A Review of Micro Cantilevers for Sensing Applications(1)

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A Review of Microcantilevers for Sensing Applications


Sandeep Kumar VashistCopyright AZoM.com Pty Ltd.This is an AZo Open Access Rewards System (AZo-OARS) article distributed under the terms of the AZo–OARShttp://www.azonano.com/oars.asp which permits unrestricted use provided the original work is properly cited but islimited to non-commercial distribution and reproduction.

Submitted: May 22nd, 2007Posted: June 18th, 2007

DOI: 10.2240/azojono0115

Topics Covered

AbstractKeywordsIntroductionMass Sensitive Detection by MicrocantileversMicrocantilever Deflection Detection Methods

The Piezoresistive Deflection Detection MethodThe Optical Deflection Detection MethodThe Capacitive Deflection Detection MethodThe Interferometry Deflection Detection MethodThe Optical Diffraction Grating Deflection Detection MethodThe Charge Coupled Device (CCD) Detection Method

Mechanical Properties of CantileverBending Behavior of Cantilever BeamsMicrocantilever Sensors

Materials Used in Commercial CantileversCantilevers Use in Non-Contact ModesAdvantages of Microcantilever-Based Sensors

Types of Sensors Based on Micro and NanocantileversSensing Applications of Microcantilevers in Physics and ChemistryHumidity SensorsHerbicide SensorsMetal Ion SensorsTemperature Sensors / Heat SensorsViscosity SensorsCalorimetry SensorsSensor Detecting Magnetic Beads

Cantilever Based Telemetry SensorsMicrosensors to Monitor Missile Storage and Maintenance NeedsRemote Infrared Radiation Detection SensorsExplosives Detection Devices

Sensing Applications of Microcantilevers in the Field of Disease DiagnosisCancer Detecting MicrochipsMyoglobin Detection SensorsBiosensor for Coronary Heart DiseaseCantilever Based Sensors to Detect Single-Nucleotide PolymorphismsBiochips

Nanocantilevers: A Major Breakthrough in SensorsConclusions

ReferencesContact Details

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Sandeep Kumar Vashist

Abstract

Microelectromechanical Systems (MEMS) [1,2] have come into existence only in the lastdecade. Microcantilevers are the most simplified MEMS based devices. Diverse applications of microcantilevers in the field of sensors have been explored by many researchers. Severalgroups have also shown the possibility of using microcantilevers for the diagnosis of prostatecancer [3], myocardial infarction [4] and glucose monitoring [5]. Scientists are chasing thevision of making miniaturized biochips based on an array of microcantilevers, which can detectseveral routinely diagnosed diseases simultaneously in the clinical laboratory. Recently thedevelopment of nanocantilevers have scaled down the technology further with the capability of ultra sensitive detection of analytes combined with high throughput.

Keywords

Microcantilevers, sensors, diagnostics, MEMS

Introduction

Molecular diagnostic devices are getting smaller with the advancement of miniaturizationtechnologies. There is increasing interest in the field of biosensor research on miniaturizedplatforms. Miniaturization is essential for in vivo physiological monitoring, multiple specificitysensor arrays, sensor portability and minimized sample volumes. Conventional biosensorsneed extensive packaging, complex electronic interfacing and regular maintenance. Thesedrawbacks could be reduced by the use of MEMS devices that integrate electronics andmicromechanical structures on chips.

Microcantilevers have been employed for physical, chemical and biological sensing. They havealso have wide applications in the field of medicine, specifically for the screening of diseases,detection of point mutations, blood glucose monitoring and detection of chemical and biologicalwarfare agents. These sensors have several advantages over the conventional analyticaltechniques in terms of high sensitivity, low cost, simple procedure, low analyte requirement (inµl), non-hazardous procedures and quick response. Moreover, the technology has been

developed in the last few years for the fabrication and use of nanocantilevers for sensingapplications, thereby giving rise to nanoelectromechanical systems (NEMS). This developmenthas increased the sensitivity limit up to the extent that researchers can now visualize thecounting of molecules. With the ability of high throughput analysis of analytes and ultrasensitive detection, this technology holds tremendous promise for the next generation of miniaturized and highly sensitive sensors.

Mass Sensitive Detection by Microcantilevers

A microcantilever is a device that can act as a physical, chemical or biological sensor bydetecting changes in cantilever bending or vibrational frequency. It is the miniaturizedcounterpart of a diving board that moves up and down at a regular interval. This movementchanges when a specific mass of analyte is specifically adsorbed on its surface similar to the

change when a person steps onto the diving board. But microcantilevers are a million timessmaller than the diving board having dimensions in microns and different shapes as shown infigure 1.

Figure 1. Different types of microcantilevers (top view) (a) Rectangular (b) Double-legged (c)Triangular.

Molecules adsorbed on a microcantilever cause vibrational frequency changes and deflection of the microcantilever. Viscosity, density, and flow rate can be measured by detecting changes inthe vibrational frequency.





Another way of detecting molecular adsorption is by measuring deflection of the cantilever dueto adsorption stress on just one side of the cantilever. Depending on the nature of chemicalbonding of the molecule, the deflection can be up or down. Biochips with mechanical detectionsystems commonly use microcantilever bi-material (e.g. Au–Si) beams as sensing elements.The Au side is usually coated with a certain receptor. Upon the binding of the analyte (e.g.biological molecules, such as proteins or biological agents) with the receptor, the receptorsurface is either tensioned or relieved. This causes the microcantilever to deflect, usually in

nanometers, which can be measured using optical techniques. The deflection is proportional tothe analyte concentration. The concept has been employed in screening certain diseases suchas cancer and detecting specific chemical and biological warfare agents.

Microcantilever Deflection Detection Methods

The Piezoresistive Deflection Detection Method

The piezoresistive method [6-8] involves the embedding of a piezoresistive material near thetop surface of the cantilever to record the stress change occurring at the surface of thecantilever. As the microcantilever deflects, it undergoes a stress change that will apply strainto the piezoresistor, thereby causing a change in resistance that can be measured by electronicmeans. The advantage of the piezoresistive method is that the readout system can be

integrated on the chip. The disadvantage is that the deflection resolution for the piezoresistivereadout system is only one nanometer compared with one Angstrom by optical detectionmethod. Another disadvantage with the method is that a piezoresistor has to be embedded inthe cantilever. The fabrication of such a cantilever with a composite structure is morecomplicated.

The piezoresistor material in the beam must be localized as close to one surface of thecantilever as possible for maximum sensitivity. The type of doping being used for fabricationof the piezoresistive material is an important factor. The piezoresistive coefficient of N-typesilicon is greater than that for P-type. The resistance of a piezoresistive material changes whenstrain is applied to it. The relative change in resistance as function of applied strain can bewritten as:

t t l l

R

Rδ δ Κ Κ =

Δ

where K denotes the Gage Factor, which is a material parameter. The subscripts l and t referto the longitudinal and the transversal part of the Gage Factor.

The sensitivity of a piezoresistor varies proportionally to the thickness t and the radius of curvature. The Gage Factor is proportional to Young’s Modulus, E, which is the intrinsiccharacteristic of material. The gage factor can also be calculated directly by straining thecantilevers and measuring the resistance change.

R

RGF

Δ=δ .

where δ is the strain in the material and R is the resistance. For a sensitive device, the gagefactor should be of the order of 100.

The piezoresistive cantilever beam can be used as an arm of the Wheatstone Bridge circuit asshown in figure 2.





Figure 2. The Wheatstone Bridge Circuit used for the piezoresistive microcantilever.

The resistance of the variable resistance arm ( R R Δ+0 ) in the above figure can be determined

by using the common Voltage divider formula and is shown as below:

There would be a resistance change whenever the cantilever is subjected to a deflection.

The Optical Deflection Detection Method

The optical method [8], as shown in figure 3, employs a laser beam of very low power of theorder that does not affect the biomolecules coated on the surface of the microcantilever and aposition sensitive detector (PSD). The laser beam falls on the cantilever and gets reflected asthe gold layer coated on the surface of the cantilever gives it an almost mirror like finish. Thereflected beam falls on the PSD. When the cantilever is undeflected i.e. it is not coated withany molecule, the laser beam would fall on a particular spot on the PSD. As the cantileverdeflects, the position of the beam changes, which, in turn, is calculated using appropriateelectronics. The advantage of this detection system is that it is capable of detecting deflectionin the sub-nanometer range. But this method also has its own disadvantages. The presence of a focused laser beam in a liquid cell environment can result in additional thermal managementissues giving rise to extraneous readings. Secondly, the alignment system is expensive andinvolves great precision, which can ultimately raise the cost of the whole diagnostic kit. Inaddition, it also reduces the kit’s portability.

Figure 3. Schematic of an optical detection system for detecting microcantilever deflection.The reflected laser light from the deflected microcantilever falls at a different position on the

PSD. Depending on the distance between the two positions of the laser beam on the PSD, thedeflection of the microcantilever is determined.





The Capacitive Deflection Detection Method

The capacitive method [9] is based on the principle that when the cantilever deflection takesplace due to the adsorption of the analyte, the capacitance of a plane capacitor is changed.Here the microcantilever is one of the two capacitor plates. This deflection technique is highlysensitive and provides absolute displacement. But this technique is not suitable for measuringlarge displacements. Moreover, it does not work in electrolyte solutions due to the faradic

currents between the capacitive plates. Therefore, it is limited in its sensing applications.The Interferometry Deflection Detection Method

This optical detection method [10,11] is based on the interference of a reference laser beamwith the laser beam reflected by the cantilever. The cleaved end of an optical fiber is broughtclose to the cantilever surface. One part of the light is reflected at the interface between fiberand surrounding media, and the other part is reflected at the cantilever back into the fiber.These two beams interfere inside the fiber, and the interference signal can be measured with aphotodiode. Interferometry is a highly sensitive method providing a direct and absolutemeasurement of displacement. In this method, light has to be brought close to the cantileversurface to get enough reflected light. Optical fiber few microns away from the free end of themicrocantilever could measure deflection in 0.01 Å range. However, the positioning of the

fibers is a difficult task. The method works well for small displacements but is less sensitive inliquids and hence, of limited use in biosensor applications.

The Optical Diffraction Grating Deflection Detection Method

The reflected laser light from the interdigitated cantilevers forms a diffraction pattern in whichthe intensity is proportional to the cantilever deflection [12]. This can be used for atomic forcemicroscopy, infrared detection, and chemical sensing.

The Charge Coupled Device (CCD) Detection Method

A CCD camera for measuring the deflection of the cantilever in response to analyte was usedby Kim and co-workers [13]. The position sensitive detector here is the CCD camera thatrecords the laser beam deflected from the cantilever.

Mechanical Properties of Cantilevers

The basic mechanical parameters of a cantilever are the spring constant and the resonancefrequency.

The spring constant k is the proportionality factor between applied force, F and the resultingbending of the cantilever, z. This relation is called Hooke’s law.

F = -kz

The spring constant yields the stiffness of the cantilever. For a rectangular cantilever of lengthl, the spring constant can be written as

3

...3

l

I E k =

where E is the Young’s modulus and I is the moment of inertia. A typical spring constant for astress sensitive cantilever is in the range of 1 mN/m to 1 N/m.

The resonance frequency f res for a simple rectangular cantilever can be expressed as

2

3

res.

W.hE.0.162 f

l ρ =

where ρ is the mass density, h and w denotes the height and the width of the cantileverrespectively. The moment of inertia for a rectangular cantilever can be written as

3

3

l

hw. I =





A simpler expression for the resonance frequency can be written as a function of the springconstant as

m

k 0.32 f res =

where mass, m=ρ.h.l.w. The relation shows that the resonance frequency increases as a

function of increasing spring constant and of decreasing cantilever mass.The use of microcantilevers has been understood worldwide but the biomechanics [14] and theunderlying mechanism of microcantilever deflection is not yet fully established.

Bending Behaviour of Cantilever Beams

A uniform surface stress acting on an isotropic material increases (in the case of compressivestress) or decreases (in case of tensile stress) the surface area as shown in figure 4. If thisstress is not compensated at the opposite side of a thin plate or beam, the whole structure willbend. Between the areas of compressive stress and tensile stress, there is a neutral planewhich is not deformed. Due to bending, a force F is acting at a distance of x in the neutralplane results in a bending moment M=F.x. Therefore, the radius of curvature R is given by:

1/R = d2

z/dx2

= M/EIwhere E is the apparent Young’s modulus and I is the moment of inertia given by the followingequation for rectangular beams

12

3bh

I =

The change in the surface stress at one side of the beam will cause static bending, and thebending moment can be calculated as:

2

bh M

σ Δ=

Δσ = σ1 – σ2 is the differential surface stress with σ1 and σ2 as surface stress at the upper andlower side of the cantilever respectively (figure 5). Inserting these values of I and M in the firstequation yields Stoney’s formula [15]:

2Eh

)-6(1 1/R

σ υ Δ=

Figure 4. Bending of a cantilever beam in response to compressive and tensile stresses. (a)Compressive surface stress due to repulsion between the biomolecules leads to

downward/negative deflection of the cantilever beam. (b) Tensile surface stress due toattraction between molecules leads to upward/positive deflection of the cantilever beam.





Figure 5. Lateral view of a thin cantilever beam of thickness t subjected to compressivestress. σ1 is the stress at the upper surface and σ2 is the stress at the lower surface of the

cantilever. The cantilever beam bends with a constant radius of curvature R.

Taking into account the boundary conditions of a cantilever (R » L), the above equation can be

solved and the displacement of the cantilevers can be written as:

2

2

Eh

)-(13L s

σ υ Δ=

Changes in surface stress can be the result of adsorption process or electrostatic interactionsbetween charged molecules on the surface as well as changes in the surface hydrophobicityand conformational changes of the adsorbed molecules.

In addition to surface stress-induced bending, the volume expansion of bimaterial cantileverscan result in a static bending. A bimaterial cantilever undergoes bending due to gas adsorptionif the volume expansion coefficients of the two materials are different.

Microcantilever SensorsBiosensing applications demand fast, easy-to-use, cheap and highly sensitive methods fordetecting analytes along with the capability for high-throughput screening. All these points canbe fulfilled by micromachined cantilever sensors, which are therefore ideal candidates forbiosensing applications. The various applications of microcantilever based sensors aresummarized in Figure 6.





Figure 6. Applications of microcantilever-based sensors.Microcantilever based sensors [16] are the simplest MEMS devices that offer a very promisingfuture for the development of novel physical, chemical and biological sensors. They are themost recent and most advanced analyte detection systems with the detection limit far lowerthan the most advanced techniques currently employed. The adsorbed mass of the analytescauses the nanomechanical bending of the microcantilever. The change in mass on themicrocantilever surface due to the binding of the analyte molecules is directly proportional tothe deflection of the microcantilever. Thus, qualitative as well as quantitative detection of analytes can be performed.

Materials Used in Commercial Cantilevers

The commercial cantilevers are typically made of silicon, silicon nitride, or silicon oxide and areavailable in a wide variety of different shapes, dimensions, and force sensitivities. Recentdevelopments combine the latest integrated circuit (IC) and complementary metal oxidesemiconductor (CMOS) technologies to produce intelligent extremely small cantilevers in theform of an array.

Cantilevers Use in Non-Contact Modes

Recent years have witnessed a second evolutionary step in the use of cantilevers whereby theyare no longer brought into contact with a surface. They are now used in sensor systemsproviding a completely new type of miniaturized transducer based on fundamental principles of physics like the bimetallic effect, surface stress, or the harmonic oscillator.

Advantages of Microcantilever-Based Sensors

Microcantilever based sensors have enormous potential for the detection of various analytes ingaseous, vacuum and liquid medium. They have aroused considerable interest because of theirhigh specificity, high sensitivity, simplicity, low cost, low analyte requirement (in µl), non-





hazardous procedure with fewer steps, quick response and low power requirement. Substancesat trace levels are currently detected by various techniques like high performance liquidchromatography (HPLC), thin layer chromatography (TLC), gas chromatography (GC), gasliquid chromatography (GLC) etc. However, these techniques are complex, time consuming,costly and require bulky instrumentation. Also sample preparation is a prolonged complexprocedure and requires skilled personnel. But the microcantilever-based sensors can detecttrace amounts of substances in parts-per-billion (ppb) and parts-per-trillion (ppt). They

translate biomolecular recognition into nanomechanical bending of the microcantilever [17].Intermolecular forces arising from the adsorption of analyte molecules onto the microcantileverinduce surface stress, directly resulting in nanomechanical bending of the microcantilever.

Sensing Applications of Microcantilevers in Physics and Chemistry

The cantilever-based sensors have extensive applications in physics and chemistry. They canbe used to measure sound wave velocities, fluid pressures and flow rates, and can be tuned toselectively pick up acoustic vibrations. Biotoxins could be detected with sensitivity at the pptlevel by coating one side of the cantilever with monoclonal antibodies specific for the particularbiotoxin. The effects of small atmospheric-pressure changes can be felt in the resonance of thevibrating cantilever. Effects of exposure to ultraviolet radiations can be sensed by choosing theproper polymeric coating. It has been observed that silicon nitride cantilevers coated with gold

on one side are quite sensitive to pH changes. Based on this, cantilever based sensors can bemade to detect the pH change. They have also been used to detect mercury vapor, humidity,natural gas, gas mixtures, toluene and lead in water.

Types of Sensors Based on Micro and Nanocantilevers

Humidity Sensors

The humidity in the environment can be measured if one side of microcantilever is coated withgelatin [18]. Gelatin binds to the water vapors present in the atmosphere, thereby causing thebending of the cantilever. Researchers at Oak Ridge National Laboratory (ORNL), USA showedthat cantilevers coated with hygroscopic materials such as phosphoric acid can be used as asensor for detecting water vapour with picogram mass resolution [19]. When water vapors are

adsorbed on the coated surface of the cantilever, there is change in the resonance frequencyof microcantilevers and cantilever deflection. Sensitivity of microcantilevers can be increasedby coating its surface with materials having a high affinity for the analyte.

Herbicide Sensors

Microcantilevers have been used to detect the concentration of herbicides in the liquidenvironment by Roberto Raiteri and co-workers [20]. The herbicide 2,4-dichlorophenoxyaceticacid (2,4-D) was coated on the upper surface of the cantilever. The monoclonal antibodyagainst 2,4-D was then provided to the cantilever. The specific interaction between themonoclonal antibody and the herbicide caused the bending of the cantilever. A lot of researchis going on to develop antibody coated cantilever immunobiosensors for the detection of organochlorine and organophosphorous pesticides and herbicides present at ng/l concentration

in aqueous media. Alvarez and Co-workers demonstrated the use of microcantilevers for thedetection of pesticide dichloro dipheny trichloroethane (DDT) [21].

Metal Ion Sensors

Microcantilever sensors have been employed to detect a concentration of 10-9 M CrO42- in a

flow cell [22]. In this device, a self-assembled layer of triethyl-12-mercaptododecyl ammoniumbromide on the gold-coated microcantilever surface was used. Microcantilevers could be usedfor the chemical detection of a number of gaseous analytes. A multielement sensor arraydevice employing microcantilevers can be made to detect various ions simultaneously.

Temperature Sensors / Heat Sensors

Changes in temperature and heat bend a cantilever composed of materials with different

thermal expansion coefficients by the bimetallic effect. Microcantilever based sensors canmeasure changes in temperature as small as 10-5 K and can be used for photo thermalmeasurement. They can be used as microcalorimeters to study the heat evolution in catalyticchemical reactions and enthalpy changes at phase transitions. Bimetallic microcantilevers can





perform photothermal spectroscopy [23] with a sensitivity of 150 fJ and a sub-millisecond timeresolution. They can detect heat changes with attojoule sensitivity.

Viscosity Sensors

Changes in the medium viscoelasticity shift the cantilever resonance frequency. A highlyviscous medium surrounding the cantilever as well as an added mass will damp the cantileveroscillation lowering its fundamental resonance frequency. Cantilevers can therefore be vibrated

by piezoelectric actuators to resonate and used as viscosity meters [24].

Calorimetry Sensors

In these sensors, only the temperature changes are to be measured [25,26]. Most of thechemical reactions are associated with a change in heat. So, calorimetry has got tremendouspotential to identify a wide range of compounds. Enzymes like glucose oxidase can beimmobilized and coated on the surface of the microcantilever, which will react specifically withglucose in the solution producing a recognizable calorimetric signal. Due to the tiny thermalmass and sensitivity of the cantilever, calorimetry sensors employing cantilevers will be nextgeneration of sensors for detecting temperature changes.

Sensor Detecting Magnetic Beads

Baselt and co-workers [27] explained the possibility of using microcantilevers as forcetransducers to detect the presence of receptor-coated magnetic beads. It is possible to detectthe presence of single µm size magnetic bead sticking onto the functionalized cantileversurface by applying an external magnetic field and measuring the deflection of themicrocantilever. An extremely sensitive sensor can be made by labelling the analyte withmagnetic beads.

Cantilever Based Telemetry Sensors

Cantilever based telemetry sensors [28] will deploy fieldable devices to relay pertinent data tocentral collection stations. They will enable the use of mobile units worn or carried bypersonnel and will replace wired sensors in some applications. Researchers at ORNL arebuilding a microfabricated chip with built-in electronic processing and telemetry. They are alsoworking on a method to detect different species.

Microsensors to Monitor Missile Storage and Maintenance Needs

Miniaturized microcantilever based sensors with remote wireless monitoring capability havebeen employed to gain insight into stockpile condition [29]. This technology will evaluateammunition lifetime based on environmental parameters like humidity, temperature, pressure,shock and corrosion as well as number of other indicators of propellant degradation includingNOx. Single chip detectors with electronics and telemetry could be developed with severalhundred cantilevers as an array to simultaneously monitor, identify and quantify manyimportant parameters. Corrosion sensors have limited life in moderate to severe environments.Systems have to be build to collect environmental data for better knowledge of environmentalconditions. There is a need to develop materials like zeolites [30] for use as sensitizingcoatings for specific detection. Zeolites are thermally stable aluminosilicate frameworkstructures used commercially as molecular sieves, catalysts, ion-exchangers and chemicalabsorbers. They show excellent selectivity and selective thermal desorption properties.

Remote Infrared Radiation Detection Sensors

A remote infrared (IR) radiation detection sensor has been developed by Oden and co-workers[31]. The sensor is made up of a piezoresistive cantilever coated with a heat absorbing layer.Piezoresistive microcantilevers represent an important development in uncooled IR detectiontechnology. The cantilever undergoes bending due to the differential stress between thecoating and the substrate. The cantilever bending causes a change in the piezoresistance,which is proportional to the amount of the heat absorbed. Temperature variations can bedetected by coating the cantilever with a different material, which causes the bimetallic effectresulting in the bending of the cantilever. Thus, calorimetric detection of chemical reactionscan be done. Gold-black would serve as the IR absorbing material. High thermal expansionbimaterial coatings such as Al, Pb and Zn could be used to increase the thermally induced





bending of the microcantilever. Two dimensional cantilever arrays can be used for IR imagingas they are simple, highly sensitive and fast responding.

Explosives Detection Devices

It is believed that dogs have got amazing smelling power, the reason they are widelyemployed in the detection of explosives. Dogs can detect explosives by sniffing easilyvaporized organic chemicals present at concentration as low as parts-per-billion. Many groups

are conducting active research with the intention of making a ‘nose-on-a-chip’ device havingthe smelling power exactly similar to the dog’s nose. In this ‘nose-on-a-chip’ device [32,33], amicrocantilever array could be used in which each cantilever will be coated differently to pickup a specific organic compound. It can be incorporated in our everyday use item like shoes,walking cane, purse etc. to detect the explosives without letting the culprits know about thesearch operation. The device would be a great achievement from the security point of view andwould prevent large accidents.

A microcantilever coated with platinum or a transition metal can react with trinitrotoluene(TNT) if it is heated to 570°C and held at that temperature for 0.1 second. The reaction of TNTwith the cantilever coating will cause a mini-explosion. Thundat and his group [34] aredeveloping a matchbox-size device to detect explosives in airport luggage and landminesbased on this technique.

Sensing Applications of Microcantilevers in the Field of Disease Diagnosis

Cancer Detecting Microchips

Arun Majumdar and co-workers [3] have demonstrated microcantilever based sensitive assayfor the diagnosis of cancer. They coated the surface of the microcantilever with antibodiesspecific to prostate specific antigen (PSA), a prostate cancer marker found in the blood of patients having prostate cancer. When the PSA-coated microcantilever interacted with theblood sample of the patient having prostate cancer, antigen-antibody complex was formed andthe cantilever bent due to the adsorbed mass of the antigen molecules. The nanometerbending of cantilever was detected optically by a low power laser beam with sub-nanometerprecision using a photo detector. This microcantilever based assay was more sensitive than

conventional biochemical techniques for detection of PSA as it can detect antigen levels lowerthan the clinically relevant threshold value. The technique is as good as and potentially betterthan ELISA. Moreover, the cost per assay is lesser as there is no need to attach fluorescenttags or radiolabel the molecules. The detection of PSA based on the resonant frequency shift of piezoelectric nanomechanical microcantilever had been demonstrated also by Lee and co-workers [35].

Myoglobin Detection Sensors

Raiteri and his group [4] employed microcantilevers with anti-myoglobin monoclonal antibodycoated on the upper surface by sulfosuccinimidyl 6-[3-(2-pyridyldithio)-propionamido]hexanoate (sulfo-LC-SPDP) cross-linker. When the human serum was provided, myoglobinbound to the anti-myoglobin, thereby causing a deflection of the microcantilever. 85 ng/ml of

myoglobin was easily detected, which is the physiological concentration in the healthy humanserum.

Glucose Biosensors

Pei and co-workers [36] reported a technique for micromechanical detection of biologicallyrelevant glucose concentrations by immobilization of glucose oxidase onto the microcantileversurface. The enzyme-functionalized microcantilever undergoes bending due to a change insurface stress induced by the reaction of glucose oxidase immobilized on the cantilever surfacewith glucose in solution. Experiments were carried under flow conditions and it wasdemonstrated that the common interferences for glucose detection had no effect on themeasurement of blood glucose.





Biosensors for Coronary Heart Disease

A clinical biochemical sensor application was presented [37], where the adsorption of low-density lipoproteins (LDL) and their oxidized form (oxLDL) on heparin were differentiated bymeasuring the surface stress employing biosensing microcantilevers. The ability to differentiatethese two species is of interest because their uptake from plasma principally favoured theoxidised form, which is believed to be responsible for the accumulation of cholesterol in the

aorta in time and is associated with the first stage of coronary heart disease. The method wasalso used to detect conformational changes in two plasma proteins, Immunoglobulin G (IgG)and Albumin (BSA), induced by their adsorption on a solid surface in a buffer environment.This phenomenon is of crucial importance in biomedical applications involving solid surfaces,but has been difficult to measure with conventional adsorption techniques.

Cantilever Based Sensors to Detect Single-Nucleotide Polymorphisms

Single nucleotide polymorphisms (SNPs) within the known gene sequences and the genomeare the main concern of the genomics research. Point mutations cause several diseases suchas Thalassemia, Tay Sachs, Alzheimer’s disease etc. Therefore, efforts to detect the singlenucleotide polymorphism will aid in the early diagnosis of these diseases and will help in thetreatment of patients having such disorders. An effective and reliable way of detecting such

single base pair mismatches is by using microcantilevers which are extremely sensitive tospecific biomolecular recognition interactions between the probe DNA sequence and the targetDNA sequence. They can detect concentration in the pico- to femtogram range. Thiolated DNAprobes specific for the particular target DNA sequence are immobilized on the gold-coatedmicrocantilever. Hybridization with the fully complimentary target DNA sequence will cause thenet positive deflection of the cantilever. Net positive deflection is a result of reduction in theconfigurational entropy of dsDNA versus ssDNA, which causes the reduction of compressiveforces on the gold side of the cantilever. Hybridization of the probe DNA with target DNAhaving one or two base-pair mismatches results in a net negative deflection of the cantileverdue to increased repulsive forces exerted on the gold-coated surface of the microcantilever.The deflection is greater for target DNA having two base pair mismatches than for target DNAhaving one base pair mismatch. The degree of repulsion increases as the number of base pairmismatches increase [38]. McKendry [39] demonstrated multiple label-free biodetection andquantitative DNA-binding assays on a nanomechanical cantilever array.

These DNA based microcantilever deflection assays would be a boon to the field of pharmacogenomics, which will develop drugs specifically made to target the SNPs. Theseassays have a quick response time of less than 30 minutes and are much cheaper than theother techniques currently used to detect the SNPs. It is a simple procedure and the output i.e.the cantilever deflection is a simple +/- signal. Current hybridization detection techniques likeSouthern blotting require highly stringent reaction conditions while the microcantilever-basedtechnique requires only a physiological buffer and room temperature (25°C). Details about thetransformation of biomolecular recognition into nanomechanics are given in [40]. Southernhybridization is very tedious, costly, hazardous and time consuming procedure. On the otherhand, microcantilevers hold a great promise for the medical diagnosis because not only the

presence but the location of the mismatches can be found.Biochips

Recent advances in biochips [41,42] have shown that sensors based on the bending of microfabricated cantilevers have potential advantages over previously used detection methods.Biochips with mechanical detection systems use microcantilever bimaterial (e.g. Au–Si) beamsas sensing elements. The Au side is usually coated with a certain receptor. Upon the binding of the analyte (e.g. biological molecules, such as proteins or biological agents) with the receptor,the receptor surface is either tensioned or relieved. This causes the microcantilever to deflectand the deflection was found to be proportional to the analyte concentration. Examples of bindings in biomolecular (receptor/analyte) applications are: antibody–antigen bindings or DNAhybridization of a pair of DNA strands (receptor/analyte) having complementary sequences

[42]. Biochips having microcantilevers as sensing elements do not require external power,labelling, external electronics or fluorescent molecules or signal transduction for theiroperation. These types of biochips can be used in screening certain diseases such as cancerand detecting specific chemical and biological warfare agents such as botulinum toxin, anthrax,





and aflatoxin. A chemical sensor based on a micromechanical cantilever array has beendemonstrated by Battison and co-workers [37].

Nanocantilevers: A Major Breakthrough in Sensors

Nanocantilevers, 90 nm thick and made of silicon nitride, have been used by the group of researchers led by Harold Craighead, Cornell University to detect a single piece of DNA 1578base pairs in length [43]. The group claimed that they can accurately determine a molecule

with mass of about 0.23 attograms (1 attogram = 10-18 gram) employing thesenanocantilevers. The researchers placed nanoscale gold dots at the very ends of thecantilevers, which acted as capture agents for sulfide-modified double-stranded DNA. But inprinciple, gold nanodots could be used to capture any biomolecule having a free sulfide group.Scanning laser beams were used to measure the vibrational frequency of the cantilevers. Theresearchers believe that nanodevices based on nanocantilevers would eliminate the need forPCR amplification for the detection of defined DNA sequences, thereby simplifying methodsused to screen for specific gene sequences and mutations.

Similarly, N. Nelson-Fitzpatrick et al . [44] at the University of Alberta, Canada have made ultrathin resonant nanocantilevers, of the order of 10 nm, in aluminum-molybdenum composites.The group claims that the development of NEMS-based devices in metallic materials wouldenable new areas of applications for the direct sensing of various chemical compounds thusobviating the need of intermediate surface derivatization.

Researchers at Purdue University are involved in the creation of nanocantilevers. Theyemployed an array of nanocantilevers of varying length with thickness of about 30 nm andfunctionalized them with antibodies for viruses [45]. They came up with very interestingresults pertaining to the variation in antibody density w.r.t. the length of nanocantilevers.

Conclusions

Microcantilevers have got potential applications in every field of science ranging from physicaland chemical sensing to biological disease diagnosis. The major advantages of employingmicrocantilevers as sensing mechanisms over the conventional sensors include their highsensitivity, low cost, low analyte requirement (in µl), non-hazardous procedure with fewer

steps (obviating the need for labels), quick response and low power requirement. Mostimportant is the fact that an array of microcantilevers can be employed for the diagnosis of large numbers of analytes such as various disease biomarkers of a single disease in a single gothus having tremendous high throughput analysis capabilities. The technology holds the key tothe next generation of highly sensitive sensors. With the development of the technology fornanocantilevers, sensors have achieved attogram sensitivity, which has until recently onlybeen a dream for researchers. Further increases in sensitivity will allow researchers the abilityto count the numbers of molecules.

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Contact Details

Dr. Sandeep Kumar Vashist

National Center for Sensor ResearchDublin City UniversityGlasnevin, Dublin9

Dublin, IrelandE-mail: [email protected]


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A Review of Micro Cantilevers for Sensing Applications(1)

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