Bioprinting of human iPSCs to facilitate their differentiation, recruitment and strategic assembly to form engineered cardiac patches

人类 iPSC 的生物打印，以促进其分化、招募和战略组装，以形成工程心脏补片

• 批准号: 9073287
• 负责人: Binata Joddar
• 金额: $ 13.57万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9073287
• 关键词: Accounting; Address; Adult; American; American Heart Association; Anterior; Anti-Arrhythmia Agents; Area; Arrhythmia; Arteries; Autologous; Biocompatible Materials; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiac ablation; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cells; Cellular Structures; Cicatrix; Coculture Techniques; Consensus; Custom; Deposition; Development; Endothelial Cells; Engineering; Environment; Fibroblasts; Future; Generations; Goals; Growth; Heart; Heart Arrest; Heart Research; Human; Hydrogels; Implant; Implantable Defibrillators; In Vitro; Infarction; Injection of therapeutic agent; Ischemia; Knowledge; Left; Life; Ligation; Location; Mainstreaming; Modeling; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Natural regeneration; Necrosis; Nutrient; Pharmaceutical Preparations; Procedures; Protocols documentation; Rattus; Recording of previous events; Reporting; Smooth Muscle Myocytes; Soft Tissue Injuries; Stem cells; Stream; Structure; System; Technology; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Toxicology; Transplantation; United States; Vascular Endothelial Cell; Vascular Smooth Muscle; Work; base; bioprinting; cell type; cellular engineering; design; human adult stem cell; human stem cells; implantation; improved; in vivo; individual patient; induced pluripotent stem cell; injured; interest; meetings; neovascularization; novel strategies; public health relevance; regenerative therapy; repaired; restoration; scaffold; stem cell therapy; success; tissue regeneration; tissue repair

 DESCRIPTION (provided by applicant): An estimated 80,000,000 American adults (one in three) have one or more types of cardiovascular disease (CVD); 7,900,000 have a history of myocardial infarction (American Heart Association). So in every 34 seconds, someone in the United States has a myocardial infarction or a heart attack, accounting for 1.5 million cases annually in the States alone (AHA). Myocardial infarction (MI) is the irreversible necrosis of heart muscle, due to prolonged ischemia which leads to cardiac arrest due to arrhythmia. Stem cell therapy is a promising approach for myocardial infarction repair, and the use of stem cells to repair a damaged heart is now mainstream in current cardiac research. Unfortunately, thus far direct injection of stem cells into the fibrotic area of infarcted hearts has met with limited success, probably due to the low retention and survival of stem cells in the necrotic areas, together with the limited cardiogenic differentiation and functional integration of delivered cells within the host heart tissue. Our proposal addresses these limitations with a new strategy, to design and optimize a tissue- engineered cardiac patch for delivering autologous adult human stem cell derived cardiac and vascular cells strategically layered and aligned within hydrogel scaffolds to repair the damaged myocardium. This work is also critical for the successful development of predictive drug and toxicology screens as well as safe and efficient cardiac therapies by testing them on using human stem cell-engineered cardiovascular sheets. To achieve this aim, we will use 'bioprinting' to fabricate cell sheets containing either human induced pluripotent stem cells (hiPSCs) or cardiomyocytes (CMs), vascular endothelial cells (ECs), and vascular smooth muscle cells (SMCs) derived from hiPSCs in varying ratios; for layering them into cardiac patches to test their in-vitro functionality and ability to integrate ono infarcted heart walls in vivo. Our hypothesis is that by varying CM and non-CM cell ratios within the cell sheets, and by strategically layering them will yield an optimized functional cardiac patch. Specifically we propose to increase the efficiency of differentiation of hiPSC's into CMs and non-CMs including vascular ECs and SMCs. These differentiated cells will be bioprinted to engineer a functional cardiac patch in- vitro by varying the cell ratios and layering arrangements of CMs and non-CMs. As a final part of this project we propose to develop and optimize a patch implantation protocol after left anterior descending artery (LAD) ligation in rats, for testing functionality and in-vivo integration of tissue-engineered cardiac patches in future. Taken together, the proposed project will inform and improve current stem cell therapy for myocardial infarct by revealing mechanisms of cell alignment and assembly that is critical for formation of an engineered cardiac patch. In addition, this effort promises future methodological improvements by bioprinting other molecules for use in scaffolds designed to repair similar soft tissue injuries, with autologous adult derived stem cells.

 描述（通过应用程序证明）：估计有80,000,000名美国成年人（三分之一）有一种或多种类型的心血管疾病（CVD）900,000个心肌梗死史（美国心脏协会）。具有肌肌动感的胶囊离子（MI）是肌肉附近不可逆的，这是由于延长的缺血，导致心律不齐的心律失常。 修复受损的心脏在心脏研究中是主流的。 在宿主心脏组织中。使用人类干细胞发动机的心血管片。斑块在体内积分梗塞的功能，并通过策略性地分层的是ENO的梗塞心脏壁细胞将通过改变CMS和非CMS的细胞比和分层，作为该功能性CardiACC斑块，作为该斑块的最后一部分。并在将来的组织发动机斑块的体内整合。设计用于修复类似的软组织损伤，自体成年干细胞。