The National Institutes of Health has awarded $1.5 million to a team of researchers at Arizona State University to develop a high-throughput, live cell array for metabolic studies.
Deirdre Meldrum, ASU's senior scientist, told BioArray News this week that the group aims to develop a new microarray platform called Cellarium that will enable users to perform "dynamic multiparameter measurements" on live cells in a high-throughput fashion.
Using the chip, the ASU researchers hope to be able to measure "key parameters in cell metabolism" such as oxygen consumption, pH, adenosine triphosphate, and glucose, to gain insight into how these parameters change over time, yielding information about cell life and death processes, neoplastic progression, and pyroptosis or proinflammatory cell death, Meldrum said.
The award is funded through Aug. 30, 2013, and Meldrum's team recently received $669,794 to support the project's first year.
Meldrum is the director of the Center for Biosignatures Discovery Automation at ASU's Biodesign Institute in Tempe. She said that the Cellarium project has been underway for the past decade, and that the underlying technology was developed with partners at the University of Washington, Fred Hutchinson Cancer Research Center, and Brandeis University through an NIH Center of Excellence in Genomic Sciences project called the Microscale Life Sciences Center.
Specifically, the team designed microfabricated, environmentally controlled chambers in arrays with optical sensors for live single-cell experiments. The new grant's abstract describes the Cellarium as a "sandwich microarray," where the bottom layer of the "sandwich" supports cells in shallow microwells etched in glass, and the top seals the cells in the 150-picoliter microwells. Extracellular fluorescent sensors are subsequently introduced for multiparameter detection of metabolic analytes.
According to the abstract, chemical isolation is achieved when the two layers of the sandwich array are compressed together with a flat metal spring, allowing "dynamic measurement of transmembrane fluxes without intracellular probes." The researchers claim that they will be able to use the array to conduct single-cell analysis.
There are a number of other companies and researchers developing single-cell analysis tools, including some chip-based technologies. Grenoble, France's Cytoo, for instance, sells micropattern arrays for cell-based assays. The firm recently raised $10 million to support R&D and marketing activities (BAN 11/29/2011).
Other research teams are building high-throughput cell arrays. One group at the VTT Technical Research Centre in Finland has developed a platform that it claims can be used in large-scale gene knockdown analyses (BAN 4/12/2011). Another at McGill University in Montreal earlier this year designed a "living microarray" to study transcriptional changes in real time in single mammalian cells, claiming the approach could be used to study cell proliferation, differentiation, and apoptosis (BAN 2/22/2011).
However, Meldrum said that she and fellow researchers decided to develop the technology because, "as far as we know, there is no other technology available to perform metabolic … measurements on single live cells." She said that it is "important" to be able to measure a single cell due to the heterogeneity in cell populations, as population-based cell experiments "average the results and in many cases lose important information about rare cells or miss certain cellular events entirely."
According to the grant abstract, the researchers aim to over the next two years develop a disposable Cellarium microarray; modify a commercial microarray scanner to read out the Cellarium; verify the effectiveness of this technology across a range of cell types by simultaneously monitoring oxygen, pH, glucose, and ATP responses; validate the platform by analyzing the distribution of metabolic signatures of single cells in response to perturbations; and develop written and graphical standard operating procedures that enable reproducible data generation.
Meldrum anticipates that the Cellarium will be able to perform multiparameter dynamic measurements on 10,000 cells per run once it is fully developed by the end of 2012.
Ultimately, the researchers hope to make available a "general-purpose instrument" with the ability to perform a wide variety of experiments on one, two, and three cells per well on arrays containing thousands of wells.
She said the arrays could be used in stimulus-response experiments, where the stimulus could be "biochemical, an infection, a temporal cue, a drug, or any type of perturbation." The platform could also be used on a variety of cells such as normal, metaplasia, dysplasia, and cancerous cells. "Then one can analyze how the parameters measured vary over time and across different cell types," Meldrum said.
She added that the first version of the Cellarium will measure oxygen consumption, pH, ATP, and glucose, but that the researchers hope to develop new sensors to increase the number of measurements that can be made simultaneously on the array.
"The Cellarium will be useful for university researchers for many biological studies including understanding how a cell works, tumor metabolism, [and] the Warburg effect seen in cancer," said Meldrum. "It will also be very useful for diagnostics, [for] pharmaceutical companies for looking at drug response, developing personalized therapy for individuals, pathogen detection, and microbial analyses," she said.
According to Meldrum, the researchers hope to produce the first version of the Cellarium using the budgeted NIH funds, but she said that they will require more funds to develop future versions of the chip, and to add more sensors to the wells.
She also said that the ASU researchers are open to commercializing the platform.
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