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| Image created by Dr. Michael J. Miller |
In a world grappling with a multitude of health threats—ranging from fast-spreading viruses to chronic diseases and drug-resistant bacteria—the need for quick, reliable, and easy-to-use home diagnostic tests has never been greater. Imagine a future where these tests can be done anywhere, by anyone, using a device as small and portable as your smartwatch. To do that, you need microchips capable of detecting miniscule concentrations of viruses or bacteria in the air.
Now, new research shows it's possible to develop and build microchips that can not only identify multiple diseases from a single cough or air sample, but can also be produced at scale. The team from NYU Tandon faculty includes Professor of Electrical and Computer Engineering Davood Shahrjerdi; Herman F. Mark Professor in Chemical and Biomolecular Engineering Elisa Riedo; and Giuseppe de Peppo, Industry Associate Professor in Chemical and Biomolecular Engineering and who was previously at Mirimus.
"This study opens new horizons in the field of biosensing. Microchips, the backbone of smartphones, computers, and other smart devices, have transformed the way people communicate, entertain, and work. Similarly, today, our technology will allow microchips to revolutionize health care, from medical diagnostics, to environmental health" says Riedo,
"The innovative technology demonstrated in this article uses field-effect transistors (FETs)—miniature electronic sensors that directly detect biological markers and convert them into digital signals—offering an alternative to traditional color-based chemical diagnostic tests like home pregnancy tests," said Shahrjerdi.
"This advanced approach enables faster results, testing for multiple diseases simultaneously, and immediate data transmission to health care providers" says Sharjerdi, who is also the Director of the NYU Nanofabrication Cleanroom, a state-of-the-art facility where some of the chips used in this study were fabricated. Riedo and Shahrjerdi are also the co-directors of the NYU NanoBioX initiative.
Field-effect transistors, a staple of modern electronics, are emerging as powerful tools in this quest for diagnostic instruments. These tiny devices can be adapted to function as biosensors, detecting specific pathogens or biomarkers in real time, without the need for chemical labels or lengthy lab procedures. By converting biological interactions into measurable electrical signals, FET-based biosensors offer a rapid and versatile platform for diagnostics.
Recent advancements have pushed the detection capabilities of FET biosensors to incredibly small levels—down to femtomolar concentrations, or one quadrillionth of a mole—by incorporating nanoscale materials such as nanowires, indium oxide, and graphene. Yet, despite their potential, FET-based sensors still face a significant challenge: they struggle to detect multiple pathogens or biomarkers simultaneously on the same chip.
Current methods for customizing these sensors, such as drop-casting bioreceptors like antibodies onto the FET's surface, lack the precision and scalability required for more complex diagnostic tasks.
To address this, these researchers are exploring new ways to modify FET surfaces, allowing each transistor on a chip to be tailored to detect a different biomarker. This would enable parallel detection of multiple pathogens.
Enter thermal scanning probe lithography (tSPL), a breakthrough technology that may hold the key to overcoming these barriers. This technique allows for the precise chemical patterning of a polymer-coated chip, enabling the functionalization of individual FETs with different bioreceptors, such as antibodies or aptamers, at resolutions as fine as 20 nanometers. This is on par with the tiny size of transistors in today's advanced semiconductor chips.
By allowing for highly selective modification of each transistor, this method opens the door to the development of FET-based sensors that can detect a wide variety of pathogens on a single chip, with unparalleled sensitivity.
Riedo, who was instrumental in the development and proliferation of tSPL technology, sees its use here to be further evidence of the groundbreaking way this nanofabrication technique can be used in practical applications. "tSPL, now a commercially available lithographic technology, has been key to functionalize each FET with different bio-receptors in order to achieve multiplexing," she says.
In tests, FET sensors functionalized using tSPL have shown remarkable performance, detecting as few as 3 attomolar (aM) concentrations of SARS-CoV-2 spike proteins and as little as 10 live virus particles per milliliter, while effectively distinguishing between different types of viruses, including influenza A. The ability to reliably detect such minute quantities of pathogens with high specificity is a critical step toward creating portable diagnostic devices that could one day be used in a variety of settings, from hospitals to homes.
The study, now published in the journal Nanoscale, was supported by Mirimus, a Brooklyn-based biotechnology company, and LendLease, a multinational construction and real estate company based in Australia. They are working with the NYU Tandon team to develop illness-detecting wearables and home devices, respectively.
"This research shows off the power of the collaboration between industry and academia, and how it can change the face of modern medicine," says Prem Premsrirut, President and CEO of Mirimus. "NYU Tandon's researchers are producing work that will play a large role in the future of disease detection."
"Companies such as Lendlease and other developers involved in urban regeneration are searching for innovative solutions like this to sense biological threats in buildings." says Alberto Sangiovanni Vincentelli of UC Berkeley, a collaborator on the Project. "Biodefense measures like this will be a new infrastructural layer for the buildings of the future"
As semiconductor manufacturing continues to advance, integrating billions of nanoscale FETs onto microchips, the potential for using these chips in biosensing applications is becoming increasingly feasible. A universal, scalable method for functionalizing FET surfaces at nanoscale precision would enable the creation of sophisticated diagnostic tools, capable of detecting multiple diseases in real time, with the kind of speed and accuracy that could transform modern medicine.
Reference
Alexander James Wright et al, Nanoscale-localized multiplexed biological activation of field effect transistors for biosensing applications, Nanoscale (2024). DOI: 10.1039/D4NR02535K
Abstract
The rise in antibiotic-resistant pathogens, highly infectious viruses, and chronic diseases has prompted the search for rapid and versatile medical tests that can be performed by the patient. Field-effect transistor (FET)-based electronic biosensing platforms are particularly attractive due to their sensitivity, fast turn-around time, potential for parallel detection of multiple pathogens, and compatibility with semiconductor manufacturing. However, an unmet critical need is a scalable, site-selective multiplexed biofunctionalization method with nanoscale precision for immobilizing different types of pathogen-specific bioreceptors on individual FETs, preventing parallel detection of multiple targets. Here, we propose a paradigm shift in FET biofunctionalization using thermal scanning probe lithography (tSPL) with a thermochemically sensitive polymer. This polymer can be spin-coated on fully-fabricated FET chips, making this approach applicable to any FET sensor material and technology. Crucially, we demonstrate the spatially selective multiplexed functionalization capability of this method by immobilizing different types of bioreceptors at prescribed locations on a chip with sub-20 nm resolution, paving the way for massively parallel FET detection of multiple pathogens. Antibody- and aptamer-modified graphene FET sensors are then realized, achieving ultra-sensitive detection of a minimum measured concentrations of 3 aM of SARS-CoV-2 spike proteins and 10 human SARS-CoV-2 infectious live virus particles per ml, and selectivity against human influenza A (H1N1) live virus.