A microfluidic 3D hepatocyte chip for drug toxicity testing

被引:325
作者
Toh, Yi-Chin [1 ]
Lim, Teck Chuan [1 ]
Tai, Dean [1 ]
Xiao, Guangfa [1 ,2 ,3 ]
van Noort, Danny [1 ]
Yu, Hanry [1 ,2 ,4 ,5 ,6 ,7 ]
机构
[1] ASTAR, Inst Bioengn & Nanotechnol, Singapore 138669, Singapore
[2] Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore
[3] Cent S Univ, Dept Gen Surg, XiangYa Hosp, Changsha 410008, Hunan, Peoples R China
[4] Singapore MIT Alliance, Singapore 117576, Singapore
[5] Natl Univ Singapore, DSO Labs, NUS Tissue Engn Programme, Singapore 117597, Singapore
[6] Natl Univ Singapore Hosp, Dept Haematol Oncol, Singapore 119074, Singapore
[7] CeLS, NUS Grad Sch Integrat Sci & Engn, Grad Program Bioengn, Singapore 117456, Singapore
基金
英国医学研究理事会;
关键词
IN-VITRO MODELS; CHEMICAL ENTITIES; PERFUSION-CULTURE; ENZYME-INDUCTION; RAT HEPATOCYTES; HEPATOTOXICITY; CYTOTOXICITY; LIVER; DISCOVERY; CELLS;
D O I
10.1039/b900912d
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
We have developed a microfluidic 3D hepatocyte chip (3D HepaTox Chip) for in vitro drug toxicity testing to predict in vivo drug hepatotoxicity. The 3D HepaTox Chip is based on multiplexed microfluidic channels where a 3D microenvironment is engineered in each channel to maintain the hepatocytes' synthetic and metabolic functions. The multiplexed channels allow for simultaneous administration of multiple drug doses to functional primary hepatocytes while an incorporated concentration gradient generator enables the in vitro dose-dependent drug responses to predict in vivo hepatotoxicity. The IC50 values of 5 model drugs derived from the dose-dependent on-chip testing correlate well with the reported in vivo LD50 values. The 3D HepaTox Chip can be integrated with on-chip sensors and actuators as the next generation cell-based on-chip drug testing platform.
引用
收藏
页码:2026 / 2035
页数:10
相关论文
共 40 条
[1]   Structural polarity and functional bile canaliculi in rat hepatocyte spheroids [J].
Abu-Absi, SF ;
Friend, JR ;
Hansen, LK ;
Hu, WS .
EXPERIMENTAL CELL RESEARCH, 2002, 274 (01) :56-67
[2]   Trends in the development of microfluidic cell biochips for in vitro hepatotoxicity [J].
Baudoin, Regis ;
Corlu, Anne ;
Griscom, Laurent ;
Legallais, Cecile ;
Leclerc, Eric .
TOXICOLOGY IN VITRO, 2007, 21 (04) :535-544
[3]   Investigation of the hepatotoxicity profile of chemical entities using Liverbeads® and WIF-B9 in vitro models [J].
Biagini, Christine P. ;
Boissel, Elodie ;
Borde, Francoise ;
Bender, Virginie E. ;
Bouskila, Michale ;
Blazy, Fabien ;
Nicaise, Laetitia ;
Mignot, Aurelien ;
Cassio, Doris ;
Chevalier, Stephan .
TOXICOLOGY IN VITRO, 2006, 20 (06) :1051-1059
[4]   Microfluidics: in search of a killer application [J].
Blow, Nathan .
NATURE METHODS, 2007, 4 (08) :665-668
[5]   An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons [J].
Brandon, EFA ;
Raap, CD ;
Meijerman, I ;
Beijnen, JH ;
Schellens, JHM .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2003, 189 (03) :233-246
[6]   A label-free photonic crystal biosensor imaging method for detection of cancer cell cytotoxicity and proliferation [J].
Chan, Leo L. ;
Gosangari, Saujanya L. ;
Watkin, Kenneth L. ;
Cunningham, Brian T. .
APOPTOSIS, 2007, 12 (06) :1061-1068
[7]   Hepatocyte encapsulation for enhanced cellular functions [J].
Chia, SM ;
Leong, KW ;
Li, J ;
Xu, X ;
Zeng, KY ;
Er, PN ;
Gao, SJ ;
Yu, H .
TISSUE ENGINEERING, 2000, 6 (05) :481-495
[8]   New technologies and screening strategies for hepatotoxicity: Use of in vitro models [J].
Dambach, DM ;
Andrews, BA ;
Moulin, F .
TOXICOLOGIC PATHOLOGY, 2005, 33 (01) :17-26
[9]   The price of innovation: new estimates of drug development costs [J].
DiMasi, JA ;
Hansen, RW ;
Grabowski, HG .
JOURNAL OF HEALTH ECONOMICS, 2003, 22 (02) :151-185
[10]   Lab-on-a-chip: microfluidics in drug discovery [J].
Dittrich, PS ;
Manz, A .
NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (03) :210-218