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 进行性心力衰竭是世界范围内导致死亡的主要原因。这是一种存活率为50%的流行病 超过5年，影响了650万美国人。在心脏病发作、心肌梗死(MI)期间，人类 心脏平均损失10亿个心肌细胞(心脏跳动细胞)。在这里，心脏无法 再生丢失的心肌细胞是众所周知的，导致功能输出显著下降，因为一旦- 健康、可收缩的心肌现在是一种疤痕组织，它不会促进心脏的力量产生 心跳加速。目前的治疗方案仅限于姑息疗法(血管紧张素转换酶抑制剂、β受体阻滞剂) 或脑室辅助装置(感染、血栓形成、电源供应的风险)，历史上唯一真正的治愈方法 一直是心脏移植(供应有限)。因此，我们已经证明了以干细胞为基础的方法-- 用于心肌梗死后移植的衍生型CMS在心脏再生方面显示出良好的前景。这些移植形成长长的- 在小鼠、大鼠和豚鼠身上可以与宿主心肌同步跳动的定期移植物。更重要的是，我们 最近在猕猴身上完成了一项为期4年的关键研究，揭示了干细胞来源的CMS显示 射血分数(每搏动一次的血流量)几乎完全恢复。然而，尽管 这一进展，仍然有几个突出的限制，阻止干细胞来源的心肌细胞 是一种有效的治疗方法。值得注意的是，单细胞悬浮液是目前给药到心脏的方法 使有效的植入成为一个挑战：&lt；20%的注入细胞作为长期、稳定的移植物持续存在，因此， 放贷给高制造成本，并限制新心肌(心肌)的数量 可以形成。使用生物材料平台可以显著提高细胞的存活率和保留率。在……里面 过去，用于工程心脏组织的生物材料选择是心脏贴片或细胞片，但他们的 几何结构限制了这些结构与宿主心肌的电耦合，必须直接缝合 进入心肌(更具侵袭性)。然而，使用可注射的生物材料，如水凝胶 可以原位凝胶(直接与细胞混合)，很有吸引力。它们可以通过导管直接输送到 心肌，为移植细胞直接在心肌梗死部位提供容易的支持和分散，并提供 为细胞搭建支架。两性离子可注射微球(ZIP)微凝胶是可生物降解的，易于调节 化学，并可进行功能化，以支持封装的CMS的需求。在目标1中，我们将解决 ZIP在体外帮助细胞存活和保持的适宜性，以寻找最佳凝胶配方(微凝胶尺寸， 细胞在凝胶上的附着)，以及细胞在凝胶中的存活和增殖。在目标2中，我们将测试 假设我们的ZIP凝胶在用作干细胞注射剂时可以促进体内心脏再生- 通过评估(1)细胞存活、增殖和组织学植入，以及(2)总体 通过核磁共振和超声心动图观察功能结果。这项提案中的研究将直接影响和挑战 干细胞来源的CMS移植用于心脏修复的当前递送方法。