SCH: Integrating DNA Nanotechnology and CMOS Electronics for Next-generation Diagnostics

Currently, healthcare relies on annual blood and urine tests that often miss early signs of developing diseases. This project will develop innovative sensing technologies that will enable more frequent blood and urine testing, as well as testing for newly discovered disease-associated molecules, which will improve the likelihood of detecting diseases early. This project aims to combine the strengths of microelectronics and emerging molecular nanotechnology to develop sensing platforms that are highly sensitive and easy-to-use. If successful, in the future, rather than waiting for annual checkups, our health will be systematically and comprehensively monitored frequently throughout the day. The research is integrated with an educational and outreach program that introduces these technologies to students from K-12 to the graduate level, providing training and education opportunities for future health personnel. The results of this project will lead to future work that could greatly reduce healthcare costs and vastly improved health outcomes. Although continuous glucose monitoring and rapid COVID-19 tests serve as outstanding currently available examples of biomarker sensing, general purpose integration of biomarker sensing into daily life remains challenging. The challenges include (i) the lack of sensors that can offer signals at low detection limits with high specificity while requiring minimal sample preparation prior to sensing, (ii) the absence of appropriate electronic interfaces to convert low target-sensor interactions into detectable signals within a miniaturized platform that can be easily worn or carried, and (iii) significant measurement variation from different samples. This research aims to overcome the challenges by integrating biosensors enabled by DNA nanotechnology with miniaturized yet high-performance complementary metal-oxide-semiconductor (CMOS) electronics to develop new diagnostic platforms that offer enhanced sensitivity, specificity, throughput, and analyte scope. Specifically, the team will: (1) develop molecular engineering techniques to perform in-situ signal amplification for target-binding aptamer biosensors using DNA origami nanotechnology; (2) develop advanced biosensor-interfacing circuits that overcome noise/power limitations and offer near shot-noise-limited sensitivity; (3) create integration methodologies of molecules with electronics that facilitate the site-specific scalable functionalization of biosensors, enabling multiplexed detection across a scalable array with aptamers of different sequences; and (4) implement a wireless wearable device for continuous monitoring of molecules in interstitial fluids, alongside a CMOS/microfluidics system designed for blood biomarker analysis. Additionally, machine learning and data fusion techniques will be incorporated to enhance the accuracy of molecular quantification with minimal calibration when measuring complex fluids from various types and individuals. The integration of these platforms will enable continuous or more frequent sampling of specific biomarkers by users. This longitudinal data pattern paves the way for early disease detection and offers an improved alternative to current healthcare practices. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.