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UCSB Sensor Could Enable Real-time In Vivo Monitoring of Protein Markers

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Researchers at the University of California, Santa Barbara have developed an aptamer-based biosensor for real-time in vivo monitoring of analytes.

In a study published last month in Science Translational Medicine, a team led by UCSB researchers Scott Ferguson and Tom Soh demonstrated its ability to continuously measure two small molecules – the chemotherapeutic doxorubicin and the antibiotic kanamycin in live rats. They are now interested in extending this technology to monitoring proteins, Soh told ProteoMonitor.

Such technology could enable a number of potential applications, such as continuous monitoring of disease-related proteins like the cardiac marker troponin, or simultaneous monitoring of both an administered drug and chemokines indicative of a patient's response to that drug, which could enable personalized dosing regimens.

Real-time in vivo measurement is currently available for only a few targets such as glucose, lactose, and blood oxygen. And, Soh noted, the platforms used for detection of these analytes aren't broadly generalizable to additional types of molecules.

The UCSB platform, on the other hand, can potentially measure a wide spectrum of analytes simply by inserting different probes, he said. Named MEDIC, for microfluidic electrochemical detector for in vivo continuous monitoring, the system uses aptamer probes attached at one end to an integrated electrode and at the other end to a redox reporter. When the aptamer binds to its target, it undergoes a conformational change that modifies the redox current to generate a detectable signal.

Use of aptamers as the detection agent is key to the sensor's function, Soh said, noting that, as opposed to antibodies, aptamers can be engineered to distinguish between specific and non-specific binding.

"Since aptamers are evolved in vitro, you can evolve them to perform a complex function," he said. "The aptamers are engineered so that when they bind to the target they undergo a structural change that [creates] an electrical signal. It would be very difficult to evolve an antibody that way."

According to Soh, the aptamer probe, which was originally developed in the lab of his UCSB colleague and STM co-author Kevin Plaxco, makes it relatively easy to adapt the sensor to a variety of molecules. Essentially, he said, researchers can swap out one aptamer for another to detect a different target.

In the STM paper, he noted, they first used the MEDIC device to measure doxorubicin in human whole blood and in rats and then "swapped out the aptamer probe" to one for kanamycin.

"It's truly a modular platform," he said.

Soh added that multiplexed detection would be readily feasible by integrating multiple probes into a single device.

Soh's lab developed an early version of the system in 2009, using an aptamer to detect cocaine. That device couldn't function in whole blood, however, due to issues with background binding and signal degradation.

In significant part, these problems stemmed from interference caused by large blood constituents like red blood cells. To eliminate such interference, the UCSB team developed a continuous-flow diffusion filter to prevent these interferents from contacting the sensor surface while still allowing in the target molecules.

They also developed a method using squarewave voltammetry to interrogate the probes in both their bound and unbound states that enabled them to significantly reduce the drift in the sensor's measurements over time.

In the STM paper, the researchers used the sensor for up to four hours of continuous monitoring, and, Soh said, with further development, this could be extended significantly.

"I think in the near future, running it for a day continuously will be within reach," he said. He added that they hope ultimately to extend the sensor's temporal range to multiple days and weeks, but that this would require significant technical changes.

"The [aptamer] sensor technology will be similar, but the way in which we implement it and the types of filters we use will be different," he said.

Adapting the platform for measuring proteins will also require technical advancements, Soh said, adding that he and his colleagues are currently working on these adjustments with a model protein.

In particular, the sensor will need much higher sensitivity for detecting protein biomarkers – which are typically present in the low nanomolar or picomolar range – than for monitoring of small molecules – typically present in the micromolar range.

Given that aptamers have demonstrated sensitivity in the low picomolar range, Soh said he thinks that using these reagents "for detection of proteins in extremely low concentrations is definitely possible."

Assuming the researchers are able to achieve detection of proteins with the device, one obvious use for such a sensor would be tracking patient response to drugs, Soh said.

"We can measure small molecule drugs right now," he said. "And what we are interested in doing is also measuring the body's response to these therapeutics. Those responses will come in the form of chemokines, so we want to measure those as well and then we can create a sort of feedback loop – like measuring glucose levels and then administering insulin" based on those levels.

The UCSB researchers have patented the MEDIC technology through the University of California. Soh declined to comment on any commercialization plans.

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