A portable and reconfigurable multi-organ platform for drug development with onboard microfluidic flow control

被引:76
作者
Coppeta, J. R. [1 ]
Mescher, M. J. [1 ]
Isenberg, B. C. [1 ]
Spencer, A. J. [1 ]
Kim, E. S. [1 ]
Lever, A. R. [1 ]
Mulhern, T. J. [1 ]
Prantil-Baun, R. [1 ]
Comolli, J. C. [1 ]
Borenstein, J. T. [1 ]
机构
[1] Draper, Mat & Microfabricat Directorate, Cambridge, MA 02139 USA
关键词
DEVELOPMENT SUCCESS RATES; SECRETORY PROTEIN CC16; HUMAN HEPATOCYTES; CELLS; LIVER; CHIP; FABRICATION; METABOLISM; DELIVERY; ALBUMIN;
D O I
10.1039/c6lc01236a
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
The drug development pipeline is severely limited by a lack of reliable tools for prediction of human clinical safety and efficacy profiles for compounds at the pre-clinical stage. Here we present the design and implementation of a platform technology comprising multiple human cell-based tissue models in a portable and reconfigurable format that supports individual organ function and crosstalk for periods of up to several weeks. Organ perfusion and crosstalk are enabled by a precision flow control technology based on electromagnetic actuators embedded in an arrayed format on a microfluidic platform. We demonstrate two parallel circuits of connected airway and liver modules on a platform containing 62 electromagnetic microactuators, with precise and controlled flow rates as well as functional biological metrics over a two week time course. Technical advancements enabled by this platform include the use of non-sorptive construction materials, enhanced scalability, portability, flow control, and usability relative to conventional flow control modes (such as capillary action, pressure heads, or pneumatic air lines), and a reconfigurable and modular organ model format with common fluidic port architecture. We demonstrate stable biological function for multiple pairs of airway-liver models for periods of 2 weeks in the platform, with precise control over fluid levels, temperature, flow rate and oxygenation in order to support relevant use cases involving drug toxicity, efficacy testing, and organ-organ interaction.
引用
收藏
页码:134 / 144
页数:11
相关论文
共 47 条
[11]   Exploratory toxicology as an integrated part of drug discovery. Part I: Why and how [J].
Hornberg, Jorrit J. ;
Laursen, Morten ;
Brenden, Nina ;
Persson, Mikael ;
Thougaard, Annemette V. ;
Toft, Dorthe B. ;
Mow, Tomas .
DRUG DISCOVERY TODAY, 2014, 19 (08) :1131-1136
[12]   A Human Disease Model of Drug Toxicity-Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice [J].
Huh, Dongeun ;
Leslie, Daniel C. ;
Matthews, Benjamin D. ;
Fraser, Jacob P. ;
Jurek, Samuel ;
Hamilton, Geraldine A. ;
Thorneloe, Kevin S. ;
McAlexander, Michael Allen ;
Ingber, Donald E. .
SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (159)
[13]  
Ingber D. E., 2015, SYSTEMS METHODS CELL
[14]   Design, modeling and fabrication of a constant flow pneumatic micropump [J].
Inman, Walker ;
Domansky, Karel ;
Serdy, James ;
Owens, Bryan ;
Trumper, David ;
Griffith, Linda G. .
JOURNAL OF MICROMECHANICS AND MICROENGINEERING, 2007, 17 (05) :891-899
[15]   Drug-induced vascular injury - a quest for biomarkers [J].
Kerns, W ;
Schwartz, L ;
Blanchard, K ;
Burchiel, S ;
Essayan, D ;
Fung, E ;
Johnson, R ;
Lawton, M ;
Louden, C ;
MacGregor, J ;
Miller, F ;
Nagarkatti, P ;
Robertson, D ;
Sistare, F ;
Snyder, P ;
Thomas, H ;
Wagner, B ;
Ward, A ;
Zhang, J .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2005, 203 (01) :62-87
[16]  
Kono Y, 1997, IN VITRO CELL DEV-AN, V33, P467
[17]   Microfluidic tissue model for live cell screening [J].
Lee, Philip J. ;
Gaige, Terry A. ;
Ghorashian, Navid ;
Hung, Paul J. .
BIOTECHNOLOGY PROGRESS, 2007, 23 (04) :946-951
[18]   Comprehensive evaluation of poly(I:C) induced inflammatory response in an airway epithelial model [J].
Lever, Amanda R. ;
Park, Hyoungshin ;
Mulhern, Thomas J. ;
Jackson, George R. ;
Comolli, James C. ;
Borenstein, Jeffrey T. ;
Hayden, Patrick J. ;
Prantil-Baun, Rachelle .
PHYSIOLOGICAL REPORTS, 2015, 3 (04)
[19]  
Li A. P., WILEY DRUG DRUG INTE
[20]   Liposome-encapsulated actin-hemoglobin (LEAcHb) artificial blood substitutes [J].
Li, SL ;
Nickels, J ;
Palmer, AF .
BIOMATERIALS, 2005, 26 (17) :3759-3769