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

描述（由申请人提供）：本研究的总体目标是开发一种新型体外微流控平台，以测试药物或递送载体渗透血脑屏障（BBB）的能力。与目前的大型静态孵育技术相比，我们提出的设备包括一个微流体双室室。该腔室的设计方式允许在适当的微循环尺寸和流动条件下对输送/渗透进行可视化评估，同时简化了设备制造。顶端一侧播种内皮细胞（通过渗透性和通量试验证明），基底外侧支持胶质细胞共培养。增强的生理真实性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、更大的库覆盖范围、更低的成本、更快的周转时间和更多的机制知识，有利于药物发现工作。第一阶段的研究旨在开发微流控血脑屏障的原型，适应内皮细胞培养的方案，并将以明确展示改善的屏障功能而告终。第二阶段计划进行芯片和培养优化以及体内验证。与细胞生物医学系统（CFDRC）和BBB模型（范德比尔特大学）的专业知识的多学科合作伙伴关系已经形成。该项目旨在开发一种体外筛选模型，用于筛选候选药物穿过血脑屏障并随后引起治疗或毒性作用的潜力。通过提供准确的预测数据，该模型将减少对动物模型的需求，并有望减少晚期候选药物失败和加速中枢神经系统（CNS）治疗开发。该产品将商业化给制药公司、药物研究实验室和从事新型神经治疗研究和中枢神经系统毒性的大学/非营利中心。同样重要的是，它也有望刺激基础研究，在那里它可以用于研究血脑屏障（天）功能的生物学机制。

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.