biosensors in the small scal methods and thecnology trends.pdf

8/14/2019 biosensors in the small scal methods and thecnology trends.pdf

1/15

Published in IET Nanobiotechnology

Received on 23rd March 2012

Revised on 24th August 2012

Accepted on 4th September 2012

doi: 10.1049/iet-nbt.2012.0005

ISSN 1751-8741

Biosensors in the small scale: methods andtechnology trendsSukru U. Senveli1, Onur Tigli1,2

1Department of Electrical and Computer Engineering, University of Miami, Coral Gables, FL 33146, USA2Department of Pathology, University of Miami, Miami, FL 33136, USA

E-mail: [email protected]

Abstract: This study presents a review on biosensors with an emphasis on recent developments in the

eld. A brief historyaccompanied by a detailed description of the biosensor concepts is followed by rising trends observed in contemporary

micro- and nanoscale biosensors. Performance metrics to quantify and compare different detection mechanisms are presented.A comprehensive analysis on various types and subtypes of biosensors are given. The elds of interest within the scope ofthis review are label-free electrical, mechanical and optical biosensors as well as other emerging and popular technologies.Especially, the latter half of the last decade is reviewed for the types, methods and results of the most prominently researcheddetection mechanisms. Tables are provided for comparison of various competing technologies in the literature. Theconclusion part summarises the noteworthy advantages and disadvantages of all biosensors reviewed in this study.Furthermore, future directions that the micro- and nanoscale biosensing technologies are expected to take are provided alongwith the immediate outlook.

1 IntroductionThe remarkable progress of micro- and nanoelectro-mechanical systems (MEMS and NEMS) in thelast two decades followed and coincided by the recentdevelopments in nanotechnology have forced engineers andscientists from many disciplines to collaborate on adiversity of interdisciplinary projects. One of the most

promising elds that emerged is biosensors employing themicro- and nanoscale advancements. Especially in the pastdecade, major breakthroughs have been made in the eld.The associated devices range from nanowire eld effecttransistors (FETs) [1, 2] to microcantilevers [35] andwhispering gallery mode (WGM) [1,6] optical sensors, and

from optical microring resonators (OMRRs) [7] to surfaceplasmon resonance (SPR) [6,8,9] type detectors and others.

Although, the use of nanotechnology and micro- andnanoscale fabrication is relatively new and still ourishing,the history of the eld of biosensors, in a general sense,spans the last half century. Specically, the amperometricenzyme electrode developed by Clark and Lyons in 1962marks the initiation of the eld. It operated as a glucosesensor and can be regarded the rst ancestor of the modern

biosensors [10]. By and large, it is considered as amilestone for all biosensing platforms that followed.Another important breakthrough came about a decade laterfrom Bergveld with the invention of ion sensitive FETs

(ISFETs) for neurophysiological measurement purposes[11]. This innovation is considered to have paved the wayfor the modern nanowire FETs, as well as many chemicalsensors and PH sensors. As a consequence of these

developments, a big step was taken towards modern opticalbiosensing platforms with the application of SPR in adetector for the rst time in 1983 by Liedberg et al. [12].The SPR was a physically well-understood phenomenon

back then, yet its application to biosensing was a milestonefor contemporary optical biosensors. On the other hand,mechanical biosensors mostly took after their MEMScounterparts which ourished with the growing popularityof MEMS in 1990s and 2000s.

This review paper focuses on the current status anddevelopments primarily in the past decade in differentsensing mechanisms and corresponding biosensors usedalong with the levels of performance attained. Thesemechanisms have been categorised as electrical, mechanical

and optical. Other emerging technologies are also presented.The vast majority of the biosensors covered in this studyoperate in a label-free manner as label-free detection is animportant research eld in contemporary biosensors. In thenext section, we introduce the concept of a biosensortogether with the current technology trends andrequirements that are essential in a thorough understandingof the topic. With the same line of reasoning, we dene the

performance criteria that are used to evaluate the efcacy ofdifferent biosensor technologies. This discussion is followed

by a detailed review of the most prominent sensingplatforms being used or researched as a part ofcontemporary biosensor systems. Performance metrics for

each type of biosensor are analysed whereas speci

cadvantages and drawbacks are laid out with comparativebenchmarks. Finally, based on an extensive literaturesurvey, we also present promising new research directions

www.ietdl.org

IET Nanobiotechnol., 2013, Vol. 7, Iss. 1, pp. 721 7

doi: 10.1049/iet-nbt.2012.0005 & The Institution of Engineering and Technology 2013


2/15

which are at their infancies but are expected to evolve intomore mature elds of research in the near future withremarkable improvements on the current state-of-the-art.

2 Terminology and trends

Denition of the biosensor follows closely the broader

denition of its chemical counterpart. A chemical sensor isa device that basically consists of a chemical recognitionsystem and a transducer, which transforms chemicalinformation into an analytically useful signal [13, 14].Biosensors can be dened as such sensors with biologicalrecognition elements and similar transducer structures [15].Based on the signicant advancement of biosensors both incomplexity and functionality, it is appropriate to includeanother element in the list of components, the interface tothe outer world. As seen in Fig. 1, contemporary micro-and nanoscale biosensors can be broken down into threedistinct components brought together, namely biomoleculerecognition (sometimes called surface or capture),transducer and interface (or readout). Note that theconceptual schematic outlined in Fig. 1 is applicable to

both labelled and label-free mechanisms.The solution that is being inspected for the desired

biomolecules and its interaction with the biosensor surfaceconstitute the biomolecule recognition or surface portion(sometimes it is called capture, as well). It is here that

biomarkers or other biological entities of interest arecaptured whereas the surface acts inert towards othermolecules in the solution. Furthermore, this part is closelyrelated to surface science studies and contains theimperative step of biosensor surface functionalisation. Thesecond component is the transducer which is generallycharacterised and categorised by the actual sensing

mechanism implemented in the micro- or nanoscaleregardless of the overall size of the detector. This sensingmechanism varies extensively among different biosensorssuch as electrical, mechanical, optical and nuclear magnetic.Finally, interface is the connection of the biosensor from themicro- or nanoscale to the external setup and includes the

back end readout method for the sensor such as electrical oroptical readouts, signal processing and amplication.

The labelled and label-free detection methods differ in allthree components outlined above. Labelled sensing can beconsidered as a comparatively indirect method that involvesthe use of intermediary uorescent molecules that bind tothe analyte of interest and emit optical signals for detectionwhich shapes the biomolecule recognition portion as wellas the optical readout interface. On the other hand,label-free biosensors exhibit various recognition, transducerand readout techniques that are explained throughoutthis review paper and call for improvements in all of thethree components. It can be said that there is a singlemethod of detection in labelled mechanisms as opposed tolabel-free mechanisms which vary greatly in their way ofsensing. As nanotechnology and related technologies

progress, versatility in smaller scales also increases rapidly.To this end, the use of label-free methods employingnanotechnology opens up new challenges in sensing.

One of the two important trends in biosensor developmentin this era is the development towards the implementation of

label-free mechanisms. This kind of detection encompassesthe vast majority of recent research in the eld of

biosensors and forms the focus of this review. Asmentioned above, labelled biosensing generally makes use

of optical methods to detect stained or marked biologicalentities. On the other hand, label-free detection is basicallydened as a biological sensing mechanism in which no

Fig. 1 Schematic representation of the components in a typical

biosensor utilising the widely used antibodyantigen interaction

for sensing

The main components are biomolecule recognition (sometimes called surfaceor capture), transducer and interface (or readout). The biomoleculerecognition component can be implemented using a variety of moleculepairs as mentioned. It should be noted that the transduction is notnecessarily limited to one of the shown methods as well as the interfacewhich can be more or less functional than illustrated. This portrayal andcategorisation is valid for virtually all biosensors, and effectively outlineslabel-free sensing as well as labelled methods. The labelled methods can bemore easily narrowed down compared with label-free methods in theirdenition because of the need to use specic chemistries for binding thatemit light and optical methods for transduction (such as uorescence) andinterface (specialised cameras, optical sensors etc.) parts of the sensor

www.ietdl.org

8 IET Nanobiotechnol., 2013, Vol. 7, Iss. 1, pp. 721

& The Institution of Engineering and Technology 2013 doi: 10.1049/iet-nbt.2012.0005


3/15

staining, marking or any other sort of label attachment isrequired for operation. Thus the biological sample isvirtually unaltered before and after the test. This sort ofsensing eliminates the need for the binding of extramolecules which not only speeds up the process and

preserves the originality of the specimen but also preventsany interference that the labelling might introduce in the

binding site [16]. Another important factor that necessitates

the improvement of label-free detectors is the trend towardsin vivo sensing. Addition of other materials into the uidicsystem is understandably not desirable for suchapplications. The label-free biosensing trend is fueled bythe advancing microtechnology and nanotechnology (alongwith smarter nanomaterials) as evidenced by the growinginterest and expanding literature on these correlated topicsespecially in the last few years [17]. The other importanttrend in contemporary biosensors is the developmenttowards integration with the readout component. In

particular, integrated systems with complementary metaloxide semiconductor (CMOS)-based circuits attract growinginterest. Also the interface component is developingtowards electronic readouts as opposed to other methodssuch as integrated optics or labelled methods. Theadvantages of such an approach are three-fold. Firstly,monolithic integration with the readout results in moreexibility on processing the transduced signal, thus, higher

performance which is a major asset. Secondly, costreduction and production in larger scales are enabled tomeet the needs of the market, should the research becommercialised. Finally, throughput can be increased bymultiplexing and more data can be extracted from thesystem by real-time sensing. Multiplexed sensing can beuniversally dened as the collection of data from multiplechannels simultaneously. Such a detection scheme enablesthe capability of running multiple assays with the same

sensor array and same sample at the same time, thus savingtime. Real-time sensing and reaction monitoring is anotherfeature that denotes that data can be collected continuouslyfrom the sensor as opposed to elapsed time sensing withtwo phase data collection (such as two separate steps oftesting: sample immobilisation and then data acquisition).This way, concentrations of biological entities andcharacteristics of reactions taking place in the liquid can bemonitored in real time as a function of time [18].Multiplexing and real-time sensing are quite helpful assetsattracting a lot of attention in todays biomedical research[17]. Putting together all of the advantages mentionedabove, prove invaluable in reaching the ultimate goal oflab-on-a-chip (LOC) architectures and point-of-care devicesthat are easy to use while giving quick results andmaintaining reliability.

Many of the detection mechanisms naturally involvebinding of the target biomolecule to a surface or a particle.This binding is generally required to be enhanced byusing a coating, which promotes binding or adhesion. Thetype of molecule that is used for capturing the analytemolecule is sometimes referred to as the probe within thiscontext. Sometimes multiple layers of linking molecules areutilised to increase the bonding strength. Biotinstreptavidin[19, 20], antibodyantigens [2123] and aptamers [24, 25]are among the most commonly used molecule pairsfor surface functionalisation studies. Furthermore, using

self-assembled-monolayers (SAMs) is becoming a popularchoice in the recent literature [2628] as well assandwich-type surface functionalisation and nanomaterials[17, 29]. In application, surface cleaning and preparation or

treatment are required before the functionalisation step. Thechoice of surface functionalisation method depends heavilyon the type of sensing mechanism and the desired analyte.

3 Performance criteria

Well-dened gures of merit or performance metrics are

essential to quantify the efciency of a sensor in a givenreal-life situation and to objectively compare its

performance to different types of sensors. In the case ofbiosensors, sensitivity, limit of detection (LOD) andspecicity are generally regarded as the most commoncriteria.

Sensitivity is seen to be used in different contexts in theliterature. Device sensitivity or output sensitivity is theresponse of the biosensor to the unit quantity of

biomolecules applied to it. It can be visualised as the slopeof the transfer function of the biosensor. This type ofsensitivity is not stated as commonly as LOD or specicityin the literature due to non-linearities that arise from thecomplex nature of various transduction processes. Anothercontext for the sensitivity is test sensitivity which hasmore to do with reliability. It can also be called testreliability and is generally dened as the ratio of thenumber of true positives yielded by the biosensor to thenumber of true and false positives in total. Test sensitivitycan be considered as a measure of the reliability of the testwith respect to a reference test, which should be rightfullyassumed to yield correct results such as the enzyme-linkedimmunosorbent assay (ELISA) protocols.

On the other hand, LOD, sometimes called detectionsensitivity, is closely related to the device sensitivitydenition. LOD can be dened as the minimum quantity of

biomaterial that results in an output signal that is clearly

discernible from the background noise. This measure ofdiscernibility is generally a signal-to-noise ratio (SNR)greater than 2 or 3. The dimension of the biomaterialquantity can be given in mass units or moles if themolecular weight of the sample is well known. However,this might lead to ambiguities because of the deliverysystem. Most biomolecules are found inherently in a uidicenvironment, so the biosensor systems incorporate amicrouidic channel or similar component to deliver thesample to the sensor component. Since the volume of thesolution also comes into play, it is sometimes morereasonable and customary to account for it by alsospecifying the volume, thus using units of molar. If theextra complexity of including various microuidicquantities is not desired, units are given simply in mass,such as grams or daltons.

The biomolecule recognition part of the biosensor plays animportant role in the nal value of the LOD of the system. Aspecic parameter called the dissociation constant (Kd) iscommonly used for biochemical reactions in this context,and it basically shows the afnity between the probemolecule and the target molecule to bind. For the generalcase, a smaller dissociation constant denotes better afnity

between the probe and target. Although the exact relationbetween LOD and this parameter is somewhat complicated,it can be said that higher dissociation constants force anundesired increase in LOD for an otherwise identical

biosensor. On a separate note, LOD is measured as asystem-level parameter so it inherently includes the effect ofthe dissociation constant. This ultimately means thatcomparison between LOD parameters of different types of

www.ietdl.org




4/15

biosensors is more reasonable for biosensors employingsimilar probe and target pairs.

There are various units used for sensitivity and LOD. Focusforming units (FFU) and colony forming units (CFU) are twoexamples to these different units used generally in imagingtype biosensors corresponding to viable numbers of virusesand bacteria or fungus, respectively. Refractive index unit(RIU) is a common unit used in SPR type optical detectors

biosensors because of the fundamental differences in itsdetection method. It refers to the change in refractive indexof the media with respect to captured quantity of analyte.LOD can sometimes be specied in number of molecules orcells as well.

Specicityis closely related to test sensitivity and denedas the afnity of the biosensor to respond to only the desired

biomolecule, and no other specimen. Analyte-specic surfacecoatings are needed for achieving specicity in any given

biosensor. If a biosensor responds to biomolecules otherthan the one that is desired to be captured, it has anincreased chance of resulting in false positives, whichundermines the reliability of the device to a great extent.Specicity does not have a common unit and is notinherently or even easily quantiable like LOD or sensitivity. Consequently, it is difcult to comparespecicities from different studies as its denition variesslightly as well as the measurement technique. Mostresearch studies demonstrate specicity by demonstratingthe lack of sensory response to a small number of analytes(usually one or two) other than the one intended fordetection. Although it is of utmost importance in thereliability of the overall sensor, specicity tests are usuallyconducted after other performance tests partly, because inmost cases it is easier to modify the properties of thesurface coating compared with redesigning the entire

biosensor.

Considering the medical needs of our time, point-of-carediagnostics require very low-LOD parameters and smallsample volumes as the amount of available sample is scarcein most applications. For comparison of device

performances with current methods employed in medicaldiagnostics, results from ELISA protocols can be used. Forreference, ELISA generally provides LODs comparable toor better than roughly 1 pM for antibodies [30]. Signicantimprovement in LOD is generally obtained throughdecreasing the scale, that is from larger scales to micro, andthen from micro to nano. Further improvement is generally

pursued in the transducer and interface aspects of thebiosensors. On the other hand, real-life situations alsodemand a high specicity to prevent false positives. Thisfact calls for better understanding and more advancedengineering of the surface reactions through the use ofnanotechnology with various chemical methods.

4 Sensing mechanisms

4.1 Electrical sensing

An electrical-sensing technique that has been used for a longtime in biosensor systems is electrical impedancespectroscopy (EIS) [31, 32]. Such a biosensor basicallyconsists of microuidics and capture electrodes. The analyteimmobilised in some manner on an electrode or between

the electrodes is electrically characterised for its impedanceparameters at various frequencies. Components of a cellsuch as the lipid bilayer membrane or the cytoplasm arevery complicated structures in terms of electrical and

biological modelling. For this reason, they are modelled asa complex network of capacitive and resistive elementswhich bestts the application [33].

Capturing mechanism varies in different studies and can beimplemented by variants of macrolevel techniques tomicrolevel such as trapping by vacuum [34] as well aschemical immobilisation through surface functionalisation[23, 35, 36]. The use of out-of-plane electrodes is common

as well as in-plane electrodes. There are examples of combtype in-plane electrodes being used for cell counting as inmicro-Coulter counters and through cell lysate [37,38].

Impedance spectroscopy is mostly used for performingmeasurements on captured whole cells. Measurements ontissues are generally not preferred as the heterogeneity inthe ensemble can lead to incorrect results. However,heterogeneity has been exploited for sensing purposes aswell. In a study by Han et al. [34], the developed sensorwas able to distinguish between human breast tissue celllines (MCF-10 A) and cancer cell lines (MCF-7,MDA-MB-231, and MDB-MB-435) through impedancemeasurements in the 100 Hz3 MHz range. This way,metastasized samples and different pathological states can

be identied along with the progress of cancer in a givencell line.

CMOS integration of electrochemical detection isimportant as it enables better ultimate signal quality, lowcost, and multiplexing capability. Recently, the issue has

been tackled by different research groups. Studies of Stagniet al. included on-chip capacitance measurements andanalogue-to-digital conversion for detection of DNAhybridisation. This study presents improvements on signalquality and increased functionality using CMOS. A signalin the order of 1 nF was detectable for specic reactions atrelatively low frequencies in the order of kHz [39]. Work

by Levine et al. demonstrated the application of cyclic

voltammetry in CMOS for measuring DNA hybridisation.A LOD of 400 strands/m2 was attained with 4 4

potentiostat electrode arrays [40]. On the other hand,Manickam et al. presented electrodes for electrochemicalimpedance spectroscopy in 10 10 arrays fully integratedon CMOS chips. Capable of operating in 10 Hz50 MHzrange with 40 m 40 m pixels, the sensor provides aLOD value of 105 molecules for DNA detection. Proteindetection with protein-G was also demonstrated for the rsttime with integrated electronics [41]. The studies by Levineand Manickam demonstrate the multiplexing capabilityadded to the system through CMOS integration. Thecapability of real-time reaction monitoring adds to theimportance of these studies as well. Detection ofsmall-sized biomolecules was also demonstrated bydifferent groups, and results such as 3 nM for-hemolysin(HL) detection [42] and 10 pg/ml (equivalent to about 0.3

pM) for infectious salmon anaemia virus (ISAV) antigendetection [43] were obtained.

EIS type of detectors has an advantage in terms of CMOSintegration and providing extensive information as a result ofmeasurement in a wide range of frequencies. Althoughdetection of smaller molecules is also a common researchsubject in EIS, studies focus towards cell characterisation.The research on the subject is expected to progress towardscharacterisation of small biomolecules and increasing therelatively small signal levels produced by these detectors.

Overall, the EIS method can be described as acharacterisation method rather than a detection method incontrast to other electrical sensing platforms like nanowireFET biosensors [31].

www.ietdl.org




5/15

Another very popular method of electrical sensing hasgenerally been associated with a structure that greatlyresembles FETs. The FET biosensors take after theirwell-known electronic counterparts, but in this case thechannel is replaced by a semiconductor structure coatedwith a specic receptor to which the target molecules areexpected to bind. The principle of operation greatlyresembles that of ISFETs. The electrical charges of bound

molecules result in either accumulation or depletion ofcarriers, thereby changing the conductance of the channeland enabling biomolecular detection. For instance, for a

p-type channel, the binding of a positively chargedmolecule decreases the conductivity, as it decreases thenumber of carriers contributing to current ow, whereas anegatively charged molecule increases conductivity. Fig. 2ashows a simplied schematic of the detection mechanismwhereas Fig. 2b shows the scanning electron microscope(SEM) image of a ZnO nanowire FET biosensor [ 51]. Thechannel structure is occasionally a nanowire or sometimes asingle walled carbon nanotube (SWCNT) [4446]. Bottom-up and top-to-bottom type fabrication procedures are bothvalid approaches although the latter makes the integrationmore difcult.

Nanowire FET biosensors are generally operated in eitherthe back gate mode or the liquid gate mode. In the former,the gate voltage is applied to the substrate and it serves asthe gate for FET [47]. In the latter, as the name suggests,the gate voltage is applied to the liquid that the FET

biosensor is submerged in [48]. The most common channelmaterial is silicon which is also the basis for very largescale integrated (VLSI) circuit and MEMS processing.Silicon can be easily patterned and doped with knownmethods; furthermore, integration with current fabricationtechnology is almost seamless [2]. The feasibility of usingsilicon nanowires for FET biosensors was demonstrated by

Patolsky et al. by showing the versatility in detection ofproteins, DNAs and single viruses. A LOD as low as 2 fMwas attained for detection of prostate-specic antigen (PSA)

biomarkers whereas maintaining an SNR greater than 3 [2].A study, with a similar LOD result of 10 fM was carried

out by Zhang et al. on reusable n-type silicon nanowires. Inthis study, covalent immobilisation technique was used tocapture estrogen response element (ERE) dsDNAs [49].Using nanowires in arrays introduces a statistical advantagefor correcting non-uniformities along with a comparativelyreproducible fabrication method. Consequently, Agarwalet al. demonstrated an array consisting of both p- andn-type silicon nanowire FET detectors. Biotinylated

ssDNAs were successfully detected with an SNR greaterthan 6 at a level of 10 pM with n-type FETs [19].

One inherent drawback of silicon is the thin native oxidelayer that covers its surface, which can result in impaireddevice performance. Therefore research in other materials,such as metal oxides is considered a worthwhile option[48]. Among these materials is ZnO, which is ahigh-bandgap material with high electron mobility that iswidely used in biochemical applications. Liu et al. utilisedZnO nanowires for the detection of IgG protein in

phosphate buffered saline (PBS) solution at a LOD of 50ng/ml [50, 51]. Another metal oxide utilised for electrical

biosensing was metal oxide chemical vapour deposition(MOCVD) coated IrO2 because of its chemical stability in

pH changes and fast response time in solutions. Although,the premise of using conventional CMOS process is amajor advantage, the device has only been tested in varyingconcentrations of PBS, and not yet tested with any

biological specimen [52]. Ishikawa et al. used In2O3 in theirsensor platforms to detect SARS virus N-proteins. Adetection limit of about 1 nM was achieved with a 10 minlong assay in 0.01 PBS [48]. Conducting polymershave also been proposed and used for cancer antigenCA-125 detection down to a limit of 1 U/ml by Bangaret al. A more recent study by the same group suggests anextremely low LOD of 0.1 fM for breast cancer genessDNA detection [53]. SWCNTs are also nding their way

into biosensing as in many other elds of nanotechnology.Lo et al. demonstrated 10 ng/ml limit of detection forcarcino embrionic antigen (CEA) tumor markers with Nidecorated SWCNTs [54]. There have also been studies ongraphene-based devices. Ohno et al.s graphene based and

Fig. 2 Nanowire FET biosensors

a Schematic representation of the operation with binding of charged moleculesb SEM image of a nanowire FET biosensor. The ZnO nanowire is placed on top of the Au electrodes using a focused ion beam (FIB) tool. Thegure is reprintedfrom Ref. [51]

www.ietdl.org




6/15

aptamer-modied nanowire FETs are reported to be capableof detecting down to about 0.3 nM of IgE in 100 nM

bovine serum albumin (BSA) solution [24]. Even thoughpromising results are shown to be possible with non-siliconnanowires, the major problem is their fabrication methods,which usually incorporate bottom-up growth. Thesemethods are generally not compatible with CMOSfabrication.

The majority of the nanowire FET biosensors rely on timedomain measurements although there have been suggestionstowards frequency domain applications. Such a study wascarried out by Zheng et al. deriving from the fact thatnanowire FETs exhibit icker (or 1/f ) noise characteristicswithout any or non-specic binding whereas immobilisationof the target analyte biomolecules results in a Lorentziantrend in the frequency spectrum. Detection by tting forthis type of curves is claimed to improve LOD of givensilicon nanowire FETs from 5 to 0.15 pM for PSA, withoutaltering the actual structures [55]. Another method withfrequency domain sensing was Mishra et al. whichcombines the reliable FET behaviour with EIS technique[56]. In this study, a thin protective layer of polyimide wasused to prevent the exposure of polysilicon nanowire to thesolution. A bacterial toxin, SEB, was successfully detectedwith a LOD of 10 fM in 1 PBS solution.

Table 1 shows a comparison of the key results for thenanowire FETs from the literature. It can be inferred thatsilicon is the most common structural material with a highsensitivity. However, it is also seen that other types ofnanowires are on par with and in some cases more efcientthan silicon nanowires today even though their fabricationis limited by bottom-up methods. Whereas the advantagesof silicon related to versatility in fabrication and mass

production are apparent, they are readily challenged by thepromise of high sensitivity of other types of nanowires that

can be engineered to specic needs for better performance.The real breakthrough will probably be reached afterdiscovery of more efcient integration methods of thesenanowires with the electrodes. As a disadvantage, thenanowire FETs are compact biosensors with very smallsurface areas and it may take extended periods of time tocapture the required amount of analyte molecules for adiscernible output signal [57]. For this reason, verylow-LOD values are expected to require long assaydurations. However, there have been theoretical studies in

the literature showing that electrokinetic effects such aselectrophoretic force and electroosmotic ow could beexploited to reduce the assay time drastically [58].

4.2 Mechanical sensing

The subject of mechanical sensing has been researchedextensively in various MEMS applications, the most famous

examples being accelerometers and gyroscopes. For the pastdecade, sensors utilising MEMS technologies have beenapplied extensively to the biological domain as well. Thesesensors generally incorporate a cantilever structure. Inessence, biomolecules immobilised to the cantilever cause achange in one of its mechanical characteristics such as thestatic deection or the resonance frequency of oscillation. Inthe former approach, the deection is caused by the changeof the surface stress, whereas in the latter approach, theshift in the resonance characteristic is a result of theincreased beam mass as biomolecules are captured asshown in Fig. 3. These two different mechanisms areaddressed as static and resonant mode devices.

Unlike electrical-sensing mechanisms with inherentelectrical readout interfaces discussed in the previoussection, mechanical biosensors commonly rely on opticalsetups for the readout. However, regardless of the readout,the performance of a mechanical sensor, especially aresonant mode sensor, varies greatly with the medium it isoperating in. This degradation is related to the Q-factor ofthe system. The Q-factor of a system determines the qualityof the output signal. In electromechanical systems, Q-factorof a resonating structure is a measure of the efciency ofthe oscillation and is dened as its peak resonancefrequency divided by the frequency bandwidth. A higherQ-factor is desirable in the operation of a resonance modemechanical biosensor as it translates to improved resonance

characteristics, and therefore results in higher performance.Liquids, in general, cause deterioration by introducingadditional drag force because of their viscous nature hencedecreasing the Q-factor of the structure. For this reason,once the necessary amount of analyte molecules iscaptured, such biosensors might need to be desiccated

before measurements are made. This operation points to acertain tradeoff between higher sensitivity and longer assayduration [60].

Static deection mode sensors provide a smaller amount ofdata to the experimenter for analysis. However, theycompensate for it by the low LOD values they offer. Such acantilever detector with optical readout was demonstrated

by Backmann et al. in detection of the binding ofAR-GCN4 antigens to scFv antibody fragments. With thehelp of fragmented probe antibodies and differentialreadings, a LOD of about 1 nM is obtained [22]. Similarly,Zhang et al. used multiple static mode cantilevers withreference detectors for differential readout. RNAimmobilisation was achieved by hybridisation. In the end, aLOD of 10 pM was attained with ssDNA and oligonucleotide probes [61]. On the other hand, Shin et al.

proposed a similar approach for dynamic mode devices. Intheir work, use of multiple resonant cantilevers wasexploited to distinguish between the effects of surface stressand adsorbed mass through piezoelectric type electricalreadout. Their resonant microcantilever sensors with the

smallest one having a Q-factor of around 3000 were shownto detect 20 g/ml solutions of IgG proteins on biotinylatedSAM surfaces and pinpoint the actual source of theresultant frequency shift owing to the differential readout

Table 1 Comparison of key results from the literature about

nanowire FET type biosensors

LOD Nanowirecomposition

Targetanalyte

Ref.no.

2 fM Si PSA [2]0.3 nM ZnO IgG [50]10 pM Si Biotinylated

ssDNA[59]

10 fM poly-Si SEB [56]1 nM In2O3 SARS [48]55 pM SWCNT CEA [54]10 fM Si dsDNA [49]0.15 pM Si PSA [55]0.3 nM Graphene IgE [24]0.1 fM Ni decorated

Cond. PolymerssDNA [53]

Results in different units have been converted to molar unitsusing commonly used molecular weights of correspondinganalytes for reference

www.ietdl.org




7/15

architecture [27]. Piezoelectric type signal generation andreadout was also used by Lee et al. for PSA detection incantilevers with composite structures and surfacesfunctionalised with SAMs. After running uorescence andspecicity tests and comparing the results a LOD of 10 pg/ml was reported [62]. Similar arrays of bimorphnanocantilevers were reported with a different readoutmethod, namely, optical-thermo-mechanical excitation inthe study proposed by Ilic et al. [63]. Only a very smallcircular area at the tip of the resonator was functionalisedwith gold coating. Detection of single dsDNAs was shownto be possible and a resultant mass LOD of 1.65 ag wasreported whereas a 0.03 ng/l LOD was shown to beattained in the frequency response. The Q-factor afterdesiccation is given to be between 3000 and 5000 in this

study.The improvement of Q-factor is a challenge in case the

assay is desired to be carried out whereas the detector isimmersed in the liquid. This type of assay decreases the

number of process steps, increases throughput, and enablesthe real-time sensing applications. The Q-factor of thecantilevers was improved vastly by Ricciardi et al. whomanaged to obtain a value of 140 without electronicfeedback by designing microplates rather than microbeams.Furthermore, the detection of 30 l Ang-1 mAb in a PBSsolution of 25 g/ml was demonstrated [64]. Anotherstructure that was proposed to increase the Q-factor was to

use in-plane resonators. This type of cantilever has asmaller drag force acting on it, making Q-factors up to249 possible. This way Tao et al. managed to fabricatesilicon micromachined cantilevers with a detection limitof 2 103 CFU/ml was obtained for Escherichia colisamples [65].

Different materials and bimorphs in cantilever structureswere proposed in the literature. A magnetostrictivealloy-based microcantilever with a measured Q-factor of 40was demonstrated by Fu et al. for capturing Salmonellatyphimurium. Two hours of assay time resulted in a 35 Hzshift in the sensors resonance peak which is at 6915 Hz inits rst mode in water. This kind of alloy brings the

possibility of wireless actuation and sensing in amicrocantilevers [66]. As opposed to majority of sensorsthat lie in the substrate plane and oscillate out-of-plane, aninnovative vertical pillar structure, which is perpendicular tothe substrate plane was recently proposed by Melli et al.[67]. This geometry helps to increase the adsorption ratesignicantly by decreasing the required diffusion lengthfor the analyte. Optical lever type readout was employedfor DNA capturing with limits of detection of 1 M and10 nM in less than 1 min and 2 h, respectively. Anotherinteresting application worth noting is vibrating CNT-type

biosensors. CNTs are highly sought after because of theirsuperior mechanical properties and enhanced electricalcharacteristics, with respect to (and because of) their

dimensions. In a study by Chowdhury et al., the idea of aSWCNT mass sensor is explored and it is claimed aftersimulations that 10

24kg of mass resolution should be

possible with CNT-based nanobalances, although nomeasurement data are provided [68].

The most severe limitation of microcantilever type sensorsis their signicantly degraded performance in a liquidenvironment. Although there were partially successfulapproaches involving electronic feedback for Q-control andin-plane resonators as covered, it was not until 2003 that aradically innovative way to overcome this limitation was

proposed by Burg et al . in the form of suspendedmicrochannel resonator (SMR) biosensors. As the namesuggests, the suspended cantilever structure houses themicrochannel in which the immobilisation occurs. Theresultant microcantilevers are, therefore free of the liquiddamping factor with very high Q-factors. This rst studyyielded a surface mass resolution in the order of 10 ag/m2

over a bandwidth of about 4 Hz. The avidinbiotinylatedBSA pair bindings were detected with optical readout [69].

Research on SMR by the same group yielded detectorswith very high Q-factors in the order of 15 000. Goatanti-mouse IgG is detected with a LOD of 0.7 nM.Moreover, a new mass measurement method withoutimmobilisation of the analyte on the inner surfaces of theSMR is proposed [70]. Studies of von Muhlen et al. onimproved surface coating polymers along with reference

microcantilever coupling yielded SMRs with LODs of 10ng/ml for activated leukocyte cell adhesion molecule(ALCAM)-type cancer biomarkers [71]. Further studies onthe subject brought about fully electronic readout with

Fig. 3 Principle of operation of static and resonant mode

microcantilever biosensors

a Captured biomolecules change the surface stress of the microcantilever,causing it to bendb Immobilised biomolecules modulate the resonance frequency of anactuated, oscillating microcantilever. Both congurations can be read outby electrical and optical means

www.ietdl.org




8/15

piezoelectric sensing elements as was demonstrated by Leeet al. [72]. This study takes the concept one step forward asit enables multiplexed detectors and provides an ultimatemass resolution of 3.4 fg in a 1 kHz bandwidth with

piezoelectric detection of polystyrene beads and buddingyeast cells. The results were also shown to agree with thoseof optical lever method readout, ensuring the reliability ofelectronic readout. Another way to work around Q-factor

limitations was proposed by Lu et al. as a resonatorcoupled with vertically directed and ordered nanowirearrays [73]. The nanowire array formed a photonic crystal(PC) which can detect DNA down to a LOD of 0.5 fM withquite linear output characteristics using opticalinterferometer readout. A highly improved mass per areasensitivity of 1.8 ng/m2 was demonstrated at the expense ofcost efciency and simplicity of testing compared withother electronic readout sensors.

Table 2 shows a comparison of the key results aboutmechanical biosensors from the literature. Although

promising results are given in sensors with static deection,there is a lack of quantitative information gained from themalong with a high dependence on ambient temperature,which makes it difcult to use piezoelectric readoutmethods, thus making CMOS integration and multiplexingharder to achieve. Even though there are concerns on theirreproducibility, this drawback can be offset by use ofdifferential readouts. Among the resonant mode cantilevers,there is a serious tradeoff between assay time and LOD, asthe mechanical performance in liquid environments issignicantly hampered because of the Q-factor. Solutionssuch as in-plane resonators and electronic feedback have

been proposed but they do not seem comparable to thepromise of SMRs, which provide precision in the range ofsingle molecule detection and additional advantages such asreal-time reaction monitoring without the need for

immobilisation.

4.3 Optical sensing

The eld of optical biosensing involves nanobiosensors aswell as macroscale detectors. There exist a variety ofmethods including SPR sensors, PC, OMRRs and WGMdetectors that have been used to this date. Here, we focuson SPR and PCs as they are the most common and themost recently developed and innovative approaches.

By far, the most developed type of optical biosensors isSPR. A common setup consists of a dielectric lm coatedwith a thin layer of gold or silver and coupled to a prism, a

light source, and an optical detector to collect the reectedlight as seen in Fig. 4. SPR sensors make use of surface

plasmons which propagate along the substrate axis in thedielectric/metal interface. These surface plasmons interactwith or can be coupled to the p-polarised component of theincident light [74]. The propagation vectors of these surface

plasmons are sensitive to the change of the opticalrefractive index in the near-eld which is in turn sensitive

to any change in the dielectric/metal interface where thebiomolecules of interest are immobilised. Generally, thelight reected from the back side of the functionalisedsurface is measured for one of three key quantities: theresonant intensity, wavelength or angle [75]. Ultimately,direct information related to the surface bindings of the

biomolecules can be extracted. Recently, there has been asharp increase in the number of publications on SPRsensors, and this type of sensor became a commercialchoice. A reason for this is the wide range of applicationsfor SPR sensors, ranging from explosive detection(trinitrotoluene) to gas sensing and biosensing [8, 76, 77].Other reasons can be listed as the high sensitivity andreal-time reaction monitoring capability.

SPR technology seems to keep up with the trend followedby all biosensing platforms as it benets from the progress of

Fig. 4 Typical SPR setup based on reected light detection

Intensity and angle of the beam, after it exits the prism can be detected as wellas the spectral response of the metal/dielectric interface (not shown in thegure). There are various SPR setups possible for different needs such asthose that use transmission mode rather than reection mode or those thatemploy optical bres instead of prisms

Table 2 Comparison of key results from literature about mechanical biosensors

LOD Comments Q-factor Target analyte Ref. no.

1 nM static deflection N/A AR-GCN4 [22]0.3 pM resonance mode N/D PSA [62]30 nM resonance mode 7800 dsDNA [63]10 pM static deflection N/A RNA [61]0.1 M resonance mode 3000 IgG [27]0.4 M resonating plates, in liquid 140 Ang-1 [64]10 nM resonating vertical pillars, in vacuum 20 000 DNA [67]0.7 nM SMR 15 000 goat anti-mouse IgG [70]0.1 nM SMR with reference and improved surface 15 000 ALCAM [71]3.4 fg piezoelectric sensor SMR 10 840 budding yeast cells [72]0.5 fM resonator coupled with PC nanowire array 320 000 DNA [73]2 1 03 CFU/ml in-plane resonators, in liquid 249 E. Coli [65]

Results in different units have been converted to molar units when possible using commonly used molecular weights of correspondinganalytes for reference

www.ietdl.org




9/15

nanotechnology. One of these studies by Wang et al. usesadvanced surface functionalisation with aptamers andexploits the amplifying effect of gold nanoparticles toimprove the LOD for adenosine down to 1 nM level [25].In another recent study by Piliarik et al. involvingnanorods, localised surface plasmons were imaged in

polarisation contrast on a gold nanorod array. This setupwas used to amplify the detection sensitivity by two orders

of magnitude and detect 200 pM of short oligonucleotides[78]. Another such study on SPR sensing utilises low costand easy to fabricate optic probes instead of prisms and acomplicated optical setup. Sai et al. used U-bent optic

probes and gold nanoparticles to attain a LOD of 0.8 nMfor anti-IgG [79].

Although the technology is at a mature state, increasing theefciency by different designs is still sought after in the SPRdomain. Recently, Zhang et al. completed extensive studieson coupling of bright dipolar and dark quadropolar modesof the SPR sensors. According to their studies, Fanoresonances can be exploited by a careful geometrical designto improve performance [80]. On the other hand, studies are

being conducted in extended versions of SPR method tofurther improve functionality. Such an extension is theSurface Plasmon Resonance Imaging (SPRI) techniquewhich uses a charge-coupled device camera for the detector.A high throughput with low LODs and an improved abilityto observe real-time reaction kinetics are possible withthis method as well as the invaluable advantage ofmultiplexed detection. A study in this eld was done by Liet al. for detection of vascular endothelial growth factor(VEGF) in a biologically relevant concentration of 1 pMwhereas a lower limit of 500 fM was reached duringthe detection of human thrombin. The use of aptamerisationin this study increases the sensitivity by almost four ordersof magnitude [81]. Another variant of the SPR technique

is the Surface Plasmon Fluorescence Spectroscopy(SPFS) which incorporates a similar setup with increasedsensitivity. This technique makes use of uorophoresexcited in the metaldielectric liquid interface to provide anoptical signal. Although it is a step away from label-free

paradigm, it is claimed to provide a better sensitivity formeasurements of direct binding interactions of lowmolecular weight molecules. In a study by Vareiro et al.

probes functionalised with a SAM containing biotinylatedand hydroxyl-terminated thiols were used to bind rst tostreptavidin and then to anti--human chorionicgonadotrophin (hCG). A LOD of 0.6 pM was obtained forhCG [82].

PC detectors are a relatively new class of biosensors. Theygenerally incorporate a periodic dielectric structure with a

period that corresponds to a specic wavelength. This givesrise to a photonic bandgap which denes the part of thespectrum that is not allowed to propagate through thestructure, that is reected. In a PC biosensor, generally adefect is introduced into the device on purpose so that ashift in the peak wavelength value (PWV) is observed inthe reection or transmission characteristics. Both the

periodic structure and the dielectric constants areinstrumental in shaping the reection or transmissionspectra and changes in either one can be attributed tochanges in the surroundings of the defect. This way,detection of biomolecules is possible through microcavities.

Another valid method is to implement waveguides in thelattice structure.

An example of PC biosensors in which the transmissionspectrum is observed was given by Lee et al. with a

minimum detectable protein mass of 2.5 fg [20].Silicon-on-insulator (SOI)-type substrates were etched with

periodic cavities of 270 nm diametre with a single defect of140 nm diametre in the centre to observe the spectrum froma tunable laser source. After thermal and chemicaltreatments, application of glutaraldehyde enabled thedetection of BSA. Specicity was also demonstrated byusing streptavidinbiotin binding method. Fig. 5 shows an

SEM image of this PC biosensor [20].Skivesen et al. used a similar approach in their detector,

employing a blank line, which acts as a waveguide in thepropagation direction instead of a single microcavity defectin the PC. The cut-off wavelength of the waveguide in SOIwith cavities was used for detection of BSA down to aLOD of 0.15 M [83]. Reection spectrum is also used fordetection in some cases. Such a biosensor wasdemonstrated by Blocket al.on exible plastic substrates toimprove robustness and reliability [84]. Lactoferrin of 12.5g/ml was detected by biotinylated heparin probes aftersurface treatment. The structures were exible up to aradius of curvature of 15 cm, which paves the way for morerobust PC biosensors. Highly specic detection of specimensuch as rotavirus was demonstrated by Pineda et al. withthe potential for large quantity detection using PWV shiftsin environmental water supplies at a LOD of around 36FFU [85].

Real-time detection has also been investigated. In such astudy, PC biosensors fabricated with UV curable polymersheet gratings and high refractive index TiO2 lms have

been used as sensor arrays. Chan et al. demonstratedimaging of cells cultures using the reected spectrumapproach to detect apoptosis or proliferation of a type ofhuman breast cancer cells, MFC-7, upon application ofvarious plant extracts [86]. This study shows the potentialof real-time monitoring of the specimen and is claimed to

be an alternative to SPR imaging for the same purposes.Another study on real-time monitoring deals especially withthe detection of low-mass interactions through the use oftotal internal reection geometry (TIR) [87]. Proteins withmolecular weights as low as 244 Da have been shown to bedetected. Ultimately, 1 nM biotin-20T solution was detectedwith an SNR up to 2000. Nanostructured surfaces areexpected to further improve this performance. Addressing

Fig. 5 Two-dimensional PC microcavity biosensor proposed by

Lee et al.

Figure is reprinted from Ref. [20]

www.ietdl.org




10/15

the nanostructured surface issue, surface area enhancement ofPC biosensors coated with TiO2 lms has been demonstrated

by Zhang et al.[88]. The surface area is increased up to fourtimes by use of glancing angle e-beam deposition whichforms nanorod structures on the surface. The sensitivity isshown to be increased rather indirectly as this approachenables more material to be adsorbed on the effectivelyincreased surface area.

Table 3 provides a comparison for the optical sensorsreported in this section. The widely used and commercialised SPRs provide low LOD values withreal-time reaction monitoring capability. Owing to thealmost saturated state of inherent sensor performance, newapproaches to the subject are necessary such as improvedsurface functionalisation and advanced optical setups. Onthe other hand, SPR performance seems to be rivaled quitereadily by PC type detectors. The PC type detectors have

been shown to be usable for reaction monitoring as well,and furthermore have the size and scale advantage indetection of small or low surface coverage molecules [87].

4.4 Other sensing platforms

There are other promising types of biosensors that can beconsidered outside the three basic archetypes discussed inthe previous sections. This category includes Micro NuclearMagnetic Resonance (NMR), nanopore and surfaceacoustic wave (SAW) biosensor platforms.

An emerging type of biosensors that has garnered interestrecently is the NMR. NMR biosensors make use of a

principle somewhat similar to that of magnetic resonanceimaging (MRI), which went on to become one of the mostversatile medical diagnostic tools. The work in the literatureabout NMR generally includes the usage of a permanent

magnet and microcoils for transducing, RF circuits forreadout, and magnetic nanoparticles in a microuidicchannel for sensing and delivery. The nanoparticles placedin the solution have paramagnetic properties and this causesa magnetic dipole to be created in the region under theexternal magnetic eld. This irregularity gives rise to amagnetic eld gradient and disturbs the nuclear spins of the

protons in the nearby water molecules. This disturbance isread out as a magnetic eld resonance signal by shorteningof the longitudinal or transverse relaxation times [89].

Biosensing is performed by binding of these magneticnanoparticles to the target analyte. Generally, bigger

particles or, clusters of particles as opposed tohomogeneously distributed particles result in longerrelaxation times and in turn, higher output signal [89, 90].There has been interest in miniaturising NMR systemsespecially because of cost issues, rst to less claustrophobicsystems with open sides and smaller form factors, then to

desktop-sized sample processing systems, and nally tohandheld devices [91].

Although there were studies on implementing theimportant individual components with microfabricationtechnologies [92, 93], a study that resulted in fullyminiaturised sensors was carried out by Lee et al. andyielded a portable NMR sensor based on theabove-mentioned magnetic relaxation mechanism whichwas capable of detecting avidin down to 3 nM LOD usingcross-linked iron oxide. A more impressive LOD of 1 pMis claimed to be reached using magnetic microparticles formouse IgG detection [94]. Fig. 6a shows the schematic forthe proposed NMR biosensor whereas Fig. 6b illustrates aSEM image of the magnetic nanoparticles used for NMRstudies [94, 96]. There also have been other and furtherminiaturisation efforts on this subject. For instance, CMOStype coils were employed in addition to the RF integratedcircuit for a sensor developed by Sun et al. [95]. Anotherstudy by the same group, Lee et al. integrated embeddedmicrocoils with a microuidic channel to increase SNR toquadruple the values given in previous studies [96].

Another emerging biosensing platform is that ofnanopores, rst demonstrated by Kasianowicz et al. whichcan be thought of as a nanoscale Coulter counter [ 100]. Ananopore biosensor generally consists of a well-controlledmicrouidic channel and a small conned space called ananopore in which electrical measurements can be made

primarily on DNA or RNA strands, proteins and proteincomplexes [97, 98]. The microuidic portion serves tomove the strands with electrophoretic force through thenanopore. Among the most common materials for nanoporefabrication are proteins such as HL [99103] and solid-state materials such as silicon and silicon-basedinsulator lms such as silicon nitride and silicon oxide andgraphene [104108]. Fig. 7a shows a SEM image of ananopore in silicon oxide [108]. Other possibilities are alsoexplored, such as functionalising nanopore surfaces withcomplementary DNA for specic sequence detection [109]and the use of CNTs [110].

One importantgure of merit for nanopore sensors that isnot common among other types of biosensors istranslocation velocity. This parameter is determined bymany factors such as the size of the molecules, that is thesequence length in DNA-like strands, transport medium,nanopore diameter and surface and membrane optimisation.The best (lowest) translocation velocities reported are in therange of 0.1 nucleotides/ms for HL-type nanopores and100 nucleotides/ms for solid-state nanopores [111].

In basic mode of operation, a constant voltage is applied onthe nanopore and the current is read out. As molecules aretranslocated through the cavity electrophoretically, theychange the conductance within the cavity resulting in achange in current which is dependent on the type of thenucleotide. Fig. 7b shows the schematic representation of

sensor operation. This is called tunneling current modewhereas sensors using capacitance measurements are alsoseen in literature [97, 112]. Long chains of DNAs andRNAs can be identied in a label-free manner with

Table 3 Comparison of key results from literature about SPR

and PC type optical biosensors

LOD Comments Targetanalyte

Ref.no.

1 nM SPR, aptamer based Aunanoparticles

Adenosine [25]

0.8 nM SPR with U-bent probe anti-IgG [79]0.2 nM Localised SPR with Au

nanorodsDNA [78]

0.5 pM SPRI with aptamerisation thrombin [81]0.6 pM SPFS hCG [82]0.15 M PC with waveguide BSA [83]0.15 M PC on flexible substrate lactoferrin [84]1 nM PC with TIR geometry biotin-20T [87]19 fM PC with single microcavity BSA [20]36 FFU PC, large qty. detection rotavirus [85]

Results in different units have been converted to molar unitswhen possible using commonly used molecular weights ofcorresponding analytes for reference

www.ietdl.org




11/15


12/15

biosensors are sensitive and provide real-time measurementcapability, they have an inherently degraded performance inliquid environment which has to be carefully accounted for.

5 Conclusions and future outlook

Biosensors have been improving in performance andversatility at a fast pace. Advances in nanotechnology,MEMS, NEMS and other very small-scale fabricationtechnologies help the biosensors progress even further andeven faster. The eld is expanding at a fast pace withemerging innovative technologies, such as NMR imaging,nanopore sensors and even memristor-based new

approaches. Table 4 provides a quick summary of thearchetypes of sensors discussed in this review paper. Itshould be noted again that while LOD is a good metric tocompare different sensors, it does not tell the whole story:assay time, type of analyte, specics of surface chemistry(therefore the specicity), readout technique, and quality ofsignal processing are just a few of the many parameters thatare instrumental in the overall quality of the biosensor.Among these other parameters, specicity is not discussedin the table on purpose as its quantication is notnormalised as in the case of LOD, and it is measured ordemonstrated in many different ways which makes it very

difcult to compare different studies. Electrical impedanceanalysis systems generally suffer from low-signal levelscompared to other transduction techniques. This is themajor reason why integrating them with CMOStechnologies is a gateway to major improvement in thiseld. It also alleviates the need for extensive test setup andequipment. Similarly, nanowire FET-based sensors areinherently very easy to integrate with the CMOS readout

circuits. This would allow them to be less costly whiledrawing more modest amounts of power. They have nomovable parts and their form factor is small, making themmore reliable in the long run. The issue of a possibly longassay time is still present but it was proposed that this

problem can be tackled using approaches such aselectrokinetic effects. Nanowire FET type sensors fullyexploit the advantages of nanotechnology and generallyexhibit very low LODs.

Microcantilever-based mechanical sensors yield highperformance that scales inversely with size, that is smallerthe detector, better the sensitivity. Also fast response timesare possible with most mechanical sensors. However, staticmode sensors have integration and multiplexing problemswhereas the resonant mode sensors operate with hampered

performance in uidic environments. Furthermore, resonantmode sensors with optical readouts have comparablylimited dynamic ranges. Both performance and versatility ofmechanical type biosensors have been improvedsubstantially by SMRs. Recently, other technologies such asPC nanowires found applications as hybrid mechanical

biosensors and exhibited great potential. Sacricingsimplicity of measurement and cost efciency at some level,this biosensor exhibits the best DNA LOD performance interms of Molar units reported up to this date to the best ofour knowledge.

SPR biosensors have been extensively researched and

commercialised because of their reliability, capability ofmeasuring the reaction kinetics and real-time monitoringcapability. Yet, high-performance sensors requirehigh-quality optical setups. This results in rather costly andless portable systems. PC-based detectors are still at acomparatively early stage of research but show great

promise in terms of sensitivity. Unfortunately, they alsorequire high-quality lasers, polarisers, and other opticalsetups to function.

NMR biosensors require high-performance RF electronicsespecially with large magnetic particle sizes but are compliantwith CMOS RF process ows, and offer high sensitivities

Fig. 8 SEM image from the circular SAW devices proposed by

Tigli et al. with circular IDT electrodes to minimise diffraction losses

Figure is reprinted from Ref. [116]

Table 4 Summary of the categories of biosensors discussed in this review

Type Best LODsreported

Typical types of analytes Estimated relativecost

Readout interface Commercialproducts

EIS 0.3 pM cells, proteins low to average electronic yesnanowireFET

1 fM proteins, DNA, viruses low electronic no

mechanical 0.5 fM proteins, DNA/RNA, bacteria,viruses

low to high electronic/optical/massspectrum

no

SPR 0.5 pM proteins, viruses average optical yesPC 19 fM proteins, viruses high optical noNMR 1 pM proteins low electronic nonanopore N/A DNA/RNA low electronic/optical noSAW N/A proteins low electronic no

All listed types of biosensors have been shown to be capable of label-free detection. Owing to the difference of measurements and unitdimensions, respectively, LOD parameters for nanopore and SAW type sensors are not included in the table. Specificity is not includedin the overall comparison for two reasons: because of the inability to come up with a solid metric for quantifying specificity for differenttypes of analytes and due to the variety of the ways it is seen to be demonstrated in different studies

www.ietdl.org




13/15

along with high test sensitivities, meaning low false-positiveratios. This technology is currently at the brink ofcommercialisation, provided that the overall miniaturisationefforts and integration with CMOS yield competitive

performance in real-life medical diagnosis situations.Nanopore-type biosensors combine the ability to examinesingle nucleotides in a given DNA or RNA sequence.Currently, combining solid-state nanopores with biological

probes to create hybrid nanopore sensors, increasing thespecicity of the sensors, and decreasing the translocationvelocity seem to be the biggest challenges in this eld.SAW-type sensors are sensitive yet possess limitedfunctionality in liquid environments, which undermine theirthroughput. Realisation of CMOS readout integrated SAW

biosensors are demonstrated as proof-of-concept but theirmass production and full integration is not yet accomplished.

It is the widely adopted opinion that the biosensingplatforms in the micro- and nanoscale developed so far lendthemselves to being smart alternatives to labelledtechniques. This is partly because of the envisioneddevelopment towards in vivo sensing and partly because ofthe need for more rapid assays with decreased durations thatyield more quantitative data. On a separate note, almostregardless of the sensing mechanism, integration withmonolithic readout circuits adds the invaluable advantage ofmultiplexing, decreases cost, increases portability, improvessignal quality and device functionality, and enables optionsin mass production. This applies best to biosensors that can

be fabricated using standard CMOS technologies and thosewith electronic readouts.

Analysing the current state-of-the-art, our predictionssuggest the future of biosensors lies in the integration of

portable and label-free systems benetting from the fullarray of advantages of the nanotechnology toolset withhigh-functionality electronic readout circuits. With the

current pace of advancements in the eld, we expect suchpoint-of-care devices to be highly commercialised after thenext decade, which will be lled with many exciting resultsin the eld of biosensor research.

6 Acknowledgments

The authors would like to thank all members of the BioNanoResearch Team of University of Miami, Department ofElectrical and Computer Engineering, and Department ofPathology for their support. They would also like toacknowledge Mr. Marcos Feddersen for his help with thenanowire gure.

7 References

1 Erickson, D., Mandal, S., Yang, A.H.J., Cordovez, B.:Nanobiosensors: optouidic, electrical and mechanical approachesto biomolecular detection at the nanoscale, Microuid Nanouid,2008, 4 , (12), pp. 3352

2 Lieber, C.M., Patolsky, F., Zheng, G.F.: Nanowire-based biosensors,Anal. Chem., 2006, 78, (13), pp. 42604269

3 Boisen, A., Dohn, S., Keller, S.S., Schmid, S., Tenje, M.:Cantilever-like micromechanical sensors, Rep. Prog. Phys., 2011,74, (3), pp. 130

4 Waggoner, P.S., Craighead, H.G.: Micro- and nanomechanical sensorsfor environmental, chemical, and biological detection, Lab. Chip,

2007,7

, (10), pp. 1238

12555 Xu, S.: Electromechanical biosensors for pathogen detection,Microchim. Acta, 2012, 178, (34), pp. 245260

6 Bellan, L.M., Wu, D., Langer, R.S.: Current trends in nanobiosensortechnology, Wires Nanomed. Nanobiol., 2011, 3 , (3), pp. 229246

7 Fan, X.D., White, I.M., Shopova, S.I., Zhu, H.Y., Suter, J.D., Sun,Y.Z.: Sensitive optical biosensors for unlabeled targets: a review,Anal. Chim. Acta, 2008, 620, (12), pp. 826

8 Boozer, C., Kim, G., Cong, S.X., Guan, H.W., Londergan, T.:Looking towards label-free biomolecular interaction analysis in ahigh-throughput format: a review of new surface plasmon resonancetechnologies, Curr. Opin. Biotech., 2006, 17 , (4), pp. 400405

9 Roh, S., Chung, T., Lee, B.:Overview of the characteristics of micro-and nano-structured surface plasmon resonance sensors,Sensors-Basel, 2011, 11, (2), pp. 15651588

10 Clark, L., Lyons, C.: Electrode systems for continuous monitoringin cardiovascular surgery, Ann. NY Acad. Sci., 1962, 102, (102),pp. 2945

11 Bergveld, P.: Development of an ion-sensitive solid-state device forneurophysiological measurements, IEEE Trans. Bio. Med. Eng.,1970, BME-17, (1), pp. 7071

12 Liedberg, B., Nylander, C., Lundstrom, I.:Surface-plasmon resonancefor gas-detection and biosensing, Sens. Actuator, 1983, 4, (2),pp. 299304

13 Thevenot, D.R., Toth, K., Durst, R.A., Wilson, G.S.: Electrochemicalbiosensors: recommended denitions and classication, Biosens.Bioelectron., 2001, 16, (12), pp. 121131

14 Guilbault, G.G.: Biosensors, Curr. Opin. Biotechnol., 1991, 2, (1),pp. 38

15 Eggins, B.R.: Chemical sensors and biosensors(John Wiley & SonsLtd., 2002, 1st edn.)

16 Ray, S., Mehta, G., Srivastava, S.:

Label-free detection techniques forprotein microarrays: prospects, merits and challenges, Proteomics,2010, 10, (4), pp. 731748

17 Kimmel, D.W., LeBlanc, G., Meschievitz, M.E., Cliffel, D.E.:Electrochemical sensors and biosensors, Anal. Chem., 2012, 84,(2), pp. 685707

18 Duan, X.X., Li, Y., Rajan, N.K., Routenberg, D.A., Modis, Y., Reed,M.A.: Quantication of the afnities and kinetics of proteininteractions using silicon nanowire biosensors, Nat. Nanotechnol.,2012, 7 , (6), pp. 401407

19 Agarwal, A., Buddharaju, K., Lao, I.K., Singh, N., Balasubramanian, N.,Kwong, D.L.: Silicon nanowire sensor array using top-down CMOStechnology, Sens. Actuator A-Phys., 2008, 145, (146), pp. 207213

20 Lee, M., Fauchet, P.M.: Two-dimensional silicon photonic crystalbased biosensing platform for protein detection, Opt. Express, 2007,15, (8), pp. 45304535

21 Kale, N.S., Joshi, M., Rao, P.N., Mukherji, S., Rao, V.R.:Bio-functionalization of silicon nitride-based piezo-resistivemicrocantilevers, Sadhana Acad. Proc. Eng. S, 2009, 34, (4),pp. 591597

22 Backmann, N., Zahnd, C., Huber, F.,et al.: A label-free immunosensorarray using single-chain antibody fragments, Proc. Natl. Acad. Sci.USA, 2005, 102, (41), pp. 1458714592

23 Wang, M.J., Wang, L.Y., Wang, G., et al.: Application of impedancespectroscopy for monitoring colloid Au-enhanced antibodyimmobilization and antibody-antigen reactions, Biosens.Bioelectron., 2004, 19, (6), pp. 575582

24 Ohno, Y., Maehashi, K., Matsumoto, K.: Label-free biosensors basedon aptamer-modied graphene eld-effect transistors, J. Am. Chem.Soc., 2010, 132, (51), pp. 1801218013

25 Wang, J.L., Zhou, H.S.: Aptamer-based Au nanoparticles-enhancedsurface plasmon resonance detection of small molecules, Anal.Chem., 2008, 80, (18), pp. 71747178

26 Zhang, G.J., Huang, M.J., Ang, J.J., Liu, E.T., Desai, K.V.:Self-assembled monolayer-assisted silicon nanowire biosensor fordetection of protein-DNA interactions in nuclear extracts from breastcancer cell, Biosens. Bioelectron., 2011, 26 , (7), pp. 32333239

27 Shin, S., Kim, J.P., Sim, S.J., Lee, J.: A multisized piezoelectricmicrocantilever biosensor array for the quantitative analysis of massand surface stress, Appl. Phys. Lett., 2008, 93, (10), pp.102902102902-3

28 Seitz, O., Fernandes, P.G., Tian, R.H.,et al.: Control and stability ofself-assembled monolayers under biosensing conditions, J. Mater.Chem., 2011, 21, (12), pp. 43844392

29 Bedford, E.E., Spadavecchia, J., Pradier, C.M., Gu, F.X.: Surfaceplasmon resonance biosensors incorporating gold nanoparticles,Macromol. Biosci., 2012, 12 , (6), pp. 724739

30 Goldsby, R.A., Kindt, T.J., Osborne, B.A., Kuby, J.: Immunology(W.H. Freeman, 2002, 5th edn.)

31 Lisdat, F., Schafer, D.:

The use of electrochemical impedancespectroscopy for biosensing, Anal. Bioanal. Chem., 2008, 391, (5),pp. 15551567

32 Li, L.J.: Recent development of micromachined biosensors, IEEESens. J., 2011, 11, (2), pp. 305311

www.ietdl.org




14/15

33 Markx, G.H., Davey, C.L.:The dielectric properties of biological cellsat radiofrequencies: applications in biotechnology,Enzyme Microbiol.Tech., 1999, 25, (35), pp. 161171

34 Han, A., Yang, L., Frazier, A.B.: Quantication of the heterogeneity inbreast cancer cell lines using whole-cell impedance spectroscopy,Clin. Cancer Res., 2007, 13, (1), pp. 139143

35 Haddad, S., Derkaoui, S.M., Avramoglou, T., Ait, E., Othmane, A.,Mora, L.: Electrochemical impedance spectroscopy as a highlysensitive tool for a dynamic interaction study between heparin andantithrombin: a novel antithrombin sensor, Talanta, 2011, 85, (2),

pp. 92793536 Liu, Q.J., Yu, J.J., Xiao, L.,et al.: Impedance studies of bio-behavior

and chemosensitivity of cancer cells by micro-electrode arrays,Biosens. Bioelectron., 2009, 24, (5), pp. 13051310

37 Cheung, K., Gawad, S., Renaud, P.: Impedance spectroscopy owcytometry: on-chip label-free cell differentiation, Cytom. Part A,2005, 65A, (2), pp. 124132

38 Cheng, X., Liu, Y.S., Irimia, D., et al.: Cell detection and countingthrough cell lysate impedance spectroscopy in microuidic devices,Lab. Chip, 2007, 7 , (6), pp. 746755

39 Stagni, C., Guiducci, C., Benini, L.,et al.: CMOS DNA sensor arraywith integrated A/D conversion based on label-free capacitancemeasurement, IEEE J. Solid-State Circ., 2006, 41, (12),pp. 29562964

40 Levine, P.M., Gong, P., Levicky, R., Shepard, K.L.: Active CMOSsensor array for electrochemical biomolecular detection, IEEE

J. Solid-State Circ., 2008, 43 , (8), pp. 1859

187141 Manickam, A., Chevalier, A., McDermott, M., Ellington, A.D.,

Hassibi, A.: A CMOS Electrochemical Impedance Spectroscopy(EIS) Biosensor Array, IEEE Trans. Biomed. Circ. S, 2010, 4, (6),pp. 379390

42 Tun, T.N., Cameron, P.J., Jenkins, A.T.A.: Sensing of pathogenicbacteria based on their interaction with supported bilayer membranesstudied by impedance spectroscopy and surface plasmon resonance,Biosens. Bioelectron., 2011, 28, (1), pp. 227231

43 Pires, N.M.M., Dong, T., Yang, Z., Karlsen, F.: Detection ofpathogens using bio-activated nickel hexacyanoferrate lm coatedinterdigitated microelectrodes. Int. Conf. on Electronic &Mechanical Engineering and Information Technology, 2011,pp. 28412844

44 Curreli, M., Zhang, R., Ishikawa, F.N., et al.: Real-time, label-freedetection of biological entities using nanowire-based FETs, IEEETrans. Nanotechnol., 2008, 7, (6), pp. 651667

45 Wang, C.W., Pan, C.Y., Wu, H.C., et al.: In situ detection ofchromogranin a released from living neurons with a single-walledcarbon-nanotube eld-effect transistor, Small, 2007, 3, (8), pp.13501355

46 An, T., Kim, K.S., Hahn, S.K., Lim, G.: Real-time, step-wise,electrical detection of protein molecules using dielectrophoreticallyaligned SWNT-lm FET aptasensors, Lab. Chip, 2010, 10, (16),pp. 20522056

47 Hsiao, C.Y., Lin, C.H., Hung, C.H., et al.: Novel poly-siliconnanowire eld effect transistor for biosensing application, Biosens.Bioelectron., 2009, 24, (5), pp. 12231229

48 Ishikawa, F.N., Chang, H.K., Curreli, M.,et al.: Label-free, electricaldetection of the sars virus n-protein with nanowire biosensors utilizingantibody mimics as capture probes, ACS Nano, 2009, 3, (5),pp. 12191224

49 Zhang, G.J., Huang, M.J., Luo, Z.H.H.,et al.: Highly sensitive and

reversible silicon nanowire biosensor to study nuclear hormonereceptor protein and response element DNA interactions, Biosens.Bioelectron., 2010, 26, (2), pp. 365370

50 Liu, J., Goud, J., Raj, P.M., Iyer, M., Wang, Z., Tummala, R.R.:Label-free protein detection by ZnO nanowire based bio-sensors,Electr. Comput. C, 2007, pp. 19711976

51 Liu, J., Goud, J., Raj, P.M., Iyer, M., Wang, Z.L., Tummala, R.R.:Real-time protein detection using ZnO nanowire/thin lm bio-sensorintegrated with microuidic system, Elec. Comput. C, 2008,pp. 13171322

52 Zhang, F.Y., Ulrich, B., Reddy, R.K.,et al: Fabrication of submicronIrO(2) nanowire array biosensor platform by conventionalcomplementary metal-oxide-semiconductor process, Jpn. J. Appl.Phys., 2008, 47, (2), pp. 11471151

53 Bangar, M.A., Shirale, D.J., Purohit, H.J., Chen, W., Myung, N.V.,Mulchandani, A.: Single conducting polymer nanowire based

sequence-speci

c, base-pair-length dependant label-free DNASensor, Electroanalysis, 2011, 23, (2), pp. 37137954 Lo, Y.S., Nam, D.H., So, H.M., et al.: Oriented immobilization of

antibody fragments on Ni-decorated single-walled carbon nanotubedevices, ACS Nano, 2009, 3 , (11), pp. 36493655

55 Zheng, G.F., Gao, X.P.A., Lieber, C.M.: Frequency domain detection

of biomolecules using silicon nanowire biosensors,Nano Lett., 2010,10, (8), pp. 31793183

56 Mishra, N.N., Maki, W.C., Cameron, E., et al.: Ultra-sensitive

detection of bacterial toxin with silicon nanowire transistor, Lab.Chip, 2008, 8 , (6), pp. 868871

57 Squires, T.M., Messinger, R.J., Manalis, S.R.: Making it stick:convection, reaction and diffusion in surface-based biosensors, Nat.

Biotechnol., 2008, 26, (4), pp. 417426

58 Liu, Y.L., Guo, Q.J., Wang, S.Q., Hu, W.: Electrokinetic effects on

detection time of nanowire biosensor, Appl. Phys. Lett., 2012, 100,(15), pp. 153502153502-4

59 Agarwal, A., Lao, I.K., Buddharaju, K., Singh, N., Balasubramanian,N., Kwong, D.L.: Silicon nanowire array bio-sensor using top-down

CMOS technology. 2007, pp. U530U531

60 Arlett, J.L., Myers, E.B., Roukes, M.L.: Comparative advantages ofmechanical biosensors,Nat. Nanotechnol., 2011, 6, (4), pp. 203215

61 Zhang, J., Lang, H.P., Huber, F., et al.: Rapid and label-freenanomechanical detection of biomarker transcripts in human RNA,Nature Nanotech., 2006, 1, pp. 214220

62 Lee, J.H., Hwang, K.S., Park, J., Yoon, K.H., Yoon, D.S., Kim, T.S.:Immunoassay of prostate-specic antigen (PSA) using resonant

frequency shift of piezoelectric nanomechanical microcantilever,Biosens. Bioelectron., 2005, 20, (10), pp. 21572162

63 Ilic, B., Yang, Y., Aubin, K., Reichenbach, R., Krylov, S., Craighead,

H.G.: Enumeration of DNA molecules bound to a nanomechanical

oscillator, Nano Lett., 2005, 5 , (5), pp. 92592964 Ricciardi, C., Canavese, G., Castagna, R., et al .: Integration

of microuidic and cantilever technology for biosensing applicationin liquid environment, Biosens. Bioelectron., 2010, 26, (4),pp. 15651570

65 Tao, Y.H., Li, X.X., Xu, T.G., et al.: Resonant cantilever sensorsoperated in a high-Q in-plane mode for real-time bio/chemical

detection in liquids, Sens. Actuators B-Chem., 2011, 157, (2),pp. 606614

66 Fu, L.L., Li, S.Q., Zhang, K.W., Chen, I.H., Petrenko, V.A., Cheng, Z.Y.: Magnetostrictive microcantilever as an advanced transducer forbiosensors, Sensors-Basel, 2007, 7, (11), pp. 29292941

67 Melli, M., Scoles, G., Lazzarino, M.:Fast detection of biomolecules in

diffusion-limited regime using micromechanical pillars, ACS Nano.,2011, 5 , (10), pp. 79287935

68 Chowdhury, R., Adhikari, S., Mitchell, J.:Vibrating carbon nanotube

based bio-sensors, Physica E, 2009, 42, (2), pp. 10410969 Burg, T.P., Manalis, S.R.: Suspended microchannel resonators for

biomolecular detection, Appl. Phys. Lett., 2003, 83, (13),pp. 26982700

70 Burg, T.P., Godin, M., Knudsen, S.M., et al .: Weighing ofbiomolecules, single cells and single nanoparticles in uid, Nature,2007, 446, (7139), pp. 10661069

71 von Muhlen, M.G., Brault, N.D., Knudsen, S.M., Jiang, S.Y., Manalis,S.R.: Label-free biomarker sensing in undiluted serum with suspendedmicrochannel resonators, Anal. Chem., 2010, 82 , (5), pp. 19051910

72 Lee, J., Chunara, R., Shen, W., et al.: Suspended microchannel

resonators with piezoresistive sensors, Lab. Chip, 2011, 11, (4),pp. 645651

73 Lu, Y.R., Peng, S.M., Luo, D., Lal, A.: Low-concentration mechanicalbiosensor based on a photonic crystal nanowire array,Nat. Commun.,2011, 2 , pp. 16

74 Abdulhalim, I., Zourob, M., Lakhtakia, A.: Surface plasmonresonance for biosensing: a mini-review, Electromagnetics, 2008,28, (3), pp. 214242

75 Hoa, X.D., Kirk, A.G., Tabrizian, M.: Towards integrated andsensitive surface plasmon resonance biosensors: a review of recent

progress, Biosens. Bioelectron., 2007, 23, (2), pp. 151160

76 Riskin, M., Tel-Vered, R., Lioubashevski, O., Willner, I.:Ultrasensitive surface plasmon resonance detection of trinitrotoluene

by a bis-aniline-cross-linked Au nanoparticles composite, J. Am.Chem. Soc., 2009, 131, (21), pp. 73687378

77 Bingham, J.M., Anker, J.N., Kreno, L.E., Van Duyne, R.P.: Gassensing with high-resolution localized surface plasmon resonancespectroscopy, J. Am. Chem. Soc., 2010, 132, (49), pp. 1735817359

78 Piliarik, M., Sipova, H., Kvasnicka, P., Galler, N., Krenn, J.R.,Homola, J.: High-resolution biosensor based on localized surface

plasmons, Opt. Express, 2012, 20, (1), pp. 672680

79 Sai, V.V.R., Kundu, T., Mukherji, S.:

Novel U-bent

ber optic probefor localized surface plasmon resonance based biosensor, Biosens.Bioelectron., 2009, 24, (9), pp. 28042809

80 Zhang, S.P., Bao, K., Halas, N.J., Xu, H.X., Nordlander, P.:Substrate-induced fano resonances of a plasmonic: nanocube: a

www.ietdl.org




15/15

route to increased-sensitivity localized surface plasmon resonancesensors revealed, Nano Lett., 2011, 11, (4), pp. 16571663

81 Li, Y., Lee, H.J., Corn, R.M.: Detection of protein biomarkersusing RNA aptamer microarrays and enzymatically ampliedsurface plasmon resonance imaging, Anal. Chem., 2007, 79, (3),pp. 10821088

82 Vareiro, M.L.M., Liu, J., Knoll, W., Zak, K., Williams, D., Jenkins, A.T.A.: Surface plasmon uorescence measurements of humanchorionic gonadotrophin: role of antibody orientation in obtainingenhanced sensitivity and limit of detection, Anal. Chem., 2005, 77,

(8), pp. 2426243183 Skivesen, N., Tetu, A., Kristensen, M., Kjems, J., Frandsen, L.H.,

Borel, P.I.: Photonic-crystal waveguide biosensor, Opt. Express,2007, 15, (6), pp. 31693176

84 Block, I.D., Pineda, M., Choi, C.J., Cunningham, B.T.: Highsensitivity plastic-substrate photonic crystal biosensor, IEEE Sens.J., 2008, 8 , (910), pp. 15461547

85 Pineda, M.F., Chan, L.L.Y., Kuhlenschmidt, T., Choi, C.J.,Kuhlenschmidt, M., Cunningham, B.T.: Rapid specic and label-free detection of porcine rotavirus using photonic crystalbiosensors, IEEE Sens. J., 2009, 9 , (4), pp. 470477

86 Chan, L.L., Pineda, M., Heeres, J.T., Hergenrother, P.J., Cunningham,B.T.: A general method for discovering inhibitors of protein-DNAinteractions using photonic crystal biosensors, ACS Chem. Biol.,2008, 3 , (7), pp. 437448

87 Guo, Y.B., Ye, J.Y., Divin, C.,et al.: Real-time biomolecular binding

detection using a sensitive photonic crystal biosensor

, Anal. Chem.,2010, 82, (12), pp. 5211521888 Zhang, W., Ganesh, N., Block, I.D., Cunningham, B.T.: High

sensitivity photonic crystal biosensor incorporating nanorodstructures for enhanced surface area, Sens. Actuators B-Chem.,2008, 131, (1), pp. 279284

89 Gossuin, Y., Gillis, P., Hocq, A., Vuong, Q.L., Roch, A.: Magneticresonance relaxation properties of superparamagnetic particles,Wires Nanomed. Nanobiol., 2009, 1 , (3), pp. 299310

90 Haun, J.B., Yoon, T.J., Lee, H., Weissleder, R.: Magnetic nanoparticlebiosensors, Wires Nanomed. Nanobiol., 2010, 2, (3), pp. 291304

91 Magin, R.L., Webb, A.G., Peck, T.L.: Miniature magnetic resonancemachines, IEEE Spectr., 1997, 34 , (10), pp. 5161

92 Fan, L., Hsu, S.S.H., Jin, J., et al.: Miniaturization of magneticresonance microsystem components for 3D cell imaging. IEEEISSCC 2007, Digest of Technical Papers, San Francisco, CA, 2007,pp. 166594

93 Boero, G., Frounchi, J., Furrer, B., Besse, P.A., Popovic, R.S.: Fullyintegrated probe for proton nuclear magnetic resonancemagnetometry, Rev. Sci. Instrum., 2001, 72, (6), pp. 27642768

94 Lee, H., Sun, E., Ham, D., Weissleder, R.: Chip-NMR biosensor fordetection and molecular analysis of cells, Nat. Med., 2008, 14, (8),pp. 869874

95 Sun, N., Liu, Y., Lee, H., Weissleder, R., Ham, D.: CMOS RFbiosensor utilizing nuclear magnetic resonance, IEEE J. Solid-StateCircuits, 2009, 44, (5), pp. 16291643

96 Lee, H., Yoon, T.J., Figueiredo, J.L., Swirski, F.K., Weissleder, R.:Rapid detection and proling of cancer cells in ne-needleaspirates, Proc. Natl. Acad. Sci. USA, 2009, 106, (30),pp. 1245912464

97 Branton, D., Deamer, D.W., Marziali, A., et al.: The potential and

challenges of nanopore sequencing, Nat. Biotechnol., 2008, 26,(10), pp. 11461153

98 Howorka, S., Siwy, Z.: Nanopore analytics: sensing of singlemolecules, Chem. Soc. Rev., 2009, 38, (8), pp. 23602384

99 Braha, O., Walker, B., Cheley, S., et al.: Designed protein pores ascomponents for biosensors, Chem. Biol., 1997, 4 , (7), pp. 497505

100 Kasianowicz, J.J., Brandin, E., Branton, D., Deamer, D.W.:Characterization of individual polynucleotide molecules using amembrane channel, Proc. Natl. Acad. Sci. USA, 1996, 93, (24),

pp. 1377013773101 Clarke, J., Wu, H.C., Jayasinghe, L., Patel, A., Reid, S., Bayley, H.:

Continuous base identication for single-molecule nanopore DNAsequencing, Nat. Nanotechnol., 2009, 4, (4), pp. 265270

102 Wu, H.C., Astier, Y., Maglia, G., Mikhailova, E., Bayley, H.:Proteinnanopores with covalently attached molecular adapters,J. Am. Chem.Soc., 2007, 129, (51), pp. 1614216148

103 Holden, M.A., Bayley, H.: Direct introduction of single proteinchannels and pores into lipid bilayers, J. Am. Chem. Soc., 2005,127, (18), pp. 65026503

104 Keyser, U.F., Koeleman, B.N., Van Dorp, S., et al.: Direct force

measurements on DNA in a solid-state nanopore, Natl. Phys., 2006,2, (7), pp. 473477

105 Storm, A.J., Storm, C., Chen, J.H., Zandbergen, H., Joanny, J.F.,Dekker, C.: Fast DNA translocation through a solid-state nanopore,Nano Lett

Date post:	04-Jun-2018
Category:	Documents
Upload:	isma807
View:	223 times
Download:	0 times

biosensors in the small scal methods and thecnology trends.pdf

Documents