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（由申请人提供）：这项研究的总体目的是开发一种新型的体外微流体平台，以测试药物或输送工具渗透血脑屏障（BBB）的能力。与当前的大尺寸静态孵育技术相反，我们提出的设备包括一个微流体的两室室。该腔室的设计是允许在适当的微循环尺寸和流动条件下对传输/渗透的可视化评估，同时简化设备的制造。顶端用内皮细胞接种（证明是渗透性和通量测定），基底外侧侧支持神经胶质细胞共培养。生理现实主义的增加将基本上改善BBB特征，包括形成紧密连接和相关转运蛋白的表达。新平台提供了更大的吞吐量，增加的图书馆覆盖范围，较低的成本，快速的周转时间以及增加的机械知识，从而使药物发现工作受益。第一阶段的研究旨在开发微流体BBB的原型，适应用于培养内皮细胞的方案，并将清楚地证明改善的屏障功能。计划针对第二阶段进行芯片和培养优化以及体内验证。已经建立了具有蜂窝生物元（CFDRC）和BBB模型（范德比尔特大学）专业知识的多学科合作伙伴关系。公共卫生相关性该项目旨在开发一种体外筛查模型，以筛查候选药物越过BBB并随后引起治疗或有毒作用的潜力。通过提供准确和预测的数据，该模型将减少对动物模型的需求，并承诺既减少候选药物的失败，又可以加速中枢神经系统（CNS）治疗性发育。该产品将用于制药公司，药物研究实验室和大学/非营利性中心，从事新型神经学治疗研究和CNS毒性。同样重要的是，它也有望刺激基础研究，可以使用它来研究BBB（DYS）功能的生物学机制。