Biosensor for Lyme Disease: Real-time, Specific, and Label-Free Complementary Metal-Oxide-Silicon Transistor Sensing of <i>Borrelia burgdorferi s.l</i> . Outer Surface Protein A in Unprocessed Blood

The pressing need for rapid, direct diagnostic tests for infectious diseases is exemplified by Lyme disease. Human cases of this tick-vectored bacterial infection continue to rise globally, yet the conventional laboratory diagnostic is inadequate in capturing early disease, treatment outcome, and reinfection. Direct detection of a pathogen marker from human biological fluid is a coveted strategy that has, until now, presented immense challenges due to the low circulating burden of the Lyme <i>Borrelia</i> pathogen. The current study demonstrates specific, label-free, quantitative, real-time sensing of <i>Borrelia</i> outer surface protein A (OspA) in 0.5 μL whole blood samples with the recently introduced meta-nano-channel field-effect transistor (MNC-FET) biosensor. The MNC-FET biosensor is specifically designed to address the transduction of nonuniform surface distribution of molecular interactions while maintaining the biomolecules in thermal and electrochemical equilibria. The sensing is performed directly in unprocessed blood and without the conventionally employed premeasurement washings, rendering the proposed technology suitable for a fast, simple, self-use diagnostic kit for Lyme disease. The study demonstrates OspA sensing with a limit of detection of 1 fg/mL, a dynamic range of 8 orders of magnitude, and with excellent sensitivity and linearity. The MNC-FET biosensor is fabricated in a complementary metal-oxide-silicon (CMOS) process ensuring superb electronic grade in terms of noise levels and amplification, robustness, stability, and ultimate miniaturization suitable for future multiplexed sensing. The unique MNC-FET biosensor design addressing challenges associated with molecular sensing, coupled with CMOS technology potential for high volume production of high-end chips, provides a viable technology for a low-cost Lyme disease diagnostic kit with excellent quantitative performance in ultra-small unprocessed blood drops.