A CMOS-based miniaturized and disposable molecular detection system enabling sample in-situ biosensing - Project Summary Over the past two decades, point-of-care (POC) systems enabled detection of biomarkers at or near the patient, bypassing the need to transport samples to a centralized lab, thereby enabling rapid molecular diagnoses. A key innovation that enabled this technology is the integration of sample preparation processes into a miniaturized, disposable “lab-on-a-chip” device. However, most current POC systems still require an external instrument for automated processing and detection, increasing the system size, complexity, and cost. This makes such systems impractical for low-resource settings. To address this need, we propose a miniaturized, disposable CMOS-based POC system that can be ”dropped” into the sample, measure the concentrations of multiple analytes, and wirelessly transmit the results to a smartphone. Our system is powered by two key innovations: aptamer switches that generate binding-specific electrochemical-signals in complex samples, without the need for any sample preparation, and a millimeter-sized single-chip CMOS electronics that houses and measures multiple of these aptamer switches and wirelessly transmits the results to an external smartphone reader. We will specifically tailor our diagnostic system to measure two urine metabolites crucial for the early detection of preeclampsia, a prominent contributor to maternal mortality in developing nations. The project objective will be achieved by four specific aims: (1) Aim I will implement the CMOS chip, featuring signal-enhanced square-wave voltcoulometry-based electrochemical readout electronics, wireless power- harvesting circuits, and data transfer protocols, all incorporated in mature low-cost 180-nm CMOS technology. (2) Aim II involves selecting and screening novel aptamers targeting sialyllactose and uric acid ribonucleotides, exploiting our established Particle Display and Aptamer Array technologies. Concurrently, high-throughput switch domain screening will engineer aptamers into structure-changing switches, allowing direct in-sample detection without reagent requirements. (3) Aim III emphasizes system integration, entailing post-CMOS fabrication of nanoporous electrodes for additional performance enhancements and developing an integrated wireless powering reader. (4) Aim IV will optimize this new point-of-care workflow and validate detection in urine samples. Moreover, leveraging the multiplexed detection capability, we will develop deep-learning techniques to enhance concentration mapping accuracy, particularly in fluctuating environmental conditions. This project holds significant promise; its successful completion could transform future diagnostics, particularly benefiting resource- constrained environments. These settings often face high maternal morbidity and mortality rates due to prevalent health complications and medical and laboratory infrastructure insufficiency.
