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CMOS-based chemical microsensors

Andreas Hierlemann* and Henry Baltes

Physical Electronics Laboratory, ETH Zurich, Hönggerberg, HPT H 4.2, CH-8093 Zurich,Switzerland. E-mail: hierlema@iqe.phys.ethz.ch; Fax: +41 1 633 1054; Tel: +41 1 633 3494

Received 2nd September 2002, Accepted 14th November 2002First published as an Advance Article on the web 4th December 2002

1 Introduction2 CMOS technology3 Micromachining techniques3.1 Bulk micromachining3.2 Surface micromaching4 CMOS-based chemical sensors4.1 Chemomechanical or mass-sensitive sensors4.1.1 Flexural-plate-wave or Lamb-wave devices4.1.2 Resonating cantilevers4.2 Thermal sensors4.2.1 Catalytic thermal sensors (pellistors)4.2.2 Thermoelectric or Seebeck-effect-based sensors4.3 Optical sensors4.3.1 Bioluminescent bioreporter integrated circuits

(BBIC)4.4 Electrochemical sensors4.4.1 Voltammetric/amperometric sensors4.4.2 Potentiometric sensors (chemotransistors)4.4.3 Conductometric sensors4.4.3.1 Chemoresistors4.4.3.2 Chemocapacitors4.5 Monolithic integration of different transducers4.5.1 CMOS multiparameter biochemical sensor4.5.2 CMOS single-chip gas microsensor system5 Outlook6 Acknowledgements7 References

1 Introduction

The rapid development of integrated circuit (IC) technologyduring the past decades has initiated many initiatives tofabricate chemical sensors on silicon or CMOS substrates

(CMOS: Complementary Metal Oxide Semiconductor).1,2 Thelargely two-dimensional integrated circuit and chemical sensorstructures processed by combining lithographic, thin film,etching, diffusive and oxidative steps have been recentlyextended into the third dimension using micromachining orMEMS (MEMS: MicroElectro-Mechanical Systems) technolo-gies—a combination of special etchants, etch stops andsacrificial layers.3–9 A variety of micromechanical structuresincluding cantilever beams, suspended membranes, freestand-ing bridges, etc. have been produced.3–9 The realization ofmicroelectronics and micromechanics (MEMS-structures) on asingle chip allows for on-chip control and monitoring of themechanical functions as well as for data preprocessing such assignal amplification, signal conditioning, or data reduc-tion.3–12

CMOS- or CMOS-MEMS-technology, therefore, providesexcellent means to meet some of the key criteria of chemicalsensors such as miniaturization of the devices, low powerconsumption, rapid sensor response characteristics, or batchfabrication at industrial standards and low costs. Additionaladvantages come from the possibility of monolithic co-integration of circuitry and transducers. These include improvedsensor signal-to-noise characteristics due to on-chip signalprocessing and analog/digital conversion, or the realization ofsmart features on the sensor chip. Drawbacks of using CMOStechnology encompass a limited selection of materials (seeCMOS technology section) and a predefined fabrication processfor the CMOS part. Sensor-specific or transducer-specificmaterials and fabrication steps have to be introduced as post-processing after the CMOS fabrication.13

After a short introduction to CMOS and basic micro-machining technologies, we will give an overview on differenttypes of chemical sensors fabricated in CMOS and CMOS-MEMS technology.

Andreas Hierlemann received a Diploma in Chemistryin 1992 and a PhD in Physical Chemistry in 1996from the University of Tübingen, Germany. Afterworking as a Postdoc at Texas A&M University,College Station, TX (1997), and Sandia National

Laboratories, Albuquerque,NM (1998), he moved toETH Zurich in Switzerlandwhere he is currently amember of the technicalstaff. The focus of his re-search activities is on CMOStransducers, chemical sensorsand interfacial design.

Henry Baltes received a DSc degree from ETH Zurich in 1971.He has held faculty positions at Freie Universität Berlin andUniversity of Düsseldorf, Germany, University of Waterloo,Canada and EPF Lausanne, Switzerland. He worked for Landis& Gyr Zug, Switzerland (1974–1982), directing the Solid-

State Device Laboratory; he heldthe Henry Marshall Tory Chair atthe University of Alberta, Edmon-ton, Canada (1983–1988), wherehe directed a research program inmicrosensors; he was a Director ofLSI Logic Corporation of Canada(1986–1988), and since 1988 hehas been Professor of PhysicalElectronics at ETH Zurich andDirector of the Physical Electron-ics Laboratory active in siliconintegrated micro-systems.

This journal is © The Royal Society of Chemistry 2003

DOI: 10.1039/b208563c Analyst, 2003, 128, 15–28 15

2 CMOS technology

CMOS is the dominant semiconductor technology for micro-processors, memories and application-specific integrated cir-cuits (ASICs).14–16 CMOS-chips generally consist of a layeredstructure of aluminum, polysilicon, silicon (doped and un-doped), silicon oxide and -nitride layers (Fig. 1), which arefabricated in a defined sequence of material deposition, doping,lithography and etching steps.14–16

Semiconductors conduct electricity but not enthusiastically.Semiconductor areas that are doped become conductors ofeither extra electrons with a negative charge (phosphorus-doping) or of positive charge carriers (boron-doping). Thedenomination ‘complementary’ metal oxide semiconductor isdue to the fact that both, n-type and p-type transistors arerealized on the same substrate, for example on a lightly p-dopedwafer material, that exhibits n-doped areas (n-wells) (Fig. 1).Both, n-type (NMOS) and p-type (PMOS) transistors are usedto realize logic functions. A CMOS-chip cross-section is shownin Fig. 1. The p-substrate exhibits n-well areas created byimplantation. Heavily p-doped structures (p+) in the n-well, andn-doped structures (n+) in the p-substrate form transistor sourceand drain. The transistor gate is made of polysilicon on top ofthe gate oxide (SiO2). By applying a voltage to the gate via thepolysilicon, electrons or holes are accumulating in the surfacearea (field effect) below the gate and thus create a conducting n-or p-channel between source and drain. Variation of the gatevoltage thus modulates the source drain current: continuouslywithin a certain range in analog circuits, on/off in digitalcircuits. Several metal layers (Fig. 1: metal 1 and metal 2,aluminum) are used to wire the transistors. Dielectric layer suchas field oxide, contact oxide, and intermetal oxide (SiO2) serveas electrical insulation between conducting areas. The siliconnitride on top serves as passivation and provides electrical andmechanical/chemical protection of the circuitry. Silicon nitrideand to a lesser extent silicon oxide (or silicon with a native oxidelayer) are durable in case of liquid exposure and are biocompat-ible, which allows for using CMOS chips also with cells orliving material. CMOS aluminum is neither stable in liquids (orin air at higher temperatures) nor is it biocompatible, and,consequently, has to be covered with precious metal coatingssuch as gold or platinum. For more details on semiconductortechnology, see, e.g., the standard textbooks of Sze.15,16

3 Micromachining techniques

3.1 Bulk micromachining

One approach to enhance the functionality of IC-basedsubstrates includes micromachining the bulk substrate, which inmost cases consists of silicon. Silicon can be dry or wet etchedby various techniques.3–7,17 Some wet etchants such as nitric

acid/hydrofluoric acid lead to isotropic etching (same etch ratein all directions), others like potassium hydroxide lead toanisotropic etching, i.e., preferentially etch away the siliconalong certain crystal planes while preserving it in otherdirections (Fig. 2a). Typical structures obtained by, e.g.,anisotropic wet etching through the complete bulk silicon of aCMOS wafer include membranes consisting of the remainingdielectric CMOS layers. The thermal oxide serves as an etch-stop layer. The resulting membrane structures can be used forsensors requiring excellent thermal insulation, such as calori-metric chemical sensors or metal oxide-covered microhot-plates.

Another technique is dry etching. Again, there is isotropicetching performed by using, e.g., xenon difluoride or aniso-tropic etching by reactive-ion-etching (RIE). RIE can be used torelease cantilevers or create bridge structures from preformedmembranes.18

3.2 Surface micromachining

Surface micromachining comprises a number of techniques toproduce microstructures from thin films previously depositedonto a substrate and is based on a sacrificial layer method (Fig.2b). In contrast to bulk micromachining, surface micro-machining leaves the substrate intact. A sacrificial layer isdeposited and patterned on a substrate. After that, a structuralthin film, in most cases polysilicon, is deposited and patterned,which will perform the mechanical or electrical functions in thefinal device. A selective etchant then removes exclusively thesacrificial layer material. The thickness of the sacrificial layerdetermines the distance of the structural parts from the substratesurface. Common sacrificial layer materials include siliconoxide etched by hydrogen fluoride and aluminum etched by amixture of phosphoric, nitric and acetic acid.

Clamped beams, microbridges, or microchannels can befabricated this way, microrotors and even microgears can berealized by repeated layer deposition and etching.3–7,17

4 CMOS-based chemical sensors

Chemical sensors usually consist of a sensitive layer or coatingand a transducer.19–25 Upon interaction with a chemical species(absorption, chemical reaction, charge transfer etc.), thephysicochemical properties of the coating, such as its mass,volume, optical properties or resistance etc. reversibly change.These changes in the sensitive layer are detected by therespective transducer and translated into an electrical signalsuch as frequency, current, or voltage, which is then read outand subject to further data treatment and processing.

A variety of transducers based on different physical princi-ples have been devised. We will follow a classification scheme

Fig. 1 Cross-section of a CMOS-chip. The different layers and materialsinclude metals (aluminum), silicon oxides, silicon nitride, and polysiliconon a p-doped silicon wafer with n-well implanted areas.

Fig. 2 Micromachining techniques: (a) bulk micromachining, anisotropicand isotropic etching, (b) surface micromachining with sacrificial layer,structural layer and a subsequent etch step.

16 Analyst, 2003, 128, 15–28

suggested by Janata20,21 to give an overview on CMOS-basedchemical sensors in the next sections of this review. Thisscheme includes four principal categories distinguished withregard to the transduction principle:20

1. Chemomechanical or mass-sensitive sensors (e.g., masschanges due to absorption)2. Thermal sensors (e.g., temperature changes through chemicalinteraction)3. Optical sensors (e.g., light intensity change by absorption)4. Electrochemical sensors (e.g., potential or resistance changesthrough charge transfer)

We will briefly introduce each of those four sensor categoriesand then give examples of CMOS-based transducers anddevices. Typical chemically sensitive materials and sensorapplications will be mentioned in the context of the correspond-ing transducer structures.

4.1 Chemomechanical or mass-sensitive sensors

Chemomechanical or mass-sensitive sensors are in the simplestcase gravimetric sensors responding to the mass of speciesaccumulated in a sensing layer.26–28 Some of the sensor devicesadditionally respond to changes in a variety of other mechanicalproperties of solid or fluid media in contact with their surfacesuch as changes of polymer elastic moduli, liquid density andviscosity,26–28 which will not be further discussed here.Chemomechanical sensor, therefore, is a more appropriatedenomination. Any species that can be immobilized on thesensor can, in principle, be sensed. As with most of the chemicalsensors, the measurements are taken at a thermodynamicequilibrium state.

Mass changes can be monitored by either deflecting amicromechanical structure due to stress changes or mass-loading (static measurements) or by assessing the frequencychanges of a resonating structure or a traveling acoustic waveupon mass loading. Both deflection and resonance frequencychange in proportion to stress changes or mass loading on thedevice.26–28

The most common devices are the thickness shear moderesonator (TSMR) or quartz microbalance (QMB), and theRayleigh surface acoustic wave (SAW) device, both based onpiezoelectric quartz substrates. Both will not be detailed here,since they are not fabricated in CMOS technology. For moredetails on those devices, see refs. 26–28.

In the following, we will describe in more detail two CMOS-technology-based micromechanical structures for mass-sensi-tive devices, (1) flexural-plate-wave devices (FPWs), and (2)micromachined cantilevers.

4.1.1 Flexural-plate-wave or Lamb-wave devices. Thechief advantage of flexural plate wave devices (FPW) is theirhigh sensitivity to added mass at a low operating frequency(typically 3–10 MHz).29 FPW devices feature plates that areonly a fraction of an acoustic wavelength thick (typically 2–3mm). The plates are composite structures (Fig. 3) consisting ofa silicon nitride layer, an aluminum ground plane, and asputtered zinc oxide piezoelectric layer, all of which aresupported by a silicon substrate.26–32

The interdigital transducers (IDTs) on these devices generateflexural waves (Lamb waves, Fig. 3) with retrograde ellipticalparticle motions as in the SAW devices. The Lamb waves giverise to a series of plate modes, one of which has a frequency thatis much lower than those of the other possible modes. Thevelocity of this unique wave decreases with decreasing platethickness. The entire thickness of the plate is set in motion likethe ripples in a flag.26–32 The confinement of acoustic energy inthe thin membrane results in a very high mass sensitivity. Sincethe Lamb wave causes an elliptical particle movement at thetransducer surface (Fig. 3), the sensitive films are deformed.

The sensitive layer can be deposited on either side of themembrane. Deposition on the backside (non-processed side ofthe wafer) has the advantage, that on-chip-circuitry will not beexposed to chemicals.29–32

Fabrication sequences for monolithic integration of the Lambdevice with CMOS electronics are detailed in refs. 32 and 33.

A variant includes a magnetical FPW actuation scheme basedon Lorentz forces: A metal meander-line is patterned on themembrane surface, alternating current (AC) is flowing in themeander transducer and interacts with a static in-plane magneticfield to generate time-varying Lorentz forces, which in turndeform the membrane. Magnetic actuation requires an ex-ternally applied magnetic field, but eliminates the need for apiezoelectric layer.34,35 Such layers frequently contain elements(Zn etc.) that pose contamination problems in IC fabrica-tion.34

Typical FPW applications include the detection of differentorganic volatiles in the gas phase by using polymeric lay-ers,31,35,36 or the use of an FPW-based immunoassay for thedetection of breast cancer antigens.37

4.1.2 Resonating cantilevers. A mass-sensitive cantileverusually is a layered structure composed of, e.g., silicon, siliconoxide/nitride, and, eventually, metallizations. The cantileverbase is firmly attached to a silicon support (chip). The free-standing cantilever end is coated with a sensitive layer.

There are two fundamentally different operation methods: (a)static mode: measurement of the cantilever deflection uponstress changes or mass loading by means of, e.g., a laser vialaser light reflection on the cantilever;38–41 (b) dynamic mode:excitation of the cantilever in its fundamental resonance modeand measurement of the frequency change upon mass load-ing42–46 in analogy to other mass-sensitive transducers. Method(a) requires long and soft cantilevers to achieve large deflec-tions, whereas method (b) requires short and stiff cantilevers toachieve high operation frequencies. Resonators are charac-terized by their quality factor (Q-factor), which is defined as theratio of the resonance frequency and resonator bandwidth: thehigher the Q-factor, the better the frequency stability of theresonator. The dynamic mode (b) is preferable with regard tosimplicity of the measurement configuration since there is noneed for an optical setup to determine small cantileverdeflection by means of, e.g., laser light reflection.42–46 Method(a) can also be used in liquid media.39,41 The excitation of theresonant cantilever is performed by applying piezoelectricmaterials (ZnO)47 or by relying on Lorentz forces in a magneticactuation scheme, which is analogous to that already describedin the context of the FPWs: one or several conductor loops arepatterned along the cantilever edges, AC is flowing in the loopsand interacts with a static in-plane magnetic field to generate

Fig. 3 Schematic of a flexural plate wave device. The side view shows thedifferent layers and the membrane movement. Interdigitated electrodes areused for actuation.

Analyst, 2003, 128, 15–28 17

time-varying Lorentz forces, which deflect the cantilever.48,49

Another actuation variant includes making use of the differenttemperature coefficients or mechanical stress coefficients of thecantilever layer materials (bimorph effect).43–46 The differentmaterials give rise to a cantilever deflection upon heating orapplying mechanical forces. Cantilever deflection or resonancefrequency changes can be detected by embedding piezoresistorsin the cantilever base.41–46 The absolute mass resolution of thecantilevers is in the range of a few picograms.38–46 This highmass-sensitivity does not necessarily imply an exceptionallyhigh gas sensor sensitivity since the area coated with thesensitive layer (on the order of 100 3 150 mm), and hence theoverall sorption matrix volume is very small.43

Fig. 4 shows a CMOS-based cantilever, which is mono-lithically integrated with feedback electronics.43 The 150 mm-long cantilever consists of mainly silicon as well as vapor-deposited and thermal oxide. The bimorph effect is used toinitiate a cantilever vibration by periodically applying electricpulses to heating resistors embedded at the cantilever base. Thecantilever resonates at its fundamental mechanical frequency of380 kHz with a quality factor of approximately 1000 in air,which is comparable to other acoustic-wave-based devices suchas QMB or Rayleigh SAW-device. The Q-factor of thecantilever sandwich is dependent on the cantilever materialswith silicon offering very favorable properties in comparison tosilicon oxide, nitride or the polymer coating.43 The cantilevervibration is detected by embedded piezoresistors in a Wheat-stone-bridge configuration. The cantilever acts as the fre-quency-determining element in a feedback oscillation circuit,which for the first time was entirely integrated on the chip witha counter. The advantages of the monolithic integration hereinclude a better frequency stability of the resonator and lowercrosstalk (thermal and electrical) of the different componentsleading to a better signal-to-noise ratio of the overall system.For more details on the electronics, see refs. 43–46 and 50.

Typical cantilever applications include the detection oforganic volatiles or humidity in the gas phase by usingpolymeric layers,41–46,49–55 and biosensing in liquid phase suchas the detection of cells,56 or complementary strands ofoligonucleotides (DNA fragments).39

4.2 Thermal sensors

Calorimetric or thermal sensors rely on determining thepresence or concentration of a chemical by measurement of anenthalpy change produced by the chemical to be detected.19,20,57

Any chemical reaction or even absorption/desorption processreleases or absorbs from its surroundings a certain quantity ofheat. Reactions liberating heat are termed exothermic, reactionsabstracting heat are termed endothermic. This thermal effectshows a transient behavior: continuous liberation/abstraction ofheat occurs only as long as the reaction proceeds. However,there will be no heat production and hence no measurable signal

at thermodynamic equilibrium (DG = 0) in contrast to mass-sensitive, optical, or electrochemical sensors (see Fig. 15later).

Conflicting constraints are imposed on the design of athermal sensor. The sensor has to interact with the chemicalspecies (exchange of matter) and thus constitute a thermody-namically open system, but at the same time the sensing areashould be thermally as isolated as possible to achieve maximumsensitivity.

The liberation or abstraction of heat can be convenientlymeasured as a change in temperature, which then is transducedinto an electrical signal. The various types of calorimetricsensors differ in the way that the evolved heat is trans-duced.19,20,57

The catalytic sensor (often denoted ‘pellistor’58) employsplatinum resistance thermometry, while the thermoelectricsensor is based on the Seebeck effect.57 Both sensor typesbenefit from CMOS integration and will be detailed in thefollowing sections.

4.2.1 Catalytic thermal sensors (pellistors). The develop-ment of the catalytic sensor is derived from the need for a hand-held detector for methane to replace the flame safety lamp incoalmines. The catalytic device measures the heat evolvedduring the controlled combustion of flammable gaseouscompounds in ambient air on the surface of a hot catalyst bymeans of a resistance thermometer in proximity with thecatalyst. This method is, therefore, calorimetric. The heatedcatalyst here permits oxidation of the gas at reduced tem-peratures and at concentrations below the lower explosive limit(LEL). The term ‘pellistor’ originally refers to a deviceconsisting of a small platinum coil embedded in a ceramic bead,which is impregnated with a noble metal catalyst .58

Fig. 5 shows a surface-micromachined, free-standing, Pt-coated polysilicon micro-filament (10 mm wide, 2 mm thick)separated from the substrate by a 2 mm air gap.59,60 Otherdesigns include micromachined membranes.61–66 Heat losses tothe silicon frame are minimized in both designs. By passing anelectric current through the meander, the microfilament isheated to a temperature sufficient for the Pt-surface tocatalytically oxidize the combustible mixture; the heat ofoxidation is then measured as a resistance variation in the Pt.The combustion of, e.g., methane generates 800 kJ mol21 heat,which translates into a corresponding temperature change.

Detailed processing sequences for microbridges are given inrefs. 67 and 68.

Typical applications include monitoring and detection offlammable gas hazards such as methane,64,68 hydrogen,59–61,64

propane,61 or carbon monoxide61,65 in industrial, commercialand domestic environments at concentrations below the lowerexplosive limit (LEL). The LEL is the concentration of gas in airbelow which it cannot be ignited.

Fig. 4 Micrograph of a 150 mm-long CMOS-integrated cantilever with on-chip feedback circuitry.

Fig. 5 Micrograph (SEM) of two meandered polysilicon filaments. Thelower filament is coated with a thin (approx. 0.1 mm) layer of platinum(CVD). In a differential gas sensing mode, the upper, uncoated, filamentacts to compensate changes in the ambient temperature, thermal con-ductivity and flow rate. Reprinted from ref. 59 with permission.

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4.2.2 Thermoelectric or Seebeck-effect-based sensors.This type of sensor relies on the thermoelectric or Seebeck-effect.57,69 When two different semiconductors or metals areconnected at a hot junction and a temperature difference ismaintained between this hot junction and a colder point, then anopen-circuit voltage is developed between the different leads atthe cold point. This thermovoltage is proportional to thedifference of the Fermi levels of the two materials at the twotemperatures and thus proportional to the temperature differ-ence itself.57,69 This effect can be used to develop a thermalsensor by placing the hot junction on a thermally isolatedstructure like a membrane, bridge etc. and the cold junction onthe bulk chip with the thermally highly conducting siliconunderneath.46,69–72 To achieve a higher thermoelectric voltage,several thermocouples are connected in series to form athermopile. The membrane structure supporting the hot junc-tions is covered with a sensitive or chemically active layerliberating or abstracting heat upon interaction with an analyte.The resulting temperature gradient between hot and coldjunctions then generates a thermovoltage, which can bemeasured.

Fig. 6 displays the schematic of a CMOS-based thermopileconsisting of a dielectric membrane with polysilicon/aluminumthermocouples (Seebeck coefficient: 111 mV K21).46,72,73

CMOS-based thermoelectric sensors are advantageously set upin a sensor/reference configuration. The system includes twomembranes, one of which is coated with the gas-sensitivepolymer, the uncoated one serves as a reference to compensatefor gas-induced temperature fluctuations.73 The sensing andreference thermopiles are connected in parallel to the inputstage of a low-noise chopper-stabilized instrumentation ampli-fier on-chip to record the temperature differences between thetwo membranes. The thermovoltage can be translated into adigital signal on chip using a Sigma–Delta analog/digitalconverter.74

Processing sequences for the integration of thermoelectricsensors with circuitry in a CMOS standard process are detailedin refs. 72 and 75.

Typical applications include the detection of different kindsof organic volatiles in the gas phase by using polymericlayers,46,72–77 and the biosensing of glucose, urea and penicillinin the liquid phase by using suitable enzymes.71,78–80

4.3 Optical sensors

In comparison to other chemical sensing methods, opticaltechniques offer a great deal of selectivity already inherent inthe various transduction mechanisms. Characteristic propertiesof the electromagnetic waves such as amplitude, frequency,phase, and/or state of polarization can be used to ad-vantage.81–83 Geometric effects (scattering) can provide addi-tional information. The wavelength of the radiation, e.g., can betuned to specifically match the energy of a desired analyte-

specific resonance or absorption process. In addition, opticalsensors like any other chemical sensor can capitalize on all theselectivity effects originating from the use of a sensitivelayer.81–83

If a sample is irradiated with visible light or electromagneticwaves, the radiation can be absorbed (intensity decrease),scattered (direction randomization, possibly frequencychanges), refracted or reflected (metallic reflection, internalreflection mediated by evanescent waves) at the interface(s), orcan produce phosphorescence/fluorescence (absorption–emis-sion process) and chemiluminescence (conversion of chemicalenergy into light) effects.81–83

The generation of light in CMOS or silicon devices is verydifficult since there is no first order transition from the valenceband to the conduction band without the involvement of aphonon (lattice vibrations).15 However, direct-bandgap semi-conductors (III–V-semiconductors) like gallium arsenide(GaAs) or indium phosphide (InP) show first-order radiativeelectron-hole-recombinations with high quantum efficiency.15

The detection of light is possible with either silicon-baseddevices (photodiodes) or other semiconducting materials(GaAs, InP). Consequently, integrated optical sensors andsystems nowadays mostly are made of III–V-semiconductors,which will not be detailed here, but offer the opportunity forfabrication and integration of lasers, waveguides, phase mod-ulators and detectors on the same chip.84 There is also a wealthof fiber-optical techniques and integrated optical devices, whichare realized on silicon substrates without making use of CMOStechnology. For details, see review articles.81–83, 85–88

In this article we will exclusively focus on CMOS-basedoptical sensors, an example of which includes an integrateddevice making use of bioluminescence.

4.3.1 Bioluminescent bioreporter integrated circuits(BBIC). This technique employs bioluminescent bacteriaplaced on an application-specific optical integrated circuit(standard CMOS).89–91 The bacteria have been engineered toluminesce, when a target compound such as toluene ismetabolized. Chemical reaction between target compound andbacteria leads to an excited state of a participating molecule,which then emits light during transition to the ground state.Chemical energy is thus directly converted into light energy inmost cases without additional heat generation (cold lumines-cence). Such processes take place, e.g., in glowworms.

The integrated circuit detects, processes, and reports themagnitude of the optical signal.89–91 The microluminometeruses the p-diffusion (source and drain diffusions of p-channelMOSFETs, PMOS, Fig. 1) in the n-well as the photodiode. Theshallow p-diffusion has a strong response to the 490 nmbioluminescent signal. The entire sensor including all signalprocessing and communication functions can be realized on asingle chip. The integrated circuit contains the devices andcircuits to detect the optical signal, to distinguish the signalfrom noise, to perform analog or digital signal processing, tocommunicate the results, and to perform auxiliary functionssuch as temperature assessment or position measurement (Fig.7).89–91

Many types of bioluminescent transcriptional gene fusionshave been used to develop light-emitting bioreporter bacterialstrains to sense the presence, bioavailability, and biodegrada-tion of different kinds of pollutants. The cells here wereentrapped on the chip by encapsulation in natural or syntheticpolymers providing a nutrient-rich hydrated environment.89–91

Applications include chemical analysis in gas or liquid phase.Depending on the integration time of the device, trace amountsof toluene and naphthalene were detected in the gas phase usingengineered cell colonies of Pseudomonas putida.89–91

Similar CMOS-based photodiode or phototransistor struc-tures such as CMOS charge-coupled detector (CCD) imagershave been used to develop microspectrometers for biochemical

Fig. 6 Schematic of a thermoelectric sensor. Polysilicon/aluminumthermopiles are used (hot junctions on the membrane, cold junctions on thebulk chip) to record temperature variations caused by analyte sorption in thepolymer.

Analyst, 2003, 128, 15–28 19

analysis92,93 or smart optical sensor systems to measure lightintensity and color.94,95 Fabry–Perot-based single-chip micro-spectrometers (16 addressable Fabry–Perot etalons) that can beused, e.g., for chemical analysis are detailed in refs. 95 and96.

4.4 Electrochemical sensors

Electrochemical sensors constitute the largest and oldest groupof chemical sensors. Many of them are commercially available.Electrochemical sensors make use of electrochemical or charge-transfer reactions, i.e., charge transfer from an electrode to asolid or liquid sample phase or vice versa. Chemical changestake place at the electrodes or in the probed sample volume, andthe resulting charge or current is measured. Electrode reactionsand charge transport in the sample are both subject to changesby chemical processes (analyte exposure) and hence at the baseof electrochemical sensing mechanisms.19–25,97

An electrochemical sensor is always composed of at least twoelectrodes with two electrical connections: one through theprobed sample, the other via transducer and measuringequipment. The charge transport in the sample can be ionic,electronic or mixed, while that in the transducer branch isalways electronic.

Electrochemical sensors are usually classified according totheir electro-analytical principles.20,21,24 Voltammetric sensorsare based on the measurement of the current–voltage relation-ship. A potential is applied to the sensor, and a currentproportional to the concentration of the electro-active species ofinterest is measured (amperometry is a special case ofvoltammetry, where the potential is kept constant). Potentio-metric sensors are based on the measurement of the potential atan electrode at equilibrium state, i.e., no current is allowed toflow during the measurement. The measured potential isproportional to the logarithm of the concentration of the electro-active species (Nernst-equation). Conductometric sensors arebased on the measurement of a conductance by applying an ACpotential with small amplitude to a pair of electrodes in order toprevent polarization. The presence of charge carriers determinesthe sample conductance.

Another method of classification is according to electroniccomponents.6,25 There are chemoresistors, chemocapacitorsand chemotransistors. We will use the electroanalytical princi-ples as the superordinated scheme and use the componentnotation within the different sections. We will restrict toCMOS-based systems and omit a wealth of literature on otherelectrochemical sensor designs, for details of which we refer toliterature.19–25,97–99

4.4.1 Voltammetric/amperometric sensors. Two differentelectrode configurations are normally used for voltammetric/

amperometric measurements. The two-electrode configura-tion.21,97 consists of a reference electrode (RE) and a workingelectrode (WE). The disadvantage of this method is, that the REcarries current and may become polarized if it is less thanhundred times the size of the WE. Material consumption due tothe current in the RE is another problem. A better approach ishence the use of a three-electrode-system21,97 in a potentiostaticconfiguration. An additional auxiliary electrode (AE, some-times denoted counter electrode CE) is introduced for currentinjection in the analyte.97 The reference electrode is now a trueRE with a well-defined potential since no current is flowingthrough the RE. The potentiostat controls the current at theauxiliary electrode as a function of the applied potential. This isrealized in practice with an operational amplifier.97

The measured current at any given potential differencedepends on the material properties, the composition andgeometry of the electrodes, the concentration of the electro-active species (presumably the target analyte) and the masstransport mechanisms in the analyte phase.20,24,97 Among thoseare migration, the movement of charged particles in an electricfield, convection, the movement of material by forced meanslike stirring or from density or temperature gradients, anddiffusion, the movement of material from high-concentrationregions to low-concentration regions. The electrochemicalreactions at the electrodes are normally fast in comparison to thetransport and supply mechanisms. Since convection in theelectrode vicinity is avoided, and migration is suppressed by,e.g., a large excess of electro-inactive salts (at the respectivepotential), diffusion is normally regarded to be the dominantmechanism. There are two components to the measured current,a capacitive component resulting from redistribution of chargedand polar particles in the electrode vicinity and a componentresulting from the electron exchange between the electrode andthe redox species (analyte) termed faradaic current.20,24,97 Thefaradaic component is the important measurand and is in case ofdiffusion-limited conditions directly and linearly proportionalto the target analyte concentration.20,24

A picture and a schematic of a CMOS-based 3-electrodevoltammetric/amperometric sensor is shown in Fig. 8.100 Themonolithic device includes the electrochemical sensor, atemperature sensor, and interface circuitry. The circuitrycontains an operational amplifier as potentiostat, a switched-capacitor current-to-voltage converter and a clock generator.Interface circuitry and temperature sensor are realized in 3 mmCMOS technology.100 The circuit operates at a supply voltageof ±2.5 V, can apply voltages from +1 V to 21 V to the sensorand handles current ranges from 30 nA full scale to 1 mA fullscale. The output voltage of the temperature sensor isproportional to the absolute temperature and has a sensitivity of125 mV K21. The total sensor dimensions are 0.75 3 5 mm.Sensor processing sequences are given in refs. 97, 100, 101 and102. The reference electrodes in liquid phase are in most casessilver/silver chloride elements.

Typical applications include chemical analysis in gas orliquid phase. Target analytes in the gas phase include oxygen101

Fig. 7 Micrograph of a bioluminescent bioreporter integrated circuit(BBIC). The circuitry blocks are in the upper part, the photodetectors in thelower part of the chip. Reprinted from ref. 90 with permission.

Fig. 8 Micrograph (a) and layout (b) of a CMOS-based 3-electrodeamperometric sensor. Reprinted from ref. 100 with permission.

20 Analyst, 2003, 128, 15–28

and carbon dioxide using liquid electrolytes.103 Target analytesin liquid phase comprise dissolved oxygen,100,102,104 glu-cose,100,105–107 or metal ions.108,109 If the target analyte is not anelectro-active species like the glucose molecules monitoredwith the integrated system here, polymer electrolytes orenzymes (glucose oxidase) producing analyte-related ionicspecies are used in the sensitive electrode coatings.

4.4.2 Potentiometric sensors (chemotransistors). The mostimportant potentiometric sensors are based on the field-effecttransistor (FET), and are among the most intensively investi-gated chemical sensor devices (since 1970110). Field-effectbased transistors, which are the most common electroniccomponents on modern IC logic chips, rely on modulation ofthe charge carrier density in the semiconductor surface space-charge region through an electric field perpendicular to thedevice surface: The source-drain current is controlled by anisolated gate-electrode (see Fig. 1 and related text). In thefollowing we will describe the MOSFET (metal-oxide semi-conductor field-effect transistor) for gas sensing applicationsand the ISFET (ion-selective field-effect transistor) operating inliquid phase.

The MOSFET (metal oxide semiconductor-FET) as used forchemical gas sensing (Fig. 9) has a p-type silicon substrate(bulk) with two n-type diffusion regions (source and drain). Thestructure is covered with a silicon dioxide insulating layer ontop of which a metal gate electrode (electronics: poly-Si gate) isdeposited.

When a positive voltage (with respect to the silicon) isapplied to the gate electrode, electrons, which are the minoritycarriers in the substrate, are attracted to the surface of thesemiconductor. Consequently, a conducting channel (n-chan-nel) is created between the source and the drain, near the silicondioxide interface. The conductivity of this channel can bemodulated by adjusting the strength of electrical field betweenthe gate electrode and the silicon, perpendicular to the substratesurface.

Palladium-(Pd)-gate FET structures were demonstrated tofunction as a hydrogen sensor by Lundström et al.111 Hydrogenmolecules readily absorb on the gate metal (platinum, iridium,palladium) and dissociate into hydrogen atoms. These H-atomscan diffuse rapidly through the Pd and absorb at the metal/silicon oxide interface partly on the metal, partly on the oxideside of the interface.112,113 Due to the absorbed species and theresulting polarization phenomena at the interface, the draincurrent (Id) is altered and the threshold voltage (Ud) is shifted.The voltage shift is proportional to the concentration orcoverage of hydrogen at the oxide/metal interface. Sensitivityand selectivity patterns of gas-sensitive FET devices hencedepend on the type and thickness of the catalytic metal used, thechemical reactions at the metal surface, and the device operationtemperature.

CMOS-based MOSFETs detecting hydrogen have beendescribed in refs. 114–116.

MOSFET-sensor applications also include the detection ofammonia,112,113 amines, and any kind of molecule that givesrise to polarization in a thin metal film (hydrogen sulfide, etheneetc.) or causes charges/dipoles at the insulator surface.112,113

In the case of the liquid-phase ISFET (ion-selective field-effect transistor), the gate metal electrode of the MOSFET isreplaced by an electrolyte solution, which is contacted by thereference electrode. The gate oxide is directly exposed to theaqueous electrolyte solution (Fig. 9).110 An external referenceelectrode is required for a stable operation of an ISFET.20,24,97

The source–drain current is influenced by the potential at theoxide/aqueous solution interface. ISFET amplifiers with feed-back keep the source–drain current constant by compensatingsolution-induced changes in the gate oxide potential bymodulation of the gate voltage (Ug) that is applied to thereference electrode. The gate–source potential is then deter-mined by the surface potential at the insulator/electrolyteinterface. Mechanistic studies of the occurring processes at thesolution/gate oxide interface (site binding model117) and theoxide semiconductor interface can be found in litera-ture.20,24,97,117–119 The insulator solution interface is assumed torepresent in most cases a polarizable interface, i.e., there will becharge accumulation across the structure but no net chargepassing through.

Classic ISFET applications include pH-sensing (acidity orbasicity) with an exposed-gate-oxide FET.110 The surface of thegate oxide contains OH-functionalities, which can be proto-nated and deprotonated and thus, when the gate oxide contactsan aqueous solution, a change of pH will change the siliconoxide surface potential.110,120 Typical pH-sensitivities meas-ured with silicon oxide ISFETs are 37–40 mV per pH unit.121

Gate materials such as silicon nitride,122–130 oxynitride,131 oralumina132–134 have better properties than silicon oxide withregard to pH-response, hysteresis and drift. In practice, theselayers are deposited on top of the silicon oxide by means ofchemical vapor deposition (CVD).

ISFETs can also be covered with organic ion-selectivemembranes like polyurethane, silicone rubber, polystyrene, andpolyacrylates containing ionophores to detect metal ions such aspotassium,135,136 sodium137 or silver.138 Cell metabolisminduced pH-changes have been monitored,128 and glucose hasbeen detected using a proton-producing electrochemical reac-tion.130

The fabrication of CMOS integrated field-effect-basedelectrochemical sensors with circuitry is described in variouspublications.97,122–131,139 An example of an integrated ISFET isshown in Fig. 10a.131

The system includes an ISFET amplifier (source and drainfollower) and two interdigitated ISFETs realized in a 1.0 mm,two-metal CMOS process (Atmel-ES2, Atmel, France). The pH

Fig. 9 Schematic representation of a MOSFET and an ISFET structure. Ug

denotes the gate voltage, Ud the source-drain voltage. The ISFET is realizedby replacing the metal gate of the MOSFET with an ionic solution and areference electrode immersed into this solution.

Fig. 10 (a) Micrograph of a CMOS chip hosting two integrated ISFETsand an ISFET amplifier. (b) Schematic and cross-section of the ISFET. Fordetails, see text and ref. 131. Reprinted from ref. 131 with permission.

Analyst, 2003, 128, 15–28 21

measurements have been conducted using a Ag/AgCl referenceelectrode and yielded a sensitivity of 47 mV per pH unit usingsilicon oxynitride as the pH-sensitive material.131 To render thefabrication CMOS-compatible, the sensitive oxynitride sits ontop of an electrically floating multi-conductor gate structureincluding the two metal layers and the gate polysilicon, all ofwhich are electrically connected (Fig. 10b). This way, the pH-dependent electrical charge at the surface of the oxynitride incontact with the solution directly affects the silicon surfacesource–drain current (Fig. 10b).131

4.4.3 Conductometric sensors. Conductometric techniquesare a special case of alternating-current (AC) impedancetechniques. Instead of the real and imaginary component of theelectrode impedance at different frequencies, only the resistivecomponent, related to the sample (sensing material) resistanceis of interest. Since complex impedances include capacitive andinductive contributions, chemocapacitors are included here, inthe conductometric section. The section on conductometricsensors is hence organized in two subsections, one onchemoresistors and the other subsection on chemocapacitors.

4.4.3.1 Chemoresistors. Chemoresistors rely on changes inthe electric conductivity of a film or bulk material uponinteraction with an analyte. Chemoresistors are usually arrangedin a metal electrode 1/sensitive layer/metal electrode 2 config-uration.20,21,24 The resistivity/conductance measurement isdone either via a Wheatstone bridge arrangement or byrecording the current at an applied voltage in a DC (directcurrent) mode or in a low-amplitude, low-frequency AC(alternating current) mode to avoid electrode polarization. Thecontact resistance should be much lower than the sampleresistance and be minimized, so that the bulk contributiondominates the measured overall conductance.

There is two major classes of chemoresistors: (1) high-temperature chemoresistors (200–600 °C) with semiconductormetal oxide coatings and (2) low-temperature chemoresistors(room temperature) with polymeric and organic sensitivecoatings. We will focus on the technologically more challeng-ing high-temperature sensors and only briefly mention thesecond type with the applications.

The sensitive materials used with high-temperature chemor-esistors include wide-bandgap semiconducting metal oxidessuch as tin oxide, gallium oxide, indium oxide, or zinc oxide, allof which can only be operated as sensing materials at hightemperature ( > 200 °C). In general, gaseous electron donors(hydrogen) or acceptors (nitrogen oxide) adsorb on the metaloxides and form surface states, which, at high temperature, canexchange electrons with the semiconductor. An acceptormolecule will extract electrons from the semiconductor metaloxide and thus decrease its conductivity. The opposite holdstrue for an electron–donating surface state. The reactionbetween gases and oxide surface depends on the sensortemperature, the gas involved, and the sensor mate-rial.20,140–144

Semiconductor metal oxide sensors usually are not veryselective, but respond to almost any analyte (carbon monoxide,nitrogen oxide, hydrogen, hydrocarbons). One method tomodify the selectivity pattern includes surface doping of themetal oxide with catalytic metals such as platinum, palladium,gold, and iridium.20,21,140–144

The device requirements for a high-temperature chemor-esistor include a thermally well-isolated stage such as amembrane, which allows for keeping the sensing materials at ahigh temperature without heating the bulk chip (protection ofelectronic components), an integrated heater, and a temperaturesensor (Fig. 11).145,146

Fig. 11 shows a front-side-etched microhotplate on a CMOSsubstrate.145,146 The microhotplate components include apolysilicon resistive heater, an aluminum metal plate for heat

distribution and temperature measurement and four noblemetal-coated aluminum or tungsten contacts for electricalconnection to the sensing film.145,146 Tin dioxide is thendeposited on top of the metal electrodes.

Since microhotplates have a very low thermal mass, theyallow for applying temperature-programmed operation modes,which enhance the gas detection capability.147,148

The fabrication of hotplates on CMOS-substrates is describedin refs. 145, 146, 149 and 150. Complete processing sequencesare detailed in refs. 150 and 151. First results with hotplates andcircuitry on a single CMOS-chip have been presented re-cently.152,153 Multi-chip solutions have been proposed in refs.154 and 155. Reliability tests with CMOS hotplates have beenconducted.156 CMOS-hotplates realized on SOI (silicon oninsulator) and SIMOX (separation by implantation of oxygen)substrates are presented in refs. 157 and 158.

Typical microhotplate applications include the detection ofinorganic gases such as hydrogen,145,146,150 oxygen,145,146

nitrogen oxide,147,159 carbon monoxide,145–148,155,159 and avariety of organic volatiles145,146,150,159–161 using predom-inantly tin oxide as sensitive layer.

Several classes of predominantly organic materials are usedfor application with chemoresistors at room temperature(electrode spacing typically 5 to 100 mm, applied voltage 1–5V). Conducting polymers such as polypyrroles, polyaniline andpolythiophene are used to monitor a variety of polar organicvolatiles like ethanol, methanol, and components of aro-mas.162–165 Conducting carbon black can be dispersed in non-conducting polymers so that if the polymer absorbs vapormolecules and swells, the particles are, on average, further apartand the conductivity of the film is reduced (conductivity byparticle-to-particle charge percolation).166 Applications alsoinclude organic solvents such as hydrocarbons, chlorinatedcompounds, and alcohols.166–170

CMOS-based monolithic sensor systems coated with carbonblack/polymer blends are detailed in,169,170 two-chip solutionswith a CMOS circuitry chip and a separate sensor chip based onconducting polymers can be found in refs. 164 and 165. ACMOS-compatible monolithic conductivity sensor for liquidphase (Pt electrodes) was presented in ref. 171.

4.4.3.2 Chemocapacitors. Chemocapacitors (dielectrom-eters) rely on changes in the dielectric properties of a sensingmaterial upon analyte exposure. Interdigitated electrode struc-tures are predominantly used.172,173 The capacitances usuallyare measured at an AC frequency of a few kHz up to 500kHz.

The interdigitated capacitors described here exhibit anelectrode width and spacing of 1.6 mm. The total footprint of acapacitor is 800 3 800 mm2. Since the nominal capacitance ofsuch a microstructure is on the order of 1 pF and the expectedcapacitance changes (sensor signals) in the range of someattoFarads, an integrated solution with on-chip circuitry is

Fig. 11 Scanning electron micrograph of a microhotplate. The suspendedplate exhibits a polysilicon heater, an aluminum plane for homogenous heatdistribution and noble metal-coated aluminum electrodes for measuring theresistance of a semiconductor metal oxide. Reprinted from refs. 145 and 146with permission.

22 Analyst, 2003, 128, 15–28

required. There is no possibility to transfer such minute analogsignals via bond wires and cables to desktop instruments. Theintegrated solution includes two capacitors, a polymer-coatedsensing capacitor and a silicon nitride-passivated referencecapacitor in a switched-capacitor scheme (Fig. 12). The sensorresponse is read out as a differential signal between thepolymer-coated sensing and a passivated reference capacitor. Adigital output signal is then generated by comparing the minuteloading currents of both capacitors using a fully differentialsecond-order Sigma–Delta-modulator circuitry.174,175 Acounter to decimate the output bit stream is co-integrated on-chip. A schematic of a capacitive chemical sensor microsystemis shown in Fig. 12.

Two effects change the capacitance of a polymeric sensitivelayer upon absorption of an analyte: (i) swelling and (ii) changeof the dielectric constant due to incorporation of the analytemolecules into the polymer matrix.46,174,176 The capacitancechange for a polymer layer with a thickness of approximatelyhalf the periodicity of the electrodes is determined by the ratioof the dielectric constants of analyte and polymer. If thedielectric constant of the polymer is lower than that of theanalyte, the capacitance will be increased. Conversely, if thepolymer dielectric constant is larger, the capacitance will bedecreased (see Fig. 15 later). These effects have been furtherdiscussed and supported by simulations in ref. 176.

For conducting measurements at defined temperatures,sensor and reference capacitors can be placed on thermallyisolated membrane structures.175

The fabrication of capacitors integrated with CMOS circuitrycomponents is described in refs. 46, 173–178.

Typical applications include humidity sensing with poly-imide films,172,173,177–179 since water has a high dielectricconstant of 78.5 (liquid state) at 298 K leading to largecapacitance changes. CMOS-based integrated capacitive hu-midity sensors are commercially available from, e.g., SensirionAG, Switzerland.180 More recent applications also include thedetection of organic volatiles in the gas phase using polymericlayers.46,174–176

4.5 Monolithic integration of different transducers

Another significant advantage of CMOS-based chemical sen-sors is the possibility to integrate several different transducersalong with all the driving circuitry on a single chip. Additionalcomponents that can be integrated include signal conditioningcircuitry (amplifiers, references), multiplexers to reduce thenumber of output pins, analog/digital and digital/analog con-verters, chip memory (calibration values) or other smartfeatures, an intra-chip communication or bus system and a serialinterface to communicate with off-chip microcontrollers orinstruments. In the following we will present two prototypemonolithic CMOS multisensor systems, (1) a multiparameter

biochemical sensor181 and (2) smart gas sensor microsys-tem.182

4.5.1 CMOS multiparameter biochemical microsensor181.The microsensor system is aimed at continuous monitoring ofions, dissolved gases and biomolecules in liquid phase such asblood (Fig. 13),181,183 and is based on an earlier design byGumbrecht et al.184 The eight integrated chemical sensorscomprise six ion-sensitive field-effect transistors (ISFETs: 1–6in Fig. 13), one oxygen sensor (7 in Fig. 13) and oneconductometric sensor (8a,b in Fig. 13), all of which can beoperated in parallel.181 An Ag/AgCl reference electrode wasalso integrated on the CMOS chip to get rid of externalreferences. A flow channel (polyimide) restricts the liquid phaseaccess to the sensor area.

The six ISFETs allow for direct contact of the electrolyte withthe gate oxide. The gate oxide itself is pH-sensitive (see ISFETsection), or the ISFET can be used as a ‘Severinghaus’-type pH-FET to measure dissolved carbon dioxide (detection of carbondioxide via dissolution in water, formation of ‘carbonic acid’and monitoring of the pH change). The gate oxide can also becovered with different ion-selective membranes to achievesensitivity to a range of target ions such as potassium. All sixISFETs or only a subset can be used. The idea is to make astandard chip to reduce manufacturing costs and then modifythe chip with selective coatings according to user needs.

The integrated amperometric sensor can be used as a Clark-type oxygen sensor, which is based on a two-step-reduction ofgaseous oxygen in aqueous solution via hydrogen peroxide tohydroxyl ions.

The conductometric sensor consists of two parallel sensors(8a), which share one common electrode (8b). A sinusoidal ACpotential is applied to the electrodes, and the current, whichdepends on the solution composition (concentration of chargedparticles or ions) is recorded. The eight sensors can con-tinuously monitor ions, dissolved gases and biomolecules viaenzymatic reactions that produce charged particles.

The full system is produced in a 1.2 mm single-metal, single-poly CMOS process and the chip size is 4.11 3 6.25 mm.181 Thechip is operated at 5 V and hosts all driving circuitry for thesensors such as ISFET buffer amplifiers, a potentiostatic setupfor the amperometric sensor and the circuitry necessary toperform a four-point conductometric measurement on chip. Inaddition the chip exhibits a temperature control unit to keep thesystem temperature at an adjusted value (physiological condi-tions). This temperature control unit includes a temperature

Fig. 12 Schematic of a capacitive chemical sensor microsystem includinga polymer-coated sensing capacitor and a Si-nitride-protected referencecapacitor. The on-chip circuitry includes a SD-converter.

Fig. 13 Micrograph of the CMOS multi-parameter biochemical sensorchip, which includes 6 ISFETS (1–6), one conductometric sensor (8a,b) andan (amperometric) oxygen sensor (7). The on-chip circuitry includes anEPROM, a multiplexer and counter, a driver unit, a conductometric andpotentiostatic circuit and a heater. Reprinted with permission from ref.181.

Analyst, 2003, 128, 15–28 23

sensor (parasitic vertical p–n–p bipolar transistor) and a NMOStransistor heater. A single-bit EPROM (electrically program-mable read-only memory) was implemented on chip to makesure the chip is only used once and then is disposed, which is acrucial feature in medical applications. Additional on-chipelectronics include units to control the chip (multiplexer,demultiplexer, 4-bit Gray counter and decoder) and units toprovide the biasing and the communication to off-chip in-strumentation. Due to the high level of on-chip integration only5 external connections are needed: two for power supply, twofor bi-directional communication and one for a clock signal.

First tests including amperometric oxygen measurements, theassessment of potassium concentrations with ISFETs, andconductometric measurements with a buffer solution have beenperformed.181

4.5.2 CMOS single-chip gas sensor microsystem182. TheCMOS single-chip chemical microsensor system combinesthree different transducers, a mass-sensitive cantilever, acapacitive sensor, and a calorimetric sensor, all of which rely onpolymeric coatings as sensitive layers to detect airborne volatileorganic compounds (VOCs). The three transducers respond tofundamentally different analyte molecule properties. One ofthem responds to the mass of sorbed molecules, anotherresponds to the heat of absorption, and the third responds to thedielectric properties of the absorbates. The monolithic systemsuch simultaneously provides three different (“orthogonal”)sensor responses, which are used to classify or quantify analytesin the gas phase.

The capacitive sensor as previously described in section4.4.3.2 is integrated with a fully differential second-orderSigma-Delta-modulator circuitry and a counter to decimate theoutput bit stream.185

The micromachined cantilever, the operation principle ofwhich has also been already described in section 4.1.2, is 150mm long and consists of silicon as well as vapor-deposited andthermal oxide. The cantilever acts as the frequency-determiningelement in a feedback oscillation circuit, which is entirelyintegrated on the chip with a counter. For more details on theelectronics, see refs. 43 and 185.

The third transducer is a thermoelectric calorimeter based onthe Seebeck effect with 256 polysilicon/aluminum thermo-couples connected in series (500 mm by 500 mm dielectricmembranes). Details have been described in section 4.2.2. Thethermovoltage is translated into a digital signal on chip using aSigma–Delta analog/digital converter and a decimation filter.

The overall system chip additionally includes a temperaturesensor since volatile absorption in polymers is stronglytemperature-dependent. The temperature sensor relies on thelinear temperature dependence of a bipolar transistor availablein the CMOS process. The voltage is converted to a digitalsignal using a Sigma–Delta converter. After calibration, thetemperature sensor exhibits an accuracy of 0.1 °C at operationtemperatures between 240 and 80 °C.

A micrograph of the microsystem chip is displayed in Fig. 14.The overall chip size is 7 3 7 mm. The chip exhibits all thesensor-specific driving circuitry and signal-conditioning cir-cuitry, which has been described in the context of the differenttransducers. The analog/digital conversion is done on chip,which allows for achieving a favorable signal-to-noise ratio,since noisy connections are avoided and a robust digital signalis generated on chip and then transmitted to an off-chip data portvia an I2C serial interface.186 The I2C bus interface offers theadditional advantage of having only very few signal lines(essentially two) for bi-directional communication and alsoallows for operating multiple chips on the same bus system. Anon-chip digital controller manages the sensor timing and thechip power budget. The sensors are located in the center of ametal frame, which is used to apply a flip-chip packagingtechnique.187

Fig. 15 displays simultaneously recorded sensor signals of allthree transducers upon exposure to 1200 and 3000 ppm (partsper million) of ethanol, and 1000 and 3000 ppm of toluene at 30°C.181,185 The sensors were alternately exposed to analyte gasand pure carrier gas. The polymeric coating consisted ofpoly(etherurethane), PEUT46 at a thickness of approximately 4mm.

Fig. 15a shows the measured frequency signals (Sigma–Deltaconverter output) of the capacitor. Ethanol exhibiting adielectric constant of 24.5, which is larger than that of PEUT(2.9), causes a capacitance increase and hence positivefrequency shifts, toluene with a dielectric constant of 2.4 causesa capacitance decrease and negative frequency shifts. Fig. 15bdisplays the cantilever response. The resonance frequencydecreases with increasing oscillating mass as a consequence ofvolatile absorption. Ethanol shows rather low signals ascompared to toluene due to its lower molecular mass and due toits lower enrichment (partitioning) in the polymeric phase.

The calorimetric results in Fig. 15c represent a superpositionof already discussed partitioning and heat budget change due toanalyte ab/desorption. The absorbing analyte liberates heat(heat of condensation) causing a positive transient signal(positive peak), whereas the desorbing analyte abstracts vapor-ization heat from the environment generating a negativetransient signal (negative peak upon purging, see Fig. 15c). Theclose-up in the upper left corner shows the time-resolvedresponse upon 3000 ppm of toluene within the first 6 s.

The signals of all three transducers linearly correlate withanalyte concentration at low concentrations (less than 3% ofsaturation vapour pressure at the operating temperature). Tofurther improve analyte identification/quantification, an arrayof microsystem chips coated with different polymers can beused. The monolithic CMOS gas microsystem is targeted atidentifying organic solvents in transport containers or providingworkplace safety in, e.g., chemical industry. It will form part ofa handheld or credit card size detection unit.

5 Outlook

The field of CMOS-integrated chemical sensors is currentlyexpanding as can be seen from the growing number ofpublications in the last years. As can be concluded from thearticle, the research and development thrusts go in the directionof integrating more and more electronic functions on the sensorchip such as adaptive circuits for signal evaluation anddiscrimination,188,189 or telemetry units for wireless commu-nication. Telemetry functions will encompass, e.g., commu-nication from implanted chips (glucose sensors) through the

Fig. 14 Micrograph of the gas microsensor system chip (size: 7 3 7 mm).The different components include: (1) flip-chip frame, (2) referencecapacitor, (3) sensing capacitor, (4) calorimetric sensor and reference, (5)temperature sensor, (6) mass-sensitive resonant cantilever, and (7) digitalinterface. Reprinted with permission from ref. 182.

24 Analyst, 2003, 128, 15–28

skin in medical applications190 or the transmission of remoteand distributed chemical sensor responses to a central terminalin environmental and building control scenarios by using radiofrequencies191–193 or other standards like Bluetooth™.194

Another extensively belabored field of research will targetthe combination of CMOS chips with biomaterial such as livingcells or neurons. Portable, cell-based biosensor systems withCMOS chips have been reported on by Kovacs and cowork-ers.195,196 The interfacing of neurons or nerve ends with CMOScircuitry to develop neural probes,197–199 neuromuscular micro-stimulators,200 or neural prostheses is at an early stage but willgain momentum and will most probably also include monitoringof chemical parameters (ionic signals have to be translated intoelectronic signals). Sensor arrays for DNA-analysis based onCMOS-assisted electronic detection rather than optical detec-tion may also constitute an interesting application for CMOStechnology.201,202

In summary, CMOS and CMOS-MEMS technology andprocesses offer a great deal of readily available electroniccircuits provided by the huge development efforts of the IC-industry, only a small fraction of which has been used forchemical sensors so far. It has to be kept in mind, however, thatCMOS sensor development is expensive (mask and processingcosts) and only pays off, if either millions or at least hundredsof thousands of pieces are sold, or if the devices provide uniquefunctionality, which then makes up for the costly development.The ‘killer-applications’ involving large numbers of chemicalsensors have not emerged yet. They may be in the field ofautomotive applications, domestic gas alarms, HVAC (humid-ity, ventilation, air conditioning) units, or in the field ofdisposable medical devices (e.g., DNA or blood tests).

6 Acknowledgements

The authors are greatly indebted to current and former staff ofthe Physical Electronics Laboratory at ETH Zurich involved inthe chemical microsensor development, notably ChristophHagleitner, Dirk Lange, and Oliver Brand.

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Fig. 15 Sensor signals simultaneously recorded from all three polymer-coated transducers upon exposure to 1200 and 3000 ppm of ethanol and 1000 and3000 ppm of toluene at 301 K: (a) frequency shifts (Sigma–Delta converter output) of the capacitor, (b) frequency shifts of the resonating cantilever, and (c)thermovoltage transients of the calorimetric sensor. The close-up shows the development of the calorimetric transient within 6 s. Reprinted with permissionfrom ref. 182.

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