MSC Encapsulation with Thin Gel Coating

具有薄凝胶涂层的 MSC 封装

• 批准号: 9383973
• 负责人: David J Mooney
• 金额: $ 68.53万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383973
• 关键词: Address; Alginates; Biocompatible Materials; Blood Circulation; Cell Survival; Cell Therapy; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Cellular biology; Chemicals; Clinical; Clinical Trials; Devices; Disease; Effectiveness; Encapsulated; Gel; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hydrogels; Infusion procedures; Injectable; Intra-Arterial Infusions; Intravenous; Intravenous infusion procedures; Life; Mesenchymal Stem Cells; Microfluidics; Myocardial Infarction; Outcome; Patients; Process; Property; Proteins; Rodent Model; Savings; Stem cells; Technology; Thinness; Time; Transplantation; Treatment Efficacy; United States National Institutes of Health; Work; base; chemical property; clinical application; clinically relevant; flexibility; graft vs host disease; improved; in vivo; intraperitoneal; new technology; novel strategies; paracrine; particle; physical property; preclinical study; research clinical testing; scale up; stem cell biology; success; tool; viscoelasticity; web site

Mesenchymal stem cell (MSC) therapies are currently in widespread clinical testing for a number of diseases, but a common theme of trials to date is the massive loss of the MSCs following transplantation. This outcome likely relates to the approach utilized for delivery – clinical trials typically utilize intravenous (iv) infusion of suspended cells. In contrast, encapsulation of cells in various materials has been widely explored in preclinical studies to enhance transplanted cell survival, but the resulting particles and devices have been too large to allow iv infusion, providing a significant practical obstacle to their clinical implementation. Further, as the bioactivity of MSCs is now widely ascribed to paracrine secretions, control over the secretome of the cells following transplantation may be crucial to their clinical success. We recently developed a highly efficient microfluidic process to encapsulate single cells in a very thin layer of hydrogel (~ 5 microns); this thin coating still allows cells to be infused intravenously, but dramatically increases both their survival and the duration of their secreted products in the bloodstream. We hypothesize this technology will provide a timely new tool for MSC therapies and dramatically expand their clinical utility. Here, we propose to further develop this new technology, and to study its utility in context of hematopoietic stem cell therapy (HSCT). We have put together a unique team to address the hypothesis underlying this project, with leaders in microfluidics technology (Weitz), biomaterials (Mooney), and hematopoietic stem cell (HSC) biology and HSCT (Scadden). We will pursue our objectives by: (1) Tune the chemical and physical properties of microgels, and scale-up the microfluidics technology to enable clinically relevant numbers of MSCs to be encapsulated with high efficiency, (2) Determine how MSC persistence and paracrine secretions following transplantation can be tuned, both qualitatively and quantitatively, by the chemical and physical properties of the encapsulating alginate hydrogel, and (3) Study the impact of gel-encapsulated MSCs, following intravenous infusion, on the treatment of graft versus host disease (GVHD) following HSCT in a rodent model. At the completion of these studies we will have validated the effectiveness and practicality of this approach to MSC therapy. Importantly, the results of these studies will help to define how the MSC secretome impacts the effectiveness of MSCs in GVHD, and the importance of immunoprotection of the MSCs following transplantation. Further, this approach is also likely to be broadly useful to the wide array of other clinical applications of MSCs and to the use of many other types of stem cells.

间充质干细胞（MSC）疗法目前正在对多种疾病进行宽度临床测试， 但是迄今为止，试验的一个共同主题是移植后MSC的大规模损失。这个结果 可能与用于交付的方法有关 - 临床试验通常使用静脉内（IV）输注 悬浮的细胞。相反，在临床前广泛探索了各种材料中细胞的包封 提高移植细胞存活的研究，但是所产生的颗粒和设备太大了 允许静脉输注，为其临床实施提供了重大的实际障碍。此外，作为 MSC的生物活性现在已广泛归因于旁分泌分泌，控制细胞的分泌组 移植后可能对他们的临床成功至关重要。我们最近开发了一个高效的 微流体过程将单个细胞封装在非常薄的水凝胶（〜5微米）中；这个薄的涂层 仍然允许静脉注入细胞，但会大大增加其存活和持续时间 他们在血液中分泌的产品。我们假设这项技术将为及时的新工具提供 MSC疗法并大大扩展其临床实用性。在这里，我们建议进一步发展这个新的 技术，并在造血干细胞疗法（HSCT）的背景下研究其效用。我们把 一个独特的团队，旨在解决该项目的基础假设，与微流体技术领导者 （Weitz），生物材料（Mooney）和造血干细胞（HSC）生物学和HSCT（Scadden）。我们将 追求我们的目标：（1）调整微凝胶的化学和物理特性，并扩大 微流体技术使能够以高效率封装临床相关的MSC， （2）确定可以调节移植后的MSC持久性和旁分泌分泌物 定性和定量，通过封装藻酸盐的化学和物理特性， （3）研究静脉输注后凝胶包含的MSC的影响，对移植物治疗 HSCT在啮齿动物模型中与宿主疾病（GVHD）相比。完成这些研究时，我们将 已经验证了这种方法对MSC治疗的有效性和实用性。重要的是，结果 这些研究将有助于定义MSC的分泌组如何影响MSC在GVHD中的有效性，以及 移植后MSC免疫保护的重要性。此外，这种方法也可能 对于MSC的其他临床应用和使用许多其他类型的其他临床应用非常有用 干细胞。