A Novel Physicologically Realistic Microfluidic In-vitro Blood-brain Barrier Mode

一种新颖的生理真实微流控体外血脑屏障模式

• 批准号: 7612583
• 负责人: BALABHASKAR PRABHAKARPANDIAN
• 金额: $ 16.02万
• 依托单位: CFD RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612583
• 关键词: Anatomy; Animal Model; Animals; Apical; Astrocytes; Basic Science; Behavior; Biochemical; Biological; Biological Assay; Blood; Blood - brain barrier anatomy; Blood flow; Brain; Capillary Endothelial Cell; Cell model; Cells; Characteristics; Chemicals; Coculture Techniques; Computer Simulation; Conditioned Culture Media; Connexins; Decision Making; Development; Devices; Drug Delivery Systems; E-Cadherin; Endothelial Cells; Evaluation; Failure; Government; Imagery; In Vitro; Industry; Knowledge; Libraries; Measurement; Measures; Methods; Microcirculation; Microfluidics; Modeling; Monitor; Neuraxis; Neuroglia; Neurologic; Permeability; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Physiological; Plasma Proteins; Plastics; Protocols documentation; Rattus; Reagent; Research; Screening procedure; Side; Simulate; Staging; Techniques; Testing; Therapeutic; Therapeutic Human Experimentation; Tight Junctions; Time; Toxic effect; Universities; Validation; Visual; Work; base; cost; data modeling; design; drug candidate; drug discovery; hemodynamics; improved; in vivo; instrumentation; meetings; novel; protein expression; prototype; public health relevance; receptor expression; shear stress; therapeutic development

DESCRIPTION (provided by applicant): The overall objective of this study is to develop a novel in vitro microfluidic platform to test a drug or delivery vehicle's ability to permeate the Blood-Brain Barrier (BBB). In contrast with current large-sized, static incubation techniques, our proposed device comprises of a microfluidic two-compartment chamber. The chamber is designed in such a way as to permit visualization-friendly evaluation of transport/permeation under appropriate microcirculatory size and flow conditions, while simultaneously simplifying device fabrication. The apical side is seeded with endothelial cells (demonstrated for permeability and flux assays) and the basolateral side supports glial cell co-cultures. The increased physiological realism will substantially improve BBB characteristics including formation of tight junctions and expression of relevant transporters. The new platform offers greater throughput, increased library coverage, lower cost, rapid turnaround times and increased mechanistic knowledge benefiting drug discovery efforts. Phase I study seeks to develop a prototype of the microfluidic BBB, adapt protocols for culturing endothelial cells and will culminate with a clear demonstration of improved barrier function. Chip and culture optimization as well as in vivo validation are planned for Phase II. A multi-disciplinary partnership with expertise in cellular BioMEMS (CFDRC) and BBB Models (Vanderbilt University) has been formed. PUBLIC HEALTH RELEVANCE The project seeks to develop an in vitro screening model for screening the potential of drug candidates to cross the BBB and subsequently cause therapeutic or toxic effects. By providing accurate and predictive data, the model will reduce the need for animal models and promises to both reduce late stage drug candidate failures and accelerate central nervous system (CNS) therapeutic development. The product will be commercialized to pharmaceutical firms, drug research labs and universities/non-profit centers engaged in novel neurological therapeutics research and CNS toxicity. Equally important, it is also expected to spur basic research, where it can be used to study the biological mechanisms of BBB (dys) function.

描述(申请人提供)：这项研究的总体目标是开发一种新型的体外微流控平台，以测试药物或给药载体渗透血脑屏障(BBB)的能力。与目前的大型静态孵化技术不同，我们提出的设备包括一个微流控两室室。该试验室的设计允许在适当的微循环大小和流动条件下对传输/渗透进行可视化友好的评估，同时简化设备制造。顶端种植内皮细胞(渗透性和通透性分析显示)，基底外侧支持神经胶质细胞共培养。生理现实主义的增强将大大改善血脑屏障的特征，包括紧密连接的形成和相关转运蛋白的表达。新平台提供了更大的吞吐量、更大的图书馆覆盖率、更低的成本、更快的周转时间和更多有利于药物发现工作的机械知识。第一阶段的研究旨在开发微流控血脑屏障的原型，采用培养内皮细胞的方案，最终将明确证明改善的屏障功能。第二阶段计划进行芯片和培养优化以及体内验证。在细胞生物微机械(CFDRC)和BBB模型(Vanderbilt University)方面的专业知识已经形成了多学科合作伙伴关系。与公共卫生的相关性该项目寻求开发一种体外筛选模型，用于筛选候选药物跨越血脑屏障并随后引起治疗或毒性作用的可能性。通过提供准确和可预测的数据，该模型将减少对动物模型的需求，并承诺既减少晚期候选药物失败，又加快中枢神经系统(CNS)治疗开发。该产品将向从事新型神经疗法研究和中枢神经系统毒性研究的制药公司、药物研究实验室和大学/非营利性中心商业化。同样重要的是，它还有望促进基础研究，在这些研究中，它可以用于研究血脑屏障(Dys)功能的生物学机制。