Engineered Cardiac Tissue with Biomimetic Architecture and Vasculature

具有仿生结构和脉管系统的工程心脏组织

• 批准号: 9658550
• 负责人: Christopher Kenji Arakawa
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-16 至 2021-03-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9658550
• 关键词: 3-Dimensional; Accounting; Action Potentials; Address; Anatomy; Architecture; Biocompatible Materials; Biomimetics; Blood Vessels; Blood capillaries; Calcium; Caliber; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Density; Cell Survival; Cell physiology; Cells; Cellular Morphology; Cessation of life; Cicatrix; Coculture Techniques; Complex; Coupling; Deposition; Development; Electric Stimulation; Encapsulated; Endothelial Cells; Endothelial Growth Factors; Endothelium; Engineering; Environment; Excision; Exhibits; Extracellular Matrix; Gap Junctions; Gel; Generations; Growth; Heart; Heart Diseases; Heart failure; Hydrogels; In Vitro; Individual; Matrix Metalloproteinases; Medical; Metabolic; Methodology; Modeling; Muscle Fibers; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Myocardium; Natural regeneration; Nutrient; Paracrine Communication; Pathologic; Patients; Pattern; Perfusion; Periodicity; Polymers; Printing; Property; Protocols documentation; Pulsatile Flow; Regenerative Medicine; Research; Resolution; Rogaine; Shapes; Source; Structure; Techniques; Therapeutic; Thick; Tissue Engineering; Tissues; Torsion; United States; Vascularization; Ventricular; Work; base; cardiac regeneration; cardiac repair; cardiac tissue engineering; density; design; embryonic stem cell; ethylene glycol; healing; heart dimension/size; heart function; improved; in vivo; interest; mortality; multi-photon; novel; oxygen transport; photolysis; progenitor; regenerative; stem cells; two-photon; vascular tissue engineering; wasting

PROJECT SUMMARY Ischemic heart disease accounts for approximately 42.5% of all cardiovascular-related deaths and afflicts 720,000 individuals/year. While current medical treatments have significantly decreased heart attack- associated mortality, post-ischemic myocardial tissue undergoes pathologic remodeling and scarring, subjecting patients to cardiac dysfunction and heart failure. As endogenous cardiac regeneration is limited, stem cell and regenerative medicine-based approaches to cardiac repair represent promising solutions towards regaining normal heart function. Bolstering interest in cardiovascular tissue engineering has given rise to the development of novel biomaterials capable of maintaining cardiac cell function within a 3D tissue-like environment, while detailed protocols have been developed to derive mature cardiomyocytes from a myriad of stem cell sources; however, the essential ability to generate a construct that recapitulates the cellular density and composition, thickness, and helicoid structure of the native heart has limited the therapeutic applicability of tissue engineered constructs thus far. Utilizing photodegradable polymer-based hydrogels that enable a spatially-defined co-culture of hES-derived cardiomyocytes and endothelial cells, we propose to generate a densely-vascularized 3D cardiac construct exhibiting biomimetic helical tissue architecture. To support the culture of a thick myocardial tissue and enhance mass transport of oxygen and nutrients, vessels will be photopatterned into cell-laden hydrogels containing mature cardiomyocytes to generate perfusable vasculature with similar size, shape, and structure to that of the native heart. Channels will be endothelialized and perfused with fresh media using biomimetic pulsatile flow to encourage endothelial-cardiomyocyte cell interaction. We aim to demonstrate that by controlling micron-scale channel architecture in a biomimetic helical arrangement with near-native heart capillary density, paracrine signaling, ECM deposition, and direct contact of endothelial cells and cardiomyocytes, we can direct cardiomyocyte orientation, enhance construct contractility, and recapitulate the native torsional tissue contraction. As the proposed research will represent the first successful strategy to generate perfusable vasculature networks with 3D features on the single-micron scale, we expect that the developed methodologies will find wide applicability in the engineering of vascularized constructs beyond cardiac tissue.

项目摘要 缺血性心脏病约占所有与心血管相关的死亡和折磨的42.5％ 720,000个人/年。尽管目前的医疗治疗显着降低了心脏病发作 - 相关的死亡率，缺血后的心肌组织经历病理重塑和疤痕， 使患者患有心脏功能障碍和心力衰竭。由于内源性心脏再生有限， 干细胞和基于再生医学的心脏修复方法代表有希望的解决方案 恢复正常的心脏功能。增强对心血管组织工程的兴趣已引起 发展能够在3D组织中维持心脏细胞功能的新型生物材料的发展 环境，虽然已经开发了详细的方案来从无数 干细胞来源；但是，生成概括细胞的构造的基本能力 天然心脏的密度和成分，厚度和螺旋结构限制了治疗性 到目前为止，组织工程结构的适用性。利用可光降解的聚合物基水凝胶 启用一个空间定义的HES衍生心肌细胞和内皮细胞的共同培养，我们建议 产生一种呈仿生螺旋组织结构的密集血管化的3D心脏构建体。到 支持厚的心肌组织的培养，并增强氧气和养分的质量转运 将被照相将含有成熟心肌细胞的含细胞水凝胶产生 脉管系统的大小，形状和结构与天然心脏相似。频道将被内皮化 并使用仿生脉动流动来灌注新鲜培养基，以鼓励内皮细胞细胞细胞 相互作用。我们的目的是通过控制仿生中的微米级渠道体系结构来证明这一点 螺旋排列，具有近植物心脏毛细管密度，旁分泌信号传导，ECM沉积和直接 接触内皮细胞和心肌细胞，我们可以指导心肌细胞取向，增强构建体 收缩性，并概括天然的扭转组织收缩。拟议的研究将代表 在单微米上产生具有3D功能的惠及脉管网络的第一个成功策略 规模，我们预计开发的方法将在工程中找到广泛的适用性 心脏组织以外的血管化构建体。