Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening.
Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening.
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DOI：
10.1002/bit.26045
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发表时间：
2017-01
影响因子：
3.8
通讯作者：
Shuler ML
中科院分区：
文献类型：
--
作者：
Wang YI;Abaci HE;Shuler ML
有效地递送治疗剂穿过神经保护性血脑屏障（BBB）仍然是中枢神经系统药物开发的巨大挑战。高保真的体外血脑屏障模型可以促进有效的早期筛选靶向脑的候选药物。在这项研究中，我们开发了一种微流控血脑屏障模型，能够模仿在体内血脑屏障的特点，在一个较长的时间，并允许可靠的体外药物渗透性研究下再循环灌注。我们从人诱导多能干细胞（hiPSC）中获得脑微血管内皮细胞（BMEC），并将其与大鼠原代星形胶质细胞在无泵微流控平台上的多孔膜两侧共培养长达10天。微流控系统是基于人脑组织中的血液停留时间设计的，允许介质以生理相关的灌注速率再循环，而不需要泵或外部管道，同时最小化壁剪切应力，以测试微流控BBB模型中体内类屏障特性是否需要剪切应力。这种芯片上BBB模型实现了显著的屏障完整性，如通过连续紧密连接形成和体内类似的跨内皮电阻（TEER）值所证明的。TEER水平在芯片上第3天达到4000 Ω·cm 2以上的峰值，并持续高于2000 Ω·cm 2长达10天，这是微流体模型中报告的最高持续TEER值。我们评估了我们的微流控血脑屏障模型的能力，用于药物渗透性研究，使用大分子（FITC-葡聚糖）和模型药物（咖啡因，西咪替丁，阿霉素）。我们的分析表明，使用我们的模型测量的渗透系数与体内值相当。我们的BBB芯片模型密切模拟生理BBB屏障功能，将成为筛选候选药物的宝贵工具。基于停留时间的微流体平台设计将能够与其他器官模块集成，以模拟药物反应的多器官相互作用。
Efficient delivery of therapeutics across the neuroprotective blood-brain barrier (BBB) remains a formidable challenge for central nervous system drug development. High-fidelity in vitro models of the BBB could facilitate effective early screening of drug candidates targeting the brain. In this study, we developed a microfluidic BBB model that is capable of mimicking in vivo BBB characteristics for a prolonged period and allows for reliable in vitro drug permeability studies under recirculating perfusion. We derived brain microvascular endothelial cells (BMECs) from human induced pluripotent stem cells (hiPSCs) and cocultured them with rat primary astrocytes on the two sides of a porous membrane on a pumpless microfluidic platform for up to 10 days. The microfluidic system was designed based on the blood residence time in human brain tissues, allowing for medium recirculation at physiologically relevant perfusion rates with no pumps or external tubing meanwhile minimizing wall shear stress to test whether shear stress is required for in vivo-like barrier properties in a microfluidic BBB model. This BBB-on-a-chip model achieved significant barrier integrity as evident by continuous tight junction formation and in vivo-like values of trans-endothelial electrical resistance (TEER). The TEER levels peaked above 4000 Ω·cm2 on day 3 on chip and were sustained above 2000 Ω·cm2 up to 10 days, which are the highest sustained TEER values reported in a microfluidic model. We evaluated the capacity of our microfluidic BBB model to be used for drug permeability studies using large molecules (FITC-dextrans) and model drugs (caffeine, cimetidine, and doxorubicin). Our analyses demonstrated that the permeability coefficients measured using our model were comparable to in vivo values. Our BBB-on-a-chip model closely mimics physiological BBB barrier functions and will be a valuable tool for screening of drug candidates. The residence time based design of a microfluidic platform will enable integration with other organ modules to simulate multi-organ interactions on drug response.
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影响因子：
3.2
作者：
Kim, Jeong Ah;Kim, Hong Nam;Choi, Nakwon
通讯作者：
Choi, Nakwon
影响因子：
20.1
作者：
De Keulenaer, GW;Chappell, DC;Griendling, KK
通讯作者：
Griendling, KK
DOI：
10.1152/ajpheart.01047.2006
发表时间：
2007-03-01
影响因子：
4.8
作者：
Chien, Shu
通讯作者：
Chien, Shu
DOI：
10.1007/s10928-011-9229-x
发表时间：
2012-02-01
影响因子：
2.5
作者：
Graf, John F.;Scholz, Bernhard J.;Zavodszky, Maria I.
通讯作者：
Zavodszky, Maria I.
影响因子：
3.8
作者：
Hewitt, Kyle J.;Agarwal, Rachana;Morin, Patrice J.
通讯作者：
Morin, Patrice J.