A Translational Bioreactor for the Construction of Off-the-Shelf, Patient-Specific Heart Tissue for the Permanent Correction of Congenital Heart Defects

用于构建现成的患者特异性心脏组织以永久纠正先天性心脏缺陷的转化生物反应器

• 批准号: 10462475
• 负责人: Dillon K Jarrell
• 金额: $ 1.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462475
• 关键词: 3-Dimensional; Address; Amniotic Fluid; Area; Arrhythmia; Autologous; Automobile Driving; Bioreactors; Birth; Calcium; Cardiac; Cardiac Myocytes; Cardiac Volume; Catheterization; Cell Density; Cell Survival; Cells; Chest; Child; Childhood; Clinical; Complex; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Differentiation and Growth; Drug Screening; Echocardiography; Electric Conductivity; Electrocardiogram; Embryonic Development; Encapsulated; Family; Fibrin; Fibrosis; Flow Cytometry; Goals; Growth; Hand; Harvest; Heart; Heart Abnormalities; Heart Diseases; Heart Rate; Histology; Immune response; Implant; Infant; Infiltration; Intraventricular; Liquid substance; Maintenance; Methods; Modeling; Myocardial; Operative Surgical Procedures; Patients; Perfusion; Pluripotent Stem Cells; Production; Protocols documentation; Pump; Quality of life; Rattus; Reaction; Reconstructive Surgical Procedures; Reproducibility; Research; Risk; Running; Source; Stretching; Surgeon; Surgical sutures; System; Technology; Testing; Thick; Tissue Engineering; Tissues; Translating; United States; Vascularization; Ventricular; Work; base; cardiac regeneration; cardiac tissue engineering; cell type; clinical translation; density; differentiation protocol; experimental study; follow-up; heart function; improved; in vivo; induced pluripotent stem cell; morphogens; pericardial sac; pluripotency; pressure; regeneration potential; regenerative; repaired; scaffold; sham surgery; standard of care; stem cell derived tissues

PROJECT SUMMARY/ABSTRACT Congenital heart defects (CHDs) are the most common birth defect worldwide and the number one killer of live-born infants in the United States. Approximately 1% of infants are born with a CHD, and 25% of them require surgery within one year of birth. The current materials available to pediatric heart surgeons for these reconstructive surgeries are exclusively non-living and inert; they do not grow with the child or restore heart function while also increasing the risk of follow-up surgeries and arrhythmias. Furthermore, since the heart develops very early in embryogenesis, it is unlikely that CHDs will ever be fully preventable. Therefore, the most promising approach for the clinical correction of CHDs is to provide surgeons with living, engineered cardiac tissue that can fully integrate with the heart and permanently restore heart function. The overall goal of this proposal is to create suturable, autologous induced pluripotent stem cell (iPSC)-derived cardiac tissue patches (CTPs) in an automated bioreactor system that can be used for the correction of full wall-thickness CHDs. Towards this goal, my lab has identified amniotic fluid cells (AFCs) as a suitable source of patient- specific cells. AFCs belong to the baby, can be safely harvested before birth, and can be reprogrammed to iPSC, which I have successfully differentiated to several cardiac cell types. In addition, my lab has developed a suturable, fully-degradable scaffold that supports iPSC encapsulation and subsequent 3D cardiomyocyte differentiation. These preliminary results direct the project hypothesis that a hands-off bioreactor can be used to generate and maintain living and autologous CTPs, which will integrate with the heart and permanently correct full-thickness heart defects. To achieve our overall goal, we will next pursue two specific aims: 1) Construct an automated perfusion bioreactor that can drive the differentiation, growth, and maintenance of the CTPs in a hands-off manner, and 2) Assess the CTPs in vivo using our established rat model of a full-thickness right ventricular defect (a myocardial replacement model). Collectively, this technology will be promising for the permanent correction of many CHDs while also establishing a translational method for the production of engineered tissues that could be applied to the entire spectrum of tissue engineering.

项目摘要/摘要 先天性心脏病（CHD）是世界上最常见的出生缺陷， 美国的活产婴儿杀手大约1%的婴儿出生时患有CHD， 其中25%的人在出生后一年内需要手术。目前可用于小儿心脏的材料 这些重建手术的外科医生完全是非生命的和惰性的;他们不会随着年龄的增长而成长。 这不仅会影响孩子的健康，也会恢复心脏功能，同时还会增加后续手术和心律失常的风险。 此外，由于心脏在胚胎发育中非常早地发育，因此CHD不太可能永远存在。 完全可以预防。因此，最有希望的临床纠正CHD的方法是 为外科医生提供活的、工程化的心脏组织，可以与心脏完全整合， 永久恢复心脏功能这项提案的总体目标是创造可缝合的， 自体诱导多能干细胞（iPSC）衍生的心脏组织补片（CTP）， 自动化生物反应器系统，可用于校正全壁厚CHD。 为了实现这一目标，我的实验室已经确定羊水细胞（AFC）作为一个合适的来源，病人- 特定细胞AFC属于婴儿，可以在出生前安全获取，并且可以重新编程 iPSC，我已经成功地分化成几种心脏细胞类型。此外，我的实验室 开发了一种可缝合的，完全可降解的支架，支持iPSC封装和随后的3D 心肌细胞分化这些初步结果指导了项目假设，即不干涉 生物反应器可用于产生和维持活的和自体的CTP，其将与 心脏和永久纠正全层心脏缺陷。为了实现我们的总体目标，我们将 我们追求两个具体目标：1）构建一个自动化的灌注生物反应器， 以不干涉的方式分化、生长和维持CTP，以及2）评估CTP 在体内使用我们建立的全层右心室缺损（心肌缺损）大鼠模型， 替换模型）。总的来说，这项技术将有望永久纠正 许多CHD，同时还建立了用于生产工程组织的翻译方法， 可以应用于整个组织工程领域。