May 19, 2004
| DESPITE THE CONSIDERABLE
potential of microfluidics, pharmaceutical companies have been hesitant to adopt microfluidics-based screening solutions due to the unfeasibly low throughput to handle large compound libraries. But as microfluidics technologies mature and increase in throughput, they are starting to offer a highly accurate, flexible, and economical alternative to conventional high-throughput screening (HTS) platforms.
In the latest step forward for microfluidics, Caliper Life Sciences recently launched its LabChip 3000 Drug Discovery system. The instrument is based on Caliper's "sipper" chip technology for automated sampling from microtiter plates. Once on the chip, samples are manipulated through the channels for mixing, incubation, reaction, separation, and detection. A typical reaction volume is around 1 nL to 10 nL, which corresponds to approximately 50 to 100 cells.
The LabChip 3000 can perform cellular or biochemical screening assays, including protein kinases, phosphatases, and proteases, as well as lipid kinases, phosphatases, and lipid-modifying enzymes, according to Kai Chin, product manager. The detection method is based on laser-induced fluorescence.
GAINING THROUGHPUT: Caliper's LabChip 3000 enables drug screening in a miniaturized format.
The instrument's throughput ranges from 5,000 to 18,000 compounds per eight-hour run, depending on the assay and chip types. Considering that most facilities run two shifts per day and one technician can often operate two or three instruments in parallel, screening a 250,000-compound library in two to three weeks is "not unreasonable," Chin says.
While this throughput is still significantly lower than that of ultra-HTS facilities at the major pharmas, the microfluidics screening platform offers a number of benefits. First is high data quality. "Our customers routinely find that the reproducibility of hits found by our platform during screening is much higher than conventional platforms due to the exceptionally low noise in the data that the microfluidics technology offers," says Andrea W. Chow, vice president of microfluidics R&D at Caliper.
Another advantage involves reagents. Since the common reagents are used in nanoliter quantities per compound, reagent savings can be as much as a thousandfold, Chow says. "This is especially important in cellular assays, since the microfluidics platform uses much fewer cells per compound during screening," she adds. "Microfluidics may enable screening of primary cells, which is not feasible using conventional platforms requiring many more cells."
The assay development time may also be shorter compared to conventional HTS. "Users have reported saving months developing an assay and taking it to full screening," Chin says.
Testing for Industrial Strength
One of the first beta-site trials of the LabChip 3000, at Amphora Discovery, focused on testing it in an industrialized setting. According to Amphora's David Pressley, "unattended run times of high data quality were consistently between 10 and 12 hours for the 12-sipper chip, translating into approximately 19,000 data points."
William P. Janzen, Amphora's vice president of operations, says, "We discovered that microfluidics enabled testing of many targets that couldn't be tested by traditional HTS. In addition, the precision resulting from applying a closed system combined with the direct measurement of products in enzymatic assays was astounding."
However, Janzen says that microfluidics does not currently offer "huge" savings in direct costs. "Although we do realize savings in reagent consumption ... the largest savings result from the precision of the format. The reproducibility of our drug discovery system allows us to utilize a smaller compound library and identify structure-activity relationships directly from our HTS data. We no longer need to confirm HTS actives since we have sufficient confidence in the data to move directly to chemistry synthesis. This cuts six to nine months from the discovery cycle. These factors, combined with our industrialized platform, yield a system that is 10 to 100 times more efficient than classic HTS."
Julia Boguslavsky is conference director for Cambridge Healthtech Institute. E-mail: email@example.com.