Cantilever Sensors: Nanomechanical Tools for Diagnostics

MRS BULLETIN • VOLUME 34 • JUNE 2009 • www.mrs.org/bulletin 449

AbstractCantilever sensors have attracted considerable attention over the last decade

because of their potential as a highly sensitive sensor platform for high throughput andmultiplexed detection of proteins and nucleic acids. A micromachined cantilever platformintegrates nanoscale science and microfabrication technology for the label-free detec-tion of biological molecules, allowing miniaturization. Molecular adsorption, whenrestricted to a single side of a deformable cantilever beam, results in measurable bend-ing of the cantilever. This nanoscale deflection is caused by a variation in the cantileversurface stress due to biomolecular interactions and can be measured by optical or elec-trical means, thereby reporting on the presence of biomolecules. Biological specificity indetection is typically achieved by immobilizing selective receptors or probe moleculeson one side of the cantilever using surface functionalization processes. When targetmolecules are injected into the fluid bathing the cantilever, the cantilever bends as afunction of the number of molecules bound to the probe molecules on its surface. Mass-produced, miniature silicon and silicon nitride microcantilever arrays offer a clear path tothe development of miniature sensors with unprecedented sensitivity for biodetectionapplications, such as toxin detection, DNA hybridization, and selective detection ofpathogens through immunological techniques. This article discusses applications ofcantilever sensors in cancer diagnosis.

Cantilever Sensors:NanomechanicalTools forDiagnostics

Ram Datar, Seonghwan Kim, Sangmin Jeon,Peter Hesketh, Scott Manalis, Anja Boisen,

and Thomas Thundat

very attractive. Biosensing technologiesbased on cantilever arrays have thepotential of satisfying this need for multi-target detection with high sensitivity andselectivity using very small volumes ofsample.

Microcantilevers are micromechanicalbeams that are anchored at one end, suchas diving spring boards, that can be read-ily fabricated on silicon wafers and othermaterials. Their typical dimensions areapproximately 100 microns long, 20microns wide, and 1 micron thick. Themicrocantilever sensors are physical sen-sors that respond to surface stress changesdue to chemical or biological processes.1When fabricated with very small forceconstants, they can measure forces andstresses with extremely high sensitivity.The very small force constant (less than 0.1N/m) of a cantilever allows detection ofsurface stress variation due to the adsorp-tion (or specific surface-receptor interac-tion) of molecules. Adsorption ofmolecules on one of the surfaces of thetypically bimaterial cantilevers (silicon orsilicon nitride cantilevers with a thin goldlayer on one side) results in a differentialsurface stress due to adsorption-inducedforces, which manifests as a deflection. Inaddition to cantilever bending, the reso-nance frequency of the cantilever can varydue to mass loading. These two signals,adsorption-induced cantilever bendingwhen adsorption is confined to one side ofthe cantilever and adsorption-induced fre-quency change due to mass loading, canbe monitored simultaneously.2

Mass Detection Using Variation inResonance Frequency

As described earlier, the resonance fre-quency, f, of a cantilever varies sensitivelyas a function of mass loading (∆m),according to:

(1)

The spring constant of the cantilever isk, m* is the effective mass of the can-tilever, and α is a numerical constant.Increasing the surface area of a cantileverby nanopatterning can lead to higheradsorbed mass and higher sensitivity ofdetection. Lee et al. has demonstrated acantilever with nanofabricated holes forincreasing the adsorbed mass.3 Althoughmass detection using the cantilever reso-nance frequency is well suited for measur-ing mass in vacuum and air, its massresolution is very poor when operatedunder solution.4 Resonance frequencyvariations, therefore, are generally notused for the highly sensitive detection of

1 .2π * α∆

km m

f =+Introduction

The detection of multiple target mole-cules in a small volume of sample hasimmediate relevance in the early detec-tion of diseases, such as cancer. It is wellknown that many cancers can be cura-tively treated if diagnosed early when thetumors are still small and localized.However, the unfortunate reality is that asignificant proportion of cancers are diag-nosed only after the tumors have spreaddistally through blood or lymphatic fluid(metastasized) to multiple locations. Sincecancer is a complex disease, its diagnosiswill require monitoring for alterations inmultiple parameters at molecular, cellu-lar, and tissue levels to provide a compre-hensive picture of the extent of the

disease process. Detection of a single bio-marker has only limited specificity andtherefore cannot be sufficiently informa-tive. Hence, cancer diagnostics have beenshifting from traditional monitoring ofsingle biomarkers to the detection of mul-tiple markers. Detection of multiple bio-markers is particularly important inscreening for cancers of low prevalence,such as ovarian cancer. Ideally, thesemeasurements would be done in a singlereadout with samples that are readilyavailable and minimally invasive, such asblood serum. Therefore, a technique thatcan detect multiple biomarkers simulta-neously using a single sensor platformand minimal sample volume would be

adsorbed mass in liquid environments.Detecting surface stress variations istherefore a method of choice when bio-markers have to be detected in body flu-ids, such as serum. However, Burg et al.recently demonstrated a hollow cantileverconcept called the suspended microchan-nel resonator (SMR) that is capable ofdetecting biological interactions in liquidswith unprecedented sensitivity.5 (See thesection on Suspended MicrochannelResonators later in this article.)

Mechanics of Cantilever Deflection

Adsorption of molecules on a surfaceresults in a decrease in surface free energy.If the adsorption of molecules on a surfaceis restricted mostly to one side, for exam-ple, by making the opposite surface inert,a differential surface stress is generatedbetween the two surfaces of a cantileverbeam. Surface stress, g, and surface freeenergy, γ, can be related using theShuttleworth equation:

(2)

where the surface stress, epsilon, is definedas the ratio of the change in surface area tothe total area. Since the bending of thecantilever is very small compared to thelength of the cantilever, the strain contri-bution is often neglected. However, this isa subject under active discussion in the lit-erature.6–8

The differential surface stress created bymolecular adsorption results in cantileverbending. Stoney’s equation relates the dif-ference in surface stress ∆g between thechemically modified surface and theuntreated surface with the cantileverdeflection, ∆h:

(3)

where, ν is the Poisson’s ratio of the mate-rial, E is Young’s (elastic) modulus of thecantilever material, and t and L are thethickness and the length of the cantilever,respectively. The surface stress also can bethought of as a change in surface energydensity or a change in surface tension. It isclear that the longer the cantilever, themore sensitive the cantilever to measuresurface stresses.

Modalities of Cantilever Deflection-Based Sensing

The motion of the cantilever responsecan be sensitively monitored using a vari-ety of techniques, such as variations inoptical beam deflection,9 piezoresistivity,10

∆g = t 2

LE∆h

4(1–n),

g = g + ,dgde

piezoelectricity,11,12 embedded MOSFET(metal oxide semiconductor field-effecttransistor),13 capacitance,14 and electrontunneling.15 In optical beam deflection, thecantilever motion is detected by reflectinga focused beam of light from the tip of acantilever beam into a position-sensitivedetector. In the piezoresistive technique,the resistance of an asymmetrically dopedcantilever varies sensitively as a functionof bending. The piezoelectric techniqueinvolves coating the cantilevers withpiezoelectric materials, which develop ameasurable charge due to cantilever bending. In the embedded MOSFET read-out method, a field-effect transistor isembedded at the base of the cantilever.The stress from the bending of the can-tilever changes the carrier mobility anddrain current. In the capacitance method,the capacitance between a bending can-tilever and a fixed substrate varies as afunction of cantilever bending. The elec-tron tunneling method is extremely sensi-tive, and it is based on the tunneling ofelectrons between a cantilever and a fixedelectrode.16

Piezoresistive Cantilever ArrayFabrication

Piezoresistive materials, such as dopedsilicon, show piezoresistivity where theresistance of the material varies as a func-tion of applied stress. A multilayer can-

tilever beam has been developed where thedoped silicon layer is only on one side ofthe neutral axis of the cantilever beam andshows variation in its resistance as a func-tion of the extent of the deflection.17 Thesecantilevers are composed of several layersof materials at different regions where sin-gle crystal silicon serves as an active func-tional element. The active silicon region issandwiched between silicon nitride andsilicon dioxide layers for insulation andprotection, Figure 1a. These piezoresistivecantilevers are fabricated using predopedsilicon with insulating layers of siliconnitride on both sides. The thickness of theinsulating layers (silicon nitride and siliconoxide) is adjusted in such a way that theneutral axis of the bending cantilever isoutside of the doped silicon. The can-tilevers fabricated using this method havea higher signal-to-noise ratio, less can-tilever drift, and increased sensitivity, ascompared to piezoresistive cantilevers fab-ricated, where the neutral axis lies atthe boundary between the doped andundoped regions of the silicon. Since thesilicon nitride/silicon oxide layer is insulat-ing, these piezoresistive cantilevers can beused in liquid environments.

For the cantilevers fabricated, there aretwo parallel silicon stripes (20 µm wide)in each cantilever (see Figure 1). Twogold/titanium metal leads connect siliconstripes at their base and end at the contact

Cantilever Sensors: Nanomechanical Tools for Diagnostics

450 MRS BULLETIN • VOLUME 34 • JUNE 2009 • www.mrs.org/bulletin

Si3N4

Si3N4

SiO2

Si

Sensing Layer

L

LR

hw

a

b

c

Figure 1. (a) Schematic diagram of a microcantilever indicating dimensions length, L,resistor length, LR, width, w, and thickness, h. (b) An array of piezoresistive cantilevers. (c) Cross-sectional diagram through the layers of the microcantilever sensors.

pads at the edge of the chip. To completethe circuit, the silicon stripes are electri-cally shorted by a layer of gold at the freeend. The resistivity of the silicon wasdesigned at 3.4 × 10−3 Ω cm. The dopingconcentration was 2.2 × 1019 cm−3. The can-tilever bending due to residual stresses inthe buried oxide layer can be eliminatedby depositing silicon nitride film on theback of the beam to create tensilestresses.18 The typical resistance of apiezoresistive cantilever is around a fewkilo-ohms (1 and 5 kΩ depending uponthe length).

The cantilever is shown in Figure 2. Forpiezoresistive cantilevers, higher sensitiv-ity can be obtained when thickness of thecantilever is reduced.18 The piezoresistivecoefficient of silicon is a function of thedoping level and dopant type. Unlike atip-loaded piezoresitive atomic forcemicroscope cantilever, where p-typedopant is standard, with microcantileversensors, a higher gauge factor (normal-ized change in resistance per unit stress) isachieved with n-type dopant.18

Suspended MicrochannelResonators

As mentioned earlier, SMRs are can-tilevers with microchannels fabricatedinside the cantilever. Figure 3 shows ascanning electron micrograph of a SMR.Although the SMR cantilever is placedinside a vacuum for obtaining a high-quality factor (Q is defined as a ratio ofresonance frequency and the full width athalf maximum of the resonance ampli-tude) of resonance, liquid analytes can bepumped through the cantilever. Thisallows measuring masses of liquid andsuspended biomaterials such as cells andcancer markers. At present, the SMR isfabricated in such a way that the hollowcantilever is vacuum sealed inside achamber with an optical window for opti-cal beam-based cantilever motion detec-tion. Since the liquid is inside thecantilever, which is vibrating in a vacuum,a Q factor of 15,000 can be achieved forthis device. High Q values enable mass tobe measured with femtogram resolutionin a 1 Hz bandwidth.5 The ability to circu-late liquid through the cantilever allowsfor the monitoring of biological interac-tions between immobilized receptorsinside the hollow cantilever and passinganalytes. For example, changes in reso-nance frequency induced by the adsorp-tion of cancer marker molecules andimmobilized receptors can be used as aselective and sensitive method for moni-toring the presence of cancer markers inthe passing sample. Additionally, singlecells can be weighed as they pass through

gold film. Organosilane coatings also areof the order of a monolayer but canbecome multilayered upon extendedexposure to the solution. Regardless of the



a

b

x25026–Jun–05

26–Jun–05 x25 2 mm

200 um

Figure 2. (a) Piezoresistive microcantilever and (b) 10-cantilever array. Resonant frequency~20 kHz, spring constant ~0.003 N/m. (Image courtesy of P. Heskth, Georgia Institute ofTechnology.)

Figure 3. A scanning electronmicrograph of a suspended channelmicroresonator. The channels can beseen inside the cantilever. The hollowcantilever vibrates inside a vacuum.(Image courtesy of S. Manalis,Massachusetts Institute of Technology.)

the suspended microchannel. Variousmethods for trapping an individual cellwithin the SMR so that the cell mass canbe monitored as a function of time are currently under development. Such meth-ods may be used to investigate how cellgrowth relates to progression through thedivision cycle and if the response of cancercells to pathway-directed therapeutics canbe classified according to subtle changesin growth.

Receptor ImmobilizationMany approaches can be used to immo-

bilize the molecular recognition agents tothe microcantilever sensor, dependingupon the final application. Generally, can-tilevers are coated on one side with 2–3nm of chromium then with 25–30 nmof gold using an e-beam evaporator.Chromium acts as an adhesion layer forthe gold. Both the silicon side of the can-tilever (using silane chemistry) and thegold side of the cantilever (using thiolchemistry) have been utilized dependingon the final application for the molecularrecognition assay. For thiol self-assembledmonolayers (SAMs) and organosilanemodification, dip coating is the preferredmethod for functionalization to allow forhigh density immobilization on the can-tilever surface; all reactive surfaces of thecantilever and substrate that are exposedto the modifying solution(s) will have acoating. Thiol SAMs are self-limited tocoverages of a monolayer of the thiol on a

coating chemistry employed, typically allexperimental surfaces are freshly pre-pared no more than 48 hours prior toassay. Stability studies to determine theeffects of aging on the prepared surfacesremain to be done.

Biomolecular Detection AssaysAntigen-antibody interactions are a

class of highly specific protein-proteinbinding that play a critical role in molecu-lar biology. Since cantilever bending origi-nates from the free energy change inducedby specific biomolecular binding, this bio-molecular detection assay offers a com-mon platform for high-throughput,multiplexed label-free analysis of biomol-ecules, such as protein-protein binding,DNA hybridization, and DNA-proteininteractions.19–27 When antibody mole-cules are immobilized on one surface of acantilever, specific binding between anti-bodies and antigens produces cantileverdeflection. Similarly, the cantilever under-goes bending when single-stranded DNA(ssDNA) probes are immobilized on thecantilever hybridized with complemen-tary ssDNA (target) molecules in the solu-tion. Such specific deflection was not seenwhen the incoming DNA strands werenoncomplementary due to the absence ofhybridization. Therefore, it is possible todesign ssDNA probes specifically todetect mutations in the DNA sequence oftarget DNA responsible for many cancers.The following section briefly describesdevelopment of this assay.

Detection of Specific DNASequences

Several groups have shown can -tilever deflections due to adsorption ofssDNA on virgin cantilevers as wellas hybridization of complementarysequences.19,20,22,23,27 ssDNA can be immo-bilized on one side of a cantilever by coat-ing that side with gold and using a thiollinker at one end of ssDNA. It has beenexperimentally found that adsorption ofssDNA on a cantilever results in a surfacestress variation of 30–50 mN/m. Note thatthe surface stress variation is directlyinduced by the adsorption of sulfur atomson the thiol chain on the gold substrate.The ssDNA bound to the cantilever acts asa probe (or receptor) molecule for the tar-get complementary strands. The additionof noncomplementary ssDNA into thesolution with immobilized ssDNA probesproduces no mechanical signals. The can-tilever bending signal also can be used fordetecting mutations in the DNA sequence(single nucleotide polymorphism [SNP]),where a single nucleotide of noncomple-mentary nature appears in the sequence.20

PSA. PSA is a serine protease secreted byprostatic luminal epithelial cells. Whenused in population screening for thedetection of elevated serum, PSA is cred-ited with dramatic advances in the earlydiagnosis and management of men withprostatic carcinoma. The majority of therecently marketed assays are based on thecommonly used reference range (<4 ng ofPSA in a ml of blood), and almost all ofthem employ some variation of the tech-nique of enzyme-linked immunosorbentassay (ELISA).

Figure 5 shows the potential of micro-cantilevers as a platform for developing asensitive and specific assay for PSA usingthe optical beam deflection method forcantilever bending. The cantilevers wereimmobilized with polyclonal anti-PSAantibodies. Binding of PSA on the immo-bilized polyclonal antibody resulted in adeflection of the cantilever. Furthermore,changes in surface stress were relatedquantitatively to the concentration of PSA.Results in Figure 5 are from a model sol-vent system prepared with phosphate-buffered saline and shows steady-statecantilever deflection as a function of PSAconcentration against a much higher back-ground of bovine serum albumin. Similartests were performed against high back-grounds of human serum albumin andhuman plasminogen, both of which arefound abundantly in human sera. Of notewas the finding that PSA concentrationscan be detected below 4 ng/ml, the clini-cal threshold for prostate cancer. In fact,concentrations down to 0.2 ng/ml weredetected. Since for the same PSA concen-trations cantilever deflections varied withtheir geometry, it is important to stan -dardize these measurements in terms of surface stress rather than cantileverdeflections using Stoney’s formula. Thetechnique is simpler and potentially morecost-effective than ELISA, the current“gold standard” assay for PSA detection,because it does not require labeling andcan be performed in a single reactionwithout additional reagents.

Challenges of Cantilever-BasedDetection

Despite the unprecedented sensitivitydemonstrated using microcantilever sen-sors, the selectivity performance androbustness are not consistent, and the fullpotential remains to be developed and val-idated. There are a number of challenges toovercome before cantilever sensors comeinto widespread use. It is possible toachieve higher selectivity, sensitivity, androbustness through optimization of can-tilever geometries, immobilization tech-niques, and analyte delivery schemes.



0 500 1000 1500–60

–30

0

30

60

Str

ess

(mN

/m)

Time (sec)

Figure 4. A plot of the surface stressvariations of a piezoresistive cantileveras a function of time due to the immo -bilization (red) and hybridization withcomplementary ssDNA (blue). The im -mo bilization and hybridization responsecurves are superimposed to show theresponse direction. Inset schematicsshow configurations of ssDNA (below)and double stranded DNA (above).22

Figure 4 shows the surface stress variationof a piezoresistive cantilever as a functiontime due to ssDNA (thiol link) immobiliza-tion and subsequent hybridization withcomplementary ssDNA. The specific bind-ing between the complementary DNAstrands on the cantilever results in a sur-face stress variation of 30–40 mN/m. Wuet al. investigated the origins of cantileverdeflection due to biomolecular interactionsand found that the deflection resulted froma change in free energy of one cantileversurface.22 The interplay between the ener-getic and entropic contributions deter-mined the direction of cantilever motion.

Although both DNA hybridization andprotein-protein (antigen-antibody) bind-ing can be detected using cantileverdeflections, what remained unclear for awhile was whether this technique had suf-ficient specificity and sensitivity to beused for the detection of disease-relatedproteins at clinically relevant conditionsand concentrations. To address this tech-nologically critical issue, sensitive andspecific detection of a prostate cancermarker, prostate specific antigen (PSA),was conducted as an example of both protein-protein binding in general and ofa cancer diagnostic tumor marker detec-tion in particular.21 Prostate cancer hasemerged as the most common nonskincancer and the second leading cause ofcancer death in men in North America andEurope (www.cancer.gov). While transrec-tal ultrasonography and digital rectalexamination are common clinical exami-nations, the most widely used biochemicaltest involves analyzing the presence of

molecules, many of them at much higherconcentrations than the target analyte,there is a likelihood of false positives dueto binding of the immobililzed antibodyto a nontarget molecule that has a similarstructural motif. The number of false pos-itives may increase further if polyclonalantibodies are used for capture. Anotherpotential limitation for an optical readoutsensor is the turbidity of serum.

Some of the ways to alleviate theseproblems include use of capturereagents with significantly higher speci-ficity (such as single chain antibodies oraptamers), allowance for multiple washsteps similar to an ELISA procedure, orpreconcentrating the serum for the tar-get analyte by reducing the concentra-tion of the abundant nontarget proteinsin serum. The latter, for example, can beachieved by affinity chromatography toremove as many as 12 abundant proteinspecies such as serum albumin, actin, orimmunoglobulins.

One of the challenges in translating can-tilevers as practical sensors for biologicalapplications is the sensor reproducibility.Since selectivity is achieved by coating thecantilever with selective receptor coatingssuch as antibodies, peptides, DNA, orenzymes, the specificity of the receptor-target interaction controls the selectivityand sensitivity. The cantilever responsealso depends on the uniformity of thecoating on the cantilever surface. Often,coverage of surface immobilized receptormolecules can vary from cantilever to can-tilever due to contamination, resulting inirreproducible responses. Consequently,more work is urgently needed to developmore reliable immobilization techniques

As mentioned earlier, the cantileverscan be fabricated in such a way as toincrease their detection sensitivity. Forsensing methods based on adsorption-induced cantilever deflection, longer andthinner cantilevers with small force con-stants show higher sensitivity. However,as in the case of all surface adsorption-based sensors, larger area cantileversshow faster detection time for low concen-trations of target molecules. Therefore, theoptimal cantilever dimension will dependon the dimension of the cantilever cham-ber and the analyte delivery system. Sincemost measurements are carried out usinga reference cantilever, the common moderejection (differential measurement withrespect to a reference cantilever) basicallyimproves sensitivity. New designs ofpiezoresistive cantilevers show less driftand improved signal-to-noise ratios.28

Godin et al. demonstrated that the bend-ing of a cantilever beam strongly dependson the surface roughness of the goldfilm.29 Vacuum-deposited gold films withlarger grain sizes on the cantilever showincreased bending sensitivity. The sensi-tivity of bending also depends on the uni-formity of the immobilization layer andcleanliness of the sensing surface.30

Selectivity of detection in complex sam-ples still remains to be solved. It must benoted here that while PSA detection,described previously, yielded a clinicallyrelevant level of sensitivity when tested ina model protein-containing buffer solu-tion system, its sensitivity was muchlower in actual human serum. Thisdecreased sensitivity may be a result ofone or more of the following factors. Sinceserum contains thousands of various bio-

for microcantilevers, which are a universalplatform to base electromechanical sen-sors for selective and sensitive detection ofcancer markers.

Future Trends and SummaryThe trend in miniaturization of sensor

arrays for multiplexed detection couplesvery well with the versatility of cantileverarrays. Currently available microfabrica-tion technologies could be used to makemultitarget sensor arrays involving multiple cantilevers, electronic process-ing, and even local telemetry on a singlechip. The technology for designing and simulating electronic chips is welladvanced. Integration of electronic,mechanical, and fluidic designs, however,is still in its infancy. Additional receptorsand immobilization methods will need tobe developed and added to the libraries.These could include improvements suchas the application of aptamers or molecu-lar imprinting polymers as surface-boundcapture receptors. The stability of immo-bilized receptors is an issue that poten-tially limits shelf life and long-termreliability of the sensors and will need tobe addressed. Here, the advances couldcome in the form of regenerating re -ceptors. Using multiple cantilevers forsingle target detection will lower noise,greatly increase selectivity, and increase robustness.

Cantilever arrays have the potential ofsatisfying the need for multitarget detec-tion necessary in cancer diagnostics withhigh sensitivity and selectivity using verysmall volumes of sample and not requir-ing repeated body fluid sampling.Because cantilever sensors report on theexistence of biomarkers in a label-freemanner, they can be employed in a rela-tively inexpensive assay format, requiringfewer manipulative steps compared to thecurrently available diagnostic platformssuch as ELISA assays for proteins ormicroarrays for nucleic acids. Also, sincethe turnaround times for assays can beshortened due to multiplexing, substan-tial savings are possible in diagnosticworkup schedules. Ultimately, all of theseadvantages, including early detection,will have significant implications inreducing the assay costs and hence coststo the patient and healthcare providers.

AcknowledgmentsWe would like to thank our colleagues

and collaborators cited in this review fortheir contributions. R. Datar, S. Kim, andT. Thundat would like to thank DOE BERfor its support. Oak Ridge NationalLaboratory is managed by UT-Battelleunder contract No. DE-AC05-000R227255.



Figure 5. Steady state cantilever deflection (measured using optical beam deflection) as afunction of the concentration of free prostate specific antigen (fPSA) in the solution. Theresponses from five different concentrations are shown. BSA, bovine serum albumin.Please note the width of the cantilever is 20 µm.

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Cantilever Sensors: Nanomechanical Tools for Diagnostics