Biologically Inspired Engineering of Hierarchical Vascular Networks

分层血管网络的生物启发工程

• 批准号: 8604742
• 负责人: GEORGE ENG
• 金额: $ 2.26万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604742
• 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; Geometry; 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.

描述（由申请人提供）：在美国，每年有120万新的或复发性的冠状动脉攻击，导致心肌梗塞或组织死亡。替代受损组织的功能性心脏组织的产生可能会大大改变我们目前治疗心脏病的方式。因此，制造血管的强大方法可以促进大规模心脏组织的生长，以治疗美国增加的疾病负担。我们在该建议中的目的是增加一个血管网络，该血管网络可以在体外为心脏移植物提供营养转运，并与体内的血液供应相连。微制造技术允许在空间上精确地创建细胞结构环境，并将用于对移植物材料内的100 um至1 mm通道进行图案。模仿生理脉管系统，分层组织的血管血管网络将被诱导从相对较大的（毫米）到非常小（10 um）的导管分支。使用水凝胶封装方法，将在血管结构周围生长心脏组织。生物反应器将使用时间变化的流体流动方式提供生物物理信号传导，以使血管与血管生成细胞因子一起成熟，以诱导单个毛细血管发芽，从而在细胞尺度上提供运输。这种层次设计尤其重要，因为它创建了体外连通性的特定入口和出口，用于体内手术吻合术，同时保持微血管网络以进行有效的营养递送。该设计桥接了较大尺寸的奇异血管管之间通常缺乏有效运输到单个细胞的差异，并与缺乏流体灌注的内皮细胞进行了CO培养研究。心脏移植物的血管功能将在大鼠腹主动脉的端到端吻合中在体内评估。该提案的具体目的是（1）使用微制造技术来创建用于血管形成的层次设计的模板，（2）应用生物物理调节来诱导毛细血管萌芽，（3）在功能上测试在体内型型型型型型腹部，在功能上测试心脏移植的生存和功能性灌注。该项目将基于我们实验室以前的经验和通过先进的生物学微制造技术在心脏组织工程方面的专业知识，以创建可在体内使用的大型，灌注的心脏移植物。我们希望这些研究可以通过创建可用于心肌梗死和冠状动脉疾病的患者的心脏斑块来帮助减轻心血管疾病的全国负担。