3D Nanoporous microcontainers for cell encapsulation therapy

用于细胞封装治疗的 3D 纳米多孔微容器

• 批准号: 7454037
• 负责人: David H Gracias
• 金额: $ 19.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454037
• 关键词: Biochemical; Biodegradation; Cell Therapy; Cell Transplants; Cells; Characteristics; Chemicals; Class; Clinical; Clinical Trials; Defect; Devices; Diabetes Mellitus; Diffusion; Disease; Electromagnetic Fields; Electron Microscopy; Elements; Encapsulated; Engineering; Environment; Exclusion; Face; Frequencies; Glucose; Hemophilia A; Image; Immune; Immune response; Immune system; Immunoglobulin G; Immunosuppression; Implant; In Vitro; Insulin; Invasive; Islet Cell; Islets of Langerhans; Kidney Failure; Life; Literature; Magnetic Resonance Imaging; Malignant Neoplasms; Mechanics; Membrane; Monitor; Morphology; Nutrient; Operative Surgical Procedures; Optics; Parkinson Disease; Polystyrenes; Porosity; Process; Property; Public Health; Publishing; Radio; Range; Reproducibility; Research; Shapes; Technology; Therapeutic; Therapeutic immunosuppression; Time; Translating; Transplantation; Universities; X-Ray Computed Tomography; Xenograft procedure; biomaterial compatibility; capsule; cellular engineering; chemical stability; concept; day; diabetes mellitus therapy; dosage; expectation; implantation; improved; instrumentation; interest; nanolitre; nanolitre scale; prevent; research study; self assembly; simulation; size

DESCRIPTION (provided by applicant): Cell encapsulation therapy (CET) provides an attractive means to transplant cells (allo- or xenotransplantation) without the need for immunosuppression. Typically, the cell encapsulant protects the cells from immune rejection by surrounding them with an artificial, semipermeable nanoporous size exclusion membrane that allows selective permeation of nutrients and therapeutic molecules to and from cells while preventing elements of the immune system from attacking the encapsulated cells. Despite considerable interest and several clinical trials, the technology is limited by a range of challenges including a lack of reproducibility; the inability to fabricate uniform capsules in terms of shape, size, morphology, and porosity; biofouling of implanted encapsulants due to tortuous porosity; the lack of chemical and mechanical stability of the encapsulants; and the inability to image transplanted cells to monitor efficacy. The result is that progress in the field has not lived up to expectations. We have developed a new class of nanoliter scale, porous containers using a combination of lithographic fabrication and self-assembly. Additionally, we have obtained preliminary results that provide evidence that containers with a pore size as small as 20 nm can be fabricated. The containers have excellent chemical and mechanical stability, minimizing the possibility of biodegradation; identical shapes, sizes and precise volumetric control that will facilitate predictable dosages and improve reproducibility in transplantation; and straight monodisperse porosity that is known to be less susceptible to biofouling. Moreover, since the containers are metallic, they interact with remote electromagnetic fields that allow them to be monitored, controlled and imaged non- invasively using radio frequency instrumentation such as magnetic resonance imaging (MRI) and computed tomography (CT). We propose to build on the preliminary process developed to fabricate nanoporous (20 nm pores) containers to facilitate their use in CET. We also propose to evaluate the in-vitro efficacy of the nanoporous containers in the delivery of insulin from encapsulated pancreatic islet cells. The nanoporous, metallic, self-assembled containers represent an entirely new class of precisely engineered encapsulants that will overcome the limitations of present day devices used in CET. CET is highly relevant to public health as it provides a range of promising therapeutic treatments for a wide range of diseases such as diabetes, hemophilia, cancer, renal failure, and Parkinson's disease. We propose to fabricate nanoporous, metallic, self-assembled containers that represent an entirely new class of precisely engineered cell encapsulants that will overcome the limitations of present day devices used in cell encapsulation therapy (CET). CET is highly relevant to public health as it provides a range of promising therapeutic treatments for a wide range of diseases such as diabetes, hemophilia, cancer, renal failure, and Parkinson's disease.

描述（由申请人提供）：细胞包封疗法（CET）提供了一种有吸引力的方法来移植细胞（同种或异种移植），而不需要免疫抑制。通常，细胞包封剂通过在细胞周围包裹一层人工的、半透性的纳米孔大小的隔离膜来保护细胞免受免疫排斥，这种隔离膜允许营养物质和治疗分子选择性地进出细胞，同时防止免疫系统的元素攻击被包封的细胞。尽管有相当大的兴趣和一些临床试验，该技术受到一系列挑战的限制，包括缺乏可重复性；无法在形状、大小、形态和孔隙度方面制造均匀的胶囊；由于扭曲孔隙造成植入胶囊的生物污染；封装剂缺乏化学和机械稳定性；以及无法对移植细胞成像来监测疗效。结果是，该领域的进展没有达到人们的期望。我们已经开发了一种新型的纳米级多孔容器，采用光刻制造和自组装相结合的方法。此外，我们已经获得的初步结果提供了证据，证明孔径小至20纳米的容器可以被制造出来。该容器具有优异的化学和机械稳定性，最大限度地减少了生物降解的可能性；相同的形状、大小和精确的体积控制，有助于预测剂量并提高移植的可重复性；而直的单分散孔隙，已知不易受生物污染的影响。此外，由于容器是金属的，它们与远程电磁场相互作用，使它们能够使用诸如磁共振成像（MRI）和计算机断层扫描（CT）等射频仪器进行非侵入性监测、控制和成像。我们建议在初步开发的工艺基础上制造纳米孔（20纳米孔）容器，以促进其在CET中的应用。我们还建议评估纳米多孔容器在体外从包封的胰岛细胞输送胰岛素的功效。纳米多孔、金属、自组装的容器代表了一种全新的精确设计的封装剂，它将克服目前在CET中使用的设备的局限性。CET与公共卫生高度相关，因为它为糖尿病、血友病、癌症、肾衰竭和帕金森病等多种疾病提供了一系列有希望的治疗方法。我们建议制造纳米多孔、金属、自组装的容器，它代表了一种全新的精确工程细胞包封剂，将克服目前用于细胞包封治疗（CET）的设备的局限性。CET与公共卫生高度相关，因为它为糖尿病、血友病、癌症、肾衰竭和帕金森病等多种疾病提供了一系列有希望的治疗方法。