Journal of Low Power Electronics and Applications

Article Temperature Compensation Circuit for ISFET Sensor

Ahmed Gaddour 1,2,* , Wael Dghais 2,3, Belgacem Hamdi 2,3 and Mounir Ben Ali 3,4

1 National Engineering School of Monastir (ENIM), University of Monastir, Monastir 5000, Tunisia 2 Electronics and Microelectronics Laboratory, LR99ES30, Faculty of Sciences of Monastir, University of Monastir, Monastir 5000, Tunisia; [email protected] (W.D.); [email protected] (B.H.) 3 Higher Institute of Applied Sciences and Technology of Sousse (ISSATSo), University of Sousse, Sousse 4003, Tunisia; [email protected] 4 Nanomaterials, Microsystems for Health, Environment and Energy Laboratory, LR16CRMN01, Centre for Research on Microelectronics and Nanotechnology, Sousse 4034, Tunisia * Correspondence: [email protected]; Tel.: +216-50998008



Received: 3 November 2019; Accepted: 21 December 2019; Published: 4 January 2020


Abstract: PH measurements are widely used in agriculture, biomedical engineering, the food industry, environmental studies, etc. Several healthcare and biomedical research studies have reported that all aqueous samples have their pH tested at some point in their lifecycle for evaluation of the diagnosis of diseases or susceptibility, wound healing, cellular internalization, etc. The ion-sensitive field effect transistor (ISFET) is capable of pH measurements. Such use of the ISFET has become popular, as it allows sensing, preprocessing, and computational circuitry to be encapsulated on a single chip, enabling miniaturization and portability. However, the extracted data from the sensor have been affected by the variation of the temperature. This paper presents a new integrated circuit that can enhance the immunity of ion-sensitive field effect transistors (ISFET) against the temperature. To achieve this purpose, the considered ISFET macro model is analyzed and validated with experimental data. Moreover, we investigate the temperature dependency on the voltage-current (I-V). Accordingly, an improved conditioning circuit is designed in order to reduce the temperature sensitivity on the measured pH values of the ISFET sensor. The numerical validation results show that the developed solution accurately compensates the temperature variation on the measured pH values at low power consumption.

Keywords: ISFET sensor; conditioning circuit; temperature compensation; overall sensitivity

1. Introduction The ion-sensitive field-effect transistors (ISFETs) sensor has played a major role in enabling the fabrication of fully integrated CMOS-based chemical sensing systems. This has allowed several new application areas, with the most promising fields being ion imaging and full genome sequencing. However, the data from this sensor is strongly affected by the variation of the temperature. ISFET is a chemical sensitive microsensor that is based on the field effect transistor, which was invented by Bergveld in the 1970s [1]. The detection principle (shown in Figure1) of the ISFET sensor mechanism is centered on the charge adsorption at the solid ion interface between the electrolyte and the layer that contains the hydroxyl groups [2]. The assembly of hydroxyls can give or accept a proton. As a result of this process, a double layer capacity is generated with a potential variation that in its turn has an impact on the threshold voltage of the transistor according to the H+ ion concentration (i.e., pH) [2]. Moreover, ISFET is a compact sensor that enables a fast pH measurement.

J. Low Power Electron. Appl. 2020, 10, 2; doi:10.3390/jlpea10010002 www.mdpi.com/journal/jlpea J. Low Power Electron. Appl. 2020, 10, 2 2 of 16 J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 2 of 16

H+ Electrolyte H+ - - X + X H + Interfering H+ - H X- X Ion X- X- + X- H+ H H+ H+ + X- - H Ion H+ X

+ H + + + H+ H H H

ISFET Array V Variation t Figure 1. 3D representation of a 6 8 ion-sensitive field effect transistor (ISFET) array. Figure 1. 3D representation of a 6× × 8 ion-sensitive field effect transistor (ISFET) array.

However,However, this this type type of of sensor sensor is is strongly strongly a ffaffectedected by by the the temperature temperature variation. variation. Therefore, Therefore, several several researchersresearchers [3 –[37–]7] have have proposed proposed various various temperature temperature compensation compensation systems systems such as such the proper as the choice proper ofchoice a biasing of a current biasing for current a thermal for working a thermal point working to reduce point the ISFET’s to reduce temperature the ISFET dependency’s temperature [4]. Hence,dependency the use [4]. of aHence, junction the diode use of Zener a junction [4] for temperaturediode Zener compensation[4] for temperature on a single compensation ISFET sensor, on a thesingle employment ISFET sensor, of an theISFET employment with a diff erential of an ISFET configuration with a differential (use of a di ff configurationerential amplifier) (use of [8 ] a thatdifferential increases amplifier) the immunity [8] thatagainst increases temperature the immunity variation, oragainst the combination temperature of variation attenuators, or and the acombin differentialation amplifier of attenuators alongside and with a differential Caprio’s quad amplifier [7] were alongside used in with order Caprio’s to enhance quad the [7] temperature were used stability.in order The to enhance trend of thethe recenttemperature works isstability. set on ISFET The sensortrend of arrays the recent [9–13], works but most is set of theseon ISFET researches sensor arearrays focused [9–13] on, thebut wearable most of these and thermoelectrically researches are focused powered on thesystem wearable [11] and and on thermoelectrically achieving very highpowered accuracy system and [11] a small and settlingon achieving time [10very]. Theyhigh alsoaccuracy focused and on a small system-on-chip settling time for [10]. real-time They ionalso imagingfocused [13on], system but most-on of-chip them for did real not-time focus ion on imaging the temperature [13], but emostffect onof thethem response did not of focus the sensor on the andtemperature did not give effect a robuston the resp solutiononse toof reducethe sensor it. and From did these not give approaches, a robust itsolution can be to noticed reduce that it. From the temperaturethese approaches, dependency it can be is studiednoticed atthat a particular the temperature or in a narrowdependency range. is studied at a particular or in a narrowFor arange. wide range of pH values, the temperature compensation becomes more difficult, since the temperature’sFor a wide coe rangefficient of ofpH an values, electrochemical the temperature device compensation is a function ofbecom the pHes more value difficult [14]. Moreover,, since the thetemperature’s ISFET’s temperature coefficient dependency of an electrochemical tends to exhibit device a random is a function behavior of [15 the–17 pH]. The value straight-line-based [14]. Moreover, temperaturethe ISFET’s temperature compensation dependency limits its scopetends whento exhibit dealing a random with thebehavior actual [15 nonlinear–17]. The temperaturestraight-line- characteristicbased temperature of ISFET’s compensatio device atn limits different its scope values. when Furthermore, dealing with the the temperature actual nonlinear dependency temperature of measuringcharacteristic a circuit of ISFET’s also introduces device at additional different temperature values. Furthermore, influence on the the temperature measured data. dependency As a result, of themeasuring ease of combininga circuit also the introduces temperature additional compensation temperature circuit, influence the efficiency on the of measured the compensation data. As a technique,result, the the ease circuit of sensitivity, combining as wellthe astemperature the circuit simplicity compensation with respect circuit, to body the e efficiencyffects became of the the keycompensation design considerations technique, inthe an circuit integrated sensitivity circuit, as design. well as Respectively, the circuit simplicity it is particularly with respect challenging to body foreffects ISFETs bec toame work the in key an designenvironment considerations where the in required an integrated task is circuit to measure design. di ff Respectively,erent pH ranges it is alongsideparticularly diff challengingerent temperature for ISFET valuess to work [18,19 in]. an Nevertheless, environment thewhere conventional the required means task is used to measure in the signaldifferent processing pH range ofs ISFETs, alongside in particular different thetemperature elementary values current-voltage [18,19]. Nevertheless, conversion the circuits, conventional do not reachmeans optimal used performancein the signal since processing they are of sensitive ISFETs, to in light particular variations the and elementary temperature current especially-voltage whenconversion we use circuits, a sensor do array not reach (spread optimal of the performance error that is since related they to are temperature). sensitive to light In this variations study, it and is importanttemperature to understandespecially when the temperature we use a sensor behavior array (spread of an ISFET of the from error a that foundation is related work to temperature). alongside researchIn this study, of a robust it is important ISFET interface to understand circuit combined the temperature with an behavior improved of temperaturean ISFET from compensation a foundation technique.work alongside In view research of the above of a robust problems, ISFET an interface improved circuit ISFET combined interface with circuit an with improved a simple temperature structure iscompensation proposed. This technique. is in conjunction In view with of the the above investigation problems, of anan improvedimproved dynamicISFET interface biasing circuit temperature with a compensationsimple structure method. is proposed. The latter This is concerned is in conjunction with the with arrangement the investigation of numerical of an iteration improved and dynamic mutual compensationbiasing temperature in ISFET’s compensation MOS transconductance method. characteristics. The latter is This concerned results in with almost the zero arrangement temperature of coenumericalfficients atiteration any pH and value. mutual This compensation enables the ISFET’s in ISFET’s interface MOS circuit transconductance to measure simultaneouslycharacteristics. This the correctresults values in almost of pH zero at anytemperature temperature. coefficient In thiss work, at any we pH investigate value. This the enables temperature’s the ISFET’s influence interface on thecircuit ISFET. to Then, measure we proposesimultaneously a new integrated the correct circuit, values which of pH is at capable any temperature. of reducing theIn this temperature work, we dependencyinvestigate and the is temperature’s applicable for influence systems such on the assensor ISFET. arrays. Then, Then, we propose we present a new a new integrated demonstration circuit, ofwhich temperature is capable compensation of reducing using the temperature the differential dependency setup. Many and researchers is applicable have for reported systems severalsuch as ISFETsensor/reference arrays. T fieldhen, eweffect present transistor a new (ReFET) demonstration topologies of [20 temperature–25], and the compensation first circuit that using used the ISFETdifferential/ReFET setup. was introduced Many researche by Bergveldrs have [20 reported]. In this several work, ISFET/ we presentreference a new field circuit effect based transistor on (ReFET) topologies [20–25], and the first circuit that used ISFET/ReFET was introduced by Bergveld [20]. In this work, we present a new circuit based on differential measurement (ISFET/ReFET)

J.J. Low Low Power Power Electron. Electron. Appl. Appl. 20202020, ,1010, ,x 2 FOR PEER REVIEW 3 3of of 16 16 operating in a weak inversion regime, and we demonstrate with a simple manner (mathematically) differential measurement (ISFET/ReFET) operating in a weak inversion regime, and we demonstrate the temperature compensation using the ISFET/ReFET topology. with a simple manner (mathematically) the temperature compensation using the ISFET/ReFET topology. This paper is organized as follows. Section 2 presents the conventional ISFET macro model, This paper is organized as follows. Section2 presents the conventional ISFET macro model, Section 3 investigates the temperature’s effect on the validated ISFET model, Section 4 illustrates a Section3 investigates the temperature’s e ffect on the validated ISFET model, Section4 illustrates a new new conditioning circuit for temperature compensation, and Section 5 concludes the paper. conditioning circuit for temperature compensation, and Section5 concludes the paper.

2.2. ISFET ISFET Macro Macro Model Model TheThe considered considered ISFET ISFET macro macro model model that that captures captures the the ISFET ISFET sensor sensor current current voltage voltage (I (I-V)-V) characteristiccharacteristic behavior behavior is is under under temperature temperature variation variation and and based based on on the the model model developed developed under under 퐻+ PSPICEPSPICE [26, [26,2727].]. The ISFETISFET responseresponse to to the theH + ion ion is demonstratedis demonstrated by siteby site binding binding theory, theory which, which gives givesa complete a complete description description of the of ISFET the ISFET behavior behavior when when combined combine withd the with Gouy–Chapman–Stern the Gouy–Chapman– modelStern modeland MOSFET and MOSFET physics physics [26]. As [26]. a consequence, As a consequence, a set of a equations set of equations has been has drawn been updrawn in order up in to order study tothe study sensitivity the sensitivity of the sensor of the andsensor its and dependence its dependence according according to the physicochemicalto the physicochemical parameters parameters of the ofISFET. the ISFET. Subsequently, Subsequently, the SPICE the SPICE macro macro model model considers considers the ISFET the ISFET sensor sensor as two as uncoupled two uncoupled stages: stages:an electrochemical an electrochemical stage that stage represents that represents the interface the interface electrolyte–insulator electrolyte–insulator modeled modeled by site bindingby site bindingtheory, along theory with, along an electronic with an electronic stage, which stage is, modeledwhich is by modeled MOSFET. by TheMOSFET. considered The considered equivalent equivalentelectrical circuit electrical of the circuit ISFET of macrothe ISFET model macro is shown model in is Figure shown2. in Figure 2.

D -Eref CHelm CGouy R B 0 S VpH MOSFET

FigureFigure 2. 2. EquivalentEquivalent electrical electrical circuit circuit of of the the ISFET ISFET structure. structure. Where R is the reference electrode, D is the drain, S is the electrolyte–insulation source, B is the where R is the reference electrode, D is the drain, S is the electrolyte–insulation source, B is the substrate, and VpH refers to the potential of the electrolyte–insulation interface. The expression of VpH substrate, and 푉푝퐻 refers to the potential of the electrolyte–insulation interface. The expression of can be written as follows: 푉푝퐻 can be written as follows: VpH = Ere f + ϕ0 (1) 푉 = −퐸− + 휑 푝퐻 KT푟푒푓 0  (1) ϕ0 = 2.3 α pHpzc pH (2) 퐾푇 q − 휑0 = 2.3 훼(푝퐻푝푧푐 − 푝퐻) (2) where Ere f is the potential applied to the reference푞 electrode, ϕ0 is the electrostatic potential, which is directly proportional to pH and temperature, K is the Boltzmann constant, T is the absolute temperature, 퐸 휑 wherepHpzc is푟푒푓 theis pH-zerothe potential point applied of charge, to theq is reference the electron electrode, charge, and0 is theα is electrostatic the corrective potential parameter, which for ispH–ISFET, directly proportional which ranges to between pH and0 temperature and 1. The electrochemical , 퐾 is the Boltzmann properties constant of the, insulating푇 is the absolute surface temperature,were combined 푝퐻 with푝푧푐 is thethe nonlinearpH-zero point current-voltage of charge, 푞 (I-V) is the MOSFET, electron resulting charge, and in an 훼 expressionis the corrective of the parameterthreshold voltage for pH of–ISFET the ISFET,, which including ranges terms between derived 0 and from 1. The the MOSFET electrochemical theory as properties well as terms of the of insulatingan electrochemical surface were nature combined [26]: with the nonlinear current-voltage (I-V) MOSFET, resulting in an expression of the threshold voltage of the ISFET, including terms derived from the MOSFET theory " #   Qss + Qsc ϕsc as well as terms of Van (electrochemicalISFET) = E nature+ ϕ [26](ϕ: χ ) 2ϕ + (3) tI re f lj 0 e C f q − − − 푄 +ox 푄 − 휑 ( ) ( ) 푠푠 푠푐 푠푐 푉푡퐼 퐼푆퐹퐸푇 = (퐸푟푒푓 + 휑푙푗) − 휑0 − 휒푒 − [ − 2휑푓 + ] (3) 퐶표푥 ϕm 푞 V (ISFET) = V (MOSFET) + E + ϕ + χ ϕ (4) tI tM re f lj e 휑 0 = 푉 (푀푂푆퐹퐸푇) + 퐸 + 휑 + 휒 − 휑 −− 푚 − q 푡푀 푟푒푓 푙푗 푒 0 푞 (4) where ϕ f is the fermi potential of a semiconductor, Qss is the charge density per surface unit at the where 휑 is the fermi potential of a semiconductor, 푄 is the charge density per surface unit at the insulator푓/semiconductor interface, Qsc is the charge density푠푠 in the semiconductor depletion region, insulator/semiconductor interface, 푄푠푐 is the charge density in the semiconductor depletion region, ϕlj is the tension between the reference solution and the electrolyte, Cox is the gate oxide capacity, 휑 is the tension between the reference solution and the electrolyte, 퐶 is the gate oxide capacity, and푙푗 χe is the interface potential electrolyte/insulator dipole. It is worth표푥 noting that the potential ϕ0 and 휒푒 is the interface potential electrolyte/insulator dipole. It is worth noting that the potential 휑0

J. Low Power Electron. Appl. 2020, 10, 2 4 of 16 J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 4 of 16 isis the the only only variable variable that that depends depends on on pH. pH. Considering Considering the the weak weak inversion inversion region region of of MOSFET, MOSFET, the the I-V I-V characteristiccharacteristic of of ISFET ISFET can can be be written written as as follows: follows:

Vgs푉푔푠V−t 푉푡 ( ( − I )퐼) ηUɳt푈 (5) Ids퐼푑푠==I 0퐼e0푒 푡 (5)

where 퐼0 is a characteristic current, 푈푡 is the thermal voltage, and ɳ is the slope factor of the where I0 is a characteristic current, Ut is the thermal voltage, and η is the slope factor of the subthreshold.subthreshold. This This mode mode of of operation operation o offersffers an an opportunity opportunity to to have have a a high high intrinsic intrinsic voltage voltage gain gain and and aa low low power power processing. processing.

2.1.2.1. Fabrication Fabrication and and Testing Testing TheThe N-channel N-channel ISFET ISFET fabrication fabrication was was carried carried out out at at the the Semiconductor Semiconductor Physics Physics Department, Department,

ResearchResearch Institute Institute of of Microdevices Microdevices (Kyiv, (Kyiv, Ukraine). Ukraine). The The gate gate dielectric dielectric is is based based on on a S aiO 푆2푖푂/2S /i3푆푖N3 푁4 4 sensitivesensitive film film structure structure [28 [28]]. The. The sensor sensor chip chip was attachedwas attached to a Sital to a (fused Sital (fused silica) supportsilica) support and was and bound was tobound the aluminum to the aluminum conductors. conductors. The length The of thelength canal of is the about canal 7 µ ism, about and its 7 widthµm, and is 250 its µwidthm. To is measure 250 µm. theTo currentmeasure voltage the current (Ids) characteristics voltage (퐼푑푠) ofcharacteristics the ISFET, the of substratethe ISFET, and the the substrate source areand grounded the source and are thegrounded source–drain and the voltage source (V–dsdrain) was voltage maintained (푉푑푠) atwas 1 V. maintained To measure at the 1 V. sensitivity To measure of the the ISFET sensitivity sensor, of wethe used ISFET three sensor, buff erwe solutions used three from buffer pH solution= 3 to pHs from= 11. pH To = investigate 3 to pH = 11. the To reliability investigate and the stability reliability of theand pH stability sensor, of we the evaluated pH sensor, the we temperature evaluated e theffects temperature on the responses effects ofon the the ISFET. responses Temperature of the ISFET. can affTemperatureect the characteristics can affect ofthe a sensor,characteristics the pH of thea sensor, electrolyte, the pH the of potential the electroly of ate, reference the potential electrode, of a andreference the measuring electrode system., and the Formeasuring latter changes, system. theFor temperaturelatter changes, was the kept temperature constant was inside kept the constant room. Toinside keep the the electrolyte, room. To electrode,keep the electrolyte,and ISFETat electrode, constant temperature,and ISFET at a heat-regulating constant temperature, loop including a heat- aregulating temperature-sensing loop including system a andtemperatu a heatingre-sensing system havesystem been and used. a heating In addition, system experimental have been used. results In canaddition only be, experimental compared validly results to can theory only if be the compared temperature validly during to theorymeasurements if the temperature is fixed. Figure during3 showsmeasurements the experimental is fixed. setupFigure and 3 shows the simulated the experimental equivalent setup circuit and model the simulated implemented equivalent in the circuit ADS basedmodel on implemented modified SPICE in the model. ADS based on modified SPICE model:

(b)

VpH D B Vds S Vgs A ISFET Ids

Figure 3. (a) Experimental setup using the ISFET sensor, (b) ADS circuit simulation using the ISFET model. Figure 3. (a) Experimental setup using the ISFET sensor, (b) ADS circuit simulation using the ISFET model.

ForFor the the experimentalexperimental setup,setup, we used a a GW GW Instek Instek SPS SPS-606-606 generation generation for for the the 푉푔푠V gsvariationvariation;; for formeasuring measuring the the 퐼푑푠Ids variationvariation,, we we used used a a Keithley Keithley 2400 2400 Source Meter,Meter, andand forfor V푉ds푑푠,, we we used used a a simple simple DCDC generator. generator. The The results results extracted extracted from from the the simulation simulation of of the the macro macro model model were were compared compared with with the the experimentalexperimental recorded recorded data, data as, as shown shown in in Figure Figure4. 4. The good agreement between the experimental and simulated data is confirmed by estimating

1,0 model (V =2V) Error (6), which is model about (V =2V) 1.12% (worst case) for pHmodel (V==2V)11.01 V [ 1.8 V, 0.5 V].ds For the next parts of ds ds gs 2,0 experimental (Vds=2V) experimental (Vds=2V) experimental (V = 2V) ∈ − 1,2− ds model (V =1V) this work, we used model the (V =1V) validated macro model. ds 0,8 ds model (Vds=1V) experimental (Vds=1V) experimental (Vds=1V) experimental (Vds= 1V) model (V =0,5V) 1,5 model (Vds=0,5V) ds model (V =0,5V) = ds experimental (V =0,5V) n 8 0,8 experimental (V =0,5V) 0,6 ds experimentalI (VI = 0,5V) ds X dsexp ds model − Tris buffer

ε(%) =1,0 Tris( Buffer ) 100 (6)

(mA) (mA)

(mA) Tris Buffer I × T=20°C ds ds T=21°C

0,4 ds exp I

I i= ds 1 0,4 I T=23 °C pH=6,91 pH=11,01 0,5 Moreover,0,2 pH=3 Table1 reports the technological(b) parameters used for the ISFET(c) macro model. (a) 0,0 0,0 0,0 -2,5 -2,0 -1,5 -1,0 -0,5 -2,5 -2,0 -1,5 -1,0 -0,5 -2,5 -2,0 -1,5 -1,0 -0,5 V (V) V (V) V (V) gs gs gs Figure 4. Model simulated in ADS versus experimental data.

J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 4 of 16 is the only variable that depends on pH. Considering the weak inversion region of MOSFET, the I-V characteristic of ISFET can be written as follows:

푉푔푠−푉푡 ( 퐼) ɳ푈 (5) 퐼푑푠 = 퐼0푒 푡 where 퐼0 is a characteristic current, 푈푡 is the thermal voltage, and ɳ is the slope factor of the subthreshold. This mode of operation offers an opportunity to have a high intrinsic voltage gain and a low power processing.

2.1. Fabrication and Testing The N-channel ISFET fabrication was carried out at the Semiconductor Physics Department,

Research Institute of Microdevices (Kyiv, Ukraine). The gate dielectric is based on a 푆푖푂2 /푆푖3 푁4 sensitive film structure [28]. The sensor chip was attached to a Sital (fused silica) support and was bound to the aluminum conductors. The length of the canal is about 7 µm, and its width is 250 µm.

To measure the current voltage (퐼푑푠) characteristics of the ISFET, the substrate and the source are grounded and the source–drain voltage (푉푑푠) was maintained at 1 V. To measure the sensitivity of the ISFET sensor, we used three buffer solutions from pH = 3 to pH = 11. To investigate the reliability and stability of the pH sensor, we evaluated the temperature effects on the responses of the ISFET. Temperature can affect the characteristics of a sensor, the pH of the electrolyte, the potential of a reference electrode, and the measuring system. For latter changes, the temperature was kept constant inside the room. To keep the electrolyte, electrode, and ISFET at constant temperature, a heat- regulating loop including a temperature-sensing system and a heating system have been used. In addition, experimental results can only be compared validly to theory if the temperature during measurements is fixed. Figure 3 shows the experimental setup and the simulated equivalent circuit model implemented in the ADS based on modified SPICE model:

(b)

VpH D B Vds S Vgs A ISFET Ids

Figure 3. (a) Experimental setup using the ISFET sensor, (b) ADS circuit simulation using the ISFET model.

For the experimental setup, we used a GW Instek SPS-606 generation for the 푉푔푠 variation; for measuring the 퐼푑푠 variation, we used a Keithley 2400 Source Meter, and for 푉푑푠, we used a simple J.DC Low generator. Power Electron. The Appl. results2020, extracted10, 2 from the simulation of the macro model were compared with5 of the 16 experimental recorded data, as shown in Figure 4.

1,0 model (V =2V) model (V =2V) ds ds model (Vds=2V) 2,0 experimental (Vds=2V) experimental (Vds=2V) experimental (V = 2V) 1,2 ds model (V =1V) model (V =1V) ds 0,8 ds model (Vds=1V) J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW experimental (Vds=1V) 5 of 16 experimental (Vds=1V) experimental (Vds= 1V) model (V =0,5V) 1,5 model (Vds=0,5V) ds model (V =0,5V) ds 0,8 experimental (V =0,5V) 0,6 experimental (Vds=0,5V) ds experimental (Vds= 0,5V) Tris buffer

The good agreement between the experimental1,0 Tris Buffer and simulated data is confirmed by estimating

(mA) (mA)

(mA) Tris Buffer T=20°C ds T=21°C

0,4 ds

I I Error (6), whichds is about 1.12% (worst case) for pH = 11.01 푉푔푠⋲ [−1.8 0,4V, −0.5 V]. For the next parts of I T=23 °C pH=6,91 pH=11,01 0,5 this work, 0,2wepH=3 used the validated macro model.(b) (c) (a) 푛=8 0,0 0,0 0,0 퐼푑푠푒푥푝 − 퐼푑푠푚표푑푒푙 휀(%) = ∑( ) × 100 (6) -2,5 -2,0 -1,5 -1,0 -0,5 -2,5 -2,0 -1,5 -1,0 -0,5 -2,5 -2,0 -1,5 -1,0 -0,5 퐼푑푠푒푥푝 푖=1 V (V) V (V) V (V) gs gs gs Moreover, Table 1 reports the technological parameters used for the ISFET macro model. Figure 4. Model simulated in ADS versus experimental data. Table 1. Technological parameters of the simulated macro model. Table 1. Technological parameters of the simulated macro model. PARAMETERS VALUES Parameters Values 푉푡표: THRESHOLD VOLTAGE (V) −1.7 Vto: Threshold Voltage (V) 1.7 휑0: SURFACE POTENTIAL (MV) 555− ϕ0 : Surface Potential (mV) 555 흀0: CHANNEL LENGTH (µM) 7.59 λ0: Channel length (µm) 7.59 2 CM2 C퐶푗j:: J JunctionUNCTION Capacity CAPACITY (F/cm (F/) ) 4.444.44 퐶C푗푠푤jsw: :JUNCTION Junction Sidewall SIDEWALL Capacity CAPACITY (pF/ m)(PF/M) 515515 Tox: oxide thickness (nm) 150 푇표푥: OXIDE THICKNESS (NM) 150

2.2. Sensor Sensor Sensitivity In order to estimate the sensitivity of validated macro model, Figure 55 showsshows thethe variationsvariations ofof

휕∂(log (퐼I푑푠ds))))⁄/휕∂V푉푔푠gs as a function of V푉푔푠gs atat constant V푉ds푑푠 == 1 V V.. TheThe thresholdthreshold voltagevoltage extraction method present in Figure5 5 is is inspiredinspired fromfrom thethe secondsecond derivativederivative methodmethod [[29]29],, unless this technique can provide anan exactexact thresholdthreshold value value more more accurately. accurately The. The proposed proposed method method enables enable others other perspectives perspectives for forthe the extraction extraction of the of the technological technological parameters parameters of the of the transistor. transistor.

0,40

0,35 pH=13

) pH=1 0,30

pH=7 gs

V 0,25 (

/d 0,20

) )

ds 0,15

I (

0,10 log

( 0,05 d 0,00 -0,05 -2,10 -1,89 -1,68 -1,47 -1,26 -1,05 -0,84 V (V) gs   Figure 5. ∂(log(Ids)) / ∂Vgs = f Vgs, PHi characteristics for different values of pH 1, 7, 13 at Figure 5. 휕(log (퐼푑푠)) ⁄ 휕 푉푔푠 = 푓(푉푔푠, 푃퐻푖) characteristics for different values of 푝퐻 ∈ {1, 7,∈13{} at T =} 27 °C. T = 27 ◦C. The 푉푡퐼 is extracted for different pH values using the method of the first derivation. These valuesThe areV thentI is extracted plotted on for a digraphfferent as pHa function values usingof the the pH. method of the first derivation. These values are thenAs seen plotted in Figure on a graph 6, the asdetermined a function sensitivity of the pH. based on the ISFET macro model simulation (i.e., As seen in Figure6, the determined sensitivity based on the ISFET macro model simulation 푠푚 = 54 푚푉/푝퐻) has approximately the same the sensitivity, which was calculated based on the (i.e., sm = 54 mV/pH) has approximately the same the sensitivity, which was calculated based on experimental data (i.e., 푠푒푥푝 ≈ 51 푚푉/푝퐻) . In fact, the experimental ISFET characteristics were the experimental data (i.e., sexp 51 mV/pH). In fact, the experimental ISFET characteristics were validated against the implemented≈ macro model in order to accurately predict the pH values. validated against the implemented macro model in order to accurately predict the pH values.

J. Low Power Electron. Appl. 2020, 10, 2 6 of 16 J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 6 of 16

-1,2

-1,3 Model Data -1,4 Experimental Data Linear Fit -1,5 R2 =0,9993

-1,6 (V) -1,7 -1,8 -1,9 -2,0 -2,1 0 2 4 6 8 10 12 14 pH

Figure 6. Variation of VtI of the sensor as a function of the pH (model and experimental data). Figure 6. Variation of 푉푡퐼of the sensor as a function of the pH (model and experimental data). 3. ISFET Temperature-Dependent Behavior 3. ISFET Temperature-Dependent Behavior Several works have demonstrated that the ISFET electrochemical behavior shows a temperature dependency.Several works In fact, have the temperaturedemonstrated variation that the aISFETffects electrochemical the ISFET sensing behavior circuit suchshows as a thetemperature reference electrode,dependency. electrolyte In fact, the insulator temperature potential, variation and MOSFET affects the transistor. ISFET sensing It can be circuit expressed such as as: the reference electrode, electrolyte insulator potential, and MOSFET transistor. It can be expressed as:

TC = TC + TC + TC (7) 푇T퐶푇 = 푇퐶R푅 + 푇퐶퐼I + 푇퐶퐹F (7)

where 푇퐶 refers to the total temperature coefficient of ISFET. 푇퐶 is the temperature coefficient of where TC푇T refers to the total temperature coefficient of ISFET. TC푅R is the temperature coefficient of reference electrode E퐸re푟푒푓 f ,, whichwhich hashas beenbeen reportedreported byby [[2222]] withwith aa standard value about 0.14 mV/°C. mV/◦C. 푇 refers to the temperature coefficient of the interface potential electrolyte insulator. It has also been T퐶C퐼I refers to the temperature coefficient of the interface potential electrolyte insulator. It has also been 푇 provenproven thatthatT C퐶I 퐼is is a a function function of of pH pH value. value. It canIt can diff differer from from 0.54 0.54 mV mV to 1.1 to mV1.1 asmV the as pH the increases pH increases from

4from to 10 4 [30 to ]. 10 The [30]. third The item third in (7) itemTC inF represents (7) 푇퐶퐹 represents the coeffi cient the coefficient of the temperature of the temperature in MOS structure in MOS of ISFET.structure Based of ISFET. on the Based device on physics, the device the principalphysics, the parameters principal that parameters are responsible that are for responsible the temperature for the dependencytemperature ofdependency the MOSFET of the transistor MOSFET are transistor the mobility are andthe thresholdmobility and voltage. threshold For anyvoltage. temperature, For any ittemperature, can be modeled it can as be follows: modeled as follows: ! n T −푛 µ(T) = µ(T0) 푇 (8) µ(푇) = µ(푇0) (T0 ) (8) 푇0 Vt (T) = Vt (T ) + K (T T ) (9) M ( ) M ( 0) VT 0 푉푡푀 푇 = 푉푡푀 푇0 + 퐾푉푇 (푇 −−푇0) (9) where T0 is the reference temperature and n is a constant, with standard values between 1.9 and 2.2, where 푇0 is the reference temperature and 푛 is a constant, with standard values between− –1.9 and− – depending on the doping concentrations of silicon. KVT refers to the temperature coefficient of the 2.2, depending on the doping concentrations of silicon. 퐾푉푇 refers to the temperature coefficient of threshold voltage, which is usually between 0.5 mV/◦C and 3 mV/◦C. the threshold voltage, which is usually between− −0.5 mV/°C and− −3 mV/°C. Analysis of the Temperature Effect on the ISFET Sensor Analysis of the Temperature Effect on the ISFET Sensor Studies by Jung-Lung CHIANG et al. [31] have shown that ISFET has a high temperature dependency,Studies by which Jung leads-Lung to CHIANG a pH measurement et al. [31] have inaccuracy, shown so that it is ISFET very has important a high to temperature study the temperaturedependency, behavior which leads of ISFETs to a and pH determine measurement relevant inaccuracy, methods so to improve it is very their important temperature to study stability. the temperature behavior of ISFETs and determine relevant methods to improve their temperature It is worth noting that by analyzing Figure7, the drain current Ids of the ISFET macro model varies considerablystability. with the temperature. It deteriorates with an increase in temperature. This behavior is dominatedIt is worth by noting two phenomena: that by analyzing the degradation Figure 7, the of thedrain mobility currentµ 퐼and푑푠 of the the shift ISFET of themacro threshold model varies considerably with the temperature. It deteriorates with an increase in temperature. This voltage VtM , which result in the offset of the gate-source voltage Vgs below and above the isothermal point,behavior respectively. is dominated by two phenomena: the degradation of the mobility 휇 and the shift of the threshold voltage 푉 , which result in the offset of the gate-source voltage 푉 below and above the For Vgs [ 2 V,푡푀 0.75 V], we notice an offset of the threshold voltage V푔푠t above the isothermal ∈ − − I point,isothermal which point results, respectively. in an increase of this later when the temperature increases. For Vgs [ 0.75 V, 0.5 V], the degradation of the mobility µ is observed underneath the ∈ − isothermal point. In fact, the temperature dependence of of the mobility significantly increases with the temperature [32].

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J. Low PowerJ. Low Electron. Power Electron. Appl. 20 Appl.20, 202010, ,x10 FOR, 2 PEER REVIEW 7 of 16 7 of 16

Figure 7. 퐼푑푠 = 푓 (푉푔푠, 푉푑푠 = 1 V) curves of the ISFET sensor at temperatures between 0 and 50 °C.

For 푉푔푠 ⋲ [−2 V, −0.75 V], we notice an offset of the threshold voltage 푉푡퐼 above the isothermal point, which results in an increase of this later when the temperature increases.

For 푉푔푠 ∈ [−0.75 V, 0.5 V], the degradation of the mobility 휇 is observed underneath the isothermal point. In fact, the temperature dependence of of the mobility significantly increases with   the temperatureFigure 7. [32].Ids = f Vgs, Vds = 1 V curves of the ISFET sensor at temperatures between 0 and 50 ◦C. Figure 7. 퐼 = 푓 (푉 , 푉 = 1 V) curves of the ISFET sensor at temperatures between 0 and 50 °C. The curvatures푑푠 of푔푠 Figure푑푠 8 are almost similar to the plots of Figure 7, but the only difference is The curvatures of Figure8 are almost similar to the plots of Figure7, but the only di fference is shown by the dislocation of the isothermal point for the pH values equal to 3 and 8 (both Figures 7 Forshown 푉 ⋲ by [− the2 V dislocation, −0.75 V], of we the notice isothermal an pointoffset for of the the pH threshold values equal voltage to 3 and 푉 8 (bothabove Figures the isothermal7 and 8 are푔푠 obtained from the simulation of ISFET macro model). The dislocation푡퐼 of the isothermal point, whichand8 are results obtained in froman increase the simulation of this of ISFETlater when macro model).the temperature The dislocation increases. of the isothermal point point causes a decrease of the drain-source current 퐼푑푠 and an increase of the gate source voltage 푉푔푠. causes a decrease of the drain-source current Ids and an increase of the gate source voltage Vgs. For 푉푔푠 ∈ [−0.75 V, 0.5 V], the degradation of the mobility 휇 is observed underneath the isothermal point. In fact, the temperature dependence of of the mobility significantly increases with the temperature [32]. The curvatures of Figure 8 are almost similar to the plots of Figure 7, but the only difference is shown by the dislocation of the isothermal point for the pH values equal to 3 and 8 (both Figures 7 and 8 are obtained from the simulation of ISFET macro model). The dislocation of the isothermal point causes a decrease of the drain-source current 퐼푑푠 and an increase of the gate source voltage 푉푔푠.

  Figure 8. Vgs curves of the ISFET sensor at a temperature between 0 and 50 C with a step of 10 C Figure 8. (푉푔푠) curves of the ISFET sensor at a temperature between 0 and 50◦ °C with a step of◦ 10 °C for pH = 3 and 8. for pH = 3 and 8. Figure9 demonstrates the variation of the threshold voltage as a function of pH over a wide temperatureFigure 9 demonstrates range. The shifting the variation of the threshold of the threshold voltage also voltage results inas the a function degradation of pH of the over sensor a wide temperaturesensitivity range. for high The pH shifting values whenof the thethreshold temperature voltage varies also from results 0 to 50in ◦theC. Fromdegradation visual inspection, of the sensor sensitivitythe sensitivity for high of thepH sensorvalues linearly when variesthe temperature with respect tovaries the temperature, from 0 to 50 which °C. From is reported visual in Tableinspection,2. the sensitivity of the sensor linearly varies with respect to the temperature, which is reported in Table 2. Table 2. Variation of the sensor’s sensitivity according to the temperature’s variation.

T(◦C) 0 10 20 30 40 50 Figure 8. (푉푔푠) curvesSensitivity of the ISFET (mV/pH) sensor 63at a temperature 58 54 between 51 0 and 40 50 °C 38 with a step of 10 °C for pH = 3 and 8. Table 2. Variation of the sensor’s sensitivity according to the temperature’s variation.

Figure 9 demonstrates the variation of the threshold voltage as a function of pH over a wide temperature range. The shifting of the threshold voltage also results in the degradation of the sensor sensitivity for high pH values when the temperature varies from 0 to 50 °C. From visual inspection, the sensitivity of the sensor linearly varies with respect to the temperature, which is reported in Table 2.

Table 2. Variation of the sensor’s sensitivity according to the temperature’s variation.

J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 8 of 16 J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 8 of 16 T (°C) 0 10 20 30 40 50 J. Low Power Electron. Appl. 2020, 10, 2 T (°C) 0 10 20 30 40 50 8 of 16 Sensitivity (mV/pH) 63 58 54 51 40 38 Sensitivity (mV/pH) 63 58 54 51 40 38

0°C( sensitivity = 63mV/pH) 0,4 10°C(0°C( sensitivity sensitivity = = 63mV/pH) 58mV/pH) 0,4 20°C(10°C( sensitivity = 54mV/pH)58mV/pH) 30°C(20°C( sensitivity = 51mV/pH)54mV/pH) 0,2 40°C(30°C( sensitivity = 40mV/pH)51mV/pH) 0,2 50°C(40°C( sensitivity = 38mV/pH)40mV/pH) 0,0 50°C( sensitivity = 38mV/pH) 0,0

(V) -0,2

(V) -0,2 -0,4 -0,4 -0,6 -0,6 -0,8 -0,8 2 4 6 8 10 12 2 4 6 8 10 12 pH pH Figure 9. pH sensitivity of the ISFET sensor measured for a temperature from 0 to 50 C with a step Figure 9. pH sensitivity of the ISFET sensor measured for a temperature from 0 to 50 °C with◦ a step of 10 °C. Figureof 10 9.◦ pHC. sensitivity of the ISFET sensor measured for a temperature from 0 to 50 °C with a step of 10 °C. The presented data in Figure 10 were extracted from Figure 9, and present the traces of the The presented data in Figure 10 were extracted from Figure 9, and present the traces of the thresholdThe presented voltage for data pH in= 6, Figure when 10the were temperature extracted varies from from Figure 0 to9, 50 and °C. present Figure the10 also traces illustrates of the threshold voltage for pH = 6, when the temperature varies from 0 to 50 °C. Figure 10 also illustrates thresholdthe dependence voltage of for the pH ISFET= 6, sensor when theon the temperature temperature varies about from 10 0mV/°C to 50 ◦ (nearlyC. Figure 20% 10 ofalso sensit illustratesivity is the dependence of the ISFET sensor on the temperature about 10 mV/°C (nearly 20% of sensitivity is theaffected dependence by temperature). of the ISFET sensor on the temperature about 10 mV/◦C (nearly 20% of sensitivity is aaffectedffected byby temperature).temperature).

0,0 0,0 Threshold Voltage ThresholdLinear Fit Voltage -0,1 Linear Fit -0,1

-0,2 R2=0,9999 -0,2 R2=0,9999 pH=6 -0,3 pH=6

(V) -0,3 (V) -0,4 -0,4 -0,5 -0,5 -0,6 -0,6-10 0 10 20 30 40 50 60 -10 0 10 20 30 40 50 60 T(°C) T(°C) Figure 10. Threshold voltage as a function of temperature.temperature. Figure 10. Threshold voltage as a function of temperature. In casescases wherewhere we have a sensor array (6 × 88 ISFETs) ISFETs),, the noise generated by the temperature can In cases where we have a sensor array (6 × 8 ISFETs), the noise generated by the temperature can distort any measurement. Therefore, it is necessary to add a complimentary circuit in order to reduce distort any measurement. Therefore, it is necessary to add a complimentary circuit in order to reduce the temperature eeffect.ffect. The next section presents the proposed conditioning circuit that is capable of the temperature effect. The next section presents the proposed conditioning circuit that is capable of limitinglimiting the temperature dependencydependency ofof thethe ISFETISFET microsensor.microsensor. limiting the temperature dependency of the ISFET microsensor. 4. Proposed Temperature CompensationCompensation CircuitCircuit 4. Proposed Temperature Compensation Circuit This section analyzesanalyzes the conditioning circuit architecture. The didifferentialfferential ISFET-basedISFET-based pH This section analyzes the conditioning circuit architecture. The differential ISFET-based pH measurement is shown in in Figure Figuress 1111 andand 12.12 .In In fact, fact, the the ISFET ISFET sensor sensor is isused used in in a conjunction a conjunction that that is measurement is shown in Figures 11 and 12.+ In fact, the ISFET sensor is used in a conjunction that is issensitive sensitive to toa specific a specific species species (such (such as asH+ H) and) and a reference a reference field field effect effect transistor transistor (ReFET) (ReFET),, which which is sensitive to a specific species (such as H+) and a reference field effect transistor (ReFET), which is isinsensitive insensitive to tothis this species. species. ReFET ReFET was was introduced introduced to minimize to minimize the thedrift drift effects effects and and the thenoise noise on the on insensitive to this species. ReFET was introduced to minimize the drift effects and the noise on the themeasurement. measurement. Both Both sensors sensors must must have have the the same same electrical electrical and and chemical chemical characteristics. characteristics. A A ReFET measurement. Both sensors must have the same electrical and chemical characteristics. A ReFET wouldwould experience a similar condition as an ISFET except the chance of respondingresponding to an occurringoccurring would experience a similar condition as an ISFET except the chance of responding to an occurring chemical reactionreaction [ 33[33].]. The The ISFET ISFET/ReFET/ReFET topology topology can can be be implemented implemented in two in two configurations. configuration Thes. firstThe chemical reaction [33]. The ISFET/ReFET topology can be implemented in two configurations. The configurationfirst configuration is to fabricateis to fabricate a REFET a REFET similar similar to ISFET to ISFET but with but a with different a different membrane membrane [2]. The [2]. second The first configuration is to fabricate a REFET similar to ISFET but with a different membrane [2]. The configurationsecond configuration is to make is to the make REFET the/ REFET/ISFET completely ISFET completely similar, butsimilar, insulated but insulated and exposed and exposed to another to second configuration is to make the REFET/ ISFET completely similar, but insulated and exposed to analystanother whereanalyst no where reaction no mayreaction happen may [happ34]. However,en [34]. However, in addition in addition to the DC to o fftheset DC problem offset thatproblem may another analyst where no reaction may happen [34]. However, in addition to the DC offset problem biasthat may the ISFET bias the and ISFET REFET and out REFET of the out active of the region active causing region thecausing circuit the to circuit stack to to stack the power-ground to the power- that may bias the ISFET and REFET out of the active region causing the circuit to stack to the power- rail,ground the gate rail, drain the gate capacitance drain capacitance may distort may the sensor distort response. the sensor The response. drain node The is unmaintained,drain node is andground it cannot rail, thefollow gate the drain gate. capacitance Hence, with may the Miller distort eff theects, sensor the gain response. between The the drain drain andnode the is

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J. Lowunmaintain Power Electron.ed, Appl. and2020 it cannot, 10, 2 follow the gate. Hence, with the Miller effects, the gain between9 of 16 the drain and the gate terminals of the deferential topology cause the appearance of the decoupling capacitors on the floating gate, and this may distort the signal. Nevertheless, to overcome the random gate terminals of the deferential topology cause the appearance of the decoupling capacitors on the DC offset, most of the ISFETs require a calibration of the reference electrode; ISFET/ReFET topology floating gate, and this may distort the signal. Nevertheless, to overcome the random DC offset, most of may also require more calibration between the ISFET and the reference FET, which makes it a little the ISFETs require a calibration of the reference electrode; ISFET/ReFET topology may also require bit complicated for implementation in the ISFET arrays [2,35]. To overcome these limitations, the more calibration between the ISFET and the reference FET, which makes it a little bit complicated presented circuit in Figure 11 presents a solution for ISFET/ReFET topology. The feedback made by for implementation in the ISFET arrays [2,35]. To overcome these limitations, the presented circuit the amplifiers (OTA 1 and OTA 2) can control the calibration of the reference electrode to overcome in Figure 11 presents a solution for ISFET/ReFET topology. The feedback made by the amplifiers the DC offset and make it easier the implementation of the ReFET/ISFET for the deferential (OTA 1 and OTA 2) can control the calibration of the reference electrode to overcome the DC offset and measurement. make it easier the implementation of the ReFET/ISFET for the deferential measurement.

VDD J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 10 of 16

R3 2 k

푅3 R2 ∗ Ω 푉푔푠 = 휂 푇 Log ( 2 2 kΩ 푉퐷퐷) + 푉푡퐼 + 푉푝퐻. (13)

2휂훽푈푇푅2(푅4+푅3) Ω

R4 2

The DC simulation resultsk of the circuit depicted in Figure 11 are shown in Figure 12. Figure

k 3 3 12a,b present respectively the variation +of the output signalVpH versus the Rinput1 Ω signal and the variation of 푉표푢푡(푉표푢푡 = 푉푇 퐼푆퐹퐸푇 − 푉푇 푅푒퐹퐸푇) versus- the temperature variation for a range from 0 to 50 °C. Indeed, the SPICE models for each componentOTA1 of the circuitISFET were used, and all the components are dependent on the temperature. According to FigureVTISFET 12a, the output voltage is a linear function of 푝퐻.

This circuit has a temperature drift of approximatelyVTReFET 2 mV/°C, as shown in Figure 12b, where 푉표푢푡 is Vref considerably affected by the temperature.+ For pH sensitivity characterization, we worked under a pH range from 6 to 8. When we chose this- measurement range, weReFET were aware that for biomedical applications such as pH measurementOTA and acidity2 monitoring of saliva, blood, urine, and intestinal fluids, a pH range of 6 to 8 would be sufficient [37–39]. Figure 11. Differential measurement interface based on ISFET/reference field effect transistor (ReFET).

0,96 0,94 Figure 11. Differential measurement interface based on ISFET/reference field effect transistor (ReFET). (a) 0°C The circuit shown in Figure 11 is the 10°C one proposed0,92 by Irena [36], but the two weak power 0,92 20°C pH=6 30°C amplifier types AD8542 were replaced by the operational0,90 transconductanc(b) e amplifier pH=7 (OTA). The 40°C circuit was designed using ADS in TSMC 50°C 0.18 µm CMOS process technology. pH=8 Indeed, all the 0,88

components shown in Figure 11 are temperature dependent.0,88 The power consumption for each OTA

(V)

(V) out

is around 8 휇푊. Thanks to the feedback made by theout 0,86 two OTAs, this circuit can accurately control V 0,84 V the temperature dependence. The voltage that is applied to the negative inputs0,84 of the amplifiers OTA1 and OTA2 is formed by 0,80the voltage divider (푅 , 푅 ), and is written as follows: 3 4 0,82 − 푅4 푉 = 푉퐷퐷 = 푉푑푠. (10) 0,76 푅4+푅3 0,80 5,5 6,0 6,5 7,0 7,5 8,0 8,5 -10 0 10 20 30 40 50 60 This constant voltage 푉−depends only on the power supply and is considered constant. The T(°C) drain-source current 퐼푑푠 pHin the branch of the resistor 푅2 is written as follows:

FigureFigure 12. 12.( a(a)) VariationVariation ofofV 푉out표푢푡as as a a function function of of pH pH for for di differentff푅erent3 temperatures, temperatures, (b(b)) variationvariation ofof V푉out표푢푡as 퐼푅2 = 퐼푑푠 = 푉퐷퐷 (11) aas function a function of the of the temperature. temperature. 푅2(푅4 + 푅3)

4.1.w hereTheLow-circuit Power퐼푑푠 is from and shown Temperature Equations in Figure (11)Drift 11 is and ISFET the (5), one Compensation and proposed the gate by Circuitvoltage Irena [36 of], the but sensor the two is weak deduced power as amplifierfollows: types AD8542 were replaced by the operational transconductance푅3 amplifier (OTA). The circuit was In order to improve immunity푉푔푠 against= 휂 푇 temperatureLog ( and푉퐷퐷 increase) + 푉푡퐼. the overall sensitivity, we( 12) designed using ADS in TSMC 0.18 µm CMOS process퐼0푅 technology.2(푅4+푅3) Indeed, all the components shown in propose an improvement circuit technique, which is presented in Figure 13. An instrumentation Figure 11We are notice temperature from dependent.Equation (12) The power that 푉 consumption varies with for the each threshold OTA is around voltage, 8 µW i.e.,. Thanks with to the amplifier put on cascode with an inverter amplifier푔푠 composes this circuit. The circuits presented in the feedback made by the two OTAs, this circuit 휑 can accurately control the temperature dependence. Figureelectrochemicals 11 and 13 present potential two of pixel the ssolution in an ISFET0 array.and the temperature. For the circuit (Figure 12), we The voltage that is applied to the negative inputs of the amplifiers OTA1 and ∗ OTA2 is formed ∗ by assumed that the threshold voltage of this transistor was 푉푡퐼 = 푉푡퐼 + 푉푝퐻 with 푉푡퐼 and R R the푉 voltage correspond dividering ( 3 ,respectively4),T ISFET and is written to the as theoretical follows: threshold voltage of the transistor and the 푝퐻 V + electrochemical potential of the -solution. The gate voltage becomes as follows: OTA3 R5 = 50Ω RR48 = 70Ω V− = V = V R.10 = 250Ω (10) R4 + R3 DD ds R7 =470Ω R9 = 25Ω - - Vout2 R = 105 + 6 Ω Vout1 + R7 =470Ω OTA5 OTA6

R5 = 50Ω R8 = 70Ω - VTReFET + OTA4

Figure 13. Operational transconductance amplifier (OTA)-based instrumentation amplifier for an ISFET temperature compensation circuit.

The instrumentation amplifier circuit increases the immunity against the temperature by an

infinite common mode rejection ratio (CMRR) [40–42]. Therefore, the output signal 푉표푢푡1 is assumed to be not affected by the common noise or temperature:

J. Low Power Electron. Appl. 2020, 10, x FOR PEER REVIEW 10 of 16 J. Low Power Electron. Appl. 2020, 10, 2 10 of 16

푅3 ∗ 푉푔푠 = 휂 푇 Log ( 2 푉퐷퐷) + 푉푡퐼 + 푉푝퐻. (13) 2휂훽푈푇푅2(푅4+푅3) ThisThe DC constant simulation voltage resultsV− dependsof the circuit only depicted on the powerin Figure supply 11 are and shown is considered in Figure 12. constant. Figure The12a,b drain-source present respectively current Ids thein variation the branch of ofthe the output resistor signalR2 is versus written the as input follows: signal and the variation of 푉 (푉 = 푉 − 푉 ) versus the temperature variation for a range from 0 to 50 °C. 표푢푡 표푢푡 푇 퐼푆퐹퐸푇 푇 푅푒퐹퐸푇 R3 Indeed, the SPICE models for each IcomponentR2 = Ids = of the circuitV wereDD used, and all the components(11) are R2(R4 + R3) dependent on the temperature. According to Figure 12a, the output voltage is a linear function of 푝퐻. whereThis circuitIds is has from a temperature Equations (5) drift and of (11), approximately and the gate 2 voltagemV/°C, ofas theshown sensor in Figure is deduced 12b, where as follows: 푉표푢푡 is considerably affected by the temperature. For pH sensitivity characterization, we worked under a R3 pH range from 6 to 8. WhenV wegs =choseη T thisLog me( asurement range,VDD) we + V wet .re aware that for biomedical (12) I R (R + R ) I applications such as pH measurement and acidity0 2 monitoring4 3 of saliva, blood, urine, and intestinal

fluids,Wenotice a pH range from of Equation 6 to 8 would (12) that be Vsufficientgs varies with[37–39]. the threshold voltage, i.e., with the electrochemical potential of the solution ϕ0 and the temperature. For the circuit (Figure 12), we assumed that the 0,96 0,94 threshold voltage of this transistor was Vt = V + V with V and V corresponding respectively I tI∗ pH tI∗ pH (a) 0°C to the theoretical threshold voltage of the transistor 10°C and the0,92 electrochemical potential of the solution. The gate0,92 voltage becomes as follows: 20°C pH=6 30°C 0,90 (b) pH=7 40°C 50°CR3 pH=8 0,88 Vgs = η T Log ( VDD) + V ∗ + VpH. (13) 2ηβU2 R (R + R )0,88 tI 2 4 (V) 3

(V) T out

out 0,86 V The0,84 DC simulation results of the circuit depicted in FigureV 11 are shown in Figure 12. Figure 12a,b present respectively the variation of the output signal versus0,84 the input signal and the variation of Vout(V0,80out = V VT ReFET) versus the temperature variation for a range from 0 to 50 C. Indeed, T ISFET − ◦ the SPICE models for each component of the circuit were used,0,82 and all the components are dependent on the temperature. According to Figure 12a, the output voltage is a linear function of pH. This circuit 0,76 0,80 -10 0 10 20 30 40 50 60 has a temperature5,5 6,0 drift6,5 of approximately7,0 7,5 28,0 mV/◦C,8,5 as shown in Figure 12b, where Vout is considerably affected by the temperature. For pH sensitivity characterization, we worked under a pH range from 6 pH T(°C) to 8. When we chose this measurement range, we were aware that for biomedical applications such as pH measurementFigure 12. (a) andVariation acidity of monitoring푉표푢푡 as a function of saliva, of pH blood, for different urine, andtemperatures, intestinal ( fluids,b) variation a pH of range 푉표푢푡 of 6 to 8 wouldas a function be suffi ofcient the temperature. [37–39].

4.1.4.1. Low-PowerLow-Power and Temperature DriftDrift ISFETISFET CompensationCompensation CircuitCircuit InIn order order to to improve improve immunity immunity against against temperature temperature and increase and increase the overall the overall sensitivity, sensitivity, we propose we anpropose improvement an improvement circuit technique, circuit techniquewhich is presented, which is in presented Figure 13 . in An Figure instrumentation 13. An instrumentation amplifier put onamplifier cascode put with on an cascode inverter with amplifier an inverter composes amplifier this circuit. composes The circuitsthis circuit. presented The circuits in Figures present 11 anded 13in presentFigures two11 and pixels 13 present in an ISFET two array.pixels in an ISFET array.

VT ISFET + - OTA3 R5 = 50Ω R8 = 70Ω R10 = 250Ω R7 =470Ω R9 = 25Ω - - Vout2 R = 105 + 6 Ω Vout1 + R7 =470Ω OTA5 OTA6

R5 = 50Ω R8 = 70Ω - VTReFET + OTA4

FigureFigure 13. 13.Operational Operational transconductance transconductance amplifier amplifier (OTA)-based (OTA)-based instrumentation instrumentation amplifier amplifier for an forISFET an temperatureISFET temperature compensation compensation circuit. circuit.

The instrumentation amplifier circuit increases the immunity against the temperature by an

infinite common mode rejection ratio (CMRR) [40–42]. Therefore, the output signal 푉표푢푡1 is assumed to be not affected by the common noise or temperature:

J. Low Power Electron. Appl. 2020, 10, 2 11 of 16

The instrumentation amplifier circuit increases the immunity against the temperature by an infinite common mode rejection ratio (CMRR) [40–42]. Therefore, the output signal Vout1 is assumed to be not affected by the common noise or temperature: ! R8 2R5   Vout1 = 1 VTReFET VTISFET . (14) R7 − R6 −

As shown in Equation (14), Vout1 is proportional to both resistance and thresholds, while the unified temperature-dependent threshold voltage of ISFET in any value can be written as follows [43]:

KT1   VT (T) = VT (T ) + KVT (T T ) + 2.303 α pHpzc pH (15) (ISFET) T=T1 (pH7) 0 (pH) 1 − 0 q − where α is a coefficient with a value range between 0 and 1. The resistance could also be expected to increase with temperature. An intuitive approach to temperature dependence leads one to expect a fractional change in the resistance that is proportional to the temperature change:

R = R (1 + λ(T T )) (16) 0 1 − 0 where R and R0 are the resistance at temperature T1 and T0 (e.g., 27 ◦C), respectively. λ stands for the temperature coefficient, which depends on the resistance material. Equation (14) becomes as follows:   R (1+λ(T T )) 2R ((1+λ(T T )) V = 8 1− 0 1 5 1− 0 (V (T ) + KVT (T T ) out1 R (1+λ(T T )) R (1+λ(T T )) T(pH7) 0 (pH) 1 0 7 1− 0 − 6 1− 0 − KT1 +2.303 α pH(re f ) VT (T0) KVT(pH)(T1 T0) (17) q − (pH 7) −  − KT1 2.303 α pHpzc pH − q − where pHre f refers to the pH value measured by the ReFET. According to Equation (17) and since ( ) the ISFET and ReFET have the same technological parameters, we can neglect the VT(pH7) T0 and the temperature coefficient of the threshold voltage KVT and assume that the resistances R5, R6, R7, and R8 have the same material; then, Equation (17) becomes: ! R8 2R5 KT1   Vout1 = 1 2.303 α pH(re f ) pH + pHpzc . (18) R7 − R6 q −

Equation (18) illustrates the effectiveness of the proposed circuit for temperature reduction, since the ( ) = two terms KVT and VT(pH7) T0 are neglected. In addition, the thermal voltage UT KT1/q will always be present, because it is related to the MOSFET structure and cannot be neglected. Before the proposed ( ) circuit, the temperature coefficient of the threshold voltage KVT and the VT(pH7) T0 significantly affect the output voltage. Then, the temperature coefficient can be obtained as follows:

∂Vout1 R 2R K   = 8 (1 5 ) 2.303 α pH(re f ) pH + pH . (19) pzc ∂T T=T1 R7 − R6 q −

6 For pH(re f ) = 4 and pHpzc = 9.2, Equation (19) varies between 0.23 10 V/ C and × − ◦ 14.03 10 6 V/ C for pH [1, 13]. Therefore, we can assume that the temperature has no significant × − ◦ ∈ effect on the output voltage. The estimated temperature coefficient for pH = 6 is about 9.43 10 6 V/ C. × − ◦ Figure 14a shows the variation of the output voltage Vout1 as a function of the voltage pH for different temperatures ranging from 0 to 50 ◦C, while Figure 14b presents the dependence of Vout1 on the temperature. Figure 14b shows that a 10 C increase in the temperature results in a decrease of 5 10 6 V ◦ × − of the overall system output voltage Vout1, and subsequently, the coefficient of the temperature drift in this circuit becomes in the order of 5 10 6 V/ C. Here, we note very well the effectiveness of the × − ◦ instrumentation amplifier as a function of the temperature compensation. In addition, we notice that there is concordance between the mathematical demonstration and the simulation results in terms of J. Low Power Electron. Appl. 2020, 10, 2 12 of 16 a temperature coefficient. Here, we can assume that presented the Equations (18) and (19) can predict the temperature coefficient of ISFET/ReFET topology. Hence, the variation of the output voltage cannot exploit it easily, so we added an inverter amplifier to amplify the output voltage Vout1. Figure 15 shows the output voltage variation Vout2 (Figure 15a) as a function of the input voltage for different temperatureJ. Low Power Electron. values. Appl. 2020, 10, x FOR PEER REVIEW 12 of 16

2,4 2,3 0°C (a) 10°C 2,2 2,2 10°C pH=6 2,2 20°C 2,1 pH=7 30°C (b) 40°C pH=8 2,0 40°C 2,0 50°C 50°C

(V) 1,9

50°C (V)

(V) 1,9

1,8 (V) out1

out1 1,8 out1

out1 1,8

V

V

V V 1,6 1,7 1,6 1,4 1,5 1,2 1,2 1,4 5,5 6,0 6,5 7,0 7,5 8,0 8,5 -10 0 10 20 30 40 50 60 pH T(°C) pH T(°C) Figure 14. (a) Variation of the output voltage 푉 as a function of 푝퐻 for different temperatures, Figure 14. ((aa)) V Variationariation of of the the output output voltage voltage 푉V표푢푡out11 asas a a function function of of 푝퐻pH for different different temperatures, (b) variation of 푉 as a function of the temperature. ((b)) variationvariation ofof V푉out표푢푡11as as a a function function of of the the temperature. temperature.

4,0 3,5 0°C 3,5 (a) 3,5 10°C (a) 3,0 20°C 3,0 20°C (b) pH=6 3,0 30°C (b) 3,0 30°C pH=7 40°C 2,5 pH=7 pH=8

2,5 50°C pH=8

(V)

(V) (V)

(V) 2,0

out2 out2 out2 2,0

2,0 out2

V

V

V V 1,5 1,5

1,0 1,0

0,5 0,5 5,5 6,0 6,5 7,0 7,5 8,0 8,5 -10 0 10 20 30 40 50 60 pH pH T(°C) Figure 15. (a) Variation of the output voltage 푉 as a function of 푝퐻 for different temperatures, Figure 15. ((aa)) V Variationariation of of the the output output voltage voltage 푉V표푢푡out22 asas a a function function of of 푝퐻pH for different different temperatures, (b) variation of 푉 as a function of the temperature. ((b)) variationvariation ofof V푉out표푢푡22as as a a function function of of the the temperature. temperature.

The resolution found in this circuitcircuit is of the order of 324 mVmV//pH.pH. ThisThis circuit hashas an in–outin–out ratio 5 −5 about 6.6. As shownshown inin FigureFigure 15 15bb,, the the proposed proposed circuit circuit has has a a temperature temperature drift drift of of about about 3 3 10× 10− −V5/ ◦V/°CC in about 6. As shown in Figure 15b, the proposed circuit has a temperature drift of about ×3 V/°C pHin pH= 6 = for 6 a for range a range of 0 to of 50 0◦ C,to which 50 °C is, which insignificant is insignificant compared compared to the ISFET to without the ISFET the conditioning without the 3 −3 circuitconditioning (10 10 circuit− V/◦ (10C). × We10 should−3V/°C). note We thatshould all thenote components that all the components of the circuit of present the circuit in Figurespresent 11in conditioning× circuit (10 V/°C). We should note that all the components of the circuit present in andFigure 13s are 11 dependentand 13 are ondependent temperature. on temperature. This circuit This has an circuit estimated has an power estimated consumption power consumption in the order ofin 1.8the mWorder. of 1.8 푚푊.

4.2. Discussion As it shows from the figures and results above that, the presented circuit undeniably represents an efficient and robust solution for biochemical reaction sensing. Target applications can include + diagnostics based on DNA detection. Thanks to the possibilities for 퐻+ ion detection, this presented circuit will offer great opportunities in the field of lab-on-chip design. Table 3 compares this work with a previous work in terms of temperature compensation.

Table 3. Comparative study for temperature compensation.

References [7] [44] [45] This Work

J. Low Power Electron. Appl. 2020, 10, 2 13 of 16

4.2. Discussion As it shows from the figures and results above that, the presented circuit undeniably represents an efficient and robust solution for biochemical reaction sensing. Target applications can include diagnostics based on DNA detection. Thanks to the possibilities for H+ ion detection, this presented circuit will offer great opportunities in the field of lab-on-chip design. Table3 compares this work with a previous work in terms of temperature compensation.

Table 3. Comparative study for temperature compensation.

References [7][44][45] This Work Simulator HSPICE Cadence HSPICE ADS MOSIS CMOS MOSIS CMOS Process AMS (0.35 µm) TSMC (0.18 µm) (AMI 1.0 µm) (AMI 1.0 µm) Power supply – 3.3 V – 1.8(V) Power consumption 18.6 (mW) – – 1.8 (mW) Temperature range [20 ◦C, 60 ◦C] – [20 ◦C, 120 ◦C] [0 ◦C, 50 ◦C] Temperature coefficient 28 10 6 (V/ C) 0.25 10 9 (A/ C) 23.37 10 6 (pH/ C) 5 10 6 (V/ C) × − ◦ × − ◦ × − ◦ × − ◦

Table4 presents a comparative study with other work for overall sensitivity.

Table 4. Comparative study for overall sensitivity.

References [46][47][48] This Work Process 0.18 µm CMOS SOI TSMC (65 nm) TSMC (0.18 µm) Output signal Digital Analog Digital Analog Over all sensitivity (mV/pH) 103.8 258 123.8 324 Temperature range – – – [0 ◦C, 50 ◦C]

Table4 shows that the proposed circuit has a low temperature dependence compared to other works, and it shows that the temperature change has no significant effects on the output signal. In addition, we should note that in this work, we used ADS for the first time, and referring to Table4, most of work used the HSPICE simulation tool. Thus, ADS will open a new perspective in signal processing for ISFET sensors. On the other hand, Table4 illustrates the overall sensitivity; most of the published work that focused on the enhancement of the sensitivity did not focus on the temperature variation and must be addressed. Meanwhile, Tables3 and4 give a characteristic comparison between the proposed circuit based on OTA and others works. Using TSMC 0.18 µm technology, the proposed circuit based on OTA with low power consumptions and ISFET/ReFET working in a weak inversion regime gives a robust solution to reduce the temperature dependency and enhance the overall sensitivity. The proposed circuit presents a prototype for any biosensor (MEMFET, BioFET, ChemFET).

5. Conclusions The presented instrumentation with a new conditioning circuit technique has been developed to compensate for the temperature dependence and obtain a good in–out ratio of ISFET microsensors with an assurance of a low consumption. To check the validation of the new conditioning circuit, an ADS simulation of functionality for sensitivity was performed. The ADS macro model treats the ISFET as two isolated stages (an electrochemical stage and an electronic stage), which were presented. In the first step, we validated the macro model by comparing it with experimental values. Then, we investigated the temperature effect on the ISFET, and we showed that this sensor has a strong temperature dependency. After that, we used the validated macro model to develop a new circuit that is capable of staying stable at any temperature from 0 to 50 ◦C. We also demonstrated that the proposed circuit has a good accuracy to measure the concentration of the pH and guaranteeing at the same time a low consumption at any temperature for a range from 0 to 50 ◦C. Finally, comparative studies were made in terms of the overall sensitivity. J. Low Power Electron. Appl. 2020, 10, 2 14 of 16

Author Contributions: Conceptualization, A.G. and W.D.; methodology, A.G.; software, W.D.; validation, A.G., W.D. and B.H.; formal analysis, A.G. and W.D.; investigation, M.B.A.; data curation, A.G.; writing—original draft preparation, A.G. and W.D.; writing—review and editing, A.G. and W.D.; supervision, B.H. and M.B.A. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

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