Rapid, quantitative therapeutic screening for Alzheimer's enzymes enabled by optimal signal transduction with transistors
Son T. Le, Michelle A. Morris, Antonio Cardone, Nicholas B. Guros, Jeffery B. Klauda, Brent A. Sperling, Curt A. Richter, Harish C. Pant, Arvind K. Balijepalli
We show that commercially sourced n-channel silicon field-effect transistors (nFETs) operating under closed-loop control achieve a resolution of (7.2+/-0.3)x10-3 pH units with a bandwidth of 10 Hz. The results represent an ~3-fold improvement in performance over open-loop operation commonly employed by conventional ion- sensitive field-effect transistors (ISFETs). The improved pH resolution was realized while the devices were operated in a remote configuration with the pH sensing surface off-chip and connected electrically to FET gate terminal. We compared these results with custom-built dual-gate 2D field-effect transistors (dg2DFETs s) fabricated with 2D semi-conducting MoS2 channels and a device gain of 8. Under identical solution conditions the pH resolution of the nFETs was only 2-fold worse than the dg2DFETs resolution of (3.9+/-0.7)x10-3 pH units. We leveraged the improved nFET performance to measure the change in solution pH arising from the activity of a pathological form of the kinase Cdk5, an enzyme implicated in Alzheimers disease, and showed quantitative agreement with previous measurements. Finally, using the same measurement setup we demonstrated the effectiveness of a custom polypeptide, p5, as a therapeutic agent in restoring the function of Cdk5. We expect that the simple modifications to commercially-sourced nFETs demonstrated here will lower the barrier to widespread adoption of these devices and enable laboratory-grade bioanalytical measurements for drug discovery and clinical diagnostics.