Surgical Microneedle Patch Delivery of CMMP for Heart Repair

项目总结 基于细胞的治疗代表了再生医学中一种很有前途的策略。然而，活细胞需要 在使用前仔细保存和加工。此外，作为“活药”，细胞移植携带着一定的 免疫原性和/或致瘤性风险。无细胞和非生物疗法的发展具有 有可能使当前的再生医学实践发生革命性的变化。越来越多的证据表明，成年人 干细胞主要通过分泌促再生因子发挥其有益作用。在此基础上， 皮城实验室通过包裹干细胞分泌的方式制备了细胞模拟微粒(CMMP) 可生物降解聚合物块中的因素。我们之前的研究表明，这些“合成细胞” 它们携带的分泌蛋白质和细胞膜与它们的亲代细胞相似。在心肌梗死小鼠模型中 心肌梗死(MI)后，心肌内注射CMMPs可使存活心肌得到保护和增强 心脏功能类似于细胞疗法。尽管成功地进行了概念验证，但最大的挑战是 有效地将这些治疗性微粒输送到心脏。心脏贴片已经过测试，可以提供 治疗性细胞进入心脏表面。需要注意的是，由于缺少补丁程序与主机之间的通信 导致心脏补片与宿主心肌结合不良。MPI Gu实验室在 制作微针(MN)贴片。我们以前的研究表明，MN贴剂可以提供治疗作用 有效地转移到组织中。本R01提案代表了我们先前工作的逻辑进展，而 带来新技术。在这里，我们将开发和测试一种新的实体：MN-CMMP心脏贴片 将CMMP嵌入到可生物降解和生物兼容的微针心脏贴片中形成。此外, 我们的研究将从先前的啮齿动物急性心肌梗死模型扩展到大/小鼠的慢性心肌梗死模型 动物。最重要的假设是MN-CMMP可以进一步提高CMMP治疗的疗效。 慢性心脏损伤的大鼠和猪。目的1：制备微针贴片MN-CMMP 用CMMPS检测MN-CMMP在培养细胞中的体外效力。目标2：确定安全和 MN-CMMP对慢性心肌梗死大鼠模型的治疗作用目标3：将研究结果转化为临床相关研究 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。我们方法的无细胞本质更容易移植到临床上。 虽然这种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 可应用于创造多种类型的合成干细胞和器官的平台技术 用于修复各种其他器官的基质。

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.