Preformed vascular modules designed for inosculation with host tissue

专为与宿主组织接种而设计的预制血管模块

• 批准号: 8480588
• 负责人: Andrew J Putnam
• 金额: $ 35.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480588
• 关键词: Anastomosis - action; Angiogenic Factor; Animal Model; Anisotropy; Basement membrane; Biocompatible Materials; Blood; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow; Caliber; Cell Count; Cell Survival; Cell Therapy; Cell physiology; Cells; Clinic; Clinical; Coculture Techniques; Collagen Type I; Complex; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Disease; Elements; Encapsulated; Endothelial Cells; Fibrin; Fibronectins; Gel; Goals; Head; Hindlimb; Human; Image; Implant; In Vitro; Injectable; Injection of therapeutic agent; Invaded; Ischemia; Laboratories; Lasers; Lead; Limb structure; Mechanics; Medical; Mesenchymal Stem Cells; Methods; Michigan; Modeling; Morphogenesis; Mus; Operative Surgical Procedures; Outcome; Oxygen; Paste substance; Perfusion; Pericytes; Peripheral arterial disease; Population; Principal Investigator; Process; Proteins; Recovery of Function; Research; Role; Site; Solutions; Staging; Stem cells; Structure; Techniques; Testing; Time; Tissue Engineering; Tissue Model; Tissues; Transplantation; Treatment Efficacy; Vascular blood supply; Vascularization; base; blood perfusion; capillary; cell type; density; design; experience; implantation; improved; in vitro testing; in vivo; innovation; insight; medical schools; minimally invasive; mouse model; neovascularization; novel strategies; public health relevance; restoration; vascular bed; vasculogenesis

DESCRIPTION (provided by applicant): Rapid restoration of blood flow is vital to restoring tissue function in many ischemic conditions, such as critical limb ischemia. A variety of strategies have been explored to solve the challenging problem of tissue vascularization, including delivery of one or more pro-angiogenic factors, the use of cell-based therapies, and the transplantation of pre-vascularized tissues. By combining some of the attractive elements of all three of these major strategies with recent advances in modular tissue engineering, this multi-PI project will create an innovative, minimally invasive approach to stimulate revascularization of ischemic tissue in vivo. Endothelial cells (EC) and mesechymal stem cells (MSC) will be encapsulated in biomaterial-based modules to allow formation of stable, pericyte-invested vascular units within these microtissues over time in culture. Inosculation of vessels in adjacent microtissues will be assessed and a candidate mechanism by which neighboring sprouts form anastomoses will be tested. Underlying this mechanism is the hypothesis that inosculation depends in part on cell-generated and matrix- propagated tractional forces between neighboring vascular sprouts. Our overall strategy is to perform vascularized modules in vitro that rapidly inosculate with each other and with host vessels, and thereby restore blood perfusion to an ischemic tissue following delivery in vivo. This strategy will be evaluated by completing three Specific Aims. In Aim 1, we will characterize and quantify the ability of EC and MSC encapsulated within modular biomaterials to develop into primitive vessel-like networks. Aim 2 will focus on the interactions of these prevascularized modules, assessing their ability to inosculate in a model tissue in vitro, and will test a candidate mechanism explaining how nascent capillaries interconnect. In Aim 3, we will compare the therapeutic efficacy of our approach head-to-head with two other cell-based strategies in an established model of hind limb ischemia. Successful completion of these three aims may lead to a new and powerful technique to rapidly restore vascular beds in virtually any ischemic tissue, and thereby offers the potential to broadly impact current clinical approaches to treating peripheral arterial disease, coronary artery disease, and complications due to diabetes. These studies will also improve current understanding of the synergistic roles of EC, MSC, and their microenvironment on capillary morphogenesis, which in turn may lead to important new discoveries that can enhance tissue vascularization strategies.

描述（由申请人提供）：在许多缺血性疾病（例如临界肢体缺血）中，血流的快速恢复对于恢复组织功能至关重要。已经探索了各种策略来解决组织血管化的具有挑战性的问题，包括递送一个或多种促血管生成因素，基于细胞的疗法的使用以及血管前组织的移植。通过将所有这三种主要策略的一些有吸引力的元素与模块化组织工程的最新进展相结合，该多PI项目将创建一种创新的，微创的方法来刺激体内缺血组织的血运重建。内皮细胞（EC）和间盐干细胞（MSC）将封装在基于生物材料的模块中，以允许在培养过程中随着时间的流逝，这些微动物在这些微动物中形成稳定的，周围的受访的血管单位。将评估对邻近微动物中血管的媒介，并将测试相邻芽孢形成吻合的候选机制。这种机制的基础是假设，即媒介的一部分取决于细胞生成和基质传播的牵引力，相邻血管芽芽。我们的整体策略是在体外迅速互相抗血和宿主血管进行体外进行血管化模块，从而在体内分娩后恢复缺血组织的血液灌注。该策略将通过完成三个具体目标来评估。在AIM 1中，我们将表征和量化模块化生物材料内封装成原始血管样网络的EC和MSC的能力。 AIM 2将重点放在这些预性模块的相互作用上，评估它们在体外模型组织中未能进行未能进行的能力，并将测试一种候选机制，以解释新生的毛细血管如何互连。在AIM 3中，我们将在既定的后肢缺血模型中比较我们的方法对头的治疗功效与其他两种基于细胞的策略。这三个目标的成功完成可能会导致一种新的强大技术，以快速恢复几乎所有缺血性组织的血管床，从而提供潜力 为了广泛影响目前治疗外周动脉疾病，冠状动脉疾病以及糖尿病并发症的临床方法。这些研究还将提高人们对EC，MSC及其微环境在毛细管形态发生的协同作用的当前理解，这反过来又可能导致重要的新发现，从而可以增强组织血管化策略。