessels are now widely recognized as major contributors to pathogenesis in grafted and manipulated vessels. Instructive biomaterials that attenuate maladaptive cellular responses of AFs, encourage adaptation to altered hemodynamic conditions, and provide cellular material for populating a healthy neo-adventitium and vaso vasorum would have significant clinical impact resulting in decreased procedure failure rates and a potential increase in the ability to use pre-treated autologous vessels for transplantation. We thus seek to develop injectable, PEG-based polymeric biomaterials that can be placed along the exterior of at-risk vessels either prior to or just after manipulation, as a facile clinial intervention to beneficially influence AF responses and vessel remodeling. Based on extensive preliminary data indicating our ability to guide AF phenotypes with materials strategies, our three aims are to (i) determine in detail the effects of hydrogel mechanical properties on adventitial cell phenotype, (ii) evaluate the effects of critical cell signaling molecules co-delivered to cells by hydrogels, and (iii) assess the effects of hydrogels placed on target vessels in an animal model. Improving our understanding of the central mechanisms that drive adventitial cell phenotype will afford instructive materials that can reduce stenosis, attenuate fibrosis, and encourage formation of healthy vasa vasorum to improve outcomes after vascular procedures.

描述（由申请人提供）：冠状动脉和外周动脉疾病是美国和全球发病率和死亡率的主要原因。主要的治疗方法包括旁路移植手术和基于导管的手术来打开堵塞（血管成形术）。血管成形术和心血管手术也被广泛用于维持透析的静脉通路和修复先天性心血管畸形。在所有情况下，狭窄、纤维化和血管衰竭都是严重的术后问题，近50%的外周或冠状动脉旁路手术中使用的自体静脉移植物由于适应不良的血管重塑而随着时间的推移而失败。血管衰竭在很大程度上是由操作过程中组织损伤引起的细胞反应和重建循环后改变的血流动力学应力引起的。主要关注的是，由存在于风险血管外部的外膜成纤维细胞（AF）引发的适应不良级联反应现在被广泛认为是移植和操作血管中发病机制的主要贡献者。减弱AF的适应不良细胞反应、促进适应改变的血液动力学条件并提供细胞材料用于填充健康的新生外膜和血管的指导性生物材料将具有显著的临床影响，从而降低手术失败率并潜在增加使用预处理自体血管进行移植的能力。因此，我们寻求开发可注射的基于PEG的聚合物生物材料，其可以在操作之前或之后沿着有风险的血管的外部放置，作为一种方便的临床干预，以有益地影响AF反应和血管重塑。基于大量的初步数据，表明我们有能力通过材料策略指导AF表型，我们的三个目标是（i）详细确定水凝胶机械性能对外膜细胞表型的影响，（ii）评估通过水凝胶共同递送至细胞的关键细胞信号分子的影响，以及（iii）评估放置在靶血管上的水凝胶的影响 在动物模型中。提高我们对驱动外膜细胞表型的中心机制的理解将提供指导性材料，可以减少狭窄，减轻纤维化，并鼓励形成健康的血管，以改善血管手术后的结果。