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: 8683218
• 负责人: Robert E Akins
• 金额: $ 35.23万
• 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/8683218
• 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）：冠状动脉和周围动脉疾病是美国和全球发病率和死亡率的主要原因。主要治疗方法包括旁路移植手术和基于导管的开放障碍程序（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并修复先天性心血管畸形。在所有情况下，狭窄，纤维化和血管失败都是严重的后期问题，近50％的自体静脉移植物用于外周或冠状动脉搭桥手术，由于疾病调整血管的重塑而随着时间的流逝而失败。血管衰竭在很大程度上是由于在操纵过程中组织损伤引起的细胞反应和循环重新建立后的血液动力学应力改变而引起的。出于主要关注，居住在高危血管外部的外膜成纤维细胞（AFS）发起的不良适应性级联反应现在被广泛认为是嫁接和操纵血管中发病机理的主要因素。减弱AFS的疾病不良细胞反应，鼓励适应血流动力学的改变，并提供细胞材料以使健康的新腹膜和血管血管产生显着的临床影响，从而导致手术失败率降低，并在使用预先置换的能力上增加A型临床影响。因此，我们寻求开发可开发的，基于PEG的聚合物生物材料，可以在操纵前或之后沿着高危血管的外部放置，作为一种轻松的临床干预措施，从而对AF的反应和血管重塑产生有益的影响。基于广泛的初步数据，表明我们使用材料策略指导AF表型的能力，我们的三个目的是（i）详细确定水凝胶机械性能对增生细胞表型的影响，（ii）评估关键细胞信号分子在临界细胞信号分子的影响，并评估被水凝胶和（iii）评估的对细胞的效果，以及（iii）评估（iii）（iii）（iii）（iii）（iii）（iii）（iii）（iii）（iii）。 在动物模型中。提高我们对驱动外在细胞表型的中心机制的理解将提供有指导的材料，这些材料可以减少狭窄，减弱纤维化并鼓励形成健康的Vasa vasorum，以改善血管手术后的结果。