Cardiovascular Tissue Engineering in Diabetes

糖尿病的心血管组织工程

• 批准号: 8050139
• 负责人: Agneta Simionescu
• 金额: $ 17.59万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050139
• 关键词: Adipose tissue; Advanced Glycosylation End Products; American; Animal Model; Animals; Antioxidants; Arteries; Artificial Implants; Atherosclerosis; Attenuated; Autologous; Benchmarking; Binding; Bioreactors; Blood Glucose; Blood Vessels; Cardiovascular Diseases; Cardiovascular alteration; Cardiovascular system; Carotid Arteries; Cells; Chemicals; Clinical; Clinical Research; Clinical Trials; Collagen; Complications of Diabetes Mellitus; Controlled Environment; Coronary artery; Data; Development; Devices; Diabetes Mellitus; Disease; Elastin; Engineering; Environment; Extracellular Matrix; Family suidae; Fibrosis; Frequencies; Functional disorder; Future; Glucose; Goals; Heart Valves; Impaired wound healing; Implant; Inflammation; Kidney; Life; Light; Lipids; Mechanics; Mesenchymal Stem Cells; Modeling; Myocardium; Nerve; Nucleic Acids; Operative Surgical Procedures; Organ Transplantation; Outcome; Oxidative Stress; Patients; Pentas; Predisposition; Problem Solving; Process; Property; Proteins; Reaction; Resistance; Signal Transduction; Stabilizing Agents; Stem cells; Testing; Tissue Engineering; Tissue Transplantation; Tissues; Transplanted tissue; Work; base; biomaterial compatibility; calcification; cardiovascular risk factor; crosslink; diabetic; diabetic cardiomyopathy; diabetic patient; diabetic rat; high risk; implantation; improved; in vitro Model; in vivo; innovation; non-diabetic; oxidation; polyphenol; public health relevance; repaired; response; scaffold; tissue regeneration; tissue support frame

DESCRIPTION (provided by applicant): Diabetes is a major risk factor for cardiovascular diseases and diabetics have a significantly greater frequency of cardiovascular disorders. As a consequence, diabetics are more prone to undergo surgery for repair or replacement of tissues such as blood vessels and heart valves. Tissue engineered constructs based on scaffolds and autologous progenitor cells are currently being developed, but very little information exists regarding the fate of tissue engineered devices in the compromised patient, and more specifically in diabetic environments. Results obtained from implantation studies in healthy animals have served as benchmarks for FDA approval; however, some tissue engineered implants have failed dramatically in clinical trials. Notably, it is well documented that the outcome of reparative surgery and organ and tissue transplantation is more problematical in diabetic patients. Diabetes is characterized by elevated levels of blood glucose, which interacts irreversibly with proteins, lipids and nucleic acids via oxidation and cross linking processes, resulting in formation of advanced glycosylation end products (AGEs). Glycoxidation induces severe cell and matrix alterations that result in endothelial dysfunction, accelerated atherosclerosis, activation of inflammation, fibrosis and impaired healing, all of which are not conducive to the desired integration and remodeling of tissue engineered constructs. Our long-term goal is to develop constructs adapted to withstand high glucose and oxidative stress typical of diabetes. Our working hypothesis, robustly supported by preliminary data, is that both scaffolds and cells are susceptible to diabetes-induced complications and that chemical stabilization of scaffolds would improve the outcome of tissue engineering in diabetes. To test this hypothesis we propose to test constructs in diabetic models and compare their properties to non-diabetic control environments. In Aim 1, scaffolds will be prepared from decellularized cardiovascular tissues and their susceptibility to diabetes-induced complications evaluated in vivo and in vitro models of diabetes. In Aim 2, scaffolds treated with polyphenol stabilizing agents prepared as "diabetes-resistant" constructs will be evaluated for resistance to diabetes-induced alterations in same animal models. Finally, for Aim 3 mesenchymal stem cells will be obtained from diabetic animals and those will be re- implanted as scaffold-supported autologous implants. PUBLIC HEALTH RELEVANCE: Almost 25 million Americans have diabetes, a dreadful disease which is simply characterized by high levels of blood sugar (glucose). Excessive glucose binds to tissues and cells and this binding reduces the activity of the heart muscle, heart valves, blood vessels, kidneys, and nerves. For this reason, patients with diabetes have much higher risks of cardiovascular and other diseases, as compared to non-diabetics. Surgery is required to replace diseased heart valves and arteries with artificial implants, but these implants fail after 15-20 years because they are made of non-living materials. New and improved devices are needed for millions of cardiovascular patients every year. To make better implants, we are developing living materials comprised of layers of tissue scaffolds to which we add the own patients' stem cells. Although practically all cardiovascular devices have been tested in normal healthy animals, our main concern is that implantation of tissue scaffolds and cells into diabetic patients will expose the implants to high glucose levels and damage the implants. Our ideas are based on clinical studies which have shown that tissue transplants in diabetics have many more problems in diabetics as compared to non-diabetics. Thus we propose to study the effect of diabetes on tissue scaffolds and stem cells by using animal models of diabetes. In an attempt to solve this problem, we also propose to treat the scaffolds with chemicals that protect the scaffolds and make them resistant to diabetes. These studies have not been done before and will provide a guiding light for future development of implants for patients with diabetes.

描述（由申请人提供）：糖尿病是心血管疾病的主要风险因素，糖尿病患者发生心血管疾病的频率明显更高。因此，糖尿病患者更倾向于接受手术以修复或替换组织，如血管和心脏瓣膜。目前正在开发基于支架和自体祖细胞的组织工程构建体，但关于组织工程装置在受损患者中，更具体地说在糖尿病环境中的命运的信息非常少。从健康动物的植入研究中获得的结果已经作为FDA批准的基准;然而，一些组织工程植入物在临床试验中显着失败。值得注意的是，它是有据可查的结果，修复手术和器官和组织移植是更成问题的糖尿病患者。糖尿病的特征在于血糖水平升高，其通过氧化和交联过程与蛋白质、脂质和核酸不可逆地相互作用，导致晚期糖基化终产物（AGEs）的形成。糖氧化诱导严重的细胞和基质改变，导致内皮功能障碍、加速动脉粥样硬化、炎症活化、纤维化和受损愈合，所有这些都不利于组织工程化构建体的期望整合和重塑。我们的长期目标是开发适应于承受糖尿病典型的高葡萄糖和氧化应激的结构。我们的工作假设得到了初步数据的有力支持，即支架和细胞都易受糖尿病诱导的并发症的影响，支架的化学稳定性将改善糖尿病组织工程的结果。为了验证这一假设，我们建议在糖尿病模型中测试结构，并将其属性与非糖尿病控制环境进行比较。在目标1中，将从脱细胞心血管组织制备支架，并在体内和体外糖尿病模型中评估其对糖尿病诱导的并发症的易感性。在目标2中，将在相同的动物模型中评价用多酚稳定剂处理的支架对糖尿病诱导的改变的抗性，所述多酚稳定剂被制备为“糖尿病抗性”构建体。最后，对于目标3，将从糖尿病动物获得间充质干细胞，并且将这些间充质干细胞作为支架支撑的自体植入物重新植入。 公共卫生相关性：几乎有2500万美国人患有糖尿病，这是一种可怕的疾病，其特点是血糖（葡萄糖）水平高。过多的葡萄糖与组织和细胞结合，这种结合会降低心肌、心脏瓣膜、血管、肾脏和神经的活性。因此，与非糖尿病患者相比，糖尿病患者患心血管疾病和其他疾病的风险要高得多。需要手术来用人工植入物替换患病的心脏瓣膜和动脉，但这些植入物在15-20年后就会失效，因为它们是由非生命材料制成的。每年有数百万心血管患者需要新的和改进的设备。为了制造更好的植入物，我们正在开发由多层组织支架组成的活体材料，我们将患者自己的干细胞加入其中。尽管几乎所有的心血管器械都已在正常健康动物中进行了测试，但我们主要担心的是，将组织支架和细胞植入糖尿病患者体内会使植入物暴露于高葡萄糖水平并损坏植入物。我们的想法是基于临床研究，这些研究表明，与非糖尿病患者相比，糖尿病患者的组织移植有更多的问题。因此，我们建议使用糖尿病动物模型来研究糖尿病对组织支架和干细胞的影响。为了解决这个问题，我们还建议用化学物质处理支架，保护支架，使其对糖尿病具有抵抗力。这些研究以前从未进行过，将为糖尿病患者植入物的未来发展提供指导。