IEEE SENSORS JOURNAL, VOL. 11, NO. 2, FEBRUARY 2011 305

Recent Development of Micromachined BiosensorsLijie Li, Member, IEEE

(Invited Review Article)

AbstractThe aim of this paper is to provide a panoramic viewof recent advancements for the micromachined biosensors. Interms of different sensing principles, three categories of biosen-sors that have attracted much attention in recent decade arereviewed, which are electrochemical biosensors, microcantileverbiosensors, and dielectric spectroscopic biosensors. Each type ofbiosensors has certain advantages and weaknesses, for exampleelectrochemical biosensors can be easily integrated with readoutcircuits as they directly output electronic signals; microcantileverbased biosensors are a label free sensing technique; dielectricspectroscopic biosensors provide a truly non-invasive sensingtechnique. All of above sensing techniques are compared in thispaper based on previous published literatures. This paper willserve as a useful resource to help biosensor designers choose themost appropriate technology to meet their requirements.

Index TermsDielectric spectroscopic, electrochemical, micro-cantilever, review.

I. INTRODUCTION

B IOSENSORS are increasingly important devices that havegenerated huge impact on our lives. Many of them havealready been used in clinical applications for early detection ofdiseases. As the micromachining technology has been growingin an unprecedented pace, the marriage of micromachiningtechnology and traditional biosensing technologies providesreal opportunities to realize a new generation of biosensors withclear advantages of low cost, miniaturized, and high sensitivity.In the recent ten years, researchers have devoted many effortsto develop various biosensors based on micromachining tech-nologies. Examples include arrays of micromachined electrodesthat were fabricated to achieve multifunction electrochemicalbiosensors [1]; microcantilevers that were designed and fabri-cated using silicon micromachining to achieve high sensitivity,label free biosensors [2]; and dielectric spectroscopic biosensors[3]. In this paper, a general overview of these biosensor develop-ments is presented as guidance for designers to select the mostsuitable technology to achieve their requirements. Section II ofthis paper presents the review for electrochemical biosensors,microcantilever biosensors is reviewed in the Section III, review

Manuscript received July 13, 2010; accepted July 25, 2010. Date of publica-tion September 27, 2010; date of current version November 17, 2010. This workwas supported in part by the U.K. Royal Society and Engineering Physical Sci-ences Research Council (EPSRC). The associate editor coordinating the reviewof this paper and approving it for publication was Prof. Evgeny Katz.

The author is with the Multidisciplinary Nanotechnology Centre, School ofEngineering, Swansea University, Singleton Park, Swansea, Wales, SA2 8PP,U.K. (e-mail: L.Li@swansea.ac.uk; lijie.li@ieee.org).

Color versions of one or more of the figures in this paper are available onlineat http://ieeexplore.ieee.org.

Digital Object Identifier 10.1109/JSEN.2010.2063424

Fig. 1. Schematic graph of the electrochemical biosensors.

of dielectric spectroscopic biosensors and conclusion remarksare described in Sections IV and V, respectively.

II. ELECTROCHEMICAL BIOSENSORS

The principle of the electrochemical sensors is based onmonitoring current/voltage with an array of electrodes. Theelectrical current and voltage between electrodes change wheneither chemical reactions between materials coated/attached onthe electrodes and biological samples or impedance changingof the biological samples surrounding the electrodes occur.General working principle of electrochemical biosensors canbe schematically shown in Fig. 1. Basically there are threetypes of electrochemical biosensors that have been extensivelyinvestigated: 1) electrochemical biosensors that are integratedwith CMOS circuits; 2) electrochemical biosensors that employnovel materials; and 3) multifunctional electrochemical biosen-sors. For the first category, Hassibi and Lee [4] have reportedan electrochemical biosensor that integrates electrochemicalsensor and CMOS servo circuits such as differential amplifier.The advantage of this technique is that it provides a low costsolution to the electrochemical sensors since the circuits arere-configurable and the sensor can be re-used many times. Thewhole device was fabricated monolithically by using a standard5 metal CMOS process without requirement of any post-pro-cessing. Another research work was conducted on integratingbiosensors with CMOS IC by Levine et al. [5], [6] , whoreported a CMOS electrochemical sensor arrays that integratespotentiostat electronics and SDCs stimulate in one silicon chip.Post-process was applied to fabricate a biologically compatiblesurface-electrode array in CMOS, which has potential appli-cation in a harsh electro-chemical environment. The biosensorchip was fabricated using a TSMC 2.5 V, five metals, 0.25 m

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306 IEEE SENSORS JOURNAL, VOL. 11, NO. 2, FEBRUARY 2011

CMOS foundry process and in depth design of the amplificationcircuits was presented in the article. ADC circuit was also uti-lized to digitalize the electrical current signal from the sensingelectrodes. It is worth noted that quite often the biosensorsmade by CMOS technology needs some post-processes tocreate a biocompatible interface between CMOS circuits andliquid environment. Schindler et al. [7] reported a post-processfor the passivation of a CMOS biosensor using the aluminumoxide and hafnium oxide multilayer films, which were pre-pared by atomic layer deposition at low process temperatureof less than 400 above which CMOS circuits are prone tobe damaged. The film can withstand dc voltage up to 6 V andthe thickness of the film is 50 nm. Signal processing circuitsfor electrochemical biosensors have also been investigated.Theoretical study of the signal processing for the microsensorarrays were conducted by Anderson [8]. It was identified thatcrosstalk between channels that is originated from the finitegain of the op-amp is predominated problem, which couldresult in misinterpretation of the microarray data. Theoreticalanalyses showed that increasing dc amplifier gain and reducingthe value of the interface capacitance will impair the crosstalkeffect. More work has been done on the signal processing of theelectrode array biosensors. Ayers et al. [9] reported a sensorsservo circuitry that includes a standard differential amplifier formaintaining the potential of the electrode, and a current-modesigma-delta analog-digital converter (ADC) with a variableoversampling ratio. The advantage of the circuit is its muchlower power consumption than classical amplification circuitssince all individual amplifiers share a common half circuit.Detailed analyses together with experimental validation wereperformed and reported in that article.

For the second type of electrochemical biosensors develop-ment, Strand et al. [10] reported a biological gas sensor fordetecting concentration of volatile breath metabolites, whichwas based on a conducting polymer material polypyrrole(PPy). This material has advantage of electroactivity and re-versible redox properties; therefore it is ideal to form biologicalgas sensors. The absorbed molecule on the sensor surface canbe released by increasing the temperature and the sensor canbe re-used many times. As the PPy is a conducting polymer,the resistive type sensor and joule-heater can be made with thesame material. Living cells can be used as sensing elementsdue to their physiological responses that can be detected elec-trochemically. Feng et al. [11] reported a living cell-basedbiosensor that was attached on an array of gold microelectrodeson a silicon oxide substrate. In their work, the living cells weredeposited onto microelectrode arrays and electrical current wasgenerated when the cells released some subject to anyexternal stimuli. Pyrolyzed carbon film that has been used asthe working electrode material for aptamer-absed thrombindetection was presented by Lee et al. [12]. The device consistedof a pair of electrodes made of thin film of pyrolyzed carbon.The impedance between the electrodes pair changes due tohindrance of electron-transfer by negatively charged thrombinbinding onto the pyrolyzed carbon surface. Produced by pho-tolithography and phtoresist thermal decomposition at hightemperatures in inert ambient, pyrolyzed carbon has advantagesof batch fabrication, fine resolution, and reproducibility, it also

has applications in microbatteries and image sensors. Carbonpost-microarrays were used to be a biosensor to detect theconcentration of glucose solutions, which were fabricated byusing a carbon MEMS process [13]. The principle of enzymaticglucose sensing technique is based on electrochemical reactionbetween glucose and oxygen with the typical catalyser (GOx).Research results showed that the sensitivity of the glucosesensor depends on the post-height and various densities. As thepost-height gets higher, the sensitivity becomes better; and asthe density increases, the sensitivity becomes lower. Detectionof cholesterol concentration in blood using Au nanowires thatwas assembled/aligned on silicon platform was reported byAravamudhan et al. [14]. The authors have also conductedsome experiment for storage stability. Results showed that thesensor response was remained constant for 10 days.

For the third category, Gue et al. [15] has reported anenzymatic biosensor that can detect multiple enzymes si-multaneously. The sensor is comprised of sealed chamberthat consists of biosamples and electrodes. The chamber wasformed by gluing a dialysis membrane onto a silicon substratethat has microelectrodes fabricated on the top surface. It was re-ported that the sensitivity was about 2 cm and thiscould be enhanced by improving the cleaning procedure of theworking electrode. Differentially sized electrochemical microchambers for monitoring properties of different biosamplessimultaneously have been previously reported by Ben-Yoav etal. [16]. The advantage of this technique lies in its ability offunctional screening of numerous unknown analytes. Usingthis sensing technique, that paper demonstrated detection oftwo genotoxicants, nalidixic acid and 2-amino-3-methylimi-dazo[4,5-f]quinoline. A lab on a chip system that containsmany nano-volume electrochemical cells based on siliconsubstrate has been developed to conduct many different mea-surements [17]. Each of these cells which are disposable canhold 100 nL, and includes three embedded electrodes (madeof gold), which perform different measurements. These sil-icon chips are connected to a reusable part that comprises amultiplexer, potensiostat and pocket PC, which perform thefunction of data processing and recording. Electrode arrayscould be configured in several different ways; they were de-signed into lattice shape as well as interdigitated shape. Miret al. [18] presented an electrochemical biosensor microarraymade by interdigitated electrodes that was fabricated by meansof biomolecule friendly photolithography. Shi et al. [19], [20]reported a microeletrode array on a silicon chip for screeningof liver fibrosis markers in human serum. The electrode arraywas formed in an interdigitated shape. - responses of thebiosensor were measured simultaneously for three differentfibrosis markers HA, LN, and IV-C . In order to integrateseveral biosensors or integrate biological components withCMOS servo circuits, interface design has to be carefully con-sidered. Plasma-polymerized film produced in glow dischargeor plasma in vapor phase is generally used in the interfacialdesign of biosensors [21], [22] . It has advantages of extremelythin ( m), good adhesion to the substrate, pin-hole free,mechanically and chemically stable, and biocompatible. Thistype of interface has been generally used in catalytic biosensorsand affinity biosensors.

LI: RECENT DEVELOPMENT OF MICROMACHINED BIOSENSORS 307

Fig. 2. Schematic graph of an oscillating microcantilever biosensor. Top graphshows there is no biological samples, bottom shows there are some biosamplesdeposited on the microcatilever.

III. MICROCANTILEVER BIOSENSORS

Microcantilevers have been very popular biosensing struc-tures in the recent decade following a Nature publication,which demonstrated a sensing technique to detect prostatecancer using microcantilevers [23]. The operating principle ofa classical microcantilever biosensor is schematically shownin Fig. 2. It is seen from the Fig. 2 that as the cantilever isoscillating, adding a small amount of particles (could be somekinds of biosamples) changes resonant frequency of the beam.Resonance of the microcantilevers is usually used in sensingvery small mass variation that is attached on the microcan-tilevers. The governing equation for resonant frequency of anoscillating microcantilever can be shown as

(1)

where is the stiffness and is the effective mass of the micro-cantilever. The effective mass can be expressed by the real massof the cantilever . It is seen from the (1) that the resonant fre-quency of the beam is related to stiffness and effective mass of thebeam. When the biological molecules are deposited or absorbedby the cantilever, the effective mass changes, in some cases stiff-ness changes as well. The shift in frequency can be written as

(2)The frequency shift can be detected either by optical or electricalmethods, from which the exact value of the additional mass canbe extracted. The main advantages of using microcantilever asbiosensors are small size, label-free detection of the analyte,and potential for arrayed operation. Recent developments ofmicrocantilever biosensors are described as follows. Microcan-tilever biosensors have been fabricated and characterized withthe capability to sense masses of the order of few hundreds ofpicograms with less than 0.5% of relative uncertainty, reportedin [24]. Using resonant microcantilevers, detection of hepatitisB virus DNA at femtomolar concentrations has been achieved.

The resonant frequency was measured using an impedance an-alyzer. The resonant shift ( ) varies from 10 Hz to 160 Hzdue to the mass of the biosample changes from around 23 fMto around 2.3 . [25] Readout methods for the micro-cantilever biosensors are mainly based on optical interferometryand electronic circuits. An optical readout method using the in-terferometric principle was presented to detect the displacementof the microcantilevers. The minimum resolution was reportedusing that technique was on the order of 1 nm [26]. Despite usingoptical method to detect the displacement of microcantilevers,electrical method such as integrating MOSFET with the can-tilevers was also utilized. Tosolini et al. [27] developed a mi-crocantilever force sensor that is based on MOSFET detection.In this method, the bending of the cantilever is converted intovoltage change of the MOSFET device due to stress inducedpiezoresistive effect. Microcantilever that has been fabricatedon a silicon chip before the CMOS process was demonstratedby Ghatnekar-Nilsson et al. [28]. The cantilever and its drivingmechanisms were fabricated using electron beam lithographyand direct laser write lithography. Electrostatic comb drive wasused as the driving mechanism for the microresonator.

There have been some efforts devoted to the microcantileverbiosensor developments on modifications of the microcan-tilevers for the purpose of increasing their sensitivity and thesignal to noise ratio. Modified microcantilever design has beenintroduced by Yang and Chang [29] to eliminate the biaxial effectof the surface stress and the thermal effect of the piezoresistor.Microcantilevers of different shapes including rectangular,triangular, and step profile were investigated by Ansari and Cho[30]. The results showed that triangular and step cantilevershave better deflection and frequency characteristics than rect-angular ones. Also the authors presented a novel design ofmicrocantilever with a rectangular hole at the fixed end of thecantilever, which was proven to have 75% more sensitive thanthe conventional design [31]. Goericke and King [32] reported afinite element modeling (FEM) of piezoresistive cantilevers, andconcluded that the cantilever width is an important parameterand should be maximized for optimal sensitivity, and the lengthof cantilever is not critical for high sensitivity. As for the piezore-sistive microcantilever based biosensors, the temperature isinduced by passing electrical current through the piezoresistors,which can have some impact on the sensor stability and signalto noise ratio. Yang et al. [33] reported a method to compen-sate the temperature effect by designing parallel piezoresistivemicrocantilevers together with a signal conditioning circuits.A sandwich structured piezoresistive microcantilever has beenreported by Wang et al. with the piezoresistive layer in the middle[34]. Static and dynamic performances of the microcantileverwere analytically investigated using formulas. Johnson noise,

noise, and force resolution have been studied in the paper.New materials have been deposited on the microcantilevers toachieve advanced sensing functions. Due to the magnetic natureof the magnetostrictive material, the mechanical oscillationof the Magnetostrictive microcantilevers induces a magneticflux, which can be detected by external coils. Therefore, wire-less driving and sensing is possible with this technology [35].Self-excited piezoelectric microcantilever was designed andfabricated for biosensing applications, which is comprised of athin film silicon nitride and a layer of PZT material [36].

308 IEEE SENSORS JOURNAL, VOL. 11, NO. 2, FEBRUARY 2011

Fig. 3. Schematic graph of flip-chip distributed MEMS transmission line biosensor [54].

Due to the fact that a mechanical chaotic system has veryhigh sensitivity to small parametric variations, research [37] hasbeen conducted on developing a nonlinear feedback excitationto force a piezoelectric cantilever into chaotic motions. Non-linear vibration of a piezoelectrically driven microcantileverbeam has been studied by Mahmoodi et al. [38]. The resultsshowed that in the governing motion equation, the nonlinearityis introduced by the quadratic form due to the response of thepiezoelectric layer and cubic form due to geometry of the beam.In [39], the nonlinear equations of motion of a non-homogenousnonlinear microcantilever beam have been derived. It was alsomentioned that in microscale structures, a very small change inthe amplitude of excitation could result in significant change invibration amplitude and frequency.

Static displacement of microcantilevers has also been utilisedto be a sensing mechanism. Tuantranonot et al. [40] developeda bimorph microcantilever using PolyMUMPs that bends downwhen the top metal layer absorbs some biological materials.The bending can be detected by extracting resistance changeof piezoresistors that are embedded in the cantilever. Glucosesensor has been developed based on microcantilevers, where theprinciple is extracting the static deformation of the cantileverinduced by the different thermal expansions of top gold layerand bottom silicon layer. The temperature rising of the goldlayer is caused by the chemical reactions between the pre-coatedenzyme layer and the glucose biosample [41]. Microcantileverbiosensors can also be used in the liquid environment. Kwon etal. [42] reported the in situ real time monitoring of a specificprotein antigen-antibody interaction by using a resonating mi-crocantilever dipped in a fluid where the resonator still exhibitsrelatively high .

IV. DIELECTRIC SPECTROSCOPIC BIOSENSORS

Dielectric sensors play an important role in many industrialareas such as biological, agriculture, and food industries as

this technology is noninvasive compared with optical andchemical sensing mechanisms. It usually detects changes ofhumidity, temperature, and concentration of aqueous solutionsby measuring changes of impedance. Many radio frequency(RF) and microwave devices or circuits have been used forsensor application in the past. The detection of the permittivityof aqueous solutions at 10 GHz was achieved with a microwaveresonator composed of sapphire cylinder and a quartz plate[43]. A microwave dielectric measurement kit composed of acoaxial reflectometric sensor terminated by a metallic cylin-drical cell to contain the liquid has been developed to detect thecomplex permittivity of the liquids under extreme conditions[44]. Using periodic structures to enhance the sensitivity ofmicrowave planar sensors is an approach that has been theo-retically proposed previously with an electromagnetic bandgap(EBG) structure [45], where the basic principle is to reducethe wave group velocity to induce greater interaction betweenthe sensor and the material under test (MUT). A microwaveresonator based on a coplanar waveguide (CPW)-to-slotlineresonator ring has been reported to form a humidity sensor [46].The concept of using CPW lines as dielectric sensors has beenpresented in [47]. A microwave biosensor for detecting theconcentration of aqueous glucose solutions has been developedbased on a cylindrical air gap coupled to a microstrip line atresonant frequency of 1.68 GHz [48]. A gas sensor has beenreported based on a micromachined membrane supported CPWstructure filled with a mixture of carbon nanotube [49]. Basedon CPW structures, a Goubau transmission line for biosensinghas been reported in [50]. Microwave CPW structures havealso been used as biosensors in the frequency range between40 Hz to 26.5 GHz in [51]. A particle sensing and cell countingsystem has been developed based on micromachined CPWstructures in [52]. A comprehensive review on the microwavedielectric measurements on polar liquids has been reportedpreviously [53]. Distributed capacitor loaded transmission lines

LI: RECENT DEVELOPMENT OF MICROMACHINED BIOSENSORS 309

Fig. 4. Schematic graph of DMTL biosensor based on thick metal MEMSprocess [55].

Fig. 5. Scanning electron micrograph of the DMTL structure mad by thickmetal process [55].

are important types of structures that are generally used in mi-crowave circuits and systems. It was the first time that this typeof structures has been utilized in biosensing application due toits intrinsic properties of slow wave structure, which potentiallyallows extensive interaction between biosamples and electro-magnetic waves propagating through the transmission lines[54]. Flip-chip micromachining has been used to realize thedistributed MEMS transmission line (DMTL) biosensor, whichis schematically shown in Fig. 3. The structure is composedof a coplanar waveguide fabricated on an alumina substrateand a silicon bridge structure fabricated by silicon-on-insulatortechnology. The device was subsequently measured using avector network analyzer together with a probe station. Theresults showed that this device can detect the concentration ofNaCl solution from 0 M to 0.3 M. Another prototype of DMTLbiosensor has been designed and realized using thick metalsilicon foundry process together with macro machined acrylicfluidic channel, which is schematically shown in Fig. 4 [55].The device has been characterized and it was shown in theresults that the device can sense the concentration of glucoseaqueous solution by observing the frequency varies of resonantpeaks. The SEM micrograph of the MEMS transmission line isshown in Fig. 5 and one of the measurement results is shownin Fig. 6, which shows that the resonant frequency increasedfrom 0% to 3.5% when the concentration of glucose solutionchanged from 0 mg/ml to 350 mg/ml. More recently this type

Fig. 6. Measurement result of the DMTL biosensor [55].

of structure has been used to distinguish different substances(organic and inorganic) in the mixed aqueous solution [56].

V. CONCLUSION REMARKS

Biosensors constructed by different sensing principles in-cluding electrochemical, microcantilever based, dielectricspectroscopic have been widely investigated by internationalresearchers in recent ten years. A review of above sensingtechnologies are presented in this paper for the purpose ofproviding guidance to biosensor designers. In conclusion, theoutput signals of electrochemical biosensors can be readily readout as they are either electrical currents or voltages. Howevermost of electrochemical biosensors need special materialscoated on the electrodes to generate electrochemical reactions.Microcantilever biosensors are simple to fabricate, and it is alabel free detecting technique, but the readout of the mechanicaldisplacement of the cantilevers requires sophisticated opticalor electronic mechanisms. Microcantilever biosensors workingin a liquid environment also requires further investigations.Dielectric spectroscopic biosensing is a perfect noninvasivesensing technique, however due to its operating principle,multifunctional sensors are very difficult to achieve.

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Lijie Li (M05) received the Ph.D. degree in design, modelling, and charac-terization of microactuators and optical MEMS devices from the University ofStrathclyde, Glasgow, U.K., in 2004.

From 2006 to August 2007, he was a Senior MEMS Design Engineer at theInstitute of System Level Integration, UK. From 2008 to 2010, he was a Lec-turer at the Department of Electronic and Electrical Engineering, University ofStrathclyde. He is now a Senior Lecturer leading the MEMS group at the Mul-tidisciplinary Nanotechnology Centre, in the School of Engineering, SwanseaUniversity, U.K. He is author and coauthor of over 60 scientific papers andone U.K. patent in the field of MEMS. His current research interests are inmicrosensors and actuators, optical microsystems, radio frequency microsys-tems, BioMEMS, power MEMS, CMOS IC design and characterisation, andintegrated microsystems.

Dr. Li is a member of the Technical Committee in MEMS in the IEEE Indus-trial Electronics Society, and an editorial board member of Nano-Micro Letters.