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Boston College Researchers Develop Nanotube-Based Biosensor for Protein Detection

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This story originally ran on June 30.

By Adam Bonislawski

Researchers at Boston College have developed a carbon nanotube-based biosensor that uses molecular imprint technology for the detection of proteins.

The sensor, described in a paper published in the June issue of Nature Nanotechnology, could offer a sensitive, inexpensive, and label-free alternative to antibody-based assays for protein biomarker detection, Thomas Chiles, chairperson of Boston College's biology department and the paper's lead author, told ProteoMonitor.

To build the sensor, the scientists electropolymerized a non-conductive polyphenol nanocoating onto the tips of an array of carbon nanotubes. The protein to be detected was incorporated into the nanocoating as it polymerized and was then extracted, leaving an imprint that could then capture the protein of interest from a complex sample.

When the protein is captured on the imprint it registers as an increase in impedance, which can be read using electrochemical impedance spectroscopy.

The research, Chiles said, stemmed from his group's interest in developing a multiplex detector for protein biomarkers, but without using antibodies as part of the detection system.

"One thing we didn't want to do was use conventional monoclonal antibody technology," he said. "They're not necessarily stable, they're expensive, and oftentimes there aren't monoclonal antibodies available to detect biomarkers."

Instead, the researchers turned to molecular imprint technology — a technique that Chiles said has been used successfully for detecting small organic compounds like neurotransmitters but hasn't really been used for detecting large macromolecules like proteins.

"One of the main difficulties was that once you make the imprint, you then have to extract the protein. A lot of times that process of extracting the protein would perturb or damage the imprint itself," he said. Another challenge "was that proteins themselves tend to be unstable, and to get a good imprint that could in turn recognize the protein with a degree of specificity was in itself difficult."

Use of the non-conductive polyphenol nanocoating was key to overcoming these problems, allowing the team to create imprints that remain preserved during the extraction process and that preserve the conformation of the target protein, Chiles said. The thinness of the nanocoating also results in more significant impedance changes in response to binding by the target protein, which heightens the system's sensitivity.

Using the system, the researchers were able to detect human ferritin protein at levels of roughly 10 pg per liter and human papillomavirus E7 protein at sub pg-per-liter levels – sensitivities surpassing many conventional ELISA tests. They were also able to distinguish between different conformations of proteins – in this case calmodulin and calmodulin bound to Ca2+.

"Right now we can detect different proteins, detect different proteins that are very similar in terms of homology, and detect gross changes in the conformation of proteins," Chiles said. "This paper was really a proof-of-concept paper demonstrating that we could detect single proteins specifically with high affinity."

The team is presently working on improvements to the system, which, Chiles said, they will likely describe in a second paper. The sensitivity of the improved system will probably be around an order of magnitude greater than the current one, he said.

The refined system will also be able to detect protein mutations, provided those mutations change the surface of the protein sufficiently, Chiles said. He hopes in the future to develop the system so that it will be able to identify post-translational modifications, as well.

"One of the pie-in-the-sky goals is that this will allow us to detect post-translational modification of proteins," he said. Ubiquitination, phosphorylation, things like that. Whether or not that's going to happen, I don't know, but that's something that we're looking at right now."

"The idea is to refine [the technology] such that we can have a deliverable," he said. "Right now, most technologies [for biomarker detection] require sophisticated technologies like optics and fluidics, and they're not real-time and they're very expensive. We think this is going to be cost effective and it's not going to require a lot of user training and it's not going to require a lot of sophisticated supporting instrumentation."

"The next step is to make arrays of these nanotubes — we can make maybe 200 million of these nanotubes on a half-centimeter chip — and then have regions of these arrays that are imprinted for different proteins," he said. "We hope this will allow us to do a host of applications — not only in disease diagnosis but also by extension in proteomics."

The researchers are also working on applying the imprinting technology to beads that could then be used in a fluidics platform for applications like protein purification.

"We see it as a platform for not only a lot of biomedical diagnostic capabilities, but also for biochemical capabilities," Chiles said.

The researchers are also hoping to use the technology to detect viruses, he said.

"One could envision if you had a new strain of influenza, if you could just make an imprint of that then in theory you could have a diagnostic platform much sooner than having to use existing technologies," he said. "So we're actually looking at playing around with different polymers to try to specifically recognize distinct subtypes of viruses. We haven't been successful yet, but I think we're getting close.

In addition, Chiles said, he sees the technology as potentially useful for applications like the monitoring of contaminants as part of drug-development quality-control processes, monitoring bacterial contaminants in food, and monitoring biological agents and toxins as part of military and security work.

"Currently, we are actively seeking funding from federal agencies to continue the research into the R&D side of development that includes fabricating multiplex nanoscale detection platforms," he said. "In terms of licensing, we could envision licensing the technology to the pharma/biotech community."

He also noted that launching a start-up firm to commercialize the technology was a possibility, but did not elaborate.

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