Biologically inspired engineering of hierarchical vascular networks

分层血管网络的生物启发工程

• 批准号: 8256167
• 负责人: GEORGE ENG
• 金额: $ 4.72万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2015-02-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256167
• 关键词: Accounting; Address; Age; Americas; Anastomosis - action; Angiogenic Factor; Animal Model; Biological; Bioreactors; Blood; Blood Vessels; Blood capillaries; Cardiac; Cardiac Death; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Clinical; Coculture Techniques; Coronary Arteriosclerosis; Coronary Vessels; Country; Diffusion; Encapsulated; Endothelial Cells; Engineering; Environment; Gelatin; Generations; Growth; Growth Factor; Heart; Heart Diseases; Heart Transplantation; Hydrogels; Implant; In Vitro; Individual; Ischemia; Laboratories; Liquid substance; Mechanics; Methods; Microfabrication; Microfluidics; Microspheres; Modeling; Molecular; Myocardial Infarction; Myocardial tissue; Myocardium; Natural regeneration; Nutrient; Organ; Patients; Pattern; Performance; Perfusion; Physiological; Platelet-Derived Growth Factor; Rattus; Recurrence; Regulation; Signal Transduction; Smooth Muscle Myocytes; Specific qualifier value; Structure; Surgical Anastomosis; System; Techniques; Technology; Testing; Time; Tissue Engineering; Tissues; Transplanted tissue; Trees; Tube; Vascular Endothelial Growth Factors; Vascular blood supply; Work; abdominal aorta; base; burden of illness; capillary; conditioning; crosslink; cytokine; design; experience; fluid flow; immunogenicity; improved; in vivo; lithography; millimeter; physical conditioning; repaired; scaffold

DESCRIPTION (provided by applicant): There are 1.2 million new or recurrent coronary attacks each year in the U.S, resulting in myocardial infarction or tissue death. The generation of functional cardiac tissue to replace damaged tissue could significantly change the way we currently treat heart disease. Consequently, a robust method of fabricating blood vessels could facilitate growth of larger scale cardiac tissue for treating this increasing burden of disease in America. Our aim in this proposal is to add a vascular network which can supply the cardiac graft with nutrient transport in vitro and be connected to blood supply in vivo. Micro fabrication technologies allow for the spatially precise creation of a cell-instructive environment and will be used to pattern 100 um to 1 mm channels within a graft material. Mimicking physiologic vasculature, the hierarchically organized vascular network of blood vessels will be induced to branch from relatively large (millimeters) to very small (10 um) conduits. Cardiac tissue will be grown around the vessel structure, using a hydrogel encapsulation method. Bioreactors will provide biophysical signaling using a time varying fluid flow regime to mature the blood vessels along with angiogenic cytokines to induce individual capillary sprouting providing transport at the cellular scale. This hierarchical design is particularly important because it creates a specific inlet and outlet for in vitro connectivity and clear ends for surgical anastomosis in vivo, while maintaining a micro vascular network for efficient nutrient delivery. This design bridges the gap between larger scale singular vascular tubes which often lack effective transport to individual cells, and co culture studies with endothelial cells which lack fluid perfusion. The vascular functionality of the cardiac graft will be assessed in vivo an interposition graft in an end to end anastomosis in the rat abdominal aorta. The specific aims of the proposal will be to (1) Use micro fabrication technologies to create a hierarchically designed template for vascular formation, (2) Apply biophysical regulation to induce capillary sprouting, (3) Functionally test the survival and functional perfusion of the cardiac graft in an in vivo rat abdominal aorta model. This project will build upon our laboratory's previous experience and expertise in cardiac tissue engineering with advanced biological micro fabrication techniques, to create a large, perfused cardiac graft that can be used in vivo. We hope that these studies can aid to the overall effort to reduce the national burden of cardiovascular disease, by creating a cardiac patch that can be used for patients suffering from myocardial infarctions and coronary artery disease. PUBLIC HEALTH RELEVANCE: Coronary artery disease, the most common form of heart disease, causes heart vessel narrowing leading to myocardial infarction, associated with massive death of cardiac cells. This proposal intends to use advanced microfabrication techniques, in combination with molecular induction and physical conditioning, to build cardiac tissues with functional blood vessel networks arranged in a hierarchical branching design. This functional vasculature will be tested in a small animal model, towards cardiac grafts useful for reversing the loss of cardiac function.

描述（由申请人提供）：美国每年有 120 万例新发或复发冠心病发作，导致心肌梗塞或组织死亡。产生功能性心脏组织来替代受损组织可以显着改变我们目前治疗心脏病的方式。因此，一种强大的血管制造方法可以促进更大规模的心脏组织的生长，以治疗美国日益增加的疾病负担。我们在该提案中的目的是添加一个血管网络，该血管网络可以为心脏移植物提供体外营养运输并与体内血液供应连接。微制造技术可以在空间上精确地创建细胞指导环境，并将用于在移植材料内形成 100 微米至 1 毫米的通道图案。模仿生理脉管系统，分层组织的血管网络将被诱导从相对较大（毫米）的导管分支到非常小的（10 微米）导管。使用水凝胶封装方法，心脏组织将在血管结构周围生长。生物反应器将使用随时间变化的流体流动方式提供生物物理信号，使血管成熟，并与血管生成细胞因子一起诱导个体毛细血管发芽，从而在细胞尺度上提供运输。这种分层设计尤其重要，因为它为体外连接创建了特定的入口和出口，为体内手术吻合创建了清晰的末端，同时维持了微血管网络以实现有效的营养输送。这种设计弥补了通常缺乏对单个细胞的有效运输的较大规模的单一血管与缺乏液体灌注的内皮细胞的共培养研究之间的差距。心脏移植物的血管功能将通过大鼠腹主动脉端对端吻合术中的插入移植物进行体内评估。该提案的具体目标是（1）使用微制造技术创建分层设计的血管形成模板，（2）应用生物物理调节诱导毛细血管萌芽，（3）功能测试心脏的存活和功能灌注体内大鼠腹主动脉模型中的移植物。该项目将利用我们实验室先前在心脏组织工程方面的经验和专业知识，采用先进的生物微制造技术，创建可在体内使用的大型灌注心脏移植物。我们希望这些研究能够通过创建可用于患有心肌梗塞和冠状动脉疾病的患者的心脏补片，有助于减轻国家心血管疾病负担的整体努力。 公共卫生相关性：冠状动脉疾病是最常见的心脏病形式，会导致心脏血管狭窄，导致心肌梗塞，并与心肌细胞大量死亡有关。该提案旨在利用先进的微加工技术，结合分子诱导和物理调节，构建具有按分层分支设计排列的功能性血管网络的心脏组织。这种功能性脉管系统将在小动物模型中进行测试，以用于逆转心脏功能丧失的心脏移植物。