Research Article Trends in Biosensors for HPV ...downloads.hindawi.com/journals/js/2015/913640.pdf · Research Article Trends in Biosensors for HPV: Identification and Diagnosis IsaacA.M.Frías,

Research ArticleTrends in Biosensors for HPV Identification and Diagnosis

Isaac A M Friacuteas1 Karen Y P S Avelino2 Rafael R Silva3

Ceacutesar A S Andrade23 and Maria D L Oliveira2

1Programa de Pos-Graduacao em Ciencia de Materiais Universidade Federal de Pernambuco 50670-901 Recife PE Brazil2Departamento de Bioquımica Universidade Federal de Pernambuco 50670-901 Recife PE Brazil3Programa de Pos-Graduacao em Inovacao Terapeutica Universidade Federal de Pernambuco 50670-901 Recife PE Brazil

Correspondence should be addressed to Cesar A S Andrade csrandradegmailcom

Received 2 April 2015 Revised 21 June 2015 Accepted 5 August 2015

Academic Editor Michele Giordano

Copyright copy 2015 Isaac A M Frıas et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The conventional methodologies used for the detection of human papillomavirus (HPV) present actually robust and reproducibleadvantages However at the same time they involve complex protocols that sometimes are difficult to popularize Over thefirst half of XX century the adequate treatment of complex and delicate processes from a simple instrumental base seemed afundamental and intrinsic contradiction However interdisciplinary trends have allowed the manipulation of tissues proteinsand nucleic acids through innovative increasingly smaller devices The proper diagnosis of HPV has seen great advances sincebiosensor researchers are employing its virus strains asmodels to study the interactions between the biorecognition element and thetransducer Additionally all recent improvements and trends that material sciences biotechnology and data processing scientistsexcel for biosensors can be applied for the HPV detection platforms In this review we highlight the recent trends on materialsnanomaterials and transducers for the specific detection and differentiation of HPV strains The most influential methods forthe detection and identification of these papillomaviruses include optical electrochemical and piezoelectric transducers we willvisit their sensibility and advantages Additionally we highlight the factors that contributed to the increasing importance of thesebiodevices as potential substitutes to conventional diagnostic methods

1 Introduction

Perplexing as it may seem the cancer research communityhas significantly underappreciated the enormous amount ofcancer cases caused by viral infections [1] mostly becauseit is known that just a small proportion of humans infectedwith any of the oncogenic viruses will develop tumors Inthe last century at least seven human viruses have beenpointed as the cause for 10ndash15 of worldwide human cancerscases [2] Cancers are serious public health concerns in thedeveloped countries and for sure most of aggressive casescould be avoided in first place by preventing the initialinfection Behavioral changes and vaccination as well as theearly screening of precancerous lesions have shown to beplausible palliatives to prevent the disease

At first glance human papillomavirus (HPV) virusesmay sound like an evolutionary machinery programmed tocause cancer however from the 150 HPV genotypes that

have been already identified only about a dozen are high-risk or oncogenic types [3 4] A routine practice in themedical community consists in the association of majorrisk factors to cancer incidences Tobacco and alcohol con-sumption are regularly associated to oropharyngeal canceras much as sexual behavior risk is assigned to anogenitalcancer However the astonishing proportion of confirmedpresence of viruses on healthy individuals that have neverhad those risk factors is overwhelming [5] Although mostpatients infected by HPV can spontaneously eliminate thevirus by their own immune system [6] some individuals canremain asymptomatic bymaintaining the virus in latent formand some other immunocompromised patients may presentrecurrent infections [7] Several factors such as the lesiontype size spread and localization will establish the risk levelof the infection andwill help to endorse the correct treatment

Conventional treatments have different effectiveness lev-els and are selected according to the patient tolerance Some

Hindawi Publishing CorporationJournal of SensorsVolume 2015 Article ID 913640 16 pageshttpdxdoiorg1011552015913640

2 Journal of Sensors

of the leading conventional methods include chemotherapy[8 9] immunotherapy [10] surgery [11] or the collec-tive application of these techniques [12 13] Additionallynanoparticle based delivery of anticancer drugs and thera-peutic vaccines have increased the treatment efficacy whilesimultaneously decreasing the side effects of the traditionaltherapeutics [14] The occurrence of visible epidermal mani-festations as warts or condylomas is one of the symptoms ofHPV infection however since only 1 of infected patientspresent the symptomatology the diagnosis is difficult [15 16]The identification of the disease in these asymptomatic casesrequires specialized equipment to carefully search for internallesions at the mucous membranes In cases of proven cervicalinjury a routine cytological analysis known as Papanicolaoutest is performed over a local biopsy for histopathologicalanalysis [17 18] Beyond visual and cytological identificationmolecular diagnosis is taking over as an essential method forthe accurate differentiation between HPV strains which arecategorized with respect to their potential for low intermedi-ate or high oncogenic risk

Since all HPV strains are related researchers have battledto understand and find the characteristics that differentiateevery discovered strain Often the distinction relies on thepeculiar metabolism that a particular strain endures Themost common ways to differentiate the HPV involve theanalysis of the protein expression ratio that provides amolecular fingerprint of the oncogenic potential within ahistopathological sample [19 20] Considering the fact thatsome HPV strains are more related between them than tothe others DNA analyses are often required for the accurateidentification of the strain DNA analyses are quite hetero-geneous and are based on the complementarity principle ofthe DNA strands For instance we can identify the targetamplification of a precise fragment of nucleic material by thepolymerase chain reaction (PCR) and by signal amplificationof an oligonucleotide hybridization assay [21 22] AlthoughPCR associated techniques present high rates of sensitivityand specificity most of these techniques are mainly used byresearch centers andor specific health services Some of thereasons include the time consuming and complex protocolsthat usually require specialized skills for the correct operationof the instruments and fulfillment of the methods [23]

Fortunately the research on cancer has reached amaturitylevel of awareness that allows the population to realize thatviruses are in fact the cause of a great proportion of cancersThe alarming discovery that certain high-risk strains of HPVcaused assured 100of invasive cervical cancer has instigate aglobal awareness about cervical cancer prevention and mostessentially the development of other cancers prophylacticvaccines [24] Regular vaccines use viral vectors to promoteimmune response and more recently DNA vaccines havebeen developed to control tumor-expressed antigens [25]The employed plasmid vectors are safe and present lowimmunogenicity so they can be constantly administeredFurther researches have been demonstrated to increase theirefficiency by designing nanometrical delivery systems asnanoparticles micelles and fibers [26]

AfterHPV16 andHPV18 10moreHPV strains are knownto cause cervical carcinomas [61] Some researchers have

reached a milestone where the precise identification of HPVtypes has become extremely important They propose tofollow the ecological competitive exclusion principle to createan artificial substitution of high-risk HPV types for those ofreduced risk [3] In addition the detailed identification of alldifferent strains within a sample is of great importance to epi-demiological studies and involves major and interesting newobstacles to overcome for example the correct identificationof HPV strains that are known to be genetically close relatedlike HPV6 and HPV11

Because of the large amount of different HPV typesit is reasonable to think that the current competence ofvaccine design technology is insufficient to provide enoughprotection Despite the fact that the research on individualstrains proceeds slowly the research on biosensors has notdelayed its development Nowadays biosensor researchershave more tools to design better techniques to apply andhelp to control viral epidemics Live vectors characterizationpeptideprotein expression and interaction DNA vaccinedesign and whole cell-based treatment approaches [62] aresome of the explored topics that are applied on viral sensingand detection In the case of genosensors as much as thegenomic databases improve cancers will be easier to detectand diagnose

2 Biosensors for HPV as AlternativeDiagnostic Tools

Over the years the progress of biotechnological research hascontributed to the development of biologic sensor devices[63 64] Biosensors are portable analytical devices consti-tuted by at least one biological molecule The strategies toobtain these biosensors combine the specificity of the bio-logical probe with the analytical capacity of the transductionmethods [65 66] In addition materials at the nanometerscale as nanoparticles [67] nanotubes [28] nanofibers [68]and nanocomposites [69] have been used to achieve thenanostructuration of these devices The diversity of struc-tures provides tailored interfacial modification alternativeswith the purpose of amplifying the analytical signal andincreasing the sensibility of the biosensor [63] The challengeto construct these nanometrical systems relies in the needto preserve the biological activity of the probe as well asthe transducing activity of the nanostructure [70] For thesereasons a detailed study of the physical-chemical propertiesof both constituents should be performed

The device requires the efficient immobilization of anti-bodies peptides aptamers or nucleic acids over the sur-face of a transducer which are responsible for the analyterecognition and will execute a measurable response signalproportional to the analyte concentration [71ndash74] Besidescovalent functionalization of nanoparticles (known for allow-ing a strong and controlled immobilization of the probe overthe surface of the sensor) most immobilization strategiesinvolve simple methods In general mixtures or emulsionsof two or more materials previously known for their indi-vidual properties are performed for example nanoparticles

Journal of Sensors 3

SPR EIS

HPV

targ

etBi

osen

sor

S SS

Angle of incidence

Refle

ctio

n

Optical Electrochemical

Signal transduction

Amplification and processing

Response

120596 rarr infin 120596 rarr 0

RΩ RΩ + Rct

Z998400998400

Z998400

Δ120579

SSS

QCMFrequency (MHz)

Piezoelectric

Con

duct

ance

(120583S)

120575f

Γ1

Γ2

Figure 1 Schematic representation of a biosensor developed to detect HPV The response arising from the biospecific interaction betweenthe oligonucleotide probe and the HPV target DNA will be transduced into a measurable signal which will be amplified and processed bycomputer softwareThemain types of signal transductionmethods used in biosensors for HPV are optical electrochemical and piezoelectricIn addition the signal conversion can be accomplished through SPR EIS and QCM techniques [31 70 103]

of biodegradable polymers as poly(lactic acid) poly(DL-glycolide) and chitosan among others which are conjugatedwith biorecognition drugs as therapeutic cancer vaccineformulations [75 76] As another example of versatility wefind magnetic nanoparticles These nanomaterials have beenconjugated with an enormous amount of fluorescent dyespolymeric matrixes and biologic macromolecules amongothers to provide the magnetic property to innumerous insituHPV biosensor applications [77 78]

The incursion of nanotechnology into biology has beencatalyzed by the positive and important role that analyticalmethodologies and automation have over the equipmentefficiency and effectivity thus allowing the rapid progressionof sensor systems [63 79] Nowadays we are presented withinnumerous types of transducers that can be used for theconstruction of biosensors and according to the physicalprinciple of transduction we find it easy to classify them intoelectrochemical optical piezoelectric and magnetic [72 7380 81] Along with a representation of a generic biosensorconstructed for HPV detection we show in Figure 1 the mainsignal transduction methods currently used

Compared to the conventional identification techniquesthe biosensors dedicated to the molecular diagnosis anddetection of HPV strains prove themselves less complicatedand exempt from prolonged experimentation processes andpurification requirements [35 38 68] The interest towardsbiosensors is growing due to the broad potential that thesedevices provide in terms of high sensitivity simplicity lowcost and small sample volume requirement The amount ofrecent publications in biosensors is the proof of the interestthat researchers have in the development of effective andstable sensor platforms for application in clinical analysis[82 83] In this review we will provide an overview of thetrends and advances in the field of biosensors developed forthe diagnosis and detection of HPV We will compare thedetection limits obtained for each transduction techniqueand the convenience of their use

21 Electrochemical Biosensors The improvement on elec-trochemical biosensors walks along with the advances ofanalytical chemistry a science dedicated to measure the


structure composition distribution and interaction of mat-ter The purpose of the electrochemical research is to designsensitive selective and specific detection strategies measur-ing principles and analytical methodologies In addition theautomation processes provided better construction strategiesfor obtaining biosensors with increased analytical perfor-mance [63 64 84] Since Clark and Lyons first developedan electrochemical biosensor for glucose in 1962 this trans-duction method represents the main class of biosensorsreported in the literature and they are by far the mostcommercially successful [74 80 85 86] In fact Vernonet al developed a bioelectronic detection platform for thedetection of multiple HPV types The design of the modelsystem is structured on gold electrodes where self-assembledmonolayers of immobilized oligonucleotides that are specificfor HPV genotypes are formed [27]

The electrochemical biosensor is a device composed ofa biological recognition element that is associated with anelectrochemical transducer capable of providing selectivequantitative or semiquantitative analytical information [7287] These biosensors require electroanalytical techniques(such as potentiometry amperometry voltammetry conduc-tometry and impedometry) [73 88] to measure the trans-duced output signal and to characterize the electrochemicalchanges in the system caused by the molecular recognitionprocess

As we have already stated electrochemical biosensorsare the most utilized devices for screening and diagnosingclinical analysis [65 74] In this sense we show in Table 1the trends on electrochemical techniques for biodetectionof HPV [35 38 68] The electrochemical biosensors arepromising diagnostic techniques for HPV because of theirtendency to miniaturization and due to their fast responsesimplicity and low cost instrumentation [88] Although theregeneration of the sensor platform might minimize thecost of the analysis only a few publications report reusableelectrochemical biosensors [28 32]

The actual interest on multiplex assays [31] which refersto the fulfilment of a full range of laboratory tests in theform of a centimeter square microarray is evident Alsothe incorporation of technological advances as microfluidicchannels is starting to venture willing to improve the alreadystablished multiplex assays The most frequent platform toimmobilize the oligonucleotides is a gold electrode achievingthe interaction through thiol-gold covalent bondingThepro-cess can be performed in the presence of a secondary reporterprobe (which will serve as a label during the measurementprocess) as tetramethylbenzidine (TMB) horseradish perox-idase methylene blue or hematoxylin providing an amplifiedelectrochemical response combined with greater specificity[29 31 32 36]

Besides the already mentioned gold electrodes in thelast five years label-free electrochemical microarrays havebeen used extensively for the detection of different HPV16antibodies [34 35 37 39] These label-free platforms aredeveloped through the immobilization of the biorecog-nition probe atop of an interdigitated gold or platinumelectrode The signal transducers are widely diverse pen-cil graphite surfaces [30 33] carbon surfaces modified

with linear polysaccharides [35] plain glassy carbon sur-face [34] or poly(methylmethacrylate) substrate recoveredwith a thin gold film [38] Additionally more sophisti-cated nanostructured ones as graphenegold nanoparticles(AuNPs) nanorodpoly(thionine) or polyaniline-multiwallcarbon nanotube (MWCNT) film [39 68] have been usedto construct biosensors committed to detect and differentiateHPV strainsThese platforms facilitate the study of the outputsignal by cyclic voltammetry (CV) square wave voltamme-try (SWV) [33 35] differential pulse voltammetry (DPV)[30 68] and electrochemical impedance spectroscopy (EIS)[68]

After analyzing the most recent developed electrochemi-cal biosensors for the identification of HPV we noticed thatthe sensor platform constructed by Wang et al holds thelowest detection limit reported in the literature for the DNAof HPV16 Interestingly the transducer of the platform wasdesigned from single walled carbon nanotube arrays coatedwith gold nanoparticles atop of which the self-assembly ofsingle-stranded DNA probe was promoted Electrochemicalimpedance was used to verify the high sensitivity greatstability and good regeneration ability of the biosensorwith a detection limit up to one attomole of HPV16 DNA[89]

From the presented alternatives we highlight the useof nanomaterials particularly carbon nanotubes and goldnanoparticles as strategic components to improve the ana-lytical performance of electrochemical biosensors [38 3968 89] The cited nanomaterials exhibit not only combineddielectric and optical properties but also a high surface-to-volume ratio biocompatibility and high conductivityallowing direct charge transfer between the biomolecule andthe electrode surface [90ndash92] Thus it is possible to obtainbiosensors with higher sensibility and ultralow detectionlimit

In addition there is a notable interest on the developmentof ultrasensitive methods for the detection of particularpapillomavirus strains especially the high-risk associatedHPV types 16 18 and 45 [31 32 68] In spite of theseelectrochemical biosensors being prototypes and requiringadditional studies of reproducibility stability and validationthey show potential to become valuable alternatives or eventhe new conventional diagnostic methods [93]

22 Optical Biosensors Visual differentiation techniques arewidely spread over important areas of modern life like foodsafety security and environmental monitoring in medicineand of course in HPV detection [66] Several of the firstmethods to detect diseases and pathological infections wereoptical based methods The Papanicolaou test a worldwidefamous cervical cytology exam performed to detect HPVwas developed to exploit optical techniques as microscopyIn recent decades other optical alternatives in the form ofoptical biosensor also named optrodes have grown robustbecause of the facility to differentiate the positive andnegativesamples by color changes produced by differential stainingand fluorescence labeling [94 95] In Table 2 we present thecomparison of some features used on recent publications for


Table1Electro

chem

icaltechniqu

esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

21different

typeso

fHPV

Goldsurfa

cecapture

oligon

ucleotides

Twohybridizationeventsmusto

ccur

for

electro

chem

icaldetection

Thefi

rstb

etweenthe

capturep

robe

andthetargetandthes

econ

dbetweenan

adjacent

region

ofthetargetand

ferrocenelabeled

signalprobe

CVmdash

mdash2to

8ho

urs

mdash[27]

HPV

16Sing

lewalledcarbon

nano

tube

arraysgoldnano

particlesHPV

16E7

prob

e

Hybrid

izationbetweenthec

apture

prob

eand

the

HPV

target(specific

toHPV

-16E7

region

)EIS

1aM

(Atto

molar)

1aM

to1120583

M2ho

urs

6tests

[28]

HPV

16Goldsurfa

ceL-cysteineHPV

16oligon

ucleotide

Them

easurementw

asbasedon

thereductio

nsig

nals

ofmethylene

blue

(MB)

before

andaft

erhybridizationbetweenthep

robe

andthes

ynthetic

targetor

extractedDNAfro

mclinicalsam

ples

DPV

1813

nM1875n

Mto

1000

nM10

minutes

mdash[29]

HPV

16Pencilgraphitesurfa

ceH

PV16

E6prob

e

Theh

ybrid

izationbetweenthec

apture

prob

eand

the

HPV

16E6

gene

was

directlydetected

throug

hgu

anineo

xidatio

nsig

nals

DPV

16pg120583L

5pg120583Lto

40pg120583L

5minutes

mdash[30]

HPV

16and

HPV

45Goldsurfa

ceth

iolated

HPV

16E7

pandHPV

45E6

prob

es

Theh

ybrid

izationwas

detected

byincorporatinga

horseradish

peroxidase-(HRP

-)labelledrepo

rter

prob

ethatp

airswith

thetargetTh

e331015840551015840-te

tram

ethylbenzidine

(TMB)

was

used

asa

chromogenicsubstratefor

enzyme

CV

490p

Mfor

HPV

16E7

p110

pMfor

HPV

45E6

01n

Mto

50nM

1hou

rmdash

[31]

HPV

16

HPV

18and

HPV

45

Goldsurfa

ceoligoethylene

glycol-te

rminated

bipo

dal

thiolthiolated

HPV

16E7

pHPV

18E6

and

HPV

45E6

prob

es

Thed

etectio

nwas

carriedwith

thetargeth

ybrid

ized

betweenas

urface

immob

ilizedprob

eand

aHRP

-labelledsecond

aryrepo

rter

prob

eTh

eTMB

was

used

asac

hrom

ogenicsubstratefor

HRP

CV

220p

Mfor

HPV

16E7

p170p

Mfor

HPV

18E6

and

110pM

for

HPV

45E6

01n

Mto

50nM

20minutes

5tests

[32]

HPV

(L1g

ene)

Pencilgraphitesurfa

ceH

PVprob

eTh

ehybrid

izationbetweenthep

robe

andHPV

target

was

studied

bymeasuremento

fMBsig

nal

accumulated

onthep

encilgraph

iteele

ctrode

SWV

12ng

120583L

12ng

120583Lto

50ng

120583L

3minutes

mdash[33]


Table1Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

16

Glassycarbon

surfa

cecon

jugated

copo

lymer

poly(5-hydroxy-14-

naph

thoq

uino

ne-co-5-hydroxy-2-

carboxyethyl-14-

naph

thoq

uino

ne)antig

enicpeptide

L1

Interactionbetweenantig

enicpeptideL

1and

HPV

-16antib

ody

SWV

50nM

mdash1h

our

mdash[34]

HPV

16

Carbon

surfa

cechitosananthraqu

inon

e-labeledpyrrolidinylpeptiden

ucleic

acid

(acpcPNA)p

robe

Theh

ybrid

izationwith

theH

PV16

DNAwas

studied

bymeasurin

gthee

lectrochem

icalsig

nalofthe

label

anthraqu

inon

eatta

ched

tothea

cpcPNAprob

eSW

V4n

M002

mM

to12nM

15minutes

mdash[35]

HPV

(L1g

ene)

Goldsurfa

cealkanethiolHPV

prob

e

Thes

tudy

was

perfo

rmed

basedon

theinteractio

nof

hematoxylin

with

analkanethiolD

NAprob

eand

itshybridized

form

CVand

DPV

38n

M125nM

to40

0nM

2ho

urs

mdash[36]

HPV

16Glassycarbon

surfa

cegraph

eneAu

nano

rodpo

lythionineH

PV16

prob

e

Besid

esthec

apture

prob

etwoauxiliary

prob

eswere

desig

nedforthe

hybridizationwith

HPV

DNA

110-Ph

enanthrolin

eruthenium

dichlorid

e([Ru

(phen)3]2+

)was

used

asthee

lectrochem

ical

indicator

EISand

DPV

403times

10minus14molL

1times10minus13molL

to1times

10minus10molL

90minutes

mdash[37]

HPV

16

Polymethylm

ethacrylate

substrategold

nano

layer4-

aminothiop

heno

lmon

oclonal

antib

ody(m

Ab)5

051

InteractionbetweenmAb

5051

andHPV

16

CVand

EIS

mdashmdash

1hou

rmdash

[38]

HPV

16

Platinum

surfa

cepolyanilin

e-multiw

alled

carbon

nano

tube

compo

siteHPV

16-L1p

eptid

eaptam

er

Interactionbetweenthea

ntigen

peptidea

ptam

erHPV

-16-L1

andHPV

-16antib

ody

CVand

SWV

490p

M10nM

to80

nM15

minutes

mdash[39]


Table2Opticaltechniqu

esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

s1618

313335

Aqueou

ssolution

Fluo

rescentreporterd

yecovalentlylin

kedto

the51015840end

andaq

uencherd

yelin

kedto

the31015840end

Fluo

rescence

PCR

Differentia

ldetectio

nof

samples

mim

icking

mixed

infections

upto

1of

thetotalDNA

101ndash106

DNA

copies

75minutes

after

DNA

extractio

nand

preparationof

PCR

solutio

ns

mdash[40]

Ratio

sbetween

HPV

s611

1618

and

313335

Insituhisto

logical

sample

Fluo

rescently

labeled

oligon

ucleotides

with

biotin-stre

ptavidin

mod

ificatio

n

Insitu

PCRFISH

LSC

M

1-2DNAcopies

1to50

DNA

copies

per

cell

Overnight

hybridization

noDNAextractio

nneeded

mdash[41]

HPV

s1618

Insituhisto

logical

sample

Oligon

ucleotides

labeledwith

digoxigenin-ll-dUTP

byrand

omprim

ing

FISH

autom

atic

imagec

ytom

etry

1DNAcopy

1ndash500DNA

copies

per

cell

6ho

ursa

fterc

ell

cultu

ren

oDNA

extractio

nneeded

mdash[42]

HPV

s1618

Avidin

coated

(LKB

Sw

eden)sensorc

hip

Biotinylated

oligon

ucleotide

boun

dto

oncoproteins

Plasmon

resonance

018120583M

01ndash4120583

M

mdashmdash

[43]

HPV

s1618

Nitrocellulose

DNA

chip

Biotin

labeledoligon

ucleotides

sand

wichof

streptavidin

toflu

orescenced

ye

PCRchromatograph

yflu

orescence

Qualitative

mdash30

minutes

mdash[44]

HPV

s611

DNAam

plificatio

nOligon

ucleotides

labeledwith

fluorescent

prob

esop

timized

forF

RET

Real-timeP

CRFR

ET-fluo

rescence

25ndash4

3DNAcopies

1ndash3times107

DNAcopies

90minutes

mdash[45]

13different

typeso

fHPV

Nitrocellulose

chip

Fluo

rescently

labeled

oligon

ucleotides

immob

ilized

viab

iotin

-avidin

PCRam

plificatio

n10ndash102

plasmid

copies

0ndash105DNA

copies

30minutes

for

incubatio

n30

second

sfor

reading

Lateral

flow

60tests

[46]

HPV

s1618

Photon

iccrystalon

silicon

Antibod

yim

mob

ilizatio

nOpticaldetectionof

resonant

mod

es

150n

M

0ndash15

nM

16ho

urs

mdash[47]

HPV

16CM

5sensor

chip

(GE

Health

care)

Pairw

iseantib

ody

footprintin

gSP

R10120583gmL

50ndash200120583g

30minutes

3tests

[48]

24different

typeso

fHPV

Goldchip

DNA-

prob

ehybrid

ization

PCRSP

RQualitative

mdash4ho

urs

mdash[49]

HPV

16Quantum

Dot

(75n

m)Maghemite

(46n

m)

Oligon

ucleotides

labeledwith

superparam

agnetic

nano

particles

andQDs

Fluo

rescence

spectro

scop

yQualitative

mdash1h

our

mdash[50]

HPV

16Silican

anop

articles

(75n

M)

Folatefun

ctionalization

Fluo

rescence

microscop

yQualitative

mdash15

minutes

mdash[51]


Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon

ucleotidelabelledwith

goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent

insituhybridization(FISH)laserscann

ingconfocalmicroscop

y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)


the identification and detection of HPV strains by opticaltransducersWhen applied to conventionalmethods fluores-cent and color labels provide an upgrade in the analysis oftissue samples allowing fast and automatized diagnosis basedon the differential staining of cancerous cells A techniquefrequently employed to diagnose HPV is the fluorescentin situ hybridization (FISH) this technique provides thepossibility to examine the tissue sample at the same time thatthe fluorescent label probe signals the specificDNA region forwhich it was designed

When PCR assays reached HPV diagnosis [96] the useof fluorescent molecules impelled not only the detection butthe quantitation of oncogenic HPV strains by real-time PCR(RT-PCR) [40] Mostly fluorescent nanoparticles provide alabeled transduction methodology that has proven to be veryuseful for the identification of HPV viral genome after PCRamplification [44] To date RT-PCR is the only techniquecapable of identifying closely related HPV strains The groupof Poljack has demonstrated a beautiful use of fluorescenceresonance energy transfer (FRET) coupled with RT-PCR toachieve the identification of 19 different HPV strains thatare important because of their oncogenic risk [45] Theysuccessfully identified several HPV strains mixed in thesame sample with a presence as low as 25ndash43 DNA strandsper strain Despite the advances on terms of specificity andsensibility PCR based methodologies are being rapidly chal-lenge by optrode methodologies Some of these alternativebiosensors provide a significant reduction in diagnosis timebesides an increased portability and facility of use out ofcontrolled laboratory environment Although optrodes do nothold the lowest detection limit when they are combinedwith spectroscopic techniques they represent one of themethodologies with the highest sensibility For instance Liand col [54] developed a glass chip with immobilized HPVs6 11 16 and 18 oligonucleotides The hybridized target DNAwas labeled with gold and silver nanoparticles besides afluorescent molecule Their strategy attained a 005 pmol120583Ldetection limit

Themost common analytical techniques used to measurethe transduced signal of optical biosensors include absorp-tion fluorescence phosphorescence Raman refraction anddispersion spectroscopies also there is surface plasmonresonance (SPR) [97] Biosensors that make use of thesurface plasmonic waves of metallic substrates to detect theinteraction between the target analyte and the biorecognitionelement are actually monitoring the change in the refractiveindex (RI) at the analyte-sensor interface The RI changesproduce a variation in the propagation constant of thesurface plasmon wave that will produce the reading [98]One of the signatures of SPR is its convenience as a label-free sensing principle avoiding the use of radioactive andfluorescence markers Since SPR measures the mass of thematerial binding to the sensor surface [99] the techniqueis not suitable for studying small analytes lt2 kDa howeverSPR has been proposed as an optimal transducer to identifyHPV strains among other viruses [100] based on size andmass differences or as an immunologic methodology Inaddition the proper functionalization of the SPR substrateprovides high specificity towards selected HPV strains Once

the substrate is properly functionalized the methodologycan perform several diagnoses and regeneration cycles in arow resulting in a reduction of time when compared to PCRbasedmethodologies As an immunologic methodology SPRachieved the detection limit of 10120583g of HPV16 expressedprotein per mL

The use of fluorescent nanoparticles as transducersrequires the synergy between the nanostructure and one orseveral distinct biologicalmaterials as enzymes nucleic acidsor antibodies to the capsid of the target virus Some of themost important characteristics of nanoparticles are its surfaceand then the transduction method that the nature of thenanoparticle involves In the case of fluorescent nanoparti-cles quantum dots (QD) are semiconductor nanoparticleswith exceptional optical properties such as fluorescent emis-sion controlled by the size of the nanoparticle Some quantumdots are assembled as core-shell structures where magneticcore plays an important role in recovering the particlesfrom the sample Nanoparticles are generally exploited bybioconjugation that is by the intelligent mixing of thenanostructure with some biological molecules as DNA orRNA oligonucleotides this conjugation is made to favor thebinding of small oligonucleotides that are complementaryto HPV DNA These kinds of bioconjugated systems havedemonstrated to differentiate between HPV16 and HPV18strains mixed in the same sample [101] Usually utilizedas reporters or signal enhancers [52 54] nanoparticles aredesigned based on their combinationwith another techniqueIn this manner silica nanoparticles (SiNPs) are commonlymixed with fluorescentmolecules to achieve the prescreeningof many HPV genotypes [51] Nanoparticles can also becovalently linked to oligonucleotides as Yu-Hong and coldescribed [50] In their method to detect HPV16 they func-tionalize QD and magnetic nanoparticles to DNA probesWhen both probes attach to a HPV16 DNA specific regionthen the labeled DNA responds to an applied magneticfield and at the same time presents luminescence fromthe QD Even though these kinds of qualitative diagnosticmethods are developed to serve a single sample they areadvantageous because they are portable and feature simplifiedhandling

Fluorescence is an important luminescent property ofcertain molecules When fluorescent systems are engineeredto recognize a certain HPV strain not only does the fluores-cence of themolecule provide in situ evidence of the existenceof the expected strain but also its quantification can beeasily achieved An exact amount of energy must be suppliedto the molecule so that it can get into the excited statefrom which the luminescence will occur Electromagneticradiation is the most common way to provide this energybut there are other quite rare and convenient ways to supplythis energy as by heat by frictional force and by electronimpact or crystallization [102] all these alternatives are stillto be exploited for the specific detection of HPV For themost part optical transducers and optical biosensors aregaining research interest actually Qiagen NV a moleculardiagnostics company has developed and commercialized thefirst molecular diagnostic to screen for high-risk HPV strainsdesigned for low-resource clinical settings [103]


Table 3 Piezoelectric biosensors for HPV detection

HPV type Sensor platform Techniques Application Sensibility Detection limit References

HPVs 6 1116 18

HPV probes with adisulfide group QCM Qualitative results from QCM versus

dot-blot hybridization

25 120583M ofpredigestedPCR products

minusΔ119865 = 48 plusmn 5Hz [55]

HPVs 16 18

Biotinylated HPVprobes viastreptavidinanchoring

QCM Simultaneous identification andgenotyping HPVs 16 and 18

50 nM of PCRproducts minusΔ119865 = le3Hz [56]

HPVs 6 11 HPV probes QCMDetection of single strand-PCRproducts in temperature changes bymetal clamping piezoelectric sensor

25 120583M minusΔ119865 = 82 plusmn 37Hz [57]

HPV 58Biotinylated LAMPHPV products viaavidin anchoring

LAMP-QCM Real-time amplification andhybridization to HPV 58 probe

1ndash106 plasmidclones Δ119865 = 283Hz [58]

11 differenttypes ofHPV

Biotinylated HPVprobes via avidinanchoring

QCMQCM sensor replacement oftraditional method HPV detection ingel electrophoresis for QCM system

103 plasmidclones Δ119865 = 447Hz [59]

HPV 16Alkanethiolself-assemblingmonolayer

QCM-DDetection of antigens (cytoplasmicproteins) from cancer cell lines byHPV

Bayesian classifier dependent [60]

lowastLoop-mediated isothermal amplification (LAMP)

23 Piezoelectric Biosensors The recent success in the molec-ular diagnosis of HPV by electrochemical and optical trans-ducers based on the sequence-specific detection of nucleicacids (DNA or RNA) encouraged the development of diag-nostic tools based in other novel transducer methods asthe piezoelectric biosensors Biosensors are important alter-natives to the conventional molecular biology techniqueslike the blotting methods because they hold associatedadvantages in terms of cost run time and real-time moni-toring [104] Piezoelectric biosensors exploit a secondary butnot less important aspect of the electrochemical biosensorthe gravimetric analysis of the biosensor surface In eachelectrochemical reaction mass changes occur as material isdeposited or lost from the surface of the transducer andthe monitoring of these changes simultaneously with theelectrochemical response provides the piezoelectric biosen-sor with clear advantages over the electrochemical biosensoraloneThese gravimetric transducers have shown to be able toachieve good sensitivity and specificity for the targetmolecule[105 106]

The quartz crystal microbalance (QCM) sensors consistof cavity resonators constructed over a piezoelectric crystalsubstrate which will accumulate electrical charge in responseto the applied mechanical stress The most common methodto immobilize the biocompatible layer is achieved by thephysical adsorption of the biological probe over the quartzbalance this kind of nonspecific interaction results in thestrong collective action of a large number of relative weakbonding interactions However the recent trend for theuse of QCM biosensors for the detection of HPV virusesprefers a more specific strategy of immobilization involvingbiotinylated HPV probes In Table 3 we present the com-parison of some features used in recent publications for theidentification and detection of HPV strains by piezoelectrictransducers

The specificity of the biotinstreptavidin bonding is usedin conventional assays as the enzyme-linked immunosorbentassay (ELISA) The binding mechanism between biotin andstreptavidin results in long-term stable anchoring [107]DellrsquoAtti et al developed a biosensor based on such pro-cesses of immobilization for the recognition of HPV 16 and18 types Their methodology allowed monitoring real-timehybridization by frequency changes which resulted in HPVtype differentiation They achieve the identification within a50 nM detection limit of PCR-amplified short DNA strandsFurthermore the stability of the probe-surface interactionallowed the regeneration of the system up to fifteen timeswithout losing sensitivity [56] Moreover this techniquepresented some advantages over conventional moleculartechniques that require many steps to achieve the same result[108 109]

Fu et al have constructed one of the first HPV genosen-sors based on QCM piezoelectric This group aimed at thedetection and identification of HPV types 6 11 16 and18 from pathologic biopsy samples The strategy involvedthe adsorption of HPV oligonucleotides functionalized withdisulfide groups atop the surface of a QCM disc The systempresented high sensibility (up to 95) which is comparableto the result obtained by the combination of PCR and dot-blot technique [55 110] This label-free technique offers somebenefits like rapidness convenience low cost and feasiblemultiple sensors building on several QCM plates [103]

One important aspect that is relevant for the correct useof DNA based QCM piezoelectrics is temperature Main-taining a constant temperature during the formation of thebiocompatible layer has been shown to influence its eventualthickness As a result the frequency pattern of the samplesis modified as well [111] Consequently the complementaryprinciple of nucleic acids allows real-time monitoring ofthe hybridization processes that result from the change in


oscillation frequency of the QCM system after the doublestrand is formed [57 112 113] Chen et al [57] demonstratedthat by maintaining the PCR products (amplicon) at lowtemperatures (sim4∘C) they could avoid the self-hybridizationof DNA resulting in a diagnosis with increased sensibilityand accuracy

Because of the deep impact that temperature has over thestability of the resonance frequency techniques that dependon thermal cycling are severely limited For this reasonalternatives that provide the amplification of a genomicregion at constant temperature have been of great advan-tage Loop-mediated isothermal amplification (LAMP) hasadhered to QCM piezoelectrics with tremendous successLAMP provides genomic amplification with high sensitivityspecificity and rapidity [114] Recently Prakrankamanant etal developed a prototype system tomonitor the differences inthe resonance frequency by QCM-LAMP to detect the high-risk strain HPV 58 The amplicon obtained by LAMP wasbiotinylated and then anchored to the avidin-coated surfaceof the sensor platform Differently from conventional LAMPthe incorporation of QCM real-time monitoring systemallowed a rapid and quantitative detection of HPV [58]

The same research groups aimed to increase the scopeof their biosensor by immobilizing biotinylated probes for11 high-risk types of HPV This technique showed goodaccuracy for all probes with sensitivity up to 103 copies120583Ltheir results are showed to be comparable to coupled PCRamplification and electrophoresis based analysis Althoughthe operational time of QCM-LAMP is similar to the conven-tional PCRelectrophoresis technique the QCM prototypestands out since no labeling is required and because theconstant system temperature is close to 4∘C For certain thisnew tool represents a milestone for piezoelectric biosensorsand opens the path to complement the exploration of theinteractions occurring on top of the electrochemical biosen-sor [59]

As an alternative to the previously described DNAbiosensors Mobley et al used a different approach forthe QCM piezoelectric technique it is by the dissipationfrequency monitoring (QCM-D) instead of the resonancefrequency Commonly applied in the fields of biophysics bio-materials cell adhesion and drug discovery this interfacialacoustic technique is a special type of QCM that serves toanalyze the thickness of a film in a liquid environment [60]In their study they attained to distinguish between HPV-positive and HPV-negative cells based on antigen proteinexpression from a prelysed cancer cell line Furthermoretheir theoretical guidelines based on linear discriminationwere useful for the analysis of the output signals of otherimmunosensor platforms and for the diagnosis of diseasesHowever these models still require standardization to vali-date their results

24 Magnetic Biosensors Biosensors based on magneticmaterials have presented a distinctive alternative to identifyand diagnose diseasesThe response signal occurs in a similarfashion than in other transducers at the surface of the mag-neticmaterial there is a specific biological probe immobilized

and ready to interact with its counterpart found on a samplesuspected to contain biologic traces of HPV Not only havethese methodologies allowed the physical separation of thesubstrates bymagnetic field but also there are somemagnetictransducers that are able to compete with the specificity andsensibility threshold that optical transducers might detent interms of quantification of the transduced signal [115ndash117]

Throughout Section 2 we have given several examplesabout how magnetic materials are employed in the formof nanoparticles to provide not only but mostly theirmagnetic characteristic in order to physically separate thefunctionalized magnetic beads from the working solutionHowever over the last decade magnetoresistive materi-als have been explored in the form of multilayered films(alternating layers of magnetic and nonmagnetic materials)or granulated substrates (magnetic islands inserted into anonmagnetic material) to determine the advantages of theiruse as transducer materials in biosensors In simple wordsthemagnetoresistance effect occurswhen under the presenceof a magnetic field the magnetic material experiences achange in its global electrical resistance

These materials are very susceptible to magnetic fieldsfor this reason even a 10 nm size magnetic nanoparticlemight create a measurable signature of its close proximity tothe magnetoresistive substrate [118] and actually this is thesensing principle behind its known great sensibility

In spite of the novelty of the methodology there arefew reports about its use in the detection of HPV [119] Forinstance Xu et al developed a multilayered system for theselective detection of HPV 16 18 33 and 45 subtypes Therespective DNA probes were immobilized over the surface ofthe biosensor to propitiate the capture by hybridization ofthe complementary targeted DNA (if present on the sample)the methodology of immobilization follows the trend used inother transducers (Figure 2)

To immobilize the probe on the surface the interactionbetween amine and carboxylic acid groups is used whilethe target DNA is functionalized at the loose end withbiotin To quantify the amount of hybridized target DNAthe biosensor is then exposed to magnetic nanoparticlesthat will bind to the biotin because they were previouslyfunctionalized with avidin Finally the close presence of themagnetic nanoparticles interferes with the magnetoresistivematerial creating a response signal equivalent to the amountof hybridized target DNA This methodology was able toreach 90 of accuracy and a sensitivity around 10 pM oftarget DNA in addition the development of these biodevicespresents low cost rapid detection and reliability [120]

3 Conclusion

The proper diagnosis of HPV infection is essential for theprevention of cervical cancerThe implementation of effectivetherapeutic strategies requires the development of biosensorsfor the detection and identification of HPV types To thisdate optical electrochemical and piezoelectric materials arethe main transducers used to develop biosensors Among


Biotinylated DNA target

Magnetic particles modified with

streptavidinDNA probe

Graphicalrepresentation

(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760

Figure 2 Schematic representation of a magnetic genosensor for the detection of HPVThe DNA probe was immobilized on the transducersurface (a) Then biotinylated DNA target was hybridized (b) Magnetic particles modified with streptavidin were added on the genosensor(c) Measuring the magnetic signal could characterize the bioactivity of biodevice (d) It is important to highlight that the magnetic signalintensity is proportional to the number of biospecific interactions between the streptavidin molecules and the biotin groups

the most sensitive techniques available to study the biorecog-nition activity of the sensors we highlight the fluorescentspectroscopy EIS and QCM

We notice a rapid growth in technological improvementsfor the development of simple cost-effective and accuraterapid diagnostic tests The sensitivity and detection limit areessential parameters for the evaluation of these biodetectionmethodologies However other characteristics as the speci-ficity propensity to cross-binding interference experimentalsimplicity and cost should be considered For instance itwas verified that the use of nanostructures (as carbon nan-otubes and gold nanoparticles) enables the construction ofelectrochemical biosensors with lower detection limitsNotwithstanding improvements in the design and manu-facturing should be considered to achieve the commercialincursion of these devices since their reuse is limited

The ability to fast regenerate the substrate after a diag-nosed sample is of great importance and affects directly thecost of the methodology In this sense QCM and nitrocellu-lose substrates have managed to get more than 10 diagnoseswithout losing sensibility also microfluidics are helping tocreate in-flow diagnostics to first allow the sensing to occurquickly wash the substrate and then offer a new sample todiagnose

Thus future researches should explore new strategies toenhance the immobilization and to increase the stability ofbioreceptors The development of methodologies that facil-itate the use of biosensors out of controlled laboratory envi-ronment is of great importance for the popularization of thesemethodologies Furthermore evaluating the performance ofthe biosensors by facing real samples such as blood andother body fluids will verify the real potential of these newmolecular methods to confirm the clinical diagnosis of HPV

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors are grateful for the support provided by theBrazilian National Council for Scientific and Technological

Development (CNPq Grants 3103052012-8 and 3103612012-5) Fundacao de Amparo a Ciencia e Tecnologia do Estadode Pernambuco (FACEPE) and Rede de NanobiotecnologiaCAPES Silva and Morales would like to thank FACEPE andCAPES for their respective scholarships

References

[1] P S Moore and Y Chang ldquoWhy do viruses cause cancerHighlights of the first century of human tumour virologyrdquoNature Reviews Cancer vol 10 no 12 pp 878ndash889 2010

[2] D M Parkin ldquoThe global health burden of infection-associatedcancers in the year 2002rdquo International Journal of Cancer vol118 no 12 pp 3030ndash3044 2006

[3] J E Tota A V Ramanakumar M Jiang et al ldquoEpidemiologicapproaches to evaluating the potential for human papillo-mavirus type replacement postvaccinationrdquo American Journalof Epidemiology vol 178 no 4 pp 625ndash634 2013

[4] M Schmitt B Dondog T Waterboer M Pawlita M Tom-masino and T Gheit ldquoAbundance of multiple high-risk humanpapillomavirus (HPV) infections found in cervical cells ana-lyzed by use of an ultrasensitive HPV genotyping assayrdquo Journalof Clinical Microbiology vol 48 no 1 pp 143ndash149 2010

[5] A R Kreimer A Villa A G Nyitray et al ldquoThe epidemiologyof oral hpv infection among a multinational sample of healthymenrdquo Cancer Epidemiology Biomarkers amp Prevention vol 20no 1 pp 172ndash182 2011

[6] I Frazer ldquoCorrelating immunity with protection for HPVinfectionrdquo International Journal of Infectious Diseases vol 11supplement 2 pp S10ndashS16 2007

[7] O Aynaud D Piron R Barrasso and J-D Poveda ldquoCompari-son of clinical histological and virological symptoms ofHPV inHIV-1 infected men and immunocompetent subjectsrdquo SexuallyTransmitted Infections vol 74 no 1 pp 32ndash34 1998

[8] W-Y Zhu A Blauvelt B A Goldstein C Leonardi and NS Penneys ldquoDetection with the polymerase chain reaction ofhuman papillomavirus DNA in condylomata acuminatatreated in vitro with liquid nitrogen trichloroacetic acid andpodophyllinrdquo Journal of the American Academy of Dermatologyvol 26 no 5 part 1 pp 710ndash714 1992

[9] K Niwa K Tagami Z Lian J Gao H Mori and T TamayaldquoTopical vidarabine or 5-fluorouracil treatment against persis-tent HPV in genital (pre)cancerous lesionsrdquo Oncology Reportsvol 10 no 5 pp 1437ndash1441 2003


[10] C-MChuangAMonie C-FHung andT-CWu ldquoTreatmentwith Imiquimod enhances antitumor immunity induced bytherapeutic HPV DNA vaccinationrdquo Journal of BiomedicalScience vol 17 no 1 article 32 2010

[11] L O Sarian S F M Derchain L A A Andrade J TambasciaS S Morais and K J Syrjanen ldquoHPV DNA test and Papsmear in detection of residual and recurrent disease followingloop electrosurgical excision procedure of high-grade cervicalintraepithelial neoplasiardquo Gynecologic Oncology vol 94 no 1pp 181ndash186 2004

[12] C Facchini G A Eremita and A Bernabei ldquoCombinationof beta-interferon and laser-CO2 therapy in female HPVgenitalisrdquo Minerva Ginecologica vol 48 no 9 pp 345ndash3491996

[13] P Nieminen M Aho M Lehtinen E Vesterinen A Vaheriand J Paavonen ldquoTreatment of genital HPV infection withcarbon dioxide laser and systemic interferon alpha-2brdquo SexuallyTransmitted Diseases vol 21 no 2 pp 65ndash69 1994

[14] J Chen W Gu L Yang et al ldquoNanotechnology in the manage-ment of cervical cancerrdquo Reviews in Medical Virology vol 25pp 72ndash83 2015

[15] K Morshed D Polz-Gruszka M Szymanski and M Polz-Dacewicz ldquoHuman Papillomavirus (HPV)mdashstructure epi-demiology and pathogenesisrdquo Otolaryngologia Polska vol 68no 5 pp 213ndash219 2014

[16] M Stanley ldquoThe epidemiology and burden of HPV diseaserdquoNursing Times vol 104 no 36 pp 38ndash40 2008

[17] D Ertoy Baydar I Kulac A Ozagari and G Guler TezelldquoOccurrence of dysplasia and human papilloma virus typing inpenile condylomasrdquo Urology vol 81 no 1 pp 211e9ndash211e152013

[18] E Beerens L van Renterghem M Praet et al ldquoHuman papil-lomavirus DNA detection in women with primary abnormalcytology of the cervix prevalence and distribution of HPVgenotypesrdquo Cytopathology vol 16 no 4 pp 199ndash205 2005

[19] I Salimovic-Besic A Tomic-Cica A Smailji and M HukicldquoComparison of the detection of HPV-16 18 31 33 and 45by type-specific DNA- and E6E7 mRNA-based assays of HPVDNA positive women with abnormal Pap smearsrdquo Journal ofVirological Methods vol 194 no 1-2 pp 222ndash228 2013

[20] P G Rossi M Benevolo A Vocaturo et al ldquoPrognostic valueofHPVE6E7mRNAassay inwomenwith negative colposcopyor CIN1 histology result a follow-up studyrdquo PLoS ONE vol 8no 2 Article ID e57600 2013

[21] A Vince and S Z Lepej ldquoDiagnostic methods and techniquesin cervical cancer prevention Part II molecular diagnostics ofHPV infectionrdquoMedicinski Glasnik vol 7 no 1 pp 18ndash25 2010

[22] W Weichert C Schewe C Denkert L Morawietz M Dieteland I Petersen ldquoMolecular HPV typing as a diagnostic tool todiscriminate primary frommetastatic squamous cell carcinomaof the lungrdquoTheAmerican Journal of Surgical Pathology vol 33no 4 pp 513ndash520 2009

[23] K D Tardif K E Simmon Oslash Kommedal M T Pyne andR Schlaberg ldquoSequencing-based genotyping of mixed humanpapillomavirus infections by use of ripseq softwarerdquo Journal ofClinical Microbiology vol 51 no 4 pp 1278ndash1280 2013

[24] L Shi H L Sings J T Bryan et al ldquoGARDASIL prophylactichuman papillomavirus vaccine developmentmdashfrom bench topto bed-siderdquo Clinical Pharmacology amp Therapeutics vol 81 no2 pp 259ndash264 2007

[25] A Monie S-W D Tsen C-F Hung and T-C Wu ldquoTherapeu-tic HPVDNA vaccinesrdquo Expert Review of Vaccines vol 8 no 9pp 1221ndash1235 2009

[26] A Tahamtan A Ghaemi A Gorji et al ldquoAntitumor effect oftherapeutic HPV DNA vaccines with chitosan-based nanode-livery systemsrdquo Journal of Biomedical Science vol 21 no 1article 69 2014

[27] S D Vernon D H Farkas E R Unger et al ldquoBioelectronicDNA detection of human papillomaviruses using eSensor amodel system for detection of multiple pathogensrdquo BMCInfectious Diseases vol 3 article 12 2003

[28] S Wang L Li H Jin et al ldquoElectrochemical detection ofhepatitis B and papilloma virus DNAs using SWCNT arraycoated with gold nanoparticlesrdquo Biosensors and Bioelectronicsvol 41 no 1 pp 205ndash210 2013

[29] D S Campos-Ferreira G A Nascimento E V M Souza et alldquoElectrochemical DNA biosensor for human papillomavirus 16detection in real samplesrdquo Analytica Chimica Acta vol 804 pp258ndash263 2013

[30] D S Campos-Ferreira E V M Souza G A Nascimento et alldquoElectrochemical DNA biosensor for the detection of humanpapillomavirus E6 gene inserted in recombinant plasmidrdquoArabian Journal of Chemistry 2014

[31] L Civit A Fragoso and C K OrsquoSullivan ldquoElectrochemicalbiosensor for the multiplexed detection of human papillo-mavirus genesrdquo Biosensors and Bioelectronics vol 26 no 4 pp1684ndash1687 2010

[32] L Civit A Fragoso S Holters M Durst and C K OrsquoSullivanldquoElectrochemical genosensor array for the simultaneous detec-tion of multiple high-risk human papillomavirus sequences inclinical samplesrdquo Analytica Chimica Acta vol 715 pp 93ndash982012

[33] R E Sabzi B SehatniaMH Pournaghi-Azar andM SHejazildquoElectrochemical detection of human papilloma virus (HPV)target DNA using MB on pencil graphite electroderdquo Journal ofthe Iranian Chemical Society vol 5 no 3 pp 476ndash483 2008

[34] B Piro A Kapella V H Le et al ldquoTowards the detection ofhuman papillomavirus infection by a reagentless electrochem-ical peptide biosensorrdquo Electrochimica Acta vol 56 no 28 pp10688ndash10693 2011

[35] S Jampasa W Wonsawat N Rodthongkum et al ldquoElectro-chemical detection of human papillomavirus DNA type 16using a pyrrolidinyl peptide nucleic acid probe immobilized onscreen-printed carbon electrodesrdquo Biosensors amp Bioelectronicsvol 54 pp 428ndash434 2014

[36] N Nasirizadeh H R Zare M H Pournaghi-Azar and MS Hejazi ldquoIntroduction of hematoxylin as an electroactivelabel for DNA biosensors and its employment in detectionof target DNA sequence and single-base mismatch in humanpapilloma virus corresponding to oligonucleotiderdquo Biosensorsand Bioelectronics vol 26 no 5 pp 2638ndash2644 2011

[37] K-J Huang Y-J Liu J-Z Zhang J-T Cao and Y-M LiuldquoAptamerAunanoparticlescobalt sulfide nanosheets biosensorfor 17beta-estradiol detection using a guanine-rich complemen-tary DNA sequence for signal amplificationrdquo Biosensors andBioelectronics vol 67 pp 184ndash191 2015

[38] L F Urrego D I Lopez K A Ramirez C Ramirez andJ F Osma ldquoBiomicrosystem design and fabrication for thehuman papilloma virus 16 detectionrdquo Sensors and Actuators BChemical vol 207 pp 97ndash104 2015

[39] L D Tran D T Nguyen B H Nguyen Q P Do and HLe Nguyen ldquoDevelopment of interdigitated arrays coated with


functional polyanilineMWCNT for electrochemical biodetec-tion application for human papilloma virusrdquo Talanta vol 85no 3 pp 1560ndash1565 2011

[40] A Josefsson K Livak and U Gyllensten ldquoDetection andquantitation of human papillomavirus by using the fluorescent51015840 exonuclease assayrdquo Journal of Clinical Microbiology vol 37no 3 pp 490ndash496 1999

[41] G Lizard M-C Chignol C Souchier P Roignot Y Chardon-net and D Schmitt ldquoDetection of low copy numbers ofHPV DNA by fluorescent in situ hybridization combined withconfocal microscopy as an alternative to in situ polymerasechain reactionrdquo Journal of Virological Methods vol 72 no 1 pp15ndash25 1998

[42] M Siadat-Pajouh A Periasamy A H Ayscue et al ldquoDetectionof human papillomavirus Type 1618 DNA in cervicovaginalcells by fluorescence based in situ hybridization and automatedimage cytometryrdquo Cytometry vol 15 no 3 pp 245ndash257 1994

[43] M Chinami M Inoue K Masunaga T Fukuma M Shinguand T Toyoda ldquoNucleic acid binding by zinc finger-like motifof human papillomavirus type 16 E7 oncoproteinrdquo Journal ofVirological Methods vol 59 no 1-2 pp 173ndash176 1996

[44] S J KimK BNahm J B Lim SWOh andE Y Choi ldquoA rapidand sensitive detection of HPV by combined assay of PCR andfluorescence DNA chiprdquo Biochip Journal vol 8 no 1 pp 48ndash542014

[45] B J Kocjan K Seme and M Poljak ldquoDetection and differen-tiation of human papillomavirus genotypes HPV-6 and HPV-11by FRET-based real-time PCRrdquo Journal of Virological Methodsvol 153 no 2 pp 245ndash249 2008

[46] Y Xu Y Liu Y Wu X Xia Y Liao and Q Li ldquoFluorescentprobe-based lateral flow assay for multiplex nucleic acid detec-tionrdquo Analytical Chemistry vol 86 no 12 pp 5611ndash5614 2014

[47] S Pal A R Yadav M A Lifson J E Baker P M Fauchetand B L Miller ldquoSelective virus detection in complex samplematrices with photonic crystal optical cavitiesrdquo Biosensors andBioelectronics vol 44 pp 229ndash234 2013

[48] V Towne Q Zhao M Brown and A C Finnefrock ldquoPair-wise antibody footprinting using surface plasmon resonancetechnology to characterize human papillomavirus type 16 virus-like particles with direct anti-HPV antibody immobilizationrdquoJournal of ImmunologicalMethods vol 388 no 1-2 pp 1ndash7 2013

[49] S Wang H Yang H Zhang et al ldquoA surface plasmonresonance-based system to genotype human papillomavirusrdquoCancer Genetics and Cytogenetics vol 200 no 2 pp 100ndash1052010

[50] W Yu-Hong C Rui and L Ding ldquoA quantum dots and super-paramagnetic nanoparticle-based method for the detection ofHPV DNArdquoNanoscale Research Letters vol 6 no 1 article 4612011

[51] S Palantavida N V Guz C D Woodworth and I SokolovldquoUltrabright fluorescent mesoporous silica nanoparticles forprescreening of cervical cancerrdquo Nanomedicine Nanotechnol-ogy Biology and Medicine vol 9 no 8 pp 1255ndash1262 2013

[52] R Ricco A Meneghello and F Enrichi ldquoSignal enhancementin DNAmicroarray using dye doped silica nanoparticles appli-cation to Human Papilloma Virus (HPV) detectionrdquo Biosensorsand Bioelectronics vol 26 no 5 pp 2761ndash2765 2011

[53] W Wang D-W Pang and H-W Tang ldquoSensitive multiplexedDNAdetection using silica nanoparticles as the target capturingplatformrdquo Talanta vol 128 pp 263ndash267 2014

[54] X Z Li S Kim W Cho and S-Y Lee ldquoOptical detection ofnanoparticle-enhanced human papillomavirus genotyping

microarraysrdquo Biomedical Optics Express vol 4 no 2 pp187ndash192 2013

[55] W Fu Q Huang J Wang M Liu J Huang and B ChenldquoDetection of human papilloma virus with piezoelectric quartzcrystal genesensorsrdquo Sensors amp Transducers Magazine vol 42no 4 6 pages 2004

[56] D DellrsquoAtti M Zavaglia S Tombelli et al ldquoDevelopment ofcombined DNA-based piezoelectric biosensors for the simulta-neous detection and genotyping of high risk Human PapillomaVirus strainsrdquo Clinica Chimica Acta vol 383 no 1-2 pp 140ndash146 2007

[57] Q Chen Z Bian X Hua et al ldquoDetection of hybridization ofsingle-strand DNA PCR products in temperature change pro-cess by a novel metal-clamping piezoelectric sensorrdquo Biosensorsand Bioelectronics vol 25 no 9 pp 2161ndash2166 2010

[58] P Prakrankamanant C Leelayuwat C Promptmas et al ldquoThedevelopment of DNA-based quartz crystal microbalance inte-grated with isothermal DNA amplification system for humanpapillomavirus type 58 detectionrdquoBiosensors and Bioelectronicsvol 40 no 1 pp 252ndash257 2013

[59] P Parsongdee T Limpaiboon C Leelayuwat C Promptmasand P Jearanaikoon ldquoDevelopment of biosensor for high riskHPV detection in cervical cancerrdquo KKU Research Journal(Graduate Studies) vol 8 no 1 2008

[60] S Mobley S Yalamanchili H Zhang et al ldquoProcedure fordeveloping linear and Bayesian classification models basedon immunosensor measurementsrdquo Sensors and Actuators BChemical vol 190 pp 165ndash170 2014

[61] N Li S Franceschi R Howell-Jones P J F Snijders and GM Clifford ldquoHuman papillomavirus type distribution in 30848invasive cervical cancers worldwide variation by geographicalregion histological type and year of publicationrdquo InternationalJournal of Cancer vol 128 no 4 pp 927ndash935 2011

[62] J-H Su A Wu E Scotney et al ldquoImmunotherapy for cervicalcancerrdquo BioDrugs vol 24 no 2 pp 109ndash129 2010

[63] C Jianrong M Yuqing H Nongyue W Xiaohua and L SijiaoldquoNanotechnology and biosensorsrdquo Biotechnology Advances vol22 no 7 pp 505ndash518 2004

[64] S-H Yeom B-H Kang K-J Kim and S-W Kang ldquoNanos-tructures in biosensormdasha reviewrdquo Frontiers in Bioscience vol16 no 3 pp 997ndash1023 2011

[65] M Mehrvar and M Abdi ldquoRecent developments characteris-tics and potential applications of electrochemical biosensorsrdquoAnalytical Sciences vol 20 no 8 pp 1113ndash1126 2004

[66] R L Caygill G E Blair and P A Millner ldquoA review onviral biosensors to detect human pathogensrdquoAnalytica ChimicaActa vol 681 no 1-2 pp 8ndash15 2010

[67] S Guo and S Dong ldquoBiomolecule-nanoparticle hybrids forelectrochemical biosensorsrdquoTrACmdashTrends in Analytical Chem-istry vol 28 no 1 pp 96ndash109 2009

[68] H Huang W Bai C Dong R Guo and Z Liu ldquoAn ultrasen-sitive electrochemical DNA biosensor based on grapheneAunanorodpolythionine for human papillomavirus DNA detec-tionrdquo Biosensors and Bioelectronics vol 68 pp 442ndash446 2015

[69] Rajesh T Ahuja and D Kumar ldquoRecent progress in thedevelopment of nano-structured conducting polymersnano-composites for sensor applicationsrdquo Sensors and Actuators BChemical vol 136 no 1 pp 275ndash286 2009

[70] D C Ferrier M P Shaver and P J W Hands ldquoMicro- andnano-structure based oligonucleotide sensorsrdquo Biosensors andBioelectronics vol 68 pp 798ndash810 2015


[71] I J Higgins and C R Lowe ldquoIntroduction to the principles andapplications of biosensorsrdquo Philosophical Transactions of theRoyal Society of London Series B Biological Sciences vol 316no 1176 pp 3ndash11 1987

[72] A Hulanicki S Glab and F Ingman ldquoChemical sensorsdefinitions and classificationrdquo Pure and Applied Chemistry vol63 no 9 pp 1247ndash1250 1991

[73] D R Thevenot K Toth R A Durst and G S WilsonldquoElectrochemical biosensors recommended definitions andclassificationrdquo Biosensors amp Bioelectronics vol 16 no 1-2 pp121ndash131 2001

[74] P DrsquoOrazio ldquoBiosensors in clinical chemistryrdquo Clinica ChimicaActa vol 334 no 1-2 pp 41ndash69 2003

[75] K S Soppimath T M Aminabhavi A R Kulkarni and WE Rudzinski ldquoBiodegradable polymeric nanoparticles as drugdelivery devicesrdquo Journal of Controlled Release vol 70 no 1-2pp 1ndash20 2001

[76] S Rahimian M F Fransen J W Kleinovink et al ldquoPolymericnanoparticles for co-delivery of synthetic long peptide antigenand poly IC as therapeutic cancer vaccine formulationrdquo Journalof Controlled Release vol 203 pp 16ndash22 2015

[77] J Devkota J Wingo T T T Mai et al ldquoA highly sensitive mag-netic biosensor for detection and quantification of anticancerdrugs tagged to superparamagnetic nanoparticlesrdquo Journal ofApplied Physics vol 115 no 17 Article ID 17B503 2014

[78] X Zhang L Jiang C Zhang et al ldquoA silicon dioxide modifiedmagnetic nanoparticles-labeled lateral flow strips for HBsantigenrdquo Journal of Biomedical Nanotechnology vol 7 no 6 pp776ndash781 2011

[79] K K Jain ldquoApplications of nanobiotechnology in clinicaldiagnosticsrdquo Clinical Chemistry vol 53 no 11 pp 2002ndash20092007

[80] R S Sethi ldquoTransducer aspects of biosensors (reprinted fromGec Journal Research Vol 9 Pg 81 1991)rdquo Biosensors amp Bioelec-tronics vol 9 no 3 pp 243ndash264 1994

[81] M-P Marco and D Barcelo ldquoEnvironmental applications ofanalytical biosensorsrdquo Measurement Science amp Technology vol7 no 11 pp 1547ndash1562 1996

[82] P DrsquoOrazio ldquoBiosensors in clinical chemistrymdash2011 updaterdquoClinica Chimica Acta vol 412 no 19-20 pp 1749ndash1761 2011

[83] C I L Justino T A Rocha-Santos A C Duarte and TA Rocha-Santos ldquoReview of analytical figures of merit ofsensors and biosensors in clinical applicationsrdquo TrAC Trends inAnalytical Chemistry vol 29 no 10 pp 1172ndash1183 2010

[84] C Fournier-Wirth and J Coste ldquoNanotechnologies forpathogen detection future alternativesrdquo Biologicals vol 38no 1 pp 9ndash13 2010

[85] D Grieshaber R MacKenzie J Voros and E Reimhult ldquoElec-trochemical biosensorsmdashsensor principles and architecturesrdquoSensors vol 8 no 3 pp 1400ndash1458 2008

[86] L C Clark Jr and C Lyons ldquoElectrode systems for continuousmonitoring in cardiovascular surgeryrdquo Annals of the New YorkAcademy of Sciences vol 102 pp 29ndash45 1962

[87] D R Thevenot K Toth R A Durst and G S WilsonldquoElectrochemical biosensors recommended definitions andclassificationrdquo Pure and Applied Chemistry vol 71 no 12 pp2333ndash2348 1999

[88] N J Ronkainen H B Halsall and W R Heineman ldquoElectro-chemical biosensorsrdquo Chemical Society Reviews vol 39 no 5pp 1747ndash1763 2010

[89] S Wang L Li H L Jin et al ldquoElectrochemical detection ofhepatitis B and papilloma virus DNAs using SWCNT arraycoatedwith gold nanoparticlesrdquoBiosensorsampBioelectronics vol41 no 1 pp 205ndash210 2013

[90] E T Thostenson Z Ren and T-W Chou ldquoAdvances inthe science and technology of carbon nanotubes and theircomposites a reviewrdquo Composites Science and Technology vol61 no 13 pp 1899ndash1912 2001

[91] J J Gooding ldquoNanostructuring electrodes with carbon nan-otubes a review on electrochemistry and applications forsensingrdquo Electrochimica Acta vol 50 no 15 pp 3049ndash30602005

[92] J M Pingarron P Yanez-Sedeno and A Gonzalez-CortesldquoGold nanoparticle-based electrochemical biosensorsrdquo Elec-trochimica Acta vol 53 no 19 pp 5848ndash5866 2008

[93] F S R R Teles ldquoBiosensors and rapid diagnostic tests onthe frontier between analytical and clinical chemistry forbiomolecular diagnosis of dengue disease a reviewrdquo AnalyticaChimica Acta vol 687 no 1 pp 28ndash42 2011

[94] M F Mitchell S B Cantor N Ramanujam G Tortolero-Luna and R Richards-Kortum ldquoFluorescence spectroscopy fordiagnosis of squamous intraepithelial lesions of the cervixrdquoObstetrics amp Gynecology vol 93 no 3 pp 462ndash470 1999

[95] J Rao A Dragulescu-Andrasi andH Yao ldquoFluorescence imag-ing in vivo recent advancesrdquo Current Opinion in Biotechnologyvol 18 no 1 pp 17ndash25 2007

[96] F Chang S SyrjAnen J Nuutinen J KArjA and K SyrjAnenldquoDetection of human papillomavirus (HPV) DNA in oral squa-mous cell carcinomas by in situ hybridization and polymerasechain reactionrdquo Archives of Dermatological Research vol 282no 8 pp 493ndash497 1990

[97] I Abdulhalim M Zourob and A Lakhtakia ldquoOverview ofoptical biosensing techniquesrdquo in Handbook of Biosensors andBiochips John Wiley amp Sons 2008

[98] T J Park M S Hyun H J Lee S Y Lee and S Ko ldquoAself-assembled fusion protein-based surface plasmon resonancebiosensor for rapid diagnosis of severe acute respiratory syn-dromerdquo Talanta vol 79 no 2 pp 295ndash301 2009

[99] A Olaru C Bala N Jaffrezic-Renault and H Y Aboul-EneinldquoSurface plasmon resonance (SPR) biosensors in pharmaceuti-cal analysisrdquo Critical Reviews in Analytical Chemistry vol 45no 2 pp 97ndash105 2015

[100] A Mitra B Deutsch F Ignatovich C Dykes and L NovotnyldquoNano-optofluidic detection of single viruses and nanoparti-clesrdquo ACS Nano vol 4 no 3 pp 1305ndash1312 2010

[101] D-S Xiang G-P Zeng andZ-KHe ldquoMagneticmicroparticle-based multiplexed DNA detection with biobarcoded quantumdot probesrdquo Biosensors and Bioelectronics vol 26 no 11 pp4405ndash4410 2011

[102] C Dodeigne L Thunus and R Lejeune ldquoChemiluminescenceas a diagnostic tool A reviewrdquo Talanta vol 51 no 3 pp 415ndash439 2000

[103] Y-L Qiao J W Sellors P S Eder et al ldquoA new HPV-DNAtest for cervical-cancer screening in developing regions a cross-sectional study of clinical accuracy in rural Chinardquo The LancetOncology vol 9 no 10 pp 929ndash936 2008

[104] F R R Teles and L P Fonseca ldquoTrends in DNA biosensorsrdquoTalanta vol 77 no 2 pp 606ndash623 2008

[105] A Tinelli G Leo D DellrsquoEdera et al ldquoMolecular methodsfor a correct diagnosis of multiple HPV infections and clinicalimplications for vaccinerdquo International Journal of GynecologicalCancer vol 21 no 3 pp 545ndash550 2011


[106] A Molijn B Kleter W Quint and L-J van Doorn ldquoMoleculardiagnosis of human papillomavirus (HPV) infectionsrdquo Journalof Clinical Virology vol 32 supplement 1 pp S43ndashS51 2005

[107] A Holmberg A Blomstergren O Nord M Lukacs J Lunde-berg and M Uhlen ldquoThe biotin-streptavidin interaction canbe reversibly broken using water at elevated temperaturesrdquoElectrophoresis vol 26 no 3 pp 501ndash510 2005

[108] K Sotlar D Diemer A Dethleffs et al ldquoDetection and typingof human papillomavirus by E6 nested multiplex PCRrdquo Journalof Clinical Microbiology vol 42 no 7 pp 3176ndash3184 2004

[109] A Roda M Mirasoli S Venturoli et al ldquoMicrotiter formatfor simultaneous multianalyte detection and development ofa PCR-chemiluminescent enzyme immunoassay for typinghuman papillomavirus DNAsrdquo Clinical Chemistry vol 48 no10 pp 1654ndash1660 2002

[110] Y Okahata M Kawase K Niikura F Ohtake H Furusawaand Y Ebara ldquoKinetic measurements of DNA hybridizationon an oligonucleotide-immobilized 27-MHz quartz crystalmicrobalancerdquo Analytical Chemistry vol 70 no 7 pp 1288ndash1296 1998

[111] I Burda A Silaghi A Tunyagi S Simon and O PopesculdquoNote sensitivity multiplication module for quartz crystalmicrobalance applicationsrdquoReview of Scientific Instruments vol85 no 2 Article ID 026116 2014

[112] D S Lee and C S Chen ldquoDevelopment of a temperature sensorarray chip and a chip-based real-time PCR machine for DNAamplification efficiency-based quantificationrdquo Biosensors andBioelectronics vol 23 no 7 pp 971ndash979 2008

[113] Y Mao C Luo and Q Ouyang ldquoStudies of temperature-dependent electronic transduction on DNA hairpin loop sen-sorrdquo Nucleic Acids Research vol 31 no 18 article e108 2003

[114] T Notomi H Okayama H Masubuchi et al ldquoLoop-mediatedisothermal amplification of DNArdquo Nucleic Acids Research vol28 no 12 article e63 2000

[115] H-T Kuo J Z Yeh C-M Jiang and M-C Wu ldquoMagneticparticle-linked anti hCG beta antibody for immunoassay ofhuman chorionic gonadotropin (hCG) potential application toearly pregnancy diagnosisrdquo Journal of Immunological Methodsvol 381 no 1-2 pp 32ndash40 2012

[116] X Yi Y Ding Y Zeng et al ldquoMagnetic resonance imaging con-trast agent cRGD-ferric oxide nanometer particle and its rolein the diagnosis of tumorrdquo Journal of Nanoscience andNanotech-nology vol 11 no 5 pp 3800ndash3807 2011

[117] D L Graham H A Ferreira and P P Freitas ldquoMagne-toresistive-based biosensors and biochipsrdquo Trends in Biotech-nology vol 22 no 9 pp 455ndash462 2004

[118] S X Wang and G Li ldquoAdvances in giant magnetoresistancebiosensors with magnetic nanoparticle tags review and out-lookrdquo IEEE Transactions on Magnetics vol 44 no 7 pp 1687ndash1702 2008

[119] K S Kim S Choi G J Lee et al ldquoEffects of stray field distribu-tion generated by magnetic beads on giant magnetoresistancesensor for biochip applicationsrdquo in 26th Southern BiomedicalEngineering Conference SBEC 2010 April 30ndashMay 2 2010College Park Maryland USA vol 32 of IFMBE Proceedings pp293ndash296 Springer Berlin Germany 2010

[120] L Xu H Yu M S Akhras et al ldquoGiant magnetoresistivebiochip for DNA detection and HPV genotypingrdquo Biosensorsand Bioelectronics vol 24 no 1 pp 99ndash103 2008

International Journal of

AerospaceEngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

RoboticsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Active and Passive Electronic Components

Control Scienceand Engineering

Journal of



RotatingMachinery


Hindawi Publishing Corporation httpwwwhindawicom

Journal ofEngineeringVolume 2014

Submit your manuscripts athttpwwwhindawicom

VLSI Design



Shock and Vibration


Civil EngineeringAdvances in

Acoustics and VibrationAdvances in



Electrical and Computer Engineering

Journal of

Advances inOptoElectronics


Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

SensorsJournal of


Modelling amp Simulation in EngineeringHindawi Publishing Corporation httpwwwhindawicom Volume 2014


Chemical EngineeringInternational Journal of Antennas and

Propagation




Navigation and Observation



DistributedSensor Networks



of the leading conventional methods include chemotherapy[8 9] immunotherapy [10] surgery [11] or the collec-tive application of these techniques [12 13] Additionallynanoparticle based delivery of anticancer drugs and thera-peutic vaccines have increased the treatment efficacy whilesimultaneously decreasing the side effects of the traditionaltherapeutics [14] The occurrence of visible epidermal mani-festations as warts or condylomas is one of the symptoms ofHPV infection however since only 1 of infected patientspresent the symptomatology the diagnosis is difficult [15 16]The identification of the disease in these asymptomatic casesrequires specialized equipment to carefully search for internallesions at the mucous membranes In cases of proven cervicalinjury a routine cytological analysis known as Papanicolaoutest is performed over a local biopsy for histopathologicalanalysis [17 18] Beyond visual and cytological identificationmolecular diagnosis is taking over as an essential method forthe accurate differentiation between HPV strains which arecategorized with respect to their potential for low intermedi-ate or high oncogenic risk

Since all HPV strains are related researchers have battledto understand and find the characteristics that differentiateevery discovered strain Often the distinction relies on thepeculiar metabolism that a particular strain endures Themost common ways to differentiate the HPV involve theanalysis of the protein expression ratio that provides amolecular fingerprint of the oncogenic potential within ahistopathological sample [19 20] Considering the fact thatsome HPV strains are more related between them than tothe others DNA analyses are often required for the accurateidentification of the strain DNA analyses are quite hetero-geneous and are based on the complementarity principle ofthe DNA strands For instance we can identify the targetamplification of a precise fragment of nucleic material by thepolymerase chain reaction (PCR) and by signal amplificationof an oligonucleotide hybridization assay [21 22] AlthoughPCR associated techniques present high rates of sensitivityand specificity most of these techniques are mainly used byresearch centers andor specific health services Some of thereasons include the time consuming and complex protocolsthat usually require specialized skills for the correct operationof the instruments and fulfillment of the methods [23]

Fortunately the research on cancer has reached amaturitylevel of awareness that allows the population to realize thatviruses are in fact the cause of a great proportion of cancersThe alarming discovery that certain high-risk strains of HPVcaused assured 100of invasive cervical cancer has instigate aglobal awareness about cervical cancer prevention and mostessentially the development of other cancers prophylacticvaccines [24] Regular vaccines use viral vectors to promoteimmune response and more recently DNA vaccines havebeen developed to control tumor-expressed antigens [25]The employed plasmid vectors are safe and present lowimmunogenicity so they can be constantly administeredFurther researches have been demonstrated to increase theirefficiency by designing nanometrical delivery systems asnanoparticles micelles and fibers [26]

AfterHPV16 andHPV18 10moreHPV strains are knownto cause cervical carcinomas [61] Some researchers have

reached a milestone where the precise identification of HPVtypes has become extremely important They propose tofollow the ecological competitive exclusion principle to createan artificial substitution of high-risk HPV types for those ofreduced risk [3] In addition the detailed identification of alldifferent strains within a sample is of great importance to epi-demiological studies and involves major and interesting newobstacles to overcome for example the correct identificationof HPV strains that are known to be genetically close relatedlike HPV6 and HPV11

Because of the large amount of different HPV typesit is reasonable to think that the current competence ofvaccine design technology is insufficient to provide enoughprotection Despite the fact that the research on individualstrains proceeds slowly the research on biosensors has notdelayed its development Nowadays biosensor researchershave more tools to design better techniques to apply andhelp to control viral epidemics Live vectors characterizationpeptideprotein expression and interaction DNA vaccinedesign and whole cell-based treatment approaches [62] aresome of the explored topics that are applied on viral sensingand detection In the case of genosensors as much as thegenomic databases improve cancers will be easier to detectand diagnose

2 Biosensors for HPV as AlternativeDiagnostic Tools

Over the years the progress of biotechnological research hascontributed to the development of biologic sensor devices[63 64] Biosensors are portable analytical devices consti-tuted by at least one biological molecule The strategies toobtain these biosensors combine the specificity of the bio-logical probe with the analytical capacity of the transductionmethods [65 66] In addition materials at the nanometerscale as nanoparticles [67] nanotubes [28] nanofibers [68]and nanocomposites [69] have been used to achieve thenanostructuration of these devices The diversity of struc-tures provides tailored interfacial modification alternativeswith the purpose of amplifying the analytical signal andincreasing the sensibility of the biosensor [63] The challengeto construct these nanometrical systems relies in the needto preserve the biological activity of the probe as well asthe transducing activity of the nanostructure [70] For thesereasons a detailed study of the physical-chemical propertiesof both constituents should be performed

The device requires the efficient immobilization of anti-bodies peptides aptamers or nucleic acids over the sur-face of a transducer which are responsible for the analyterecognition and will execute a measurable response signalproportional to the analyte concentration [71ndash74] Besidescovalent functionalization of nanoparticles (known for allow-ing a strong and controlled immobilization of the probe overthe surface of the sensor) most immobilization strategiesinvolve simple methods In general mixtures or emulsionsof two or more materials previously known for their indi-vidual properties are performed for example nanoparticles


SPR EIS

HPV

targ

etBi

osen

sor

S SS

Angle of incidence

Refle

ctio

n


Signal transduction


Response


RΩ RΩ + Rct

Z998400998400

Z998400

Δ120579

SSS

QCMFrequency (MHz)

Piezoelectric

Con

duct

ance

(120583S)

120575f

Γ1

Γ2


















Table1Electro

chem

icaltechniqu

esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

21different

typeso

fHPV

Goldsurfa

cecapture

oligon

ucleotides


ccur

for

electro

chem

icaldetection

Thefi

rstb

etweenthe

capturep

robe

andthetargetandthes

econ

dbetweenan

adjacent

region

ofthetargetand

ferrocenelabeled

signalprobe

CVmdash

mdash2to

8ho

urs

mdash[27]

HPV

16Sing

lewalledcarbon

nano

tube

arraysgoldnano

particlesHPV

16E7

prob

e

Hybrid

izationbetweenthec

apture

prob

eand

the

HPV

target(specific

toHPV

-16E7

region

)EIS

1aM

(Atto

molar)

1aM

to1120583

M2ho

urs

6tests

[28]

HPV

16Goldsurfa

ceL-cysteineHPV

16oligon

ucleotide

Them

easurementw

asbasedon

thereductio

nsig

nals

ofmethylene

blue

(MB)

before

andaft


robe

andthes

ynthetic

targetor

extractedDNAfro

mclinicalsam

ples

DPV

1813

nM1875n

Mto

1000

nM10

minutes

mdash[29]

HPV


ceH

PV16

E6prob

e

Theh

ybrid

izationbetweenthec

apture

prob

eand

the

HPV

16E6

gene

was

directlydetected

throug

hgu

anineo

xidatio

nsig

nals

DPV

16pg120583L

5pg120583Lto

40pg120583L

5minutes

mdash[30]

HPV

16and

HPV

45Goldsurfa

ceth

iolated

HPV

16E7

pandHPV

45E6

prob

es

Theh

ybrid

izationwas

detected

byincorporatinga

horseradish

peroxidase-(HRP

-)labelledrepo

rter

prob

ethatp

airswith

thetargetTh

e331015840551015840-te

tram

ethylbenzidine

(TMB)

was

used

asa


enzyme

CV

490p

Mfor

HPV

16E7

p110

pMfor

HPV

45E6

01n

Mto

50nM

1hou

rmdash

[31]

HPV

16

HPV

18and

HPV

45

Goldsurfa

ceoligoethylene

glycol-te

rminated

bipo

dal

thiolthiolated

HPV

16E7

pHPV

18E6

and

HPV

45E6

prob

es

Thed

etectio

nwas

carriedwith

thetargeth

ybrid

ized

betweenas

urface

immob

ilizedprob

eand

aHRP

-labelledsecond

aryrepo

rter

prob

eTh

eTMB

was

used

asac

hrom

ogenicsubstratefor

HRP

CV

220p

Mfor

HPV

16E7

p170p

Mfor

HPV

18E6

and

110pM

for

HPV

45E6

01n

Mto

50nM

20minutes

5tests

[32]

HPV

(L1g

ene)

Pencilgraphitesurfa

ceH

PVprob

eTh

ehybrid

izationbetweenthep

robe

andHPV

target

was

studied

bymeasuremento

fMBsig

nal

accumulated

onthep

encilgraph

iteele

ctrode

SWV

12ng

120583L

12ng

120583Lto

50ng

120583L

3minutes

mdash[33]


Table1Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

16

Glassycarbon

surfa

cecon

jugated

copo

lymer

poly(5-hydroxy-14-

naph

thoq

uino

ne-co-5-hydroxy-2-

carboxyethyl-14-

naph

thoq

uino

ne)antig

enicpeptide

L1


enicpeptideL

1and

HPV

-16antib

ody

SWV

50nM

mdash1h

our

mdash[34]

HPV

16

Carbon

surfa

cechitosananthraqu

inon


ucleic

acid

(acpcPNA)p

robe

Theh

ybrid

izationwith

theH

PV16

DNAwas

studied

bymeasurin

gthee

lectrochem

icalsig

nalofthe

label

anthraqu

inon

eatta

ched

tothea

cpcPNAprob

eSW

V4n

M002

mM

to12nM

15minutes

mdash[35]

HPV

(L1g

ene)

Goldsurfa

cealkanethiolHPV

prob

e

Thes

tudy

was

perfo

rmed

basedon

theinteractio

nof

hematoxylin

with

analkanethiolD

NAprob

eand

itshybridized

form

CVand

DPV

38n

M125nM

to40

0nM

2ho

urs

mdash[36]

HPV

16Glassycarbon

surfa

cegraph

eneAu

nano

rodpo

lythionineH

PV16

prob

e

Besid

esthec

apture

prob

etwoauxiliary

prob

eswere

desig

nedforthe

hybridizationwith

HPV

DNA

110-Ph

enanthrolin

eruthenium

dichlorid

e([Ru

(phen)3]2+

)was

used

asthee

lectrochem

ical

indicator

EISand

DPV

403times

10minus14molL

1times10minus13molL

to1times

10minus10molL

90minutes

mdash[37]

HPV

16

Polymethylm

ethacrylate

substrategold

nano

layer4-

aminothiop

heno

lmon

oclonal

antib

ody(m

Ab)5

051


5051

andHPV

16

CVand

EIS

mdashmdash

1hou

rmdash

[38]

HPV

16

Platinum

surfa

cepolyanilin

e-multiw

alled

carbon

nano

tube

compo

siteHPV

16-L1p

eptid

eaptam

er


ntigen

peptidea

ptam

erHPV

-16-L1

andHPV

-16antib

ody

CVand

SWV

490p

M10nM

to80

nM15

minutes

mdash[39]



esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

s1618

313335

Aqueou

ssolution

Fluo

rescentreporterd

yecovalentlylin

kedto

the51015840end

andaq

uencherd

yelin

kedto

the31015840end

Fluo

rescence

PCR

Differentia

ldetectio

nof

samples

mim

icking

mixed

infections

upto

1of

thetotalDNA

101ndash106

DNA

copies

75minutes

after

DNA

extractio

nand

preparationof

PCR

solutio

ns

mdash[40]

Ratio

sbetween

HPV

s611

1618

and

313335

Insituhisto

logical

sample

Fluo

rescently

labeled

oligon

ucleotides

with

biotin-stre

ptavidin

mod

ificatio

n

Insitu

PCRFISH

LSC

M

1-2DNAcopies

1to50

DNA

copies

per

cell

Overnight

hybridization

noDNAextractio

nneeded

mdash[41]

HPV

s1618

Insituhisto

logical

sample

Oligon

ucleotides

labeledwith

digoxigenin-ll-dUTP

byrand

omprim

ing

FISH

autom

atic

imagec

ytom

etry

1DNAcopy

1ndash500DNA

copies

per

cell

6ho

ursa

fterc

ell

cultu

ren

oDNA

extractio

nneeded

mdash[42]

HPV

s1618

Avidin

coated

(LKB

Sw

eden)sensorc

hip

Biotinylated

oligon

ucleotide

boun

dto

oncoproteins

Plasmon

resonance

018120583M

01ndash4120583

M

mdashmdash

[43]

HPV

s1618

Nitrocellulose

DNA

chip

Biotin

labeledoligon

ucleotides

sand

wichof

streptavidin

toflu

orescenced

ye

PCRchromatograph

yflu

orescence

Qualitative

mdash30

minutes

mdash[44]

HPV

s611

DNAam

plificatio

nOligon

ucleotides

labeledwith

fluorescent

prob

esop

timized

forF

RET

Real-timeP

CRFR

ET-fluo

rescence

25ndash4

3DNAcopies

1ndash3times107

DNAcopies

90minutes

mdash[45]

13different

typeso

fHPV

Nitrocellulose

chip

Fluo

rescently

labeled

oligon

ucleotides

immob

ilized

viab

iotin

-avidin

PCRam

plificatio

n10ndash102

plasmid

copies

0ndash105DNA

copies

30minutes

for

incubatio

n30

second

sfor

reading

Lateral

flow

60tests

[46]

HPV

s1618

Photon

iccrystalon

silicon

Antibod

yim

mob

ilizatio

nOpticaldetectionof

resonant

mod

es

150n

M

0ndash15

nM

16ho

urs

mdash[47]

HPV

16CM

5sensor

chip

(GE

Health

care)

Pairw

iseantib

ody

footprintin

gSP

R10120583gmL

50ndash200120583g

30minutes

3tests

[48]

24different

typeso

fHPV

Goldchip

DNA-

prob

ehybrid

ization

PCRSP

RQualitative

mdash4ho

urs

mdash[49]

HPV

16Quantum

Dot

(75n

m)Maghemite

(46n

m)

Oligon

ucleotides

labeledwith

superparam

agnetic

nano

particles

andQDs

Fluo

rescence

spectro

scop

yQualitative

mdash1h

our

mdash[50]

HPV

16Silican

anop

articles

(75n

M)

Folatefun

ctionalization

Fluo

rescence

microscop

yQualitative

mdash15

minutes

mdash[51]


Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon


goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent



y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)











HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










SPR EIS

HPV

targ

etBi

osen

sor

S SS

Angle of incidence

Refle

ctio

n


Signal transduction


Response


RΩ RΩ + Rct

Z998400998400

Z998400

Δ120579

SSS

QCMFrequency (MHz)

Piezoelectric

Con

duct

ance

(120583S)

120575f

Γ1

Γ2


















Table1Electro

chem

icaltechniqu

esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

21different

typeso

fHPV

Goldsurfa

cecapture

oligon

ucleotides


ccur

for

electro

chem

icaldetection

Thefi

rstb

etweenthe

capturep

robe

andthetargetandthes

econ

dbetweenan

adjacent

region

ofthetargetand

ferrocenelabeled

signalprobe

CVmdash

mdash2to

8ho

urs

mdash[27]

HPV

16Sing

lewalledcarbon

nano

tube

arraysgoldnano

particlesHPV

16E7

prob

e

Hybrid

izationbetweenthec

apture

prob

eand

the

HPV

target(specific

toHPV

-16E7

region

)EIS

1aM

(Atto

molar)

1aM

to1120583

M2ho

urs

6tests

[28]

HPV

16Goldsurfa

ceL-cysteineHPV

16oligon

ucleotide

Them

easurementw

asbasedon

thereductio

nsig

nals

ofmethylene

blue

(MB)

before

andaft


robe

andthes

ynthetic

targetor

extractedDNAfro

mclinicalsam

ples

DPV

1813

nM1875n

Mto

1000

nM10

minutes

mdash[29]

HPV


ceH

PV16

E6prob

e

Theh

ybrid

izationbetweenthec

apture

prob

eand

the

HPV

16E6

gene

was

directlydetected

throug

hgu

anineo

xidatio

nsig

nals

DPV

16pg120583L

5pg120583Lto

40pg120583L

5minutes

mdash[30]

HPV

16and

HPV

45Goldsurfa

ceth

iolated

HPV

16E7

pandHPV

45E6

prob

es

Theh

ybrid

izationwas

detected

byincorporatinga

horseradish

peroxidase-(HRP

-)labelledrepo

rter

prob

ethatp

airswith

thetargetTh

e331015840551015840-te

tram

ethylbenzidine

(TMB)

was

used

asa


enzyme

CV

490p

Mfor

HPV

16E7

p110

pMfor

HPV

45E6

01n

Mto

50nM

1hou

rmdash

[31]

HPV

16

HPV

18and

HPV

45

Goldsurfa

ceoligoethylene

glycol-te

rminated

bipo

dal

thiolthiolated

HPV

16E7

pHPV

18E6

and

HPV

45E6

prob

es

Thed

etectio

nwas

carriedwith

thetargeth

ybrid

ized

betweenas

urface

immob

ilizedprob

eand

aHRP

-labelledsecond

aryrepo

rter

prob

eTh

eTMB

was

used

asac

hrom

ogenicsubstratefor

HRP

CV

220p

Mfor

HPV

16E7

p170p

Mfor

HPV

18E6

and

110pM

for

HPV

45E6

01n

Mto

50nM

20minutes

5tests

[32]

HPV

(L1g

ene)

Pencilgraphitesurfa

ceH

PVprob

eTh

ehybrid

izationbetweenthep

robe

andHPV

target

was

studied

bymeasuremento

fMBsig

nal

accumulated

onthep

encilgraph

iteele

ctrode

SWV

12ng

120583L

12ng

120583Lto

50ng

120583L

3minutes

mdash[33]


Table1Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

16

Glassycarbon

surfa

cecon

jugated

copo

lymer

poly(5-hydroxy-14-

naph

thoq

uino

ne-co-5-hydroxy-2-

carboxyethyl-14-

naph

thoq

uino

ne)antig

enicpeptide

L1


enicpeptideL

1and

HPV

-16antib

ody

SWV

50nM

mdash1h

our

mdash[34]

HPV

16

Carbon

surfa

cechitosananthraqu

inon


ucleic

acid

(acpcPNA)p

robe

Theh

ybrid

izationwith

theH

PV16

DNAwas

studied

bymeasurin

gthee

lectrochem

icalsig

nalofthe

label

anthraqu

inon

eatta

ched

tothea

cpcPNAprob

eSW

V4n

M002

mM

to12nM

15minutes

mdash[35]

HPV

(L1g

ene)

Goldsurfa

cealkanethiolHPV

prob

e

Thes

tudy

was

perfo

rmed

basedon

theinteractio

nof

hematoxylin

with

analkanethiolD

NAprob

eand

itshybridized

form

CVand

DPV

38n

M125nM

to40

0nM

2ho

urs

mdash[36]

HPV

16Glassycarbon

surfa

cegraph

eneAu

nano

rodpo

lythionineH

PV16

prob

e

Besid

esthec

apture

prob

etwoauxiliary

prob

eswere

desig

nedforthe

hybridizationwith

HPV

DNA

110-Ph

enanthrolin

eruthenium

dichlorid

e([Ru

(phen)3]2+

)was

used

asthee

lectrochem

ical

indicator

EISand

DPV

403times

10minus14molL

1times10minus13molL

to1times

10minus10molL

90minutes

mdash[37]

HPV

16

Polymethylm

ethacrylate

substrategold

nano

layer4-

aminothiop

heno

lmon

oclonal

antib

ody(m

Ab)5

051


5051

andHPV

16

CVand

EIS

mdashmdash

1hou

rmdash

[38]

HPV

16

Platinum

surfa

cepolyanilin

e-multiw

alled

carbon

nano

tube

compo

siteHPV

16-L1p

eptid

eaptam

er


ntigen

peptidea

ptam

erHPV

-16-L1

andHPV

-16antib

ody

CVand

SWV

490p

M10nM

to80

nM15

minutes

mdash[39]



esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

s1618

313335

Aqueou

ssolution

Fluo

rescentreporterd

yecovalentlylin

kedto

the51015840end

andaq

uencherd

yelin

kedto

the31015840end

Fluo

rescence

PCR

Differentia

ldetectio

nof

samples

mim

icking

mixed

infections

upto

1of

thetotalDNA

101ndash106

DNA

copies

75minutes

after

DNA

extractio

nand

preparationof

PCR

solutio

ns

mdash[40]

Ratio

sbetween

HPV

s611

1618

and

313335

Insituhisto

logical

sample

Fluo

rescently

labeled

oligon

ucleotides

with

biotin-stre

ptavidin

mod

ificatio

n

Insitu

PCRFISH

LSC

M

1-2DNAcopies

1to50

DNA

copies

per

cell

Overnight

hybridization

noDNAextractio

nneeded

mdash[41]

HPV

s1618

Insituhisto

logical

sample

Oligon

ucleotides

labeledwith

digoxigenin-ll-dUTP

byrand

omprim

ing

FISH

autom

atic

imagec

ytom

etry

1DNAcopy

1ndash500DNA

copies

per

cell

6ho

ursa

fterc

ell

cultu

ren

oDNA

extractio

nneeded

mdash[42]

HPV

s1618

Avidin

coated

(LKB

Sw

eden)sensorc

hip

Biotinylated

oligon

ucleotide

boun

dto

oncoproteins

Plasmon

resonance

018120583M

01ndash4120583

M

mdashmdash

[43]

HPV

s1618

Nitrocellulose

DNA

chip

Biotin

labeledoligon

ucleotides

sand

wichof

streptavidin

toflu

orescenced

ye

PCRchromatograph

yflu

orescence

Qualitative

mdash30

minutes

mdash[44]

HPV

s611

DNAam

plificatio

nOligon

ucleotides

labeledwith

fluorescent

prob

esop

timized

forF

RET

Real-timeP

CRFR

ET-fluo

rescence

25ndash4

3DNAcopies

1ndash3times107

DNAcopies

90minutes

mdash[45]

13different

typeso

fHPV

Nitrocellulose

chip

Fluo

rescently

labeled

oligon

ucleotides

immob

ilized

viab

iotin

-avidin

PCRam

plificatio

n10ndash102

plasmid

copies

0ndash105DNA

copies

30minutes

for

incubatio

n30

second

sfor

reading

Lateral

flow

60tests

[46]

HPV

s1618

Photon

iccrystalon

silicon

Antibod

yim

mob

ilizatio

nOpticaldetectionof

resonant

mod

es

150n

M

0ndash15

nM

16ho

urs

mdash[47]

HPV

16CM

5sensor

chip

(GE

Health

care)

Pairw

iseantib

ody

footprintin

gSP

R10120583gmL

50ndash200120583g

30minutes

3tests

[48]

24different

typeso

fHPV

Goldchip

DNA-

prob

ehybrid

ization

PCRSP

RQualitative

mdash4ho

urs

mdash[49]

HPV

16Quantum

Dot

(75n

m)Maghemite

(46n

m)

Oligon

ucleotides

labeledwith

superparam

agnetic

nano

particles

andQDs

Fluo

rescence

spectro

scop

yQualitative

mdash1h

our

mdash[50]

HPV

16Silican

anop

articles

(75n

M)

Folatefun

ctionalization

Fluo

rescence

microscop

yQualitative

mdash15

minutes

mdash[51]


Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon


goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent



y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)











HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation





















Table1Electro

chem

icaltechniqu

esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

21different

typeso

fHPV

Goldsurfa

cecapture

oligon

ucleotides


ccur

for

electro

chem

icaldetection

Thefi

rstb

etweenthe

capturep

robe

andthetargetandthes

econ

dbetweenan

adjacent

region

ofthetargetand

ferrocenelabeled

signalprobe

CVmdash

mdash2to

8ho

urs

mdash[27]

HPV

16Sing

lewalledcarbon

nano

tube

arraysgoldnano

particlesHPV

16E7

prob

e

Hybrid

izationbetweenthec

apture

prob

eand

the

HPV

target(specific

toHPV

-16E7

region

)EIS

1aM

(Atto

molar)

1aM

to1120583

M2ho

urs

6tests

[28]

HPV

16Goldsurfa

ceL-cysteineHPV

16oligon

ucleotide

Them

easurementw

asbasedon

thereductio

nsig

nals

ofmethylene

blue

(MB)

before

andaft


robe

andthes

ynthetic

targetor

extractedDNAfro

mclinicalsam

ples

DPV

1813

nM1875n

Mto

1000

nM10

minutes

mdash[29]

HPV


ceH

PV16

E6prob

e

Theh

ybrid

izationbetweenthec

apture

prob

eand

the

HPV

16E6

gene

was

directlydetected

throug

hgu

anineo

xidatio

nsig

nals

DPV

16pg120583L

5pg120583Lto

40pg120583L

5minutes

mdash[30]

HPV

16and

HPV

45Goldsurfa

ceth

iolated

HPV

16E7

pandHPV

45E6

prob

es

Theh

ybrid

izationwas

detected

byincorporatinga

horseradish

peroxidase-(HRP

-)labelledrepo

rter

prob

ethatp

airswith

thetargetTh

e331015840551015840-te

tram

ethylbenzidine

(TMB)

was

used

asa


enzyme

CV

490p

Mfor

HPV

16E7

p110

pMfor

HPV

45E6

01n

Mto

50nM

1hou

rmdash

[31]

HPV

16

HPV

18and

HPV

45

Goldsurfa

ceoligoethylene

glycol-te

rminated

bipo

dal

thiolthiolated

HPV

16E7

pHPV

18E6

and

HPV

45E6

prob

es

Thed

etectio

nwas

carriedwith

thetargeth

ybrid

ized

betweenas

urface

immob

ilizedprob

eand

aHRP

-labelledsecond

aryrepo

rter

prob

eTh

eTMB

was

used

asac

hrom

ogenicsubstratefor

HRP

CV

220p

Mfor

HPV

16E7

p170p

Mfor

HPV

18E6

and

110pM

for

HPV

45E6

01n

Mto

50nM

20minutes

5tests

[32]

HPV

(L1g

ene)

Pencilgraphitesurfa

ceH

PVprob

eTh

ehybrid

izationbetweenthep

robe

andHPV

target

was

studied

bymeasuremento

fMBsig

nal

accumulated

onthep

encilgraph

iteele

ctrode

SWV

12ng

120583L

12ng

120583Lto

50ng

120583L

3minutes

mdash[33]


Table1Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

16

Glassycarbon

surfa

cecon

jugated

copo

lymer

poly(5-hydroxy-14-

naph

thoq

uino

ne-co-5-hydroxy-2-

carboxyethyl-14-

naph

thoq

uino

ne)antig

enicpeptide

L1


enicpeptideL

1and

HPV

-16antib

ody

SWV

50nM

mdash1h

our

mdash[34]

HPV

16

Carbon

surfa

cechitosananthraqu

inon


ucleic

acid

(acpcPNA)p

robe

Theh

ybrid

izationwith

theH

PV16

DNAwas

studied

bymeasurin

gthee

lectrochem

icalsig

nalofthe

label

anthraqu

inon

eatta

ched

tothea

cpcPNAprob

eSW

V4n

M002

mM

to12nM

15minutes

mdash[35]

HPV

(L1g

ene)

Goldsurfa

cealkanethiolHPV

prob

e

Thes

tudy

was

perfo

rmed

basedon

theinteractio

nof

hematoxylin

with

analkanethiolD

NAprob

eand

itshybridized

form

CVand

DPV

38n

M125nM

to40

0nM

2ho

urs

mdash[36]

HPV

16Glassycarbon

surfa

cegraph

eneAu

nano

rodpo

lythionineH

PV16

prob

e

Besid

esthec

apture

prob

etwoauxiliary

prob

eswere

desig

nedforthe

hybridizationwith

HPV

DNA

110-Ph

enanthrolin

eruthenium

dichlorid

e([Ru

(phen)3]2+

)was

used

asthee

lectrochem

ical

indicator

EISand

DPV

403times

10minus14molL

1times10minus13molL

to1times

10minus10molL

90minutes

mdash[37]

HPV

16

Polymethylm

ethacrylate

substrategold

nano

layer4-

aminothiop

heno

lmon

oclonal

antib

ody(m

Ab)5

051


5051

andHPV

16

CVand

EIS

mdashmdash

1hou

rmdash

[38]

HPV

16

Platinum

surfa

cepolyanilin

e-multiw

alled

carbon

nano

tube

compo

siteHPV

16-L1p

eptid

eaptam

er


ntigen

peptidea

ptam

erHPV

-16-L1

andHPV

-16antib

ody

CVand

SWV

490p

M10nM

to80

nM15

minutes

mdash[39]



esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

s1618

313335

Aqueou

ssolution

Fluo

rescentreporterd

yecovalentlylin

kedto

the51015840end

andaq

uencherd

yelin

kedto

the31015840end

Fluo

rescence

PCR

Differentia

ldetectio

nof

samples

mim

icking

mixed

infections

upto

1of

thetotalDNA

101ndash106

DNA

copies

75minutes

after

DNA

extractio

nand

preparationof

PCR

solutio

ns

mdash[40]

Ratio

sbetween

HPV

s611

1618

and

313335

Insituhisto

logical

sample

Fluo

rescently

labeled

oligon

ucleotides

with

biotin-stre

ptavidin

mod

ificatio

n

Insitu

PCRFISH

LSC

M

1-2DNAcopies

1to50

DNA

copies

per

cell

Overnight

hybridization

noDNAextractio

nneeded

mdash[41]

HPV

s1618

Insituhisto

logical

sample

Oligon

ucleotides

labeledwith

digoxigenin-ll-dUTP

byrand

omprim

ing

FISH

autom

atic

imagec

ytom

etry

1DNAcopy

1ndash500DNA

copies

per

cell

6ho

ursa

fterc

ell

cultu

ren

oDNA

extractio

nneeded

mdash[42]

HPV

s1618

Avidin

coated

(LKB

Sw

eden)sensorc

hip

Biotinylated

oligon

ucleotide

boun

dto

oncoproteins

Plasmon

resonance

018120583M

01ndash4120583

M

mdashmdash

[43]

HPV

s1618

Nitrocellulose

DNA

chip

Biotin

labeledoligon

ucleotides

sand

wichof

streptavidin

toflu

orescenced

ye

PCRchromatograph

yflu

orescence

Qualitative

mdash30

minutes

mdash[44]

HPV

s611

DNAam

plificatio

nOligon

ucleotides

labeledwith

fluorescent

prob

esop

timized

forF

RET

Real-timeP

CRFR

ET-fluo

rescence

25ndash4

3DNAcopies

1ndash3times107

DNAcopies

90minutes

mdash[45]

13different

typeso

fHPV

Nitrocellulose

chip

Fluo

rescently

labeled

oligon

ucleotides

immob

ilized

viab

iotin

-avidin

PCRam

plificatio

n10ndash102

plasmid

copies

0ndash105DNA

copies

30minutes

for

incubatio

n30

second

sfor

reading

Lateral

flow

60tests

[46]

HPV

s1618

Photon

iccrystalon

silicon

Antibod

yim

mob

ilizatio

nOpticaldetectionof

resonant

mod

es

150n

M

0ndash15

nM

16ho

urs

mdash[47]

HPV

16CM

5sensor

chip

(GE

Health

care)

Pairw

iseantib

ody

footprintin

gSP

R10120583gmL

50ndash200120583g

30minutes

3tests

[48]

24different

typeso

fHPV

Goldchip

DNA-

prob

ehybrid

ization

PCRSP

RQualitative

mdash4ho

urs

mdash[49]

HPV

16Quantum

Dot

(75n

m)Maghemite

(46n

m)

Oligon

ucleotides

labeledwith

superparam

agnetic

nano

particles

andQDs

Fluo

rescence

spectro

scop

yQualitative

mdash1h

our

mdash[50]

HPV

16Silican

anop

articles

(75n

M)

Folatefun

ctionalization

Fluo

rescence

microscop

yQualitative

mdash15

minutes

mdash[51]


Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon


goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent



y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)











HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










Table1Electro

chem

icaltechniqu

esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

21different

typeso

fHPV

Goldsurfa

cecapture

oligon

ucleotides


ccur

for

electro

chem

icaldetection

Thefi

rstb

etweenthe

capturep

robe

andthetargetandthes

econ

dbetweenan

adjacent

region

ofthetargetand

ferrocenelabeled

signalprobe

CVmdash

mdash2to

8ho

urs

mdash[27]

HPV

16Sing

lewalledcarbon

nano

tube

arraysgoldnano

particlesHPV

16E7

prob

e

Hybrid

izationbetweenthec

apture

prob

eand

the

HPV

target(specific

toHPV

-16E7

region

)EIS

1aM

(Atto

molar)

1aM

to1120583

M2ho

urs

6tests

[28]

HPV

16Goldsurfa

ceL-cysteineHPV

16oligon

ucleotide

Them

easurementw

asbasedon

thereductio

nsig

nals

ofmethylene

blue

(MB)

before

andaft


robe

andthes

ynthetic

targetor

extractedDNAfro

mclinicalsam

ples

DPV

1813

nM1875n

Mto

1000

nM10

minutes

mdash[29]

HPV


ceH

PV16

E6prob

e

Theh

ybrid

izationbetweenthec

apture

prob

eand

the

HPV

16E6

gene

was

directlydetected

throug

hgu

anineo

xidatio

nsig

nals

DPV

16pg120583L

5pg120583Lto

40pg120583L

5minutes

mdash[30]

HPV

16and

HPV

45Goldsurfa

ceth

iolated

HPV

16E7

pandHPV

45E6

prob

es

Theh

ybrid

izationwas

detected

byincorporatinga

horseradish

peroxidase-(HRP

-)labelledrepo

rter

prob

ethatp

airswith

thetargetTh

e331015840551015840-te

tram

ethylbenzidine

(TMB)

was

used

asa


enzyme

CV

490p

Mfor

HPV

16E7

p110

pMfor

HPV

45E6

01n

Mto

50nM

1hou

rmdash

[31]

HPV

16

HPV

18and

HPV

45

Goldsurfa

ceoligoethylene

glycol-te

rminated

bipo

dal

thiolthiolated

HPV

16E7

pHPV

18E6

and

HPV

45E6

prob

es

Thed

etectio

nwas

carriedwith

thetargeth

ybrid

ized

betweenas

urface

immob

ilizedprob

eand

aHRP

-labelledsecond

aryrepo

rter

prob

eTh

eTMB

was

used

asac

hrom

ogenicsubstratefor

HRP

CV

220p

Mfor

HPV

16E7

p170p

Mfor

HPV

18E6

and

110pM

for

HPV

45E6

01n

Mto

50nM

20minutes

5tests

[32]

HPV

(L1g

ene)

Pencilgraphitesurfa

ceH

PVprob

eTh

ehybrid

izationbetweenthep

robe

andHPV

target

was

studied

bymeasuremento

fMBsig

nal

accumulated

onthep

encilgraph

iteele

ctrode

SWV

12ng

120583L

12ng

120583Lto

50ng

120583L

3minutes

mdash[33]


Table1Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

16

Glassycarbon

surfa

cecon

jugated

copo

lymer

poly(5-hydroxy-14-

naph

thoq

uino

ne-co-5-hydroxy-2-

carboxyethyl-14-

naph

thoq

uino

ne)antig

enicpeptide

L1


enicpeptideL

1and

HPV

-16antib

ody

SWV

50nM

mdash1h

our

mdash[34]

HPV

16

Carbon

surfa

cechitosananthraqu

inon


ucleic

acid

(acpcPNA)p

robe

Theh

ybrid

izationwith

theH

PV16

DNAwas

studied

bymeasurin

gthee

lectrochem

icalsig

nalofthe

label

anthraqu

inon

eatta

ched

tothea

cpcPNAprob

eSW

V4n

M002

mM

to12nM

15minutes

mdash[35]

HPV

(L1g

ene)

Goldsurfa

cealkanethiolHPV

prob

e

Thes

tudy

was

perfo

rmed

basedon

theinteractio

nof

hematoxylin

with

analkanethiolD

NAprob

eand

itshybridized

form

CVand

DPV

38n

M125nM

to40

0nM

2ho

urs

mdash[36]

HPV

16Glassycarbon

surfa

cegraph

eneAu

nano

rodpo

lythionineH

PV16

prob

e

Besid

esthec

apture

prob

etwoauxiliary

prob

eswere

desig

nedforthe

hybridizationwith

HPV

DNA

110-Ph

enanthrolin

eruthenium

dichlorid

e([Ru

(phen)3]2+

)was

used

asthee

lectrochem

ical

indicator

EISand

DPV

403times

10minus14molL

1times10minus13molL

to1times

10minus10molL

90minutes

mdash[37]

HPV

16

Polymethylm

ethacrylate

substrategold

nano

layer4-

aminothiop

heno

lmon

oclonal

antib

ody(m

Ab)5

051


5051

andHPV

16

CVand

EIS

mdashmdash

1hou

rmdash

[38]

HPV

16

Platinum

surfa

cepolyanilin

e-multiw

alled

carbon

nano

tube

compo

siteHPV

16-L1p

eptid

eaptam

er


ntigen

peptidea

ptam

erHPV

-16-L1

andHPV

-16antib

ody

CVand

SWV

490p

M10nM

to80

nM15

minutes

mdash[39]



esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

s1618

313335

Aqueou

ssolution

Fluo

rescentreporterd

yecovalentlylin

kedto

the51015840end

andaq

uencherd

yelin

kedto

the31015840end

Fluo

rescence

PCR

Differentia

ldetectio

nof

samples

mim

icking

mixed

infections

upto

1of

thetotalDNA

101ndash106

DNA

copies

75minutes

after

DNA

extractio

nand

preparationof

PCR

solutio

ns

mdash[40]

Ratio

sbetween

HPV

s611

1618

and

313335

Insituhisto

logical

sample

Fluo

rescently

labeled

oligon

ucleotides

with

biotin-stre

ptavidin

mod

ificatio

n

Insitu

PCRFISH

LSC

M

1-2DNAcopies

1to50

DNA

copies

per

cell

Overnight

hybridization

noDNAextractio

nneeded

mdash[41]

HPV

s1618

Insituhisto

logical

sample

Oligon

ucleotides

labeledwith

digoxigenin-ll-dUTP

byrand

omprim

ing

FISH

autom

atic

imagec

ytom

etry

1DNAcopy

1ndash500DNA

copies

per

cell

6ho

ursa

fterc

ell

cultu

ren

oDNA

extractio

nneeded

mdash[42]

HPV

s1618

Avidin

coated

(LKB

Sw

eden)sensorc

hip

Biotinylated

oligon

ucleotide

boun

dto

oncoproteins

Plasmon

resonance

018120583M

01ndash4120583

M

mdashmdash

[43]

HPV

s1618

Nitrocellulose

DNA

chip

Biotin

labeledoligon

ucleotides

sand

wichof

streptavidin

toflu

orescenced

ye

PCRchromatograph

yflu

orescence

Qualitative

mdash30

minutes

mdash[44]

HPV

s611

DNAam

plificatio

nOligon

ucleotides

labeledwith

fluorescent

prob

esop

timized

forF

RET

Real-timeP

CRFR

ET-fluo

rescence

25ndash4

3DNAcopies

1ndash3times107

DNAcopies

90minutes

mdash[45]

13different

typeso

fHPV

Nitrocellulose

chip

Fluo

rescently

labeled

oligon

ucleotides

immob

ilized

viab

iotin

-avidin

PCRam

plificatio

n10ndash102

plasmid

copies

0ndash105DNA

copies

30minutes

for

incubatio

n30

second

sfor

reading

Lateral

flow

60tests

[46]

HPV

s1618

Photon

iccrystalon

silicon

Antibod

yim

mob

ilizatio

nOpticaldetectionof

resonant

mod

es

150n

M

0ndash15

nM

16ho

urs

mdash[47]

HPV

16CM

5sensor

chip

(GE

Health

care)

Pairw

iseantib

ody

footprintin

gSP

R10120583gmL

50ndash200120583g

30minutes

3tests

[48]

24different

typeso

fHPV

Goldchip

DNA-

prob

ehybrid

ization

PCRSP

RQualitative

mdash4ho

urs

mdash[49]

HPV

16Quantum

Dot

(75n

m)Maghemite

(46n

m)

Oligon

ucleotides

labeledwith

superparam

agnetic

nano

particles

andQDs

Fluo

rescence

spectro

scop

yQualitative

mdash1h

our

mdash[50]

HPV

16Silican

anop

articles

(75n

M)

Folatefun

ctionalization

Fluo

rescence

microscop

yQualitative

mdash15

minutes

mdash[51]


Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon


goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent



y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)











HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










Table1Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

16

Glassycarbon

surfa

cecon

jugated

copo

lymer

poly(5-hydroxy-14-

naph

thoq

uino

ne-co-5-hydroxy-2-

carboxyethyl-14-

naph

thoq

uino

ne)antig

enicpeptide

L1


enicpeptideL

1and

HPV

-16antib

ody

SWV

50nM

mdash1h

our

mdash[34]

HPV

16

Carbon

surfa

cechitosananthraqu

inon


ucleic

acid

(acpcPNA)p

robe

Theh

ybrid

izationwith

theH

PV16

DNAwas

studied

bymeasurin

gthee

lectrochem

icalsig

nalofthe

label

anthraqu

inon

eatta

ched

tothea

cpcPNAprob

eSW

V4n

M002

mM

to12nM

15minutes

mdash[35]

HPV

(L1g

ene)

Goldsurfa

cealkanethiolHPV

prob

e

Thes

tudy

was

perfo

rmed

basedon

theinteractio

nof

hematoxylin

with

analkanethiolD

NAprob

eand

itshybridized

form

CVand

DPV

38n

M125nM

to40

0nM

2ho

urs

mdash[36]

HPV

16Glassycarbon

surfa

cegraph

eneAu

nano

rodpo

lythionineH

PV16

prob

e

Besid

esthec

apture

prob

etwoauxiliary

prob

eswere

desig

nedforthe

hybridizationwith

HPV

DNA

110-Ph

enanthrolin

eruthenium

dichlorid

e([Ru

(phen)3]2+

)was

used

asthee

lectrochem

ical

indicator

EISand

DPV

403times

10minus14molL

1times10minus13molL

to1times

10minus10molL

90minutes

mdash[37]

HPV

16

Polymethylm

ethacrylate

substrategold

nano

layer4-

aminothiop

heno

lmon

oclonal

antib

ody(m

Ab)5

051


5051

andHPV

16

CVand

EIS

mdashmdash

1hou

rmdash

[38]

HPV

16

Platinum

surfa

cepolyanilin

e-multiw

alled

carbon

nano

tube

compo

siteHPV

16-L1p

eptid

eaptam

er


ntigen

peptidea

ptam

erHPV

-16-L1

andHPV

-16antib

ody

CVand

SWV

490p

M10nM

to80

nM15

minutes

mdash[39]



esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

s1618

313335

Aqueou

ssolution

Fluo

rescentreporterd

yecovalentlylin

kedto

the51015840end

andaq

uencherd

yelin

kedto

the31015840end

Fluo

rescence

PCR

Differentia

ldetectio

nof

samples

mim

icking

mixed

infections

upto

1of

thetotalDNA

101ndash106

DNA

copies

75minutes

after

DNA

extractio

nand

preparationof

PCR

solutio

ns

mdash[40]

Ratio

sbetween

HPV

s611

1618

and

313335

Insituhisto

logical

sample

Fluo

rescently

labeled

oligon

ucleotides

with

biotin-stre

ptavidin

mod

ificatio

n

Insitu

PCRFISH

LSC

M

1-2DNAcopies

1to50

DNA

copies

per

cell

Overnight

hybridization

noDNAextractio

nneeded

mdash[41]

HPV

s1618

Insituhisto

logical

sample

Oligon

ucleotides

labeledwith

digoxigenin-ll-dUTP

byrand

omprim

ing

FISH

autom

atic

imagec

ytom

etry

1DNAcopy

1ndash500DNA

copies

per

cell

6ho

ursa

fterc

ell

cultu

ren

oDNA

extractio

nneeded

mdash[42]

HPV

s1618

Avidin

coated

(LKB

Sw

eden)sensorc

hip

Biotinylated

oligon

ucleotide

boun

dto

oncoproteins

Plasmon

resonance

018120583M

01ndash4120583

M

mdashmdash

[43]

HPV

s1618

Nitrocellulose

DNA

chip

Biotin

labeledoligon

ucleotides

sand

wichof

streptavidin

toflu

orescenced

ye

PCRchromatograph

yflu

orescence

Qualitative

mdash30

minutes

mdash[44]

HPV

s611

DNAam

plificatio

nOligon

ucleotides

labeledwith

fluorescent

prob

esop

timized

forF

RET

Real-timeP

CRFR

ET-fluo

rescence

25ndash4

3DNAcopies

1ndash3times107

DNAcopies

90minutes

mdash[45]

13different

typeso

fHPV

Nitrocellulose

chip

Fluo

rescently

labeled

oligon

ucleotides

immob

ilized

viab

iotin

-avidin

PCRam

plificatio

n10ndash102

plasmid

copies

0ndash105DNA

copies

30minutes

for

incubatio

n30

second

sfor

reading

Lateral

flow

60tests

[46]

HPV

s1618

Photon

iccrystalon

silicon

Antibod

yim

mob

ilizatio

nOpticaldetectionof

resonant

mod

es

150n

M

0ndash15

nM

16ho

urs

mdash[47]

HPV

16CM

5sensor

chip

(GE

Health

care)

Pairw

iseantib

ody

footprintin

gSP

R10120583gmL

50ndash200120583g

30minutes

3tests

[48]

24different

typeso

fHPV

Goldchip

DNA-

prob

ehybrid

ization

PCRSP

RQualitative

mdash4ho

urs

mdash[49]

HPV

16Quantum

Dot

(75n

m)Maghemite

(46n

m)

Oligon

ucleotides

labeledwith

superparam

agnetic

nano

particles

andQDs

Fluo

rescence

spectro

scop

yQualitative

mdash1h

our

mdash[50]

HPV

16Silican

anop

articles

(75n

M)

Folatefun

ctionalization

Fluo

rescence

microscop

yQualitative

mdash15

minutes

mdash[51]


Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon


goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent



y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)











HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation











esappliedforH

PVdetection

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

HPV

s1618

313335

Aqueou

ssolution

Fluo

rescentreporterd

yecovalentlylin

kedto

the51015840end

andaq

uencherd

yelin

kedto

the31015840end

Fluo

rescence

PCR

Differentia

ldetectio

nof

samples

mim

icking

mixed

infections

upto

1of

thetotalDNA

101ndash106

DNA

copies

75minutes

after

DNA

extractio

nand

preparationof

PCR

solutio

ns

mdash[40]

Ratio

sbetween

HPV

s611

1618

and

313335

Insituhisto

logical

sample

Fluo

rescently

labeled

oligon

ucleotides

with

biotin-stre

ptavidin

mod

ificatio

n

Insitu

PCRFISH

LSC

M

1-2DNAcopies

1to50

DNA

copies

per

cell

Overnight

hybridization

noDNAextractio

nneeded

mdash[41]

HPV

s1618

Insituhisto

logical

sample

Oligon

ucleotides

labeledwith

digoxigenin-ll-dUTP

byrand

omprim

ing

FISH

autom

atic

imagec

ytom

etry

1DNAcopy

1ndash500DNA

copies

per

cell

6ho

ursa

fterc

ell

cultu

ren

oDNA

extractio

nneeded

mdash[42]

HPV

s1618

Avidin

coated

(LKB

Sw

eden)sensorc

hip

Biotinylated

oligon

ucleotide

boun

dto

oncoproteins

Plasmon

resonance

018120583M

01ndash4120583

M

mdashmdash

[43]

HPV

s1618

Nitrocellulose

DNA

chip

Biotin

labeledoligon

ucleotides

sand

wichof

streptavidin

toflu

orescenced

ye

PCRchromatograph

yflu

orescence

Qualitative

mdash30

minutes

mdash[44]

HPV

s611

DNAam

plificatio

nOligon

ucleotides

labeledwith

fluorescent

prob

esop

timized

forF

RET

Real-timeP

CRFR

ET-fluo

rescence

25ndash4

3DNAcopies

1ndash3times107

DNAcopies

90minutes

mdash[45]

13different

typeso

fHPV

Nitrocellulose

chip

Fluo

rescently

labeled

oligon

ucleotides

immob

ilized

viab

iotin

-avidin

PCRam

plificatio

n10ndash102

plasmid

copies

0ndash105DNA

copies

30minutes

for

incubatio

n30

second

sfor

reading

Lateral

flow

60tests

[46]

HPV

s1618

Photon

iccrystalon

silicon

Antibod

yim

mob

ilizatio

nOpticaldetectionof

resonant

mod

es

150n

M

0ndash15

nM

16ho

urs

mdash[47]

HPV

16CM

5sensor

chip

(GE

Health

care)

Pairw

iseantib

ody

footprintin

gSP

R10120583gmL

50ndash200120583g

30minutes

3tests

[48]

24different

typeso

fHPV

Goldchip

DNA-

prob

ehybrid

ization

PCRSP

RQualitative

mdash4ho

urs

mdash[49]

HPV

16Quantum

Dot

(75n

m)Maghemite

(46n

m)

Oligon

ucleotides

labeledwith

superparam

agnetic

nano

particles

andQDs

Fluo

rescence

spectro

scop

yQualitative

mdash1h

our

mdash[50]

HPV

16Silican

anop

articles

(75n

M)

Folatefun

ctionalization

Fluo

rescence

microscop

yQualitative

mdash15

minutes

mdash[51]


Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon


goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent



y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)











HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










Table2Con

tinued

HPV

type

Sensor

platform

Sensingmetho

dTechniqu

eDetectio

nlim

itDetectio

nrange

Detectio

ntim

eRe

usability

References

Highris

kselector

softw

are

(HPV

s1618)

Fluo

rescentd

yed

silican

anop

articles

(250

nm)

Biotin-stre

ptavidin

sand

wich

functio

nalization

MicroarrayDNA

amplificatio

n150p

M

5pMndash10n

M

3hou

rsforincub

ation

timea

fter13ho

urso

fam

plificatio

nand

samplep

reparatio

n

mdash[52]

HPV

s1618

Silican

anop

articles

(60n

m)

Biotin-avidinsand

wichwith

oligon

ucleotides

fluorescently

labeled

Fluo

rescence

spectro

scop

y13ndash15p

mol

0ndash078

nM

90minutes

mdash[53]

HPV

s61116

18Glass

ImmobilizedPC

Rprod

uct

oligon


goldsilver

nano

particles

(15n

M)

Opticalsig

nalto

backgrou

ndratio

005

pmol120583L

005ndash

050

pmol120583L

mdashmdash

[54]

lowastPo

lymerasec

hain

reactio

n(PCR

)flu

orescent



y(LSC

M)andflu

orescent

resonancee

nergytransfe

r(FR

ET)











HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation



















HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation












HPVs 6 1116 18





HPVs 16 18

































3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation




















3 Conclusion







(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation














(a) (b) (c) (d)

Sign

al(120583

V)

minus5

0

5

10

15

20

160 360

Time (s)560 760








Acknowledgments



References

































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation
































































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation

































































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation































































RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation



























RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation











RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation









Documents

Research Article Trends in Biosensors for HPV ...downloads.hindawi.com/journals/js/2015/913640.pdf · Research Article Trends in Biosensors for HPV: Identification and Diagnosis IsaacA.M.Frías,