Portland, Ore. CombiMatrix Corp. has fabricated a smart CMOS chip for influenza identification that addresses a central criterion for containment of a potential pandemic: timeliness. The company says its microarray can be updated for new flu strains in less than 24 hours and can identify any known flu strain in as little as four hours, without requiring skilled technicians to operate it.
The chip's CMOS format can electronically identify the binding events that represent a match between a sample of DNA and the DNA from a flu strain found in the body. An array of electrodes that are organized like memory cells in an SRAM determines where a binding event has occurred, eliminating the need for the fluorescent tags and optical scanners used with other methods.
Current influenza identification tests require batch operations that must be run overnight. The conventional flu chips use dumb plastic or glass substrates that require skilled technicians to inspect the microarrays visually. And labs can't update the chips for new flu strains without waiting 18 months for Federal Drug Administration (FDA) approval.
"Our CMOS chips can identify any flu strain in about four hours that's from the time you take a swab to knowing what kind of flu the patient has," said vice president of engineering Sho Fuji at CombiMatrix (Mukilteo, Wash.). "Plus, once the sequence is discovered for any new mutant version of the flu, we can have a chip ready to detect it the next day."
Laboratories with CombiMatrix chips in stock can repopulate them with any new DNA sequences they desire, literally overnight. By using CombiMatrix's desktop DNA synthesizer, any certified laboratory can populate the microarrays inside the CMOS chips with any predetermined DNA sequence.
The approach falls under "a section of clinical diagnostics called laboratory-developed tests," or tests that do not require the lengthy FDA approval period, said Fuji. "Because our platform is a CMOS chip, it allows users to develop their own array content at a laboratory site" in compliance with the FDA guidelines for lab-developed tests.
CombiMatrix's CMOS flu chips are disposable and can be ordered preloaded to identify DNA sequences for up to 12,000 strains of influenza. The chips use in situ oligonucleotide synthesis to populate a CMOS microarray with the desired DNA sequence. A forthcoming electrochemical detection system for the CombiMatrix chips will be packaged in a portable battery-operated unit. The array can be used as an adjunct to existing technology, to type difficult or ambiguous samples of flu or to study genetic drift in a flu strain as it migrates through a population, the company said in a statement. The system can process samples from animals as well as humans.
Most microarray chips today have glass or polymer surfaces onto which specific DNA sequences have been deposited in known locations. A swab is taken from a patient and is amplified by copying its DNA sequence until it is large enough to cover the full surface of the microarray chip. If the sample DNA matches a flu strain situated on the chip, it will bind to that location and activate a fluorescent marker. A laser is then shone on the chip surface, and an optical scanner identifies the glowing portion of the chip, thereby identifying the flu strain with which the sample is infected.
CombiMatrix's current-generation CMOS chip can be optically scanned, but because it is an active device, it can also make dual use of its electrodes to identify where a sample binds to a test sequence of DNA without the need for an external laser and optical-scanning system.
"We detect a current on a specific electrode on the chip rather than scan for fluorescence," Fuji said.
"Our electrodes . . . can control synthesis as well as be used for detection in the electrochemical version of the chip," he said. "You apply a sample from the patient to the chip, and depending on [where the sample binds to the chip], you can determine whether the strain is the bird flu, the Hong Kong flu or some other kind."
The electronic detection chip is in beta test with U.S. government agencies now, according to the company.
The Department of Defense has supplied more than $10 million in development funding to CombiMatrix for portable units that can perform field assays and genomic identification of biothreat agents (viruses and bacteria) as well as serological assays for toxins.