The panel I moderated at DesignCon last week was both entertaining and enlightining. One of the panelists, Zhimin Ding, is the CEO of an emerging fabless semiconductor company and here is their story:
In the past 5 to 10 years we have seen vast advancement in medical diagnostics technology. Doctors can now use DNA or anti-body analysis to get very precise answers about the type of virus, bacteria or cancerous cells that cause our illness. This is great news as precise diagnostics leads to effective drug and treatment with minimum side effect.
Unfortunately much of the world’s population still does not have access to this technology due to the cost and bulkiness of the equipments involved. Anitoa Systems, a startup in Palo Alto, CA, is working on meeting this challenge. They are creating a low cost, field portable nucleic-acid-test system built upon a proprietary CMOS molecular sensors technology.
Ultra low-light CMOS imager for molecular sensing
A majority of molecular diagnostic systems today use optical methods to detect molecular events, based on principle of fluorescence and chemiluminescence signaling. To meet the sensitivity requirement, engineers have to resort to bulky and expensive devices such as photon multiplier tubes (PMT) or cooled CCDs.
Anitoa’s ULS24 ultra-low light CMOS imager chip
Recent innovations of CMOS image sensors have made it possible to achieve much better sensitivity than what is possible before. But still more improvements in process, circuit, logic and software are needed to compete with PMT and CCDs for molecular sensing. For example, engineers at Anitoa need to reduce the noises of CMOS image sensor to provide a high signal-to-noise ratio (SnR). The excessive noise that cannot be eliminated in the chip, due to limitations of physics, is further computed and filtered through software algorithms.
With this approach, Anitoa has fabricated a CMOS image sensor built on 0.18um CIS technology from a world-leader specialty foundry. This chip has shown to achieving 3e-6 lux detection sensitivity, capable of detecting just a few molecules labeled with fluorescence reporter probes. Anitoa is now creating a miniaturized qPCR (quantitative polymerase chain reaction) system using its CMOS imager. The CMOS imager is paired with LEDs as the optical excitation source, to achieve fluorescence-based molecular sensing in a very compact platform.
qPCR for infectious disease diagnostics
When it comes to detecting very small amount of pathogenic molecules, such DNA molecules released from viruses or cancerous cells, it is important that the method is not only sensitive, but also specific. This is because the target molecules are immersed in a much larger number of surrounding DNAs from normal human blood cells.
DNA amplification and detection with qPCR
qPCR can achieve sensitivity and specificity through combined amplification and detection. By amplification, qPCR can cause target DNA strands be selectively replicated millions of times, with the help of a special enzyme called polymerase. As the target DNA strands being replicated, they bind with specially design molecular probes that are labeled with fluorescence materials.
The high sensitivity and SnR in Anitoa’s CMOS image means the instrument is able to work with small reaction volumes confined in a microfluidic structure. Small reaction volume means faster reaction and faster time to results.
Future trends
Today molecular diagnostics are performed in centralize labs located in big cities. Patient samples are collected at hospitals, sealed in ice-boxes and loaded onto trucks that deliver the samples to these labs .Transportation, material handling and batching means that sample to result take days and weeks. For many critical infectious diseases, such H1N9, the optimal symptom to treatment window is less than ten hours.
Anitoa envision in the near future, small and portable molecular diagnostics devices would be deployed at point of care, enabling rapid diagnostics of infectious disease on-the-site, so that doctors can respond quickly with life-saving drugs and treatment. The diagnostics device will be internet enabled, and the diagnostic results will be transmitted to a central database in the cloud, allowing doctors, drug companies and policy makers to make strategic decisions on global epidemic control.
Electrochemical molecular sensors have shown promise but require sophisticated surface chemistry and suffer from stability and specificity problems.
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