Surgical Microneedle Patch Delivery of CMMP for Heart Repair

外科微针贴片输送 CMMP 用于心脏修复

• 批准号: 9982489
• 负责人: Ke Cheng
• 金额: $ 76.8万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982489
• 关键词: Acute myocardial infarction; Anatomy; Animals; Applications Grants; Biological; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cell Line; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinic; Communication; Control Groups; Cues; Cultured Cells; Data; Development; Disease Progression; Disease model; Encapsulated; Endothelial Cells; Epicardium; Family suidae; Foundations; Future; Growth Factor; Heart; Heart Injuries; Human; Immunology; In Vitro; Infarction; Injections; Ischemia; Logic; Membrane; Modeling; Myocardial; Myocardial Infarction; Myocardium; Nature; Operative Surgical Procedures; Organ; Patients; Pharmaceutical Preparations; Pilot Projects; Procedures; Process; Proteins; Rattus; Regenerative Medicine; Reperfusion Injury; Reperfusion Therapy; Risk; Rodent; Safety; Science; Standardization; Stromal Cells; Structure; Surface; Technology; Testing; Therapeutic; Tissues; Translating; Transplantation; Tumorigenicity; Work; adult stem cell; base; biocompatible polymer; biodegradable polymer; biomaterial compatibility; cardiac repair; clinical translation; clinically relevant; cytotoxicity; disability; experience; heart cell; heart function; immunogenicity; implantation; improved; innovation; mouse model; new technology; particle; preservation; regenerative; release factor; repaired; stem cells

PROJECT SUMMARY Cell-based therapy represents a promising strategy in regenerative medicine. However, live cells need to be carefully preserved and processed before usage. In addition, as “live drugs”, cell transplantation carries certain immunogenicity and/or tumorigenicity risks. The development of cell-free and non-living therapeutics has the potential to revolutionize current regenerative medicine practice. Mounting lines of evidences indicate that adult stem cells exert their beneficial effects mainly through the secretion of pro-regenerative factors. Based on this, the PI Cheng Lab fabricated cell mimicking microparticles (CMMPs) by encapsulating stem cell-secreted factors in a biodegradable polymer block. Our previous studies demonstrated that those “synthetic cells” carried similar secreted proteins and membranes as their parental cells did. In a mouse model of myocardial infarction (MI), intramyocardial injection of CMMPs led to preservation of viable myocardium and augmentation of cardiac functions similar to cell therapy. Despite the successful proof of concept, a big challenge is the effective delivery of those therapeutic microparticles to the heart. Cardiac patches have been tested to deliver therapeutic cells to the surface of the heart. One caveat is that there is a lack of patch-host communication due to poor integration of the cardiac patch with the host myocardium. The MPI Gu Lab is experienced in the fabrication of microneedle (MN) patches. Our previous studies indicated that MN patch can deliver therapeutics to the tissue effectively. The present R01 proposal represents a logic progression from our previous work while bringing new technologies. Here we will be developing and testing a new entity: a MN-CMMP cardiac patch formed by embedding CMMPs into biodegradable and biocompatible microneedle cardiac patches. In addition, our studies will extend from the previous rodent acute MI model to a chronic MI model in both small/large animals. The overarching hypothesis is that MN-CMMP can further improve the efficacy of CMMP therapy in rats and pigs with chronic heart injury. AIM 1: Fabricate MN-CMMP comprised of microneedle patch loaded with CMMPs; Determine in vitro potency of MN-CMMP in cultured cells. AIM 2: Determine the safety and efficacy of MN-CMMP therapy in rat model of chronic MI. AIM 3: Translate the findings into clinically-relevant porcine models of heart injury. Our study will form the foundation for an innovative and “off the shelf” therapy based on secreted factors and myocardium matrix that can be standardized from donor stem cell lines and xenogenic cardiac tissues. The cell-free nature of our approach is more readily translatable to the clinic. Although this particular grant application targets the heart and cardiac stem cells, our approach represents a platform technology that can be applied to the creation of multiple types of synthetic stem cell and organ matrices for the repair of various other organs.

项目概要 基于细胞的治疗代表了再生医学中一种有前途的策略。然而，活细胞需要 使用前仔细保存和处理。此外，细胞移植作为“活药”，具有一定的作用。 免疫原性和/或致瘤性风险。无细胞和非生命疗法的发展 彻底改变当前再生医学实践的潜力。越来越多的证据表明，成人 干细胞主要通过分泌促再生因子发挥其有益作用。基于此， PI Cheng实验室通过封装干细胞分泌的细胞模拟微粒（CMMP） 可生物降解聚合物嵌段中的因素。我们之前的研究表明，那些“合成细胞” 携带与亲代细胞相似的分泌蛋白和膜。在小鼠心肌模型中 心肌梗死 (MI) 时，心肌内注射 CMMP 可保存存活的心肌并增强心肌功能 与细胞疗法类似的心脏功能。尽管概念验证取得了成功，但一个巨大的挑战是 将这些治疗微粒有效递送至心脏。心脏贴片经过测试可以提供 治疗细胞到达心脏表面。需要注意的是，由于补丁主机之间缺乏通信 心脏补片与宿主心肌的整合不良。 MPI Gu 实验室在以下方面经验丰富： 微针（MN）贴片的制造。我们之前的研究表明 MN 贴片可以提供治疗作用 有效地到达组织。目前的 R01 提案代表了我们之前工作的逻辑进展，同时 带来新技术。在这里，我们将开发和测试一个新实体：MN-CMMP 心脏贴片 通过将 CMMP 嵌入可生物降解且生物相容的微针心脏贴片中而形成。此外， 我们的研究将从之前的啮齿动物急性心肌梗死模型扩展到小型/大型慢性心肌梗死模型 动物。总体假设是 MN-CMMP 可以进一步提高 CMMP 治疗的疗效 患有慢性心脏损伤的大鼠和猪。目标1：制造由加载的微针贴片组成的MN-CMMP 与 CMMP 一起使用；确定 MN-CMMP 在培养细胞中的体外效力。目标 2：确定安全性和 MN-CMMP 疗法对慢性 MI 大鼠模型的疗效。目标 3：将研究结果转化为临床相关的结果 猪心脏损伤模型。我们的研究将为创新和“现成”疗法奠定基础 基于可以从供体干细胞系标准化的分泌因子和心肌基质， 异种心脏组织。我们的方法的无细胞性质更容易转化为临床。 尽管这项特殊的拨款申请针对的是心脏和心脏干细胞，但我们的方法代表了一种 可应用于多种类型合成干细胞和器官创建的平台技术 用于修复各种其他器官的基质。