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）：在许多缺血情况下，例如严重的肢体缺血，血流的快速恢复对于恢复组织功能至关重要。人们已经探索了多种策略来解决组织血管化这一具有挑战性的问题，包括递送一种或多种促血管生成因子、使用基于细胞的疗法以及移植血管化前的组织。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，这个多PI项目将创建一种创新的微创方法来刺激体内缺血组织的血运重建。内皮细胞（EC）和间充质干细胞（MSC）将被封装在基于生物材料的模块中，以便随着培养时间的推移，在这些微组织内形成稳定的、周细胞投资的血管单元。将评估邻近微组织中血管的接种，并测试邻近芽形成吻合的候选机制。这一机制的基础是这样的假设：接种部分取决于相邻维管芽之间细胞产生的和基质传播的牵引力。我们的总体策略是在体外执行血管化模块，这些模块彼此之间以及与宿主血管快速接合，从而在体内递送后恢复缺血组织的血液灌注。该战略将通过完成三个具体目标来评估。在目标 1 中，我们将表征和量化封装在模块化生物材料中的 EC 和 MSC 发育成原始血管样网络的能力。目标 2 将重点关注这些预血管化模块的相互作用，评估它们在体外模型组织中接种的能力，并将测试解释新生毛细血管如何互连的候选机制。在目标 3 中，我们将在已建立的后肢缺血模型中将我们的方法与其他两种基于细胞的策略进行头对头的治疗效果比较。成功完成这三个目标可能会产生一种新的强大技术，可以快速恢复几乎任何缺血组织中的血管床，从而提供了潜在的潜力 广泛影响当前治疗外周动脉疾病、冠状动脉疾病和糖尿病并发症的临床方法。这些研究还将提高目前对 EC、MSC 及其微环境对毛细血管形态发生的协同作用的理解，进而可能带来增强组织血管化策略的重要新发现。