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Proof-of-Principle Diagnostic Platform Developed as Potential Model for Future POC Device

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NEW YORK — Roche Diagnostics recently took over development of a proof-of-principle prototype that could become a model for future point-of-care platforms, according to Christian Tidona, founder and managing director of Heidelberg, Germany-based BioMed X.

Specifically, Roche has taken on development of a multimodal diagnostic platform invented and developed by scientists at the BioMed X Innovation Center in Heidelberg. If Roche is successful, the platform could enable testing for several conditions in one setting and provide an alternative to laboratory tests, Tidona added.

The nanomaterials biosensing proof-of-principle platform, which was developed during a project managed by BioMed X with input from Roche, could take many years to commercialize, however, Tidona cautioned.

The prototype enables analysis of several different parameters using one blood sample and a single device, which could prove particularly useful for diagnostic testing in point-of-care settings, he said. It measures not only multiple analytes but analytes of a different type, including proteins, blood gases and electrolytes, metabolites, and enzymes. In internal validation studies, the disposable device detected analytes at the point of care using field effect transistor (FET) sensors with a gold sensing surface.

In its development work, BioMed X scientists used the platform to conduct label-free detection of thyroid-stimulating hormone (TSH) in undiluted human serum. The scientists used reagents already employed on Roche's laboratory diagnostic tests for TSH. However, the researchers used the assay mainly as a test of the point-of-care platform's capabilities, Tidona said, noting that such an assay requires highly sensitive levels of detection.

They incorporated a functionalization layer consisting of antibody fragments that served as biological receptors and added a polyethylene glycol layer. As a result, they achieve a threefold enhancement of the analyte signal compared to a control surface without the polyethylene glycol layer.

Michele Pedrocchi, global head of strategy and business development at Roche Diagnostics, said that as a result of the collaboration with BioMed X, Roche "has gained technology insights and intellectual property to expand the utility of electrochemical sensors." He added that Roche is now "internalizing the technology to provide the basis for potential, future point-of-care solutions."

Tidona said BioMed X applied a "new model of innovation" for the platform's development — a model intended to take on partners' "toughest preclinical research problems for which they have no solution" — and which BioMed X has applied to projects with several pharmaceutical companies including AbbVie, Boehringer Ingelheim, and Janssen.

For its project with Roche, BioMed X posted a description of the challenge using a crowdsourcing platform so that the information could be viewed by scientists in universities around the world. Tidona said that BioMed X, working with Roche, posted a question asking for scientists to respond with proposals describing a vision for a future point-of-care diagnostic platform that is disposable, able to measure different types of analytes, and have the same precision as large laboratory instruments. BioMed X received 600 applications from people in 80 countries and reviewed the proposals along with executives from Roche.

The executives selected a proposal presented by Alexey Tarasov, a Russian scientist who was then studying at the Georgia Institute of Technology in Atlanta.

After receiving a research fellowship and a research budget of about €3.2 million ($3.5 million) to conduct a four-year project based on his proposal, Tarasov moved to the BioMed X center in Heidelberg and began working there with other colleagues that had participated in the bootcamp.

For the first two years, the group focused on the sensor layout and selection of materials, and during that time opted to include graphene, which in recent years has emerged as one of the most promising nanomaterials because of its unique combination of properties including strength, heat and electrical conductivity, and optical transparency.

For the two years that followed, the group worked in part on using patient samples to validate prototypes they had developed. During this time, they also incorporated capture antibodies and reagents that Roche uses on its TSH laboratory diagnostic tests and compared the performance of their point-of-care platform with the laboratory tests' performance.

The internal validation studies showed that tests running on the point-of-care platform were reproducible, and their levels of sensitivity were "at least as good as large laboratory instruments, and sometimes better," Tidona said. In addition, use of such a point-of-care diagnostic platform could shorten time to result compared to laboratory instruments.

By modifying the surface of the FET, Tarasov and his colleagues have overcome fundamental challenges with previous FET-based sensing platforms. The team has enabled the use of FET sensing at previously unseen levels of sensitivity to measure analytes in undiluted serum or whole blood with femtomolar limits of detection, Tidona said.  

For diagnostics associated with a variety of different medical conditions, the developers have shown that the platform can measure different analytes in one sample and at different levels of concentration, he added. "You can use a drop of whole blood, add it to the sensor, and measure analytes in a range of 10 to 100 femtomolar," he said. "At the same time, you can measure larger analytes that require micromolar-level detection."

A multimodal point-of-care instrument could be especially useful in using single blood samples to quickly measure analytes associated with acute conditions requiring rapid diagnosis, such as sepsis, Tidona said. In these instances, clinicians frequently use blood samples measured by different laboratory tests. The vision for the point-of-care device is to have it quickly complete all of those measurements at one time at the point of care, he said.

Tarasov, former group leader at BioMed X, supported the project as an academic mentor until it ended for the firm last month. In March, he also began working as professor of biomedical engineering at Hochschule Kaiserslautern in Germany, where he is affiliated with the integrated miniaturized systems research center that combines micro- and nano-technology with biological systems.

A key advantage of the point-of-care technology developed at Heidelberg is "the ability to get real-time data without labels, sample dilution, or washing steps," Tarasov said in an interview. "More work is needed to explore scalability, manufacturability, and storage conditions [among other activities]. If these issues can be solved, I think this technology could become very interesting for POC applications."

Giuseppe Spoto, a professor of chemical sciences at the University of Catania in Italy, said in an interview that field-effect transistors "offer great opportunities for miniaturization with the theoretical possibility to produce sensing devices on [non-rigid] plastic substrates."

He noted that both field-effect transistor technology and a plasmonic platform developed as a result of a European Union-sponsored project that he coordinated "have both been shown to be able to detect a broad range of analytes."

Spoto's project integrates DNA, microRNA, and protein-based tumor autoantibody detection.

Although promising, the type of sensing principle in the field-effect transistor technology may require further work to produce a robust platform "to detect a large variety of different analytes in complex biological matrices such as blood," said Spoto, who has not been involved in the development of the FET technology.

"To be very clear, this is an early prototype," Tidona said. "The system works in our lab and its test results are reproducible, but to convert that into something that can be mass manufactured and has the robustness to conduct routine diagnostics is a long way off. We're not claiming we have a ready-to-use diagnostic platform."