Immunoliposome Formation via Microfluidic Flow Focusing

通过微流体流动聚焦形成免疫脂质体

• 批准号: 0966407
• 负责人: Don DeVoe
• 金额: $ 30万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0966407&HistoricalAwards=false
• 关键词: Immunoliposome; Formation; via; Microfluidic; Flow

0966407DeVoeThe utility of liposomes as functional nanoparticles for biological and biomedical applications is presently limited by the bulk production methods used for their manufacture. For example, although considerable progress has been made towards the commercialization of liposomes as drug delivery vehicles, existing production methods result in polydisperse formulations that exhibit variations in drug encapsulation levels, blood clearance rates, and cell uptake, with negative consequences for drug efficacy and toxicity. Our goal here is to develop a fundamental understanding of the physical processes which drive liposome self-assembly in a new microfluidic process, based on the hydrodynamic focusing of two miscible solvent streams. By taking advantage of the unique interactions that occur at the submicron boundary between the solvent streams, small and uniform unilamellar liposomes may be generated in a simple integrated microfluidic chip. We propose a combined computational and experimental effort to improve our understanding of the liposome selfassembly process within the microfluidic system, and apply this understanding to optimize the process for the integrated and in-line formation of functionalized immunoliposomes.Intellectual Merit: The proposed effort is expected to result in three specific advances in the nanoparticle arena, namely (1) theoretical and direct experimental evaluation leading to an improved understanding of the liposome formation process, made possible by the ability of the microfluidic system to precisely specify chemical and molecular distributions within a well-defined laminar mixing zone, (2) a multi-scale model coupling the underlying physics with system-level parameters including channel geometries and flow conditions, and (3) application of this model to demonstrate fully integrated system for the on-demand production of immunoliposomes with minimal polydispersity, and with diameters that may be dynamically tuned by the simple adjustment of on-chip flow conditions. Thus the combined computational and experimental approach will impact our fundamental understanding of the liposome self-assembly process while also leading to the development of a unique and novel tool for controlled liposome and immunoliposome production.Broader Impact: The ability to generate liposomes with tunable and narrowly distributed diameters over a wide size range has important implications for and range of biological and biomedical applications. The high throughput process is directly scalable to large volume production of encapsulated drugs, together with in-line decoration of liposomes with antibodies or other ligands for targeted drug delivery. As a result of these features, the method offers great promise as a simple and low-cost approach to the production of personalized drug preparations in point-of-care settings. Beyond drug delivery, homogeneous liposomes are also of great value for application to immunoassays, where controlled signal amplification can only occur when the liposome populations exhibit a narrow size distribution [1]. In this application, fluorescent encapsulants within the immunoliposomes provide signal amplification for each antibody-antigen interaction, enabling highly sensitive detection. The microfluidic system itself offers a potential base for future development of an integrated immunosensor platform employing on-demand formation of immunoliposomes. The technology will find application in a range of biosensing systems, including portable and ultrasensitive quantitative diagnostic tests. Finally, the project will contribute to the education of next-generation students at the graduate, undergraduate, and K-12 levels. The project will provide interdisciplinary training of one Ph.D. Bioengineering student who will receive training across the fields of bioengineering, mechanical engineering, and chemistry, providing a solid bridge across these disciplines. Undergraduate students will also be recruited to particulate in the research project through an established NSF sponsored Molecular and Cellular Bioengineering REU Program, and local high school seniors will participate in selected experimental aspects of the project through an established internship program.

0966407DevoEthe脂质体作为生物和生物医学应用的功能性纳米颗粒的实用性目前受到用于生产的大量生产方法的限制。例如，尽管作为药物递送车的脂质体商业化已取得了很大的进展，但现有的生产方法导致多分散的配方表现出药物封装水平，血液清除率和细胞摄取的差异，对药物有效性和毒性产生负面影响。我们的目的是基于两个可不用的溶剂流的流体动力焦点，对新的微流体过程中促进脂质体自组装的物理过程进行基本理解。通过利用在溶剂流之间的亚微米边界处发生的独特相互作用，可以在简单的集成微流体芯片中生成小和均匀的Unilamelar脂质体。 We propose a combined computational and experimental effort to improve our understanding of the liposome selfassembly process within the microfluidic system, and apply this understanding to optimize the process for the integrated and in-line formation of functionalized immunoliposomes.Intellectual Merit: The proposed effort is expected to result in three specific advances in the nanoparticle arena, namely (1) theoretical and direct experimental evaluation leading to an improved了解脂质体形成过程，通过微流体系统精确指定化学和分子分布在明确定义的层状混合区域内，（2）多尺度模型将基础物理与系统级别的系统耦合到该模型，并完全集成了该模型的系统，并将其完全集成（3）具有最小多分散性的免疫脂质体，并且直径可以通过简单调整片上流动条件进行动态调节。因此，结合的计算和实验方法将影响我们对脂质体自组装过程的基本理解，同时还导致开发一种独特而新颖的工具，用于控制脂质体和免疫脂体的产生。Boader的影响：使脂质体产生具有可调性的脂质体具有可调型和狭窄的分布式直径和范围范围范围范围范围范围范围范围较大的，并且对生物学和范围进行了范围和范围，并具有生物学的范围。高通量过程直接可扩展到封装药物的大量生产，以及脂质体的在线装饰，脂质体具有抗体或其他配体用于靶向药物的配体。由于这些功能，该方法作为一种简单而低成本的方法提供了巨大的希望，可在护理点环境中生产个性化药物制剂。 除药物递送外，均质脂质体对于免疫测定法也具有很高的价值，在脂质体种群显示狭窄的尺寸分布时，才能发生受控的信号扩增[1]。在此应用中，免疫脂质体内的荧光封装为每种抗体 - 抗原相互作用提供信号放大，从而实现了高度敏感的检测。微流体系统本身为采用免疫脂质体的按需形成的综合免疫传感器平台提供了潜在的基础。该技术将在一系列生物传感系统中找到应用，包括便携式和超敏化定量诊断测试。最后，该项目将有助于研究生，本科和K-12水平的下一代学生的教育。该项目将提供一项博士学位的跨学科培训。生物工程专业的学生将在生物工程，机械工程和化学领域接受培训，并在这些学科中提供坚实的桥梁。本科生还将通过已建立的NSF赞助的分子和蜂窝生物工程REU计划在研究项目中招募，并通过一项既定的实习计划参与该项目的某些实验方面。