2614 IEEE TRANSACTIONS ON CIRCUITS AND SYSTEMS—I: REGULAR PAPERS, VOL. 52, NO. 12, DECEMBER 2005 A Biochemical Translinear Principle With Weak Inversion ISFETs Leila M. Shepherd, Student Member, IEEE, and Chris Toumazou, Fellow, IEEE Abstract—A weak inversion region is shown to exist in ion-sensi- tive field effect transistor (ISFET) sensors. It is therefore proposed that the ISFET and its chemically sensitive (ChemFET) counter- parts be used as translinear elements in the synthesis of novel biochemical input stages which perform real-time mathematical manipulation of biochemical signals. A Biochemical Translinear Principle using weakly inverted ChemFETs is presented. A low-power current-mode input stage circuit is presented as an application of the principle. This yields a linear relation between drain current and hydrogen ion concentration valid over four decades. This paper demonstrates an important and necessary step toward biochemical VLSI. Index Terms—Chemically sensitive ion-sensitive field effect tran- sistor (ChemFET), CMOS, ISFET, low power, pH, weak inversion. I. INTRODUCTION W ITH THE NEW wave of technology inspired by lifestyle and healthcare, low-power physiological monitoring, diagnosis and control is becoming increasingly important. Portable, wearable, and implantable ultra low-power devices which can sense and analyze physiological parameters via extracellular tissue fluid or blood in a real-time continuous manner have been an important objective of the healthcare industry. In this paper, we present a significant step toward the technology that can achieve this by combining the advances made in the micropower system-on-chip (SoC) design area with ion-sensitive field-effect transistor (ISFET) sensor technology. The ISFET is a chemically sensitive FET developed in the 1970s which has been used for chemical and biochemical monitoring [1]. It has an insulating membrane which is sensi- tive to hydrogen ions in the test solution, and thus any charge build-up on the membrane, which varies with solution pH, causes a modulation in the ISFETs threshold voltage. Through deposition of various ionophores (ion-selective channels) on the sensing membrane, ChemFET sensors for key ions such as sodium, potassium and calcium can be created based on the same principle. Biosensors known as EnFETs for the detection of key metabolites, can also be ISFET-based through the immo- bilization of enzymes on the sensing surface, thereby catalysing an ion-generating reaction on the ion-sensitive membrane. A comprehensive review of other FET-based biologically sensi- tive FETs can be found in [2]. Manuscript received March 1 2005; revised August 1, 2005. This paper was recommended by Guest Editor Y. Lian. L. M. Shepherd is with the Department of Electrical and Electronic Engi- neering, Imperial College London, London SW7 2BT, U.K. (e-mail: leila.shep- herd@imperial.ac.uk). C. Toumazou is with the Institute of Biomedical Engineering, Imperial Col- lege London, London SW7 2BT, U.K. Digital Object Identifier 10.1109/TCSI.2005.857919 The key advantages of ISFETs and ChemFETs over conven- tional potentiometric sensors such as ion-selective electrodes (ISEs) include their small size, short response time, and their compatibility with semiconductor fabrication methods, giving scope for monolithic integration of the sensors and processing circuitry. Initial attempts at integration introduced several ISFET-specific processing steps to create a custom CMOS process [3]–[5]. More recently however, promising progress has been made in the reliable fabrication of ISFETs in unmod- ified commercial CMOS processes, taking advantage of the well-established design environments and resources [6]–[8]. This progress gives scope for novel input stages and array- based biochemical signal processing, yet much of the literature in this field has focussed on only two circuit configurations for the sensor input stages. These are the source–drain follower [9], [10] and the differential operational amplifier type [4], [11]. The source–drain follower configuration effectively suppresses all transistor-like behavior of the ISFET by using a feedback cir- cuit to force a single operating point at fixed drain current and fixed drain-source voltage and then track the change in threshold voltage caused by ionic concentration variations. The opera- tional-amplifier configuration however is an excellent example of how conventional circuit techniques such as common-mode rejection via a differential transconductance amplifier can be ap- plied to ISFET sensor chips to reduce thermal sensitivity and eliminate the need for an off-chip reference electrode when used with an ion-insensitive ISFET known as a REFET [12]. Both configurations output a voltage which is proportional to pH. Building upon the understanding of ISFETs and ChemFETs as transistors rather than merely electrodes, we present herein some techniques to exploit behavior which circuit designers have been using for years to their advantage in the design of low-power integrated systems. We present an adaptation of the Translinear Principle to include weakly inverted ISFETs or ChemFETs for the analysis and synthesis of novel sensor input stages. Harnessing the transistor-like characteristics of the ISFET in such a manner demonstrates an important and necessary step toward “biochemical VLSI,” leading to fully integrated low-power diagnostic systems on a single chip. This paper is organized as follows. Section II presents the theory behind ISFET operation. Section III introduces ISFETs in weak inversion and formulates a Biochemical Translinear Prin- ciple using weakly inverted ISFETs/ChemFETs as translinear elements. In Section IV, a low-power current-mode pH-ISFET input stage is presented as an example of the application of the Biochemical Translinear Principle. The current-mode output of this stage is linearly proportional to hydrogen ion concentration and therefore well suited to subsequent real-time processing on-chip. Simulation results and discussion are given in Sec- tion V and conclusions drawn in Section VI. 1057-7122/$20.00 © 2005 IEEE