New DNA Biosensor Could Make High-Quality Clinical Diagnostics More Accessible

DNA can indicate the presence of or predisposition to several diseases, including cancer. By flagging down these signals, known as biomarkers, medical professionals are able to arrive at critical early diagnoses and offer personalized treatments. However, the typical screening methods are often laborious, expensive or uncover limited information. Now, a new biosensor chip featuring an accurate and inexpensive design has the potential to improve accessibility to high-quality diagnostics.

The biosensor, developed by a team of researchers, including from the National Institute of Standards and Technology (NIST, Gaithersburg, MD, USA), identifies biomarkers by measuring how binding occurs between DNA strands and the device. The biosensor differs from other similar sensors mainly due to its modular design, which reduces costs by enabling mass production and reuse of the costliest components. In a study, the team demonstrated the device’s high sensitivity and precision despite its modularity, which is usually associated with diminished performance.

Similar to other DNA biosensors, the new device takes advantage of the fact that a single DNA strand, when not paired with another within the familiar double helix, is primed for chemical bonding. Part of the device is coated with single strands of DNA. When these “probes” encounter DNA biomarkers having a corresponding, or complementary, genetic sequence, the two strands bind, sending a signal that is picked up by the device. When a strand of target DNA binds to a probe, it induces a voltage shift that a semiconductor device, called a field-effect transistor (FET), can measure. Such voltage shifts can happen hundreds of times per second as the molecules pop on and off the sensor. As a result of its high time resolution, the approach can tell whether a DNA strand is bound to a probe, as well as how long it takes to connect and disconnect - a factor called binding kinetics that is vital for discerning various markers that could bind to the same probe to varying degrees. The method also does not need much space to measure a lot.

However, FET-based methods are yet to become mainstream, mainly due to their single-use nature, which until now was viewed as a necessity but pushes up their cost. Similar to how the radio becomes noisier as one drives away from a radio station, electrical signals also become increasingly noisy the longer they travel within electronics. This unwanted random noise that is picked up along the way makes it harder to measure the signal. In order to limit noise, DNA probes in FET-based sensors are usually attached directly to the transistor, which converts the signal into readable data. However, this has a drawback as the probes are spent after being exposed to a sample, along with the entire device. In the new study, the researchers increased the distance between the probes and the transistor to allow for the more expensive elements of the circuitry to be reused. The researchers found that the distance could increase the amount of noise, although they gained a lot from the design choice, in addition of the cost savings.

The researchers had anticipated that the modular design would diminish the biosensor’s sensitivity and took a page out of the Internet of Things (IoT) playbook, which accommodates the losses associated with wireless devices. The team paired the circuitry with a specific type of extremely low-power FET developed at CEA-LETI used in smartwatches, personal assistants and other devices to amplify signals and compensate for the lost sensitivity. The researchers tested the device’s performance by placing it in liquid samples containing DNA strands associated with exposure to harmful ionizing radiation. Complementary DNA probes adorned electrodes wired to the FET. The researchers varied the amount of target DNA across several samples and found that the binding kinetics were sensitive enough to enable accurate measurements even at low concentrations. They found that the performance of the modular design was as good as that of integrated, non-modular FET-based biosensors. The researchers now plan to examine if the sensor can perform similarly with varying DNA sequences due to mutations. Given that several diseases are caused by or associated with mutated DNA, this capability is essential for clinical diagnostics. They also plan to conduct other studies to examine the sensor’s ability to detect genetic material associated with viruses, such as SARS-CoV-2 that causes COVID-19, and could indicate infection.

“There’s an opportunity to develop more sophisticated modular sensors that are much more accessible without sacrificing high quality measurements,” said NIST researcher Arvind Balijepalli, a co-author of the new study.

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