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

• 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
• 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

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）：美国有约1500万个被诊断的糖尿病患者，其中5-10％是1型（胰岛素依赖性）。胰岛移植可能会对防止糖尿病的退化并发症（在这里和发展中国家）产生很大的影响，但是由于宿主反应，当前方案中的大多数胰岛（也许是60％）在移植后丢失。我们的方法（“模块化组织工程”）可以创建均匀，可扩展和最重要的血管化构建体。它基于当内皮细胞（EC）接种的固体对象，随机组装以填充空间（植入物位点或管子），形成可灌注的构造时，它基于产生的多孔结构。模块之间的间隙间隙形成了由内皮细胞衬里的相互连接通道。所得的内皮细胞衬里使全血能够在杆周围流动，并通过这些间隙通道。当前的努力已经证明了模块化组织工程的原理，并且可以在体外通过通道灌注血液。尽管我们的长期目标是通过组织工程使胰岛移植能够成功，但我们现在建议在体内显示这种方法的实用性，尤其强调（a）评估EC血栓形成性的评估，并（b）最大程度地减少由于血液介导的炎症反应而导致的胰岛可行性丧失。具体目的：（1）证明可以通过EC覆盖的模块化构建体灌注全血（无抗凝剂），并评估犬只分流模型中的血栓形成。犬EC种子的模块化构建体将插入AVENUNT内的平行流程测试部分。 （3）使用含有嵌入式胰岛的植入大鼠EC种子模块恢复糖尿病大鼠中的正常血糖。我们期望通过存在移植的内皮细胞来改善局部宿主反应。大鼠EC覆盖的模块将植入胶囊和门静脉输注（在临床上使用）。我们将解决这些问题：植入模块后，EC衬里渠道会发生什么？血管功能是否正常？ EC播种和模块化组织工程是否赋予胰岛素分泌和糖尿病治疗的优势？我们将测量血栓形成，灌注，评估重塑并测量血糖的变化。