Modular Tissue Engineering Components for Vascularized 3-D Constructs

用于血管化 3-D 结构的模块化组织工程组件

基本信息

批准号：
7459032
负责人：
MICHAEL V SEFTON
金额：
$ 14.29万
依托单位：
UNIVERSITY OF TORONTO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7459032
关键词：
3-Dimensional Address Adipocytes Affect Age Anticoagulants Bioreactors Blindness Blood Budgets Caliber Canis familiaris Cardiac Myocytes Cardiovascular Diseases Cell Line Cells China Chronic Chronic Disease Collagen Complications of Diabetes Mellitus Country Developed Countries Developing Countries Diabetes Mellitus Diagnosis Disease Encapsulated Endothelial Cells Engineering Figs - dietary Gel Grant Health Hepatocyte Immune response Implant In Situ In Vitro India Individual Inflammatory Response Insulin Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Diseases Life Measures Mediating Modeling Nature Newly Diagnosed Patients Perfusion Pharmaceutical Preparations Portal vein structure Protocols documentation Rattus Recombinant Proteins Regenerative Medicine Shunt Device Site Solid Stem cell transplant Structure Surface Technology Testing Thrombosis Tissue Engineering Tissues Transplantation Tube United States National Institutes of Health Whole Blood Wound Healing base blood perfusion design diabetes mellitus therapy diabetic diabetic rat in vivo insulin secretion interstitial intravenous administration islet novel prevent retinal rods scaffold

项目摘要

DESCRIPTION (provided by applicant): There are ~ 15 million diagnosed diabetics in the US, 5-10% of whom are type 1 (insulin dependent). Islet transplantation could have a large impact on preventing the degenerative complications of diabetes (here and in developing countries), but the majority of islets (perhaps 60%) in current protocols are lost upon transplantation due to the host response. Our approach ("modular tissue engineering") enables the creation of uniform, scaleable and most importantly vascularized constructs. It is based on the porous structure that is created when solid objects on to which endothelial cells (EC) are seeded, randomly assemble to fill a space (an implant site or a tube), creating a perfuseable construct. The interstitial gaps among the modules form interconnected channels which are lined by the endothelial cells. The resulting endothelial cell lining enables whole blood to flow around the rods and through these interstitial channels. Current efforts have demonstrated the principle of modular tissue engineering and that blood can be perfused through the channels in vitro. While our long-term objective is to enable islet transplantation to be successful through tissue engineering, we propose now to show the utility of this approach in vivo, with particular emphasis on (a) the assessment of EC thrombogenicity and (b) minimizing the loss of islet viability due to the blood mediated inflammatory response. Specific aims: (1) Demonstrate that whole blood (without anticoagulant) can be perfused through an EC covered modular construct and assess thrombosis in a canine AV shunt model. Canine EC seeded modular constructs will be inserted in a parallel flow test section within the AV shunt. (3) Restore normoglycemia in diabetic rats using implanted rat EC seeded modules containing embedded pancreatic islets. We expect to ameliorate the adverse local host response through the presence of the transplanted endothelial cells. Rat EC covered modules will be implanted in both the omental pouch and by portal vein infusion (used clinically). We will address these questions: What happens to the EC lined channels once the modules are implanted? Are the vessels functional? Does EC seeding and modular tissue engineering confer an advantage for insulin secretion and diabetes therapy? We will measure thrombogenicity, perfusion, assess remodeling, and measure changes in glycemia.

描述（由申请人提供）：美国约有 1500 万确诊糖尿病患者，其中 5-10% 为 1 型（胰岛素依赖型）。胰岛移植可能对预防糖尿病退行性并发症（在美国和发展中国家）产生重大影响，但目前方案中的大多数胰岛（大约 60%）会因宿主反应而在移植后丢失。我们的方法（“模块化组织工程”）能够创建均匀的、可扩展的、最重要的是血管化的结构。它基于多孔结构，当在其上接种内皮细胞 (EC) 的固体物体随机组装以填充空间（植入部位或管）时，形成可灌注的结构。模块之间的间隙形成互连的通道，其内衬有内皮细胞。由此产生的内皮细胞衬里使全血能够在杆周围流动并通过这些间质通道。目前的努力已经证明了模块化组织工程的原理，并且血液可以通过体外通道进行灌注。虽然我们的长期目标是通过组织工程实现胰岛移植成功，但我们现在建议展示这种方法在体内的实用性，特别强调 (a) EC 血栓形成性的评估和 (b) 最大限度地减少损失由于血液介导的炎症反应而影响胰岛活力。具体目标：(1) 证明全血（不含抗凝剂）可以通过 EC 覆盖的模块化结构进行灌注，并评估犬 AV 分流模型中的血栓形成。犬 EC 种子模块化结构将插入 AV 分流器内的平行流测试部分。 (3) 使用植入的含有嵌入胰岛的大鼠 EC 种子模块恢复糖尿病大鼠的正常血糖。我们期望通过移植内皮细胞的存在来改善局部宿主的不良反应。大鼠EC覆盖的模块将被植入网膜袋并通过门静脉输注（临床使用）。我们将解决这些问题：一旦植入模块，EC 内衬通道会发生什么？这些血管是否功能正常？ EC 接种和模块化组织工程是否为胰岛素分泌和糖尿病治疗带来优势？我们将测量血栓形成、灌注、评估重塑并测量血糖变化。