In this paper, an innovative Direct Digital Sensing Potentiostat integrated circuit for enzymeless blood glucose sensing and direct digitization is proposed to address the requirements of Body Dust. The circuit occupies a silicon area of 460 μm2 in 180nm CMOS and operates down to 0.4V power supply voltage with 4.7nW power consumption. The functionality of the proposed circuit and its performance under typical conditions and under process and temperature variations is tested by post-layout simulations

Paolo Crovetti

Roberto Rubino

Sandro Carrara

English

PORTO@iris (Publications Open Repository TOrino - Politecnico di Torino)

29 November 2022POLITECNICO DI TORINORepository ISTITUZIONALEDirect Digital Sensing Potentiostat targeting Body-Dust / Rubino, Roberto; Carrara, Sandro; Crovetti, PAOLO STEFANO.- ELETTRONICO. - (2022). ((Intervento presentato al convegno 2022 IEEE Biomedical Circuits and Systems Conference(BioCAS2022) tenutosi a Taipei nel Oct. 13-15, 2022.OriginalDirect Digital Sensing Potentiostat targeting Body-DustIEEE postprint/Author's Accepted ManuscriptPublisher:PublishedDOI:Terms of use:openAccessPublisher copyright©2022 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in anycurrent or future media, including reprinting/republishing this material for advertising or promotional purposes, creatingnew collecting works, for resale or lists, or reuse of any copyrighted component of this work in other works.(Article begins on next page)This article is made available under terms and conditions as specified in the  corresponding bibliographic description inthe repositoryAvailability:This version is available at: 11583/2972538 since: 2022-10-23T09:00:17ZIEEEDirect Digital Sensing Potentiostattargeting Body-DustRoberto RubinoDETPolitecnico di TorinoTorino, Italyroberto rubino@polito.itSandro CarraraIntegrated Circuits LaboratoryÉcole Polytechnique Fédérale de LausanneLausanne, Switzerlandsandro.carrara@epfl.chPaolo CrovettiDETPolitecnico di TorinoTorino, Italypaolo.crovetti@polito.itAbstract—In this paper, an innovative Direct Digital SensingPotentiostat integrated circuit for enzymeless blood glucosesensing and direct digitization is proposed to address the require-ments of Body Dust. The circuit occupies a silicon area of 460µm2in 180nm CMOS and operates down to 0.4 V power supplyvoltage with 4.7 nW power consumption. The functionality ofthe proposed circuit and its performance under typical conditionsand under process and temperature variations is tested by post-layout simulations.Index Terms—Body Dust, potentiostat, glucose sensing, Digital-Based Amplifier (DB-Amp)I. INTRODUCTIONThe concept of Body Dust (BD) [1] envisions the integra-tion of micrometer-scale sensors embedded in bio-compatible,wirelessly powered CMOS integrated circuits (ICs), with asize comparable to human blood cells ( < 100µm diameter),small enough to ubiquitously circulate in tissues and bloodas swarms of particles and able to exchange data from withinthe human body to the outside world for diagnosis and health-monitoring purposes.Turning BD into reality demands analog CMOS ICs withmicrometer-scale dimensions and nanowatt power [1], whichare hard to be designed by traditional techniques. In thiscontext, digital-based analog design, which has recently beenproposed to address the requirements of Internet of Things(IoT) applications [3], [4], is more and more emerging asa viable option to meet the area and power requirements ofBD applications. Even though quasi-digital potentiostats havebeen proposed in [2], fully digital potentiostats have neverbeen presented so far. In this paper, a Direct Digital SensingPotentiostat (DDSP) for the enzymeless detection of speciesin a physiological solution is presented, aiming to glucosedetection within the framework of the Body Dust research.The paper is structured as follows: in Section II, a modelof the micrometer-scale electrode interface for the enzyme-less glucose detection is devised, extrapolating electrode pa-rameters from literature-derived measured characterizations.In Section III, the DDSP electronic architecture is presented,and its working principle is explained, focusing on its directdigital acquisition capability. Section IV follows, in which theperformance of the DDSP is tested by post-layout simulations,both under nominal conditions and in the presence of processRECE WEDirectDigitalSensingvDDDigitalStreamVREFFig. 1. Direct Digital sensing Potentiostat.and temperature variations, and compared with the state-of-the-art. Some conclusions are finally drawn in Section V.II. ELECTROCHEMICAL SENSORThe Direct Digital Sensing Potentiostat (DDSP) performsnon-enzymatic glucose detection employing a potentiostat-based current sensing topology, as in Fig.1, fixing the potentialof the solution at the reference (RE) electrode while measuringthe reduction or oxidation current flowing between the counter(CE) and working (WE) electrodes. The chronoamperometric(CA) method is considered from now on.A. Sensor design and modelingTo electrically simulate the sensing architecture, a model ofthe electrochemical interface is developed. A square WE withplatinum-nanospheres nanostructures as in [5] is considered,having a sensitivityS0 = 4µA/(mM · cm2) (1)in enzymeless detection of glucose [6].The WE geometry is chosen to be 45µm-side platinumsquare as in Fig.2a, suitable to BD particles in the orderof 100µm lateral size. The sensitivity of the WE faradaiccurrent with respect to glucose concentration, denormalisedwith respect to the electrode area is, from (1)S =4µAcm2 ·mM· (0.0045cm)2 = 0.081 nAmM. (2)iFCEWERECPRSRPRSRSa) b)c) d)100µm55µm45µm5µmWERECE100 101 102 103 104 105Frequency [Hz]100 101 102 103 104 105Frequency [Hz]105106107108Magnitude[Ω]104Phase [degree]0-20-40-60-80-100Magnitude and phase of CPE model @ WE Rp 30.4GΩ 318MΩ500pF3.3MΩ 34kΩ280pF 160pF210pF4.2GΩ79.6MΩ2nF1.5MΩ 28kΩ1.2nF 140pF1.2nFCPE model @ WE CPE model @ CE Fig. 2. Considered electrodes geometry (a), WE and CE electrical CPE model(b), high-level electrical model of the sensor (c), magnitude and phase of theCPE impedance at the WE (d).Taking into account the usual glucose physiological rangebeing in between 3mM and 8mM, a full-range current of0.8nA (up to 10mM) is expected.Along with the faradaic current, which is convenientlymodelled by a concentration-driven current generator (iF at theWE) the Randles circuit model of each electrode is extractedas in Fig.2c, including the solution resistance RS, a constantphase element (CPE) and the charge transfer resistance RP.Focusing of preliminary in vitro testing, the value of RS isset considering the conductivity of a commercially available0.01 M phosphate buffer saline (PBS) solution, being σPBS =12 mS/cm.A cubic volume of solution of 45µm side has been consid-ered to estimate the solution resistance. The value of RS isthus derived:RS =(σPBS ·Ad)−1' 18.5 kΩ (3)where A = (45µm)2 and d = 45µm. The charge transferresistance RP and the CPE CP electrical models (highlightedin dashed boxes in Fig.2c) for the WE and CE are extrapolatedfrom the magnitude and phase impedance characterization ofplatinum electrodes reported in [7].The reference magnitude and phase curves chosen to modelthe WE (blue diamonds curve in Fig.2d) are fit with theparallel RC model in Fig.2d, according to the algorithmVcmpD       QQbclkVp ABVcmpVcmpVcpVcp_bVcnVcn_bVcpVcn_bVcpVcnVcpVcnVcp_bVcnVn M1 M2 M3 M4 D       QQbclkD1D2M5 M6 VREFDp Dn M7 M8 Ip In Ipot M9 M10 tti = 0 ...  ...  ...  i = MDp Dn MTclkTclkp=2n=3RECEWEVdVDD VDD Fig. 3. Proposed digital-based potentiostat schematic and digital acquisitionpulses.presented in [8], resulting in the WE model in Fig.2b (dashedred box).An analogous procedure is employed to model the CE,resulting in the RC model in Fig.2b (dashed blue box) whilejust the solution resistance is considered for the RE, beingits current negligible thanks to the potentiostat high inputimpedance.III. DIRECT DIGITAL SENSING POTENTIOSTATThe proposed DDSP takes advantage of the digital-basedamplifier (DB-Amp) principe [3], [9], [10] for potentiostatreadout, as schematically depicted in Fig.1. The schematicof the DB-Amp adopted in this work is reported in Fig.3.Compared to [10] and [3], [9], where a resistive summingnetwork, and a Muller C element are used for the inputcommon-mode (CM) compensation, floating inverters [11] areemployed in the input stage of the DB-Amp proposed in thiswork to further enhance energy efficiency.The non-inverting (vp) and inverting (vn) analog inputsignals of the DB-Amp in the DDSP, to be connected to VREFand to the RE, respectively, are applied to the inputs of theCMOS floating inverters M1-M2 and M3-M4, which do notdraw any DC current. The digital outputs of such inverters aresampled by the D Flip-Flops D1 and D2, respectively, on theactive clock edge.As in [10], when D1=0 and D2=1 (D1=1 and D2=0), whichimplies that vd = vp − vn > 0 (vd ≤ 0), the output stageM5-M6 is operated to increase (decrease) the output voltage,i.e. the pMOS device M5 (the nMOS device M6) is turnedon for one clock cycle Tclk, thus sourcing (sinking) a nearlyconstant current IP (IN) in the CE capacitance, correspondingto a positive (negative) charge packet IPTclk (INTclk).When D1 and D2 have the same logical value, the sign ofvd cannot be detected and the output stage M5-M6 is kept inhigh impedance. Moreover, when D1=0 and D2=0 (D1=1 andD2=1) the negative (positive) supply of the input inverters is23µm20µmArea460µm2input stagelogic output stageFig. 4. Layout view of the DDSP.time [s] glucose [mM]0 2 4 6 8 100 0.1 0.2 0.3 0.4 0.5 0.6digital code [LSB]013263952digital code [LSB]01326395265Typical, 27°C2mM injection R2 = 0.99997a) b)Fig. 5. Digital acquisition under staircase concentration increase of 2mM (a)and the corresponding calibration curve (b).tied by M9 to node A (by M8 to node B), which was pre-discharged to 0 V via M10 (pre-charged to VDD via M7) inthe previous cycle. Such reconfiguration provides the inputinverters with a dynamic bias, as required to asymmetricallydischarge (charge) their output and to detect the sign of vd,resulting in D1=0 and D2=1 or D1=0 and D2=1 in the nextcycle(s).Thanks to negative feedback and to the filtering effect ofthe CE capacitance, the RE potential is forced by the DB-Amp to the non-inverting input voltage VREF (ripple below2.3mV rms) by injecting discrete charge packets in the CE.Since the charge in each packet is nearly constant, the timeaverage of the CE current Ipot, which turns out to be equalto the faradaic current IF, is directly estimated counting thenumber of the positive (negative) digital pulses p (n) over thelast M clock cycles as follows:IF =pIP − nINM(4)Based on (4), a digitized version of IF is directly obtainedpost-processing the digital streams Dp and Dn driving thegates of M5 and M6 in Fig.3, thus suppressing the analogto digital converter (ADC) which is needed in conventionalimplementations.IV. POST-LAYOUT SIMULATIONS AND COMPARISONThe proposed DDSP has been designed in 180nm CMOSand tested by post-layout simulations, performed connectingthe DDSP to the electrochemical cell equivalent circuit de-scribed in Sec.II, fixing the WE potential at −VREF = −0.2 V,which corresponds to the first oxidation peak of the glucosein [5].35 4027temperature [°C]30b)Sensitivity [LSB/mM]4.65.24.94.3reference electrode offset Voff [mV]-6 -4 -2010155# samplesc)glucose [mM]42 6 8 1097531P variations, +σ,   R2 = 0.9997 P variations, -σ,    R2 = 0.9987T variation, 35°C,  R2 = 0.9996T variation, 40°C,  R2 = 0.9972Typical, 27°C,       R2 = 0.99997a)digital code [LSB]6501326395278Fig. 6. Calibration curve spread against process (±σ) and temperature (35oCto 40oC) variations(a), sensitivity variation with temperature (b) and referenceelectrode offset variation with mismatch (c).The layout of the DDSP cell, reported in Fig.4, occupiesmerely 460µm2. Based on post-layout simulations at 27◦Cunder 0.4 V supply, 50 kHz clock, and typical process condi-tions, the power consumption of the DDSP is 4.7 nW, theinput current ranges from -22 nA to +33 nA, and the totalinput-referred noise, averaging DDSP binary streams overM = 3, 600 clock cycles, is 65 pArms including quantizationnoise, resulting in a 58 dB dynamic range.The simulated chronoamperogram and digitalcode/concentration curve under a staircase glucoseconcentration increase of 2 mM steps are reported inFig.5a and Fig.5b respectively, and reveal a sensitivity of5.2 LSB/mM and a high linearity R2 = 0.99997.Based on Monte Carlo simulations under process vari-ations, the standard deviation of the DDSP sensitivity isσ = 1.8 LSB/mM, as shown in Fig.6a. The digitalcode/concentration curves of simulated samples at ±σ sen-sitivity reported in Fig.6a reveal a linearity degradation fromR2 = 0.99997 to R2 = 0.9987. The simulated sensitivityversus temperature is reported in Fig.6b in the range 27◦C-40◦C and the simulated calibration curves at the extremetemperatures are shown in Fig.6a. A worst-case linearitydegradation from R2 = 0.99997 to R2 = 0.9972 is observedat 40◦C with respect to 27◦C. These results reveal how processand temperature variations can be effectively compensated bylinear calibration.The distribution of the RE potential offset due to devicemismatch has been obtained by Monte Carlo simulations andis reported in Fig.6c. The offset mean value and standard de-viations are Voff = 3.9 mV and σVoff = 1.1 mV, respectively.Compared to potentiostat front-ends proposed over the lastTABLE IPOTENTIOSTAT PERFORMANCE COMPARISONUnits [12] [13] [14] [15] [16] This WorkMethod - CV,CA,EIS† CA,CV CA,CV CA,CV CA,CV CAMeasured - yes yes yes yes yes noCurrent Range µA ±0.2 ±5 ±15 {−7,+10} ±1.5 {−0.022,+0.033}Dyn. Range dB 104 108 73 58 105 58Linearity R2 - 0.998 - 0.999 0.9990 0.99997Current Noise pA (rms) 7.76 41 - 25000 - 65Bandwidth Hz 10,000 - 200 50,000 1 7?Technology nm 180 180 180 180 65 180Area mm2 0.208 0.78 2.25 3.17 0.07 0.00046Supply V 1.8 > 1.1 1.8 1.2 1.2 0.4Power µW 311.4 16 73.9 19 25 0.0047Digital out - no yes yes yes yes yes†EIS: electrochemical impedance spectroscopy.? Limited by M , traded with noise.years for chronoamperometry and cyclic voltammetry, whoseperformance is summed up in Tab.I, the proposed DDSPoperates at the lowest supply voltage (3× less than [15] and[16]) while dissipating the smallest power (3,400× less than[13]) at the smallest area (150× less than [16], which is thoughfabricated in a more scaled technology).The DDSP reports the best linearity R2 = 0.99997, withan rms current noise of 65 pArms (more than the 41 pArmsof [13]) while showing a smaller dynamic range of 58 dB(comparable to [15]).These results are establishing the DDSP as a promisingsolution for Body Dust applications, thanks to its ultra lowpower and area, low supply voltage and robustness againstprocess, temperature and mismatch variations.V. CONCLUSIONIn this paper, an original fully digital potentiostat designedin 180nm CMOS technology has been presented as an ac-quisition front-end for chronoamperometric electrochemicaldetection of glucose.Based on post-layout simulations, the digital potentiostatoperates down to 0.4 V power supply voltage (3× less than[15] and [16]) having 58 dB dynamic range, with a significantadvantage in terms of power (4.7 nW, 3,400× less than [13])and area (460µm2, 150× less than [16]) compared to recentalternatives, thus meeting the requirements of Body Dustapplications.REFERENCES[1] S. Carrara, “Body Dust: Well Beyond Wearable and Implantable Sen-sors,” in IEEE Sensors Journal, vol. 21, no. 11, pp. 12398-12406, Jun.2021[2] S. Aiassa, F. Stradolini, A. Tuoheti, S. Carrara and D. Demarchi, “Quasi-Digital Biosensor-Interface for a Portable Pen to Monitor AnaestheticsDelivery,” 2019 15th Conference on Ph.D Research in Microelectronicsand Electronics (PRIME), 2019, pp. 265-268[3] Toledo, P., Rubino, R., Musolino, F., and Crovetti, P., “Re-thinkinganalog integrated circuits in digital terms: A new design concept forthe IoT era,” IEEE Transactions on Circuits and Systems II: ExpressBriefs, vol. 68, no. 3, pp. 816-822, Mar. 2021[4] P. Toledo, P. S. Crovetti, H. D. Klimach, F. Musolino and S. Bampi,“Low-Voltage, Low-Area, nW-Power CMOS Digital-Based BiosignalAmplifier,” in IEEE Access, vol. 10, pp. 44106-44115, 2022.[5] Taurino, I., Sanzó, G., Mazzei, F. et al. “Fast synthesis of platinumnanopetals and nanospheres for highly-sensitive non-enzymatic detectionof glucose and selective sensing of ions,” Sci. Rep. vol.5, no.15277, 2015[6] Dhara, K., Mahapatra, D.R. “Electrochemical nonenzymatic sensing ofglucose using advanced nanomaterials,” Microchim. 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Lee, “APower-Efficient Current Readout Circuit with VCO-Based 2nd-Order CT∆Σ ADC for Electrochemistry Acquisition,” 2020 IEEE Asian Solid-State Circuits Conference (A-SSCC), 2020, pp. 1-2.[15] Lu SY, Liao YT. “A 19 uW, 50 kS/s, 0.008-400 V/s Cyclic VoltammetryReadout Interface With a Current Feedback Loop and On-Chip PatternGeneration.” IEEE Trans. Biomed. Circ. Syst., vol.12, no.2, pp. 190–198,2021[16] J. Aymerich et al., “A 15-uW 105-dB 1.8-Vpp Potentiostatic Delta-Sigma Modulator for Wearable Electrochemical Transducers in 65-nmCMOS Technology,” in IEEE Access, vol. 8, pp. 62127-62136, 2020.

Direct Digital Sensing Potentiostat targeting Body-Dust

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Direct Digital Sensing Potentiostat targeting Body-Dust

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