A microfluidic 3D hepatocyte chip for drug toxicity testing

Toh, Yi‐Chin; Lim, Teck Chuan; Tai, Dean; Xiao, Guangfa; Noort, Danny van; Yu, Hanry

doi:10.1039/b900912d

Cited by 376 publications

(352 citation statements)

References 39 publications

(72 reference statements)

Supporting

Mentioning

337

Contrasting

Order By: Relevance

“…As a result of the miniaturization inherent in this approach, our system ( Fig. 1) is capable of generating doseresponse curves at materially higher resolutions than existing microplate-based (3) and microfluidics-based approaches (6)(7)(8)(9)(10)(11)(12)(13)(14). Each dose-response curve contains approximately 10,000 data points, 1,000 times more than in conventional systems, resulting in extremely precise measurement of dose-response relationships using minimal quantities of reagents.…”

mentioning

confidence: 99%

High-resolution dose–response screening using droplet-based microfluidics

Miller

Harrak²,

Mangeat³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

254

217

View full text Add to dashboard Cite

A critical early step in drug discovery is the screening of a chemical library. Typically, promising compounds are identified in a primary screen and then more fully characterized in a dose-response analysis with 7-10 data points per compound. Here, we describe a robust microfluidic approach that increases the number of data points to approximately 10,000 per compound. The system exploits Taylor-Aris dispersion to create concentration gradients, which are then segmented into picoliter microreactors by droplet-based microfluidics. The large number of data points results in IC 50 values that are highly precise ( 2.40% at 95% confidence) and highly reproducible (CV 2.45%, n 16). In addition, the high resolution of the data reveals complex dose-response relationships unambiguously. We used this system to screen a chemical library of 704 compounds against protein tyrosine phosphatase 1B, a diabetes, obesity, and cancer target. We identified a number of novel inhibitors, the most potent being sodium cefsulodine, which has an IC 50 of 27 0.83 μM.high-throughput screening | HTS | small molecule library I n the early 16th century the Swiss chemist Paracelsus declared "all substances are poisons, there is none which is not a poison; only the right dose makes a substance non-poisonous." This idea that the biological effects of a chemical compound are dependent upon its concentration was quantified by A. V. Hill in 1910 (1). However, despite the fact that compounds can display complex concentration-dependent relationships, varying in potency, efficacy, and steepness of response, usually just a single measurement at a single concentration (approximately 10 μM) is obtained for each compound in the chemical library during a primary drug screen, even when using state-of-the-art robotic microplate-based screening systems. This results in high numbers of false positives and false negatives (2), as well as the inability to identify subtle, complex pharmacology, such as partial agonism or antagonism. Even when dose-response curves are generated during a quantitative primary screen (3) or, more typically, during the follow-up of a single-point screen, the time and cost limitations mean that the curves typically contain only 7-10 data points each. With ≤10 nonduplicated data points, and as many as four adjustable nonlinear parameters (e.g., in the four-parameter Hill function), the results are highly sensitive to the data quality: For example, the presence of a single outlying data point can substantially alter the fit of the data, unless the outliers are identified and removed (4).We have developed a system that uses droplet-based microfluidics to generate high-quality dose-response data during drug screening. Droplet-based microfluidics is itself a new technology for creating and manipulating picoliter-volume aqueous droplets that function as independent microreactors (for a review see ref. 5). As a result of the miniaturization inherent in this approach, our system (Fig. 1) is capable of generating doseresponse curves at materiall...

show abstract

mentioning

confidence: 99%

High-resolution dose–response screening using droplet-based microfluidics

Miller

Harrak²,

Mangeat³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

254

217

View full text Add to dashboard Cite

show abstract

“…We have combined the front-and side-trapping mechanisms into a microfluidic channel with dimensions of 10 4 m ͑length͒ ϫ 600 m ͑width͒ ϫ 100 m ͑height͒, in arrays of micropillars ͑dimensions 30 ϫ 50 m and a 20 m gap size͒ located in the center of the microfluidic channel to filter and trap the cells using a withdrawal flow. 31,[42][43][44][45] These trapped cells maintain good viability, 3D morphology, sufficient cell-cell and cell-matrix interactions, as well as high levels of albumin secretion and UDP-glucuronyltransferase ͑UGT͒ activity for in vitro toxicology applications.…”

Section: Hydrodynamic Trappingmentioning

confidence: 99%

“…We have reported a microfluidic 3D hepatocyte chip ͑Hepa Tox Chip͒ in which IC 50 values of five drugs calculated from the chip correlate well with the in vivo toxicity data. 42 The Hepa Tox Chip has eight parallel cell culture channels that are independently connected to outputs of a linear concentration gradient generator yielding eight different drug concentrations.…”

Section: A Drug Researchmentioning

confidence: 99%

Exploitation of physical and chemical constraints for three-dimensional microtissue construction in microfluidics

Choudhury

Iliescu

et al. 2011

Biomicrofluidics

View full text Add to dashboard Cite

There are a plethora of approaches to construct microtissues as building blocks for the repair and regeneration of larger and complex tissues. Here we focus on various physical and chemical trapping methods for engineering three-dimensional microtissue constructs in microfluidic systems that recapitulate the in vivo tissue microstructures and functions. Advances in these in vitro tissue models have enabled various applications, including drug screening, disease or injury models, and cellbased biosensors. The future would see strides toward the mesoscale control of even finer tissue microstructures and the scaling of various designs for high throughput applications. These tools and knowledge will establish the foundation for precision engineering of complex tissues of the internal organs for biomedical applications.

show abstract

“…(54)(55)(56) The use of a perfused multiwell plate enabled the study of drug toxicity and metabolism [ Fig. 4(b)].…”

Section: Liver-on-a-chipmentioning

confidence: 99%