Zwitterionic Injectable Pellet (ZIP) microgels as an injectable cell carrier for iPSC-CMs for myocardial repair

两性离子注射颗粒 (ZIP) 微凝胶作为 iPSC-CM 的可注射细胞载体，用于心肌修复

• 批准号: 10223917
• 负责人: Mary Elizabeth O'Kelly
• 金额: $ 4.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2022-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223917
• 关键词: Address; Adrenergic beta-Antagonists; Adult; Adverse effects; Affect; American; Angiotensin-Converting Enzyme Inhibitors; Binding; Biocompatible Materials; Caliber; Cardiac; Cardiac Myocytes; Catheters; Cause of Death; Cavia; Cell Proliferation; Cell Survival; Cell Therapy; Cell Transplantation; Cell-Matrix Junction; Cells; Cellular Infiltration; Chemistry; Cicatrix; Clinic; Complex; Coupling; Diffuse; EFRAC; Echocardiography; Electrophysiology (science); Encapsulated; Engraftment; Environment; Epidemic; Exhibits; Fibrin; Formulation; Freeze Drying; Gel; Geometry; Goals; Graft Survival; Heart; Heart Diseases; Heart Transplantation; Heart failure; Histologic; Human; Hydrogels; Immobilization; Implant; In Situ; In Vitro; Infarction; Inflammation; Injectable; Injections; Libraries; Ligands; Liquid substance; Macaca; Magnetic Resonance Imaging; Measures; Mechanics; Methods; Monkeys; Mus; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Needles; Output; Peptides; Pharmaceutical Preparations; Pluripotent Stem Cells; Polymer Chemistry; Polymers; Powder dose form; Power Sources; Production; Property; Proteins; Prunella vulgaris; Rattus; Recovery; Regimen; Research; Rodent; Sampling; Signaling Molecule; Site; Surgical sutures; Survival Rate; Suspensions; Synthesis Chemistry; System; Techniques; Technology; Testing; Therapeutic; Thick; Thinness; Thoracotomy; Thrombosis; Tissues; Translations; Transplantation; Vascularization; base; biomaterial compatibility; blood pump; capsule; cardiac regeneration; cardiac repair; cardiac tissue engineering; career; cost; crosslink; design; effective therapy; functional improvement; functional outcomes; heart cell; heart function; human pluripotent stem cell; implantation; improved; in vivo; in vivo regeneration; induced pluripotent stem cell; infection risk; minimally invasive; monomer; palliative; particle; post-transplant; repaired; scaffold; stem cell based approach; stem cell therapy; stem cells; therapy development; ventricular assist device

Project Summary Progressive heart failure is the leading cause of death worldwide. It is an epidemic with a survival rate of 50% over 5 years, affecting 6.5 million Americans. During a heart attack, a myocardial infarction (MI), the human heart loses 1 billion cardiomyocytes (CMs) on average (beating cells of the heart). Here, the heart’s inability to regenerate lost cardiomyocytes is well-known, leading to a significant decline in functional output as the once- healthy, contractile myocardium is now a scar tissue that does not contribute to the force production of a beating heart. Current treatment options are limited to palliative drug regimens (ACE inhibitors, beta blockers) or ventricular assist devices (risk of infection, thrombosis, power supply), and, the only real cure historically has been a heart transplant (limited supply). Thus, we have shown that a stem-cell based approach with stem-cell- derived-CMs for transplantation post-MI shows promise in regenerating the heart. These transplants form long- term grafts that can beat synchronously with host myocardium in mice, rats, and guinea pigs. Even moreso, we recently completed a 4-year pivotal study in macaque monkeys that revealed stem-cell-derived-CMs show nearly complete recovery of ejection fraction (the amount of blood pumped with each beat). However, despite this progress, there are still several outstanding limitations keeping stem-cell-derived-cardiomyocytes from being an effective therapy. Notably, single-cell-suspensions are the current delivery method to the heart making effective engraftment a challenge: <20% of injected cells persist as long-term, stable grafts, thus, lending to high manufacturing costs, and limiting the amount of new myocardium (heart muscle) that can form. Cell survival and retention could be significantly improved with the use of a biomaterial platform. In the past, biomaterial options for engineered heart tissues have been cardiac patches or cells sheets, but their geometries limit these constructs from electrically coupling with host myocardium and must be directly sutured onto the myocardium (more invasive). However, the use of an injectable biomaterial, such as a hydrogel that can gel in situ (directly mixed with cells), is appealing. They can be delivered directly through a catheter into myocardium, provide easy support and dispersion of transplanted cells directly at the site of MI, and provide a scaffold for the cells. Zwitterionic Injectable Pellet (ZIP) microgels are biodegradable, have easily tunable chemistry, and can be functionalized to support the needs of encapsulated CMs. In Aim 1, we will address the suitability for ZIP to aid in cell survival and retention in vitro, to discover optimal gel formulation (microgel size, cell attachment to gel), as well as cell survival and proliferation within the gel. In Aim 2, we will test the hypothesis that our ZIP gel can improve cardiac regeneration in vivo when used as an injectate for stem-cell- derived-CMs by evaluating both (1) cell survival, proliferation, and engraftment histologically, and, (2) overall functional outcome via MRI and echocardiography. Studies in this proposal will directly impact and challenge current delivery methods for stem-cell-derived-CMs transplanted for cardiac repair.

项目摘要 进步的心力衰竭是全球死亡的主要原因。这是一种流行病，生存率为50％ 超过5年，影响了650万美国人。在心脏病发作，心肌梗死（MI），人类 心脏平均失去10亿个心肌细胞（CMS）（心脏跳动细胞）。在这里，内心无法 再生损失的心肌细胞是众所周知的，导致功能输出显着下降，因为 健康，收缩的心肌现在是一种疤痕组织，不影响力的力量 跳动的心。当前的治疗选择仅限于姑息药物方案（ACE抑制剂，β受体阻滞剂） 或心室辅助设备（感染风险，血栓形成，电源），以及历史上唯一的真正治愈方法 是心脏移植（供应有限）。这是我们已经表明，基于干细胞的基于干细胞的方法 MI后移植的派生CMS显示出对心脏再生的希望。这些移植形成长长 术语移植物可以与小鼠，大鼠和豚鼠中的宿主心肌同步击败。甚至莫雷索，我们 最近在猕猴中完成了一项为期4年的关键研究，该研究揭示了干细胞衍生的CMS 几乎完全恢复了射血分数（每次节拍的血液量）。但是，多皮 这一进展，仍然存在一些突出的局限 是一种有效的疗法。值得注意的是，单细胞悬浮是当前对心脏的输送方法 使有效的植入成为挑战：<20％的注射细胞持续存在为长期，稳定的移植物，因此 贷款用于高生产成本，并限制了新的心肌（心肌）的数量 可以形成。使用生物材料平台可以显着改善细胞存活和保留率。在 过去的工程心组织生物材料选择是心脏斑块或细胞表，但它们 几何形状限制了这些构建体与宿主心肌的电子耦合，必须直接缝合 进入心肌（更具侵入性）。但是，使用可注射的生物材料，例如水凝胶 可以原位凝胶（直接与细胞混合）可以出现。它们可以直接通过导管传递到 心肌，在MI部位直接提供移植细胞的轻松支撑和分散，并提供 细胞的脚手架。 Zwitterion可注射颗粒（ZIP）微凝胶是可生物降解的，很容易调节 化学，可以功能化以支持封装的CMS的需求。在AIM 1中，我们将解决 拉链有助于在体外有助于细胞存活和保留率的适用性，以发现最佳的凝胶配方（微凝胶尺寸， 细胞附着在凝胶上），以及凝胶内的细胞存活和增殖。在AIM 2中，我们将测试 假设我们的拉链凝胶可以改善体内的心脏再生，因为用作干细胞的注射 通过（1）细胞的存活，增殖和植入组织学和（2）总体评估（1）细胞存活，增殖和植入。 通过MRI和超声心动图的功能结果。该提案中的研究将直接影响和挑战 用于心脏修复的移植的干细胞衍生CMS的当前输送方法。