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Expesen
Ángela RuizWheele
1 Nano2 IDM, Ins
3
Key
1. Introdu
The developand RNA sseveral appli2], pathogendetection ofbiomedical fto personalforensic intreatments, systems ba
An expericonformatioprobes -upooligonucleotreported. Toon silicon pwhere the termination.their 3’ termmolecule toobtained towthe streptavnot, demonsMB upon hythe streptavphotonic sen
erimennsors re
z-Tórtola 1, Frr3, Tamas Da
ophotonics Techstituto Interuniv
School of biolo
y words: silicon
uction
pment of newstrands has bication fields
n detection [3, f DNA/RNAfield, due to thlized medicinvestigation among other
ased on th
imental studyonal change sufon the biorectides over evan
o this end, high photonic bandgMB probes
. Those MBs inmination in ordeo them. The difwards the targe
vidin molecule strate the confoybridization, whvidin moleculensing structure.
* Correspond
ntal stuespons
corancisco Pratslmay3, Amade
hnology Centerversitario de Inv
Química, Uogical Sciences
4 microTEC G
n photonics, ph
w strategies fobecome highlsuch as food 4] or biologic
A strands is he close link one, early dor assessme
rs [6-13]. Nue hybridizat
y of the iffered by mole
cognition of nnescent wave psensitivity pho
gap (PBG) struwere immobil
ncorporate a bioer to selectivelyfferent photonicet oligonucleotiwas bound to
ormational chanhich promotes t
e away from t
ding author: e-m
dy of tse in pnformas-Quílez1, Daneu Griol1, Juan
r, Universitat Povestigación de R
Universitat Polit, University of
Gesellschaft für
hotonic biosenso
or detecting Dly interestingquality controcal safety [5].also key in
of these molecdisease detecent of me
umerous detection between
nfluence of ecular beacon (Mnucleic acid taphotonic sensorotonic sensors buctures were ulized via theirotin moiety cloy bind a streptavc sensing respoide detection, wthe MB probe
nge suffered bythe displacementhe surface of
mail: j.garcia@n
the evaresencationalniel Gónzalez-n Hurtado1, H
Rupérez1,*
olitècnica de VaReconocimientotècnica de ValèEast Anglia, NMikrotechnolo
or, photonic ban
DNA g for ol [1, . The
n the cules ction, dical ction n a
DNAbeenstran15]. GDNAresehavethe ua stestranitsel
the MB) arget rs- is based used, r 5’ se to vidin onseswhen es or y the nt of
f the
Schemstrepta
ntc.upv.es, Phon
anescece of m chang-Lucas2, Marí
Helge Bohlman
alència, Caminoo Molecular y Dncia, 46022 Va
Norwich Researcogie mbH, Duisb
ndgap, molecul
A/RNA targen reported up nded DNA pr. Given the rA/RNA targ
earch, alternae been investuse of MB prem-loop strucnd produces lf [16]. The
matic diagram oavidin-labeled M
ne: +34 96 387
nt-wavmoleculges ía-José Bañulsnn4, Reiner G
o de Vera s/n, 4Desarrollo Tecnalencia, Spain.ch Park, Norwicburg, Germany
lar beacon, conf
et and its coto date, in wh
robes are used
relevance of gets for bioaative approachtigated. Amonobes: a specia
cture where tha conformati
use of fluo
of the PBG sensMB probes were
00 00, Fax: +3
ve photlar bea
s2, Ángel Maqötzen4, Jaime
46022 Valencianológico, Depar
ch, NR4 7TJ, Uy
formational cha
omplementary hich typically d in microarray
the detectioanalysis andhes for theirng them, we al type of nuclhe recognitiononal change orophore-labe
sing structure oe immobilized.
34 96 387 78 27
tonic acon
quieira2, Guy García-
a, Spain. rtamento de
UK
ange.
strand have linear single-y formats [14
on of these d biomedical r recognition can highlight leic acid with
n of the target of the probe
eled MBs in
on which the
7
,
t
t
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solution hasdetection ofcalled oligonan extraordihigher specilinear single- Some exMBs are immfound using surface ennanotweezerHowever, wconformationinteraction othose works,electrochemiso that a vaproduced whthe conforma[28-31]. Thoexploiting thupon hybridmolecule/paropen the doMB-based bi Within tdemonstratiochange of evanescent wmechanism transduction to our knowobserved for
2. Molecu
When a MB undergoes aand adopting33]. The mconsists of a(reporter) ahybridizationaway from depicted in Fthe describeoligonucleotits performathe small foligonucleot In the prorder to provany potentialmodified MB5’ end, for tstructure, an
s proven to f short sequennucleotides [1inary stabilityificity than si-stranded prob
xamples of hemobilized onta range of opnhanced Rrs [26]) and elwe can find nal change ofover a transd, a particle/moical transduceariation in thehen that particational changose works demhe hairpin co
dization changrticle with a or to the deviosensing devthis context, on of the inf
molecule-labwave photonichas been demapproaches,
wledge the r evanescent w
ular Beacon
hybridizes wa conformatiog the typical d
most commona hairpin proband a quenchn promotes ththe reporter,
Figure 1 [16]. ed fluorescenctide detection ance is limitedfluorescence tide concentraresent work, vide a simple l labeled MB B design incluthe immobiliznd a biotin
have high nce nucleic a17-19]. Moreoy, a better imilar assaysbes [20]. eterogeneous to a solid sub
ptical (e.g. fluoRaman speclectronic [27]
some few wf the MB is uduction elemolecule, able ter, is attached e measured ecle/molecule ie of the MB amonstrate the
onformational ging the intertransduction
velopment of vices.
we report fluence of thbeled MB c sensing strucmonstrated foas previouslyfirst time th
wave photonic
n detection
with its compleonal change odouble helix n exploitationbe structure wher on each he separationrestoring the Despite the
ce-based MB in homogeno
d by the diffichanges pro
ations. the MB desand versatile to a given phoudes a thiol tzation on the moiety close
potential foracid strands, over, MBs exselectivity an performed u
assays, wherestrate, can alsorescence [21ctroscopy sensing platfo
works whereused to chang
ment. Typicallto interact witto the MB pr
electrical signis displaced duafter hybridizae high potenti
changes of Mraction of a gelement, thathigh perform
an experimhe conformatiprobes overcture. Despite
or electrochemy indicated, thhat this effecc sensors.
scheme
ementary stranopening theconfigurationn of MB prwith a fluorop
end. Then, n of the quene fluorescencewidespread uconfiguration
ous assays [21iculty of detecoduced by s
ign is adapteway of ancho
otonic sensor.termination on
photonic sene to the 3’
r the also
xhibit nd a using
e the so be -24], [25],
forms. e the ge its ly in th an robe,
nal is ue to ation al of MBs
given t can
mance
ental ional r an e this mical his is ct is
nd, it stem [32,
robes phore
the ncher e, as se of n for -24], cting small
ed in oring . The n the nsing end,
allowmolbiorstrepthe bothMBawaThalabestrepdetemol
Figufluor
Figustrepimm
Cdistawerpolaknowconfand whiof n
3.
wing the inlecule to the recognition optavidin-labelresponse of
h the hybridiz probe, which
ay from the suat response of eled MB probeptavidin-free ermine the inlecule on the o
ure 1 Schematirescence-based
ure 2 Schemeptavidin-free an
mobilized on the
Conformationances of strepe previously arization interwledge the firformational chexploited usinch will be of g
novel label-fre
Materials a
ncorporation MB [34], as
of the targetled MB probethe photonic
zation and conh will displaceurface of the pthe photonic ses will be com
MB probesnfluence of optical sensing
ic explanation od MB probe for
e of the hybnd the streptavie surface of a ph
nal changesptavidin-labele
reported by rferometry [35rst report whehanges upon hng an evanescgreat interest
ee biosensors.
and method
of a streps shown in Ft oligonucleoe will induce sensing stru
nformational ce the streptaviphotonic senssensor havingmpared with ths are used the displacem
g response.
of the workingoligonucleotide
bridization evidin-labeled MBhotonic structur
s and pred MB upon our group ba
5]. However, ere the potentihybridization cent-wave phofor the future
ds
ptavidin (St) Figure 2. The otide by the e a change in ucture due to change of the idin molecule sing structure. g streptavidin-he case when in order to ment of the
g principle of a e detection.
vents for the B probes being re.
rotein-surface hybridization ased on dual this is to our
ial use of MB are observed
otonic sensor, development
r
d
t
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3.1 Photon
For the demeffects on euse of planartheir multipland high intedetection, uswith CMSemiconductParticularly, created by prefractive itransduction their responsthe surroundof the target surface will in turn to aspectral rangallowed owishown in Foptical fieldwave effect make PBG refractive-inmultiplexed
Figure 3 SchPBG edge whby the MB tak Figure 4structure usemode wavegnm, where wi=140 nm aperiodicity atop of a silicthe PBG seobtain a PBGnm when a was this is theequipment aelements tap
nic sensing s
onstration of evanescent war integrated nle advantagesegration levelse of very lowMOS (Comtor) technolo
we developperiodically inindex of th
principle is se to changesding medium
oligonucleotilead to a vari
a shift in the ge where the ing to the p
Figure 3. Thed with the tar
[42, 43], ansensing stru
dex-sensitive biomolecular
hematic explanhen a biorecognkes place.
4 schematicaled in this workguide of heigh
50 silicon tand length we=a=380 nm; thecon oxide lowensing structuG edge locatewater upper cle wavelengthavailable at oper, where t
structures
the MB confoave photonic anophotonic t: high sensitil, short time to
w sample volummplementary ogy fabricatioped PBG sntroducing a mhe photonic
based on ths in the refrac[39-41]. So, tide by the MBiation in the R
position of propagation oeriodicity of e enhanced irget analytes, nd their extreuctures an em
structures sensing appli
nation of the snition of the tar
lly depicts tk. It consists oht h=220 nm transversal el=1500 nm aree silicon struc
wer cladding. Ture were seleed at a waveleladding surrou
h range whereour laboratorythe length o
ormational chsensor, we m
technology, duvity, compacto result, labelmes, compatib
Metal-Oxon, etc. [36ensing structmodulation in
structure. The dependenctive index (Rthe biorecognB occurring onRI distributionthe PBG, i.eof the light isthe structure
interaction ofdue to the s
emely smallmerging clas
for labelications.
spectral shift orget oligonucle
the PBG senon a silicon siand width w=
lements of we introduced wcture is placeThe dimensionected in ordeength around unds the struce the interrogary operates. Aof the transv
hange made ue to tness l-free bility xide--38]. tures n the Their ce of
RI) of nition n the n and , the s not e, as f the slow-size,
ss of l-free
of the eotide
nsing ingle =460 width with a ed on ns of er to 1550 cture, ation A 5-
versal
elemand impwav
Figustructop acce Tperfby mvoltetchmicrstrustruperfsensstrepwasshal
Figu
3.2
Thehas
ments is lineathe output of
prove the lighveguide.
ure 4 Schematicture. The perioof a silicon o
ess taper is not i
The fabricatioformed in a stmeans of e-btage of 100 hing of the troscope (SEMcture is showctures were iform multiplesing responseptavidin-free
s accessed at tllow etch 1D g
ure 5 SEM ima
Functional
e immobilizatito be robust a
rly varied, is f the PBG senht coupling
c representationodic silicon ph
oxide lower claincluded in the
on of the PBtandard siliconbeam lithograkeV and indop silicon la
M) image of wn in Figurincluded in a
exed detectione for the strMB probes a
the input and grating couple
ge of a fabricat
lization
ion of MBs oand biocompa
also includednsing structurfrom/to the
n of the selectehotonic structuradding. Note tscheme.
BG sensing stn-on-insulatoraphy with anductively couayer. A scanna fabricated
re 5. Four Pa single photn in order to eptavidin-labe
at the same timthe output viaers.
ted PBG sensing
on the photonatible. In this
d at the input re in order to single mode
d PBG sensing re is placed on that the linear
tructures wasr (SOI) wafer
n acceleration upled plasma ning electron PBG sensing PBG sensing tonic chip to compare the
eled and the me. The chip a 70 nm-deep
g structure.
nic structuresregard, thiol-
t
r
r
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ene couplinhomogeneoumild conditiothiolated MCCT ATC Adenotes a mEurofins Scipreviously structures foTo introducethe photonicimmediately(50 mW·cmimmersed in(Sigma-Aldrthe photonicFinally, a wmeasured aftdemonstratin Then, thvinyl-functiochemistry. Tin ultrapure dry at room 254 nm (5photoimmobthe photonic(phosphate bwater and air StreptaviPBG structu(5 µL, 20 structures anthe streptavithe chip wasto remove anMBs. The targexperiments the MB seqGUG AUA diluted in sconcentration
3.3 Experi
The biofunassembled wbottom holda top fluidic 7.5 mm-longplaced on anin Figure 6, aspectrum of spectral shif81980A), cen
ng (TEC) us biofunctionons [35, 44, 4Bs (5’-3’ seACG ATT A
modified T toientific, Luxevinyl-derivatllowing a preve alkene grou
c chip was riny activated witm-2) for 10 n a 2% sorich, Germany chip was wasater contact a
fter curing theng functionalizhe MB probeonalized PBGThiolated MB
water) were dtemperature. 0 mW·cm-2)
bilization. Oncc chip was thbuffer saline wr dried. idin was attacures by depos
ppm in PBnd incubated iidin-biotin lins intensively ny streptavidi
get oligonuclhad the seq
quence (AUC GGG GUG
saline-sodium n.
imental setu
nctionalized with a microfer, where the lid having a 5
g rubber chann automated oable to continthe PBG sen
fting. A waventered at 1550
chemistry pnalization of 45]. To achievquence: SH-A
AGC ATT AAo incorporate embourg) wertized surfaceviously optimups on the phsed with ethath UV-vis irraminutes. Thelution of vi
y) in toluene shed with acetangle (WCA) e chip for 30 zation.
es were immG sensing str
probe solutiodrop casted onThe chip was for 30 secce the MBs whoroughly wawith a 0.5 % tw
ched to the Miting a solutio
BS-T) over tin a humid chnk at room tewashed with n unspecifica
leotide used quence fully c
GAC UUA UCG AU 5citrate (SSC
up
photonic senfluidic flow cphotonic chip
500 µm-wide,nnel. The assoptical readounuously acquirsing structureelength-tunabl0 nm, was cou
provides a the surface u
ve immobilizaATC GAC AAG *TCG A
a biotin more coupled toe of the
mized protocolhotonic structanol and wateradiation at 254e chip was inyltriethoxysfor 2 hours. Ttone and air dof 76.7±0.1°minutes at 90
obilized ontoructures by
ons (30 nL, 10n them and les then irradiatconds to achwere immobilashed with PBween 20), dist
MBs of two oon of streptavthe desired P
hamber to promemperature. APBS-T and wlly attached to
for the sencomplementarAUG CUA A’ to 3’) and
C) 5× at 0.5
nsing chip cell comprisinp was placed,, 500 µm-highsembled chip ut setup, as shre the transmises to monitor le laser (Keyupled to the ac
fast, under ation, ACC
AT; * oiety, o the PBG [35].
tures, r and 4 nm then ilane Then dried. was
0 °C,
o the TEC
0 µM eft to ed at hieve ized,
BS-T tilled
f the vidin PBG mote
After, water o the
nsing ry to AUC
was µM
was ng a , and h and
was hown ssion their sight ccess
grat(Thooutp(20XusinTheimpcontof thwermod
Figuon tcell
4.
An 7 foon t156
Figubiofu
ting couplersorlabs CFS2put grating coX Olympus Png an infrarede interrogationplemented in tinuous sweephe IR camera e flown usingde and set to a
ure 6 Picture ofthe interrogatiohaving the micr
Experimen
example of tror one of the bthe photonic c0 nm.
ure 7 Examplefunctionalized P
s using a f-1550-APC)
ouplers was cPlan Achromad (IR) camern platform wa
LabVIEWp of the laser via a trigger s
g a syringe pua constant flow
f the assembledon platform androfluidic chann
ntal results
ansmission spiofunctionaliz
chip, whose PB
e of transmissiPBG sensing str
fiber aspheriand the lig
collected with at, 0.4 NA) ara (Xenics Xas controlled bable to synwith the imagsignal. The tarump working
w rate of 20 µl
d photonic sensid detailed imagnel on its bottom
pectrum is shozed PBG sensiBG edge is lo
ion spectrum fructures.
c collimator ght from the
an objective and measured eva-1.7-320). by a software chronize the ge acquisition rget solutions
g in withdraw l/min.
ing chip placed ge of the flow
m side.
own in Figure ing structures
ocated around
for one of the
r
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Figure 8 evolution ooligonucleotPBG sensingwas obtaineemployed asin the experioligonucleotrecognition bPBG edgesadditional cyin order to rpresent in thunchanged, oligonucleotexperiment wwas stable Unfortunatelbiofunctionadamaged and
Figure 8 Temsensing structflown over thstructure beinprobes is depithe PBG senswith the strept2) are depicted From Firemarkable Pfor target oleven ~1000sensing rebiofunctionathe experimelabeled MB these differebiorecognitiodifferences oadditional RInormalize ththe PBG edg
shows the senof the PBGtide hybridizag structures oed flowing s carrier buffeiments. At t=tide was flowby the MB pr
s of the senycle of SSC 5remove any n
he medium; thindicating th
tide strand wwas carried oand constan
ly, one alized with d no output sig
mporal evolutiontures when thehe sensors. Thg biofunctionalicted with red dsing structures btavidin-labeled d with green an
igure 8, it PBG edge shligonucleotide
0 pm). Howesponse was
alized PBG seents, even betw
probes. So, ent responses on process byof the PBG seI calibration c
he sensing respge shift produc
nsing responsG edge, towation for the on the chip. T
SSC 5× buer for the targ14 min, a soluwn over therobes producensing structu× buffer was non-hybridizee PBG edge p
hat hybridizatwas successfuout at room tnt during the
PBG senstreptavidin-
gnal was mea
n of the PBG ee target oligonhe sensing resplized with the sdots, while the being identical MB probes (M
nd blue solid lin
can be obshifts were obte detection (fever, a signis obtained ensing structuween those hain order to dwere due to the MB prob
ensing structurcycle was carrponses. In thiced by the cha
e, i.e., the spewards the ta
biofunctionaThe initial basuffer, which get oligonucleoution of the tae sensors, wed the shift oures. Finally,flown at t=24
ed oligonucleopositions remation of the taul. Note thatemperature ane whole pronsing struc-free MBs sured.
edge position onucleotide stranponse for the streptavidin-freesensing responly biofunctiona
MB+St 1 and Mnes.
served that tained in all cfrom ~350 pmificantly diffe
for the tures considereaving streptavdetermine whedifferences ines or to sensitres themselveried out in ords calibration cange from SSC
ectral arget lized eline was
otide arget
whose f the , an
4 min otide ained arget t the nd it cess. cture was
of the nd is PBG
e MB nse of alized
MB+St
very cases m to
ferent three ed in
vidin-ether n the tivity es, an der to cycle, C 5×
buffthe oligcaliboligstrucalibedgeincluothebiofand expeoverPBGstrep Taboligocoluoligo
resu
Figupositrespstrepsensbiofudepi
MB+MB+MB MB MB
fer to ultrapurspectral sh
gonucleotide bration cycle,
gonucleotide dctures when bration cycle e shifts are audes additioner two idfunctionalizedMB 2*) obta
eriment [46]. rcome the proG sensing sptavidin-free M
le 1 Measured onucleotide stra
umn indicates thonucleotide det
lts obtained in a
ure 9 Normaliztion of the seonse for the PBptavidin-free Ming response
functionalized wicted with green
Oligondete
(p+St 1 3+St 2 6 11* 92* 1
re water was hifts measure
detection e, while Figurdetection respthat absolute was consider
also indicated nal oligonucledentical PBd with streptaained using a d
These resultoblem of havstructure bioMB in the ori
spectral shifts and and for the he normalized Ptection experim
another experim
zed temporal ensing structurBG structure bei
MB probes is depof the PBG
with the streptan and blue solid
nucleotide ection pm)
RI
345 620 020 920 120
measured. Taed for bothexperiment ae 9 shows th
ponse of the value of the
red (normalizein Table 1).
eotide detectioBG sensingavidin-free Mdifferent chip s are include
ving only a sinofunctionalizeginal experim
for the detectioRI calibration
PBG edge shiftment. The * ma
ment using anot
evolution of tres. The norming biofunctionpicted with red
G sensing stravidin-labeled Md lines.
calibration (pm)
ol
-1890 -3230 -1560 -1390 -1804
able 1 shows h the target and the RI he normalized PBG sensing e shift in the ed final PBG Table 1 also
on results for g structures MBs (MB 1*
in a different d in order to ngle working
ed with thement.
on of the target cycle. The last
ts for the target ark denotes the
ther chip.
the PBG edge alized sensing
nalized with the dots, while the
ructures being MB probes are
Normalized ligonucleotide
detection 0.183 0.192 0.654 0.662 0.621
r
t
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On one handtwo PBG senstreptavidin-different shiattributed tosensing strucfabrication pdifferent shstructures befree MB printeraction othe photonistreptavidin. In the experiments,streptavidin a significant of the PBG susing streptaorder to disrecognition probe and fluorophore-the experimecompared fosimilar resulobserved in by the additstreptavidin-explained inwas displaceMB, matterphotonic senbackshift of magnitude significantlydetection ostreptavidin-shift was obMB probes d
Figure 10 a) the streptavidwhen the MB with the targethe photonic
d, the normaliznsing structur-labeled MB ifts previousl
o the differenctures, probabprocess. On
hifts were obeing biofunctirobes (~0.65
of the MB proic sensing s light of the, it can be obmolecule attadecrease of th
sensing structuavidin-free MBscard that the
of the targelead to a
-labeled oligonents; the fluoror both MB prlts. Thus, wethe photonic
tional displac-labeled MBn Figure 10. Wed, due to ther was removnsing structurf the PBG edof that back
y large positivof the targ-free MB probbtained when due to the com
Schematic repin from the surchanges its con
et oligonucleotisensor respon
zed shifts werres being biofuprobes (~0.19
ly observed inces in sensitbly because of
the other hbtained for tionalized with), thus indic
obe with the estructure wh
e results obbserved that thached to the Mhe normalizedures, compareB probes (by ae streptavidin et oligonucleoa lower hybnucleotide tar
rescence after robes configu
e concluded thmeasurement
cement effect B probes, aWhen the strepe conformatioved from there, what was dge. Howeverkshift was s
ve shift measuget oligonucbes. So, a smusing the st
mbination of b
presentation of rface of the PBnformation dueide. b) Schemat
nse when strep
re identical founctionalized 9). Thereforein Figure 8 wtivity of the Pf deviations onand, significathe PBG senh the streptavcating a diffeevanescent fiehen incorpora
btained fromhe presence o
MB probe prodd sensing resped with the caa ~3.6× factormay hamper
otide by the bridization yrgets were usehybridization
urations, provihat the differts was determproduced for
as schematiptavidin mole
onal change oe surface of
translated inr, in this casesmaller than ured for the dcleotide by maller positivetreptavidin-labboth effects.
the displacemeBG sensing stru to the hybridiztic representatiotavidin-labeled
or the with , the were PBG n the antly nsing vidin-ferent ld of ating
the f the
duces ponse se of r). In r the MB
yield, ed in
n was iding rence
mined r the cally ecule f the
f the nto a e the
the direct
the e net beled
ent of ucture zation on of
d MB
probcomof ththe s
5.
In tinfluoveris, trepo Bto obothdispconfexpecomthe the usedthe biggthat migphot Aimpmolantiblowprodmolnegatargoligreplconfspec Fpropto hfieldthe disp
AckfundthroSAPMIN
Ref
bes are used. mbination of the he target oligonstreptavidin disp
Conclusion
this work, wuence of the r evanescent to our knowlorted for this tBy labeling Mobtain a sensih the direct oplacement offormational cerimental stu
mbination of tsensing respotarget oligon
d), a proper sMB (e.g., a
ger size molesignificantly
ght lead to antonic sensing Another pote
prove the sensilecular weighbiotics, whose
spectral shduced by tlecule/particleative shift sig
get detection.gonucleotide-blaced by anformational ccific target. Finally, this eper design of have several od profiles, wh
hybridized placed molecu
knowledgemeding receiveough the HoPHELY projecNECO (CTQ/2
ferences
The final net positive shift g
nucleotide and oplacement.
n
we have expconformationwave photoniledge, the firtype of optical
MB probes witing response oligonucleotidf that molechange of thudy, the netthese two effeonse comparednucleotide (i.election of thhigh refractiv
ecule) mightdominates th
n amplificatiostructure.
ential applicaitivity toward
ht targets, as e direct detect
hift. In that the displace
e will dominagnificantly hi. Note that based targets, n aptamer, change upon
effect might the photonic
optical modeshich can intera
target oligonule/nanoparticl
ents The d from the
orizon 2020 ct). This work2016/75749-R
response is agiven by the dirof the negative
perimentally onal changes oic sensing strst time that l sensors. th a molecule,being the co
de detection eecule produche MB. Dest shift obtai
fects means a d to the directe., when no
he matter beinve index nanoinduce a highhe detection pon of the res
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