Integrated auto-calibration and in-pixel quantisation methodologies for CMOS ISFET arrays in point-of-care diagnostics

Abstract

Ion imaging is a field which shares many similarities with optical imaging. It is based on the Ion-Sensitive Field-Effect Transistor (ISFET), which can be implemented in unmodified CMOS technology by extending the gate to the metal, providing inherent pH sensitivity. The sensors are arranged in an array structure to image the chemical reaction happening at the surface of the chip. Similarly to optical imaging, the array performance includes array size, frame rate and Signal-to-Noise Ratio (SNR).

In this thesis, we investigate novel schemes to provide scalability, high resolution and in-pixel quantisation and compensation to the ISFET analogue front-end. The topology is based on encoding the sensed signal in the time domain locally to the sensor, enabling the use of digital logic inside the pixel and paving the way for the first time to inherent scalability of the pixel to deep submicron technologies. Carrying this vision, we present the first iteration of these pixels based on an APS pixel architecture with in-pixel memory for sensor compensation in AMS 0.35 um CMOS achieving a pH resolution of 6 mpH with an SNR of 44.5 dB. A Figure-of-Merit is then introduced to demonstrate the benefits of scaling and a new design is presented in TSMC 65 nm CMOS, representing the very first autonomous ISFET pixels with signal averaging, achieving a simulated pH resolution of 0.12 mpH with an SNR of 79 dB.

We demonstrate the technology further by integrating our fabricated array as part of a portable device used for point-of-care diagnostics of infectious diseases in tropical countries. The combination of the CMOS sensing, the hardware for data acquisition and temperature regulation, and the smartphone application creates a platform able to detect the presence of pathogen nucleic acid in less than 30 minutes and geotag the place of infection for mapping of epidemics.

We compliment this work by investigating surface treatment procedures to improve sensing using the CMOS passivation. The technique relies on reactive ion etching to expose the underlying passivation layers and improve sensitivity while decreasing attenuation, drift and offset. We demonstrate an improvement in SNR of almost 10 dB with the etching and drift reduction of 60 %.

Lastly, ways to tailor sensor specificity towards certain analytes are reported, focusing on ion-sensitive membranes and antibody coating. Paired with a calibration back-end algorithm, the technology is demonstrated as a flexible solution to detect several biomarkers involved in diseases or body malfunctions. These can potentially be detected concurrently for multiplexed sensing.

This work carries the vision of ISFET arrays based on time sensing and fabricated in commercial CMOS with minor surface treatments as ion imagers for healthcare applications.