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Xiangwei Zhao Meng Lu  Editors Nanophotonics in Biomedical Engineering Nanophotonics in Biomedical Engineering (cid:129) Xiangwei Zhao Meng Lu Editors Nanophotonics in Biomedical Engineering Editors XiangweiZhao MengLu StateKeyLaboratoryofBioelectronics ElectricalandComputerEngineering SoutheastUniversity IowaStateUniversity Nanjing,Jiangsu,China Ames,Iowa,USA ISBN978-981-15-6136-8 ISBN978-981-15-6137-5 (eBook) https://doi.org/10.1007/978-981-15-6137-5 ©SpringerNatureSingaporePteLtd.2021 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant protectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors, and the editorsare safeto assume that the adviceand informationin this bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor theeditorsgiveawarranty,expressedorimplied,withrespecttothematerialcontainedhereinorforany errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional claimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Contents 1 PhotonicCrystalsforBiomoleculeSensingApplications. . . . . . . . . . 1 LeWei,ShirinPavin,XiangweiZhao,andMengLu 2 RecentAdvancesinSurfacePlasmonResonanceforBiosensing ApplicationsandFutureProspects. . . . . . . . . . . . . . . . . . . . . . . . . . 21 BiplobMondalandShuwenZeng 3 Surface-EnhancedRamanScatteringforDetectioninBiology andMedicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 JieSun,ChenyanPan,andJianDong 4 NanophotonicTechniquesforSingle-CellAnalysis. . . . . . . . . . . . . . 79 MuhammadShemyalNisarandXiangweiZhao 5 BiointerfaceCharacterizationbyNonlinearOpticalSpectroscopy. . 111 WenhuaSun,ShujingWang,andXiaofengHan 6 ChemiluminescenceandItsBiomedicalApplications. . . . . . . . . . . . 143 ChunsunZhang,YanSu,YiLiang,WeiLai,JunJiang,HongyangWu, XinyuanMao,LinZheng,andRuoyuanZhang 7 LuminescentConjugatedPolymerDotsforBiomedical Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 GuoLi,TiansheYang,WeiweiZhao,ShujuanLiu,WeiHuang, andQiangZhao 8 Dark-FieldHyperspectralImaging(DF-HSI)Modalitiesfor CharacterizationofSingleMoleculeandCellularProcesses. . . . . . . 231 NishirMehta,SushantSahu,ShahenshaShaik,RamDevireddy, andManasRanjanGartia 9 AdditiveManufacturingTechnologiesBased onPhotopolymerization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 HaiboDing,XiangweiZhao,andZhongzeGu v Chapter 1 Photonic Crystals for Biomolecule Sensing Applications LeWei,ShirinPavin,XiangweiZhao,andMengLu Abstract Photonic crystal (PhC) sensors offer important advantages in molecular diagnostic applications, such as detection of disease-related proteins, genes, and pathogenicviruses,andbacteria.Thischapterbrieflyexplainstheoperationprinci- plesofthree-dimensional(3D)andtwo-dimensional(2D)photoniccrystals,presents howthePhCstructurescanbefabricatedinexpensively,anddemonstrateseveralkey applications as for the detection of biomolecules. These applications are based on four main sensing modalities: reflectometry, fluorescence emission, surface- enhanced Raman scattering, and photoacoustic detection. The chapter discusses the implementations of PhC sensors to facilitate the detection of biomolecules via these venues. For each detection modality, we will elaborate the advantages pro- vided by the PhC sensors in the context of specific applications and sensing performances,suchassensitivityandlimitofdetection.ThePhC-basedbiosensors notonlyoffernewwaystodetectbiomoleculewithlowcostandhighthroughputbut alsoenableresearchersandclinicianstoimproveexitinglab-basedassaystoachieve betterassaysensitivities. Keywords Photoniccrystals·Opticalsensors·Surface-enhancedRaman scattering·Fluorescence·Nanofabrication L.Wei DepartmentofElectricalandComputerEngineering,IowaStateUniversity,Ames,IA,USA S.Pavin·M.Lu(*) DepartmentofElectricalandComputerEngineering,IowaStateUniversity,Ames,IA,USA DepartmentofMechanicalEngineering,IowaStateUniversity,Ames,IA,USA e-mail:[email protected] X.Zhao(*) StateKeyLaboratoryofBioelectronics,SchoolofBiologicalScienceandMedicalEngineering, SoutheastUniversity,Nanjing,China NationalDemonstrationCenterforExperimentalBiomedicalEngineeringEducation,Southeast University,Nanjing,China e-mail:[email protected] ©SpringerNatureSingaporePteLtd.2021 1 X.Zhao,M.Lu(eds.),NanophotonicsinBiomedicalEngineering, https://doi.org/10.1007/978-981-15-6137-5_1 2 L.Weietal. 1.1 Introduction Recentresearch hasdemonstratedthatphotoniccrystals(PhCs),whicharecapable of manipulating light and molecule interactions at the nanometer scale, can be harnessed as a new type of analytical chemistry tool for the detection of a variety ofanalytes,includingvolatileorganiccompounds,DNAs,proteins,andevencells. A vast array of PhC structures have been developed to fulfill the chemical and biomolecule sensing [1–4]. Among them, there are two major categories of PhC structures: the three-dimensional (3D) PhCs with the periodical modulation of dielectric material’s refractive index in 3D space and the PhC slabs, whose lattice structure is confined in a two-dimensional (2D) plane. The 3D PhC and 2D PhC slabs can be engineered to exhibit unique optical phenomena, such as photonic bandgap, high Q-factor cavity, and guided-mode resonance. In conjunction with a specific analytical assay, the PhC structures can be exploited for the quantitative analysis of an analyte in complex samples, such as blood, urine, saliva, and many more. Fundamentally, the PhC can sense target molecules in one of the three different ways: (1) Measuring the change of refractive index of the PhC or its surrounding medium; (2) Detecting the change of PhC geometry owing to the absorption of chemicals; and (3) Enhancing the scattering or emission of analyte immobilized onPhCs. Basedon these mechanisms, anumberof PhC-based detec- tionassayshavebeenintroducedfortheanalysisofthedirectabsorptionsofthegas molecule, virus, and cells or the bindings between ligand and analyte. Such PhC-based assays have great potential in many molecular diagnostic applications, suchasdiseasebiomarkerdetections,nucleicacidtests,identificationofpathogens, andmanyothers. This chapter first explains the underlining physics of PhCs and shows how the PhCsaredesignedandfabricated.Then,thesensingmechanismsusingPhCsforthe label-free, fluorescence, Raman-based, and photoacoustic detections of biomole- cules are described. Finally, the chapter presents several examples of PhC-based assayswithaspecificfocusonthemultiplexeddetectionofdiseasebiomarkers.This chapter aims to serve as a review for demonstrating the design of PhC devices, methodsoffabrication,andassaycapabilities.Forfulldetails,thereaderisdirected tofullarticlespublishedoneachtopic. 1.2 Fundamental Principle of PhC for Sensing 1.2.1 2D and 3D PhC Structures TheideaofPhCwasfirstdemonstratedin1987byYablonovitch,whoshowedthat the periodic structures with alternating refractive indices can be analogous to semiconductor crystals with the forbidden gap [5]. Light propagation with its wavelength in the photonic bandgap is prohibited by the periodic structure. Later, 1 PhotonicCrystalsforBiomoleculeSensingApplications 3 the concept of PhCs was successfully realized in 3D to achieve PhCs with full bandgaps [6–9]. The bandgap of PhCs can be considered as a result of destructive interferenceoflightreflectionbythephotoniclatticeofrefractiveindex(n).The3D PhCs can strongly reflect light whose wavelength (λ) falls in the range of the forbidden gap. The lattice constant, also known as period (Λ), of a PhC is approx- imately half of the wavelength of the light to be reflected. In general, the material refractiveindexesandthegeometryparameters,includingΛanddutycycle,ofPhCs determinethespectralpositionofthephotonicbandgap.ForthePhCwithaphotonic bandgap in the visible or near-infrared range, its period is on a scale of several hundrednanometers.The3DPhCshavebeenutilizedtoreflect,guide,andlocalize light on a subwavelength scale (Fig. 1.1a, b). For sensing applications, the 3D PhC-based sensor can be applied to measure a wide range of signals, such as pressure, temperature, humidity, pH value, ions, gas molecules, and biomolecules [10].Forexample,aselectiveabsorptionoftargetdiseasebiomarkersviatheligand– analyte binding can cause the change of refractive index around the PhC, and thus shiftthecolordisplayedbythe3DPhCstructure.Inaddition,the3DPhCstructure can also change its color when the absorption of a target analyte, such as organic compoundsresults inthechange ofitsperiod.Thecolorimetric detectionupon3D PhCsensorshaveenabledthedevelopmentofcompactandlow-costsensorsystems forpoint-of-carediagnostics[2]. ThePhCslabintegratestheperiodicmodulationofmaterialrefractiveindexinto aslabwaveguide,asshowninFig.1.1c.ThePhCslabusesthewaveguidetoconfine lightinthedirectionperpendiculartotheslab’ssurfaceandadoptthePhCstructure tocontrollightpropagationalongthewaveguide.Twomaintypesof2DPhCslabs, the in-plane confined PhC slab and out-of-plane coupled PhC surface, have been extensively studied [11–15]. The in-plane PhCs can be designed to form optical Fig.1.1 3DPhCsandPhCslabs.(a,b)showtheschematicandSEMimagesofthe3DPhCand inverseopalPhCstructures,respectively(reproducedwithpermissionfrom[10].Copyright2013, MDPISwitzerland).(c)Schematic(toppanel)andSEMimage(bottompanel)ofin-planeconfined 2DPhCslabs(reproducedwithpermissionfrom[13]Copyright2000,SpringerNatureandfrom [14]Copyright2018,IntechOpen).(d)Out-of-planecoupledPhCslabstructure(toppanel)and SEMimage(bottompanel).(Reproducedwithpermissionfrom[34].Copyright2013,TheRoyal SocietyforChemistry) 4 L.Weietal. waveguides, interferometers, and high Q-factor (high-Q) resonators. When light is coupled into an in-plane PhC, the light is confined and cannot escape from the surfaceoftheslab.ThePhCslab-based interferometersandhighQcavitiescanbe implemented to develop refractive index-based sensors. For example, the ligand– analyte binding occurring around a PhC cavity can cause a shift of the resonance wavelength (λ) [4]. The capability of measuring the change of λ allows the PhC r r cavity to be used as a refractometric sensor. It is also possible to achieve a high-Q opticalresonancewithasignificantlyenhancednearfieldonthesurfaceofa2DPhC slab. The features of enhanced nearfield can be exploited to improve the signal-to- noiseratio(SNR)forfluorescenceorRamanscattering-basedassays. Unlike the highly confined modes of in-plane confined PhCs, the out-of-plane coupled PhCs mode can be coupled from its surface. Such 2D PhC slabs are also known as leaky mode resonance waveguides, high-contrast gratings, or guided- mode resonance (GMR) filters. The underlying principle of leaky mode resonance wasfirstreportedbyMagnusson’sgroupintheearly1990s[15].Mostout-of-plane coupled PhCs consists of a grating coupler and a dielectric waveguide, which can support resonance modes with the signature of narrowband reflections or trans- missions. The grating coupler can also be integrated into the waveguide to form the leaky mode waveguide. When light is coupled into a resonance mode via the grating coupler, the constructive interference between the backward leaked and reflectedlightyieldsanearly100%reflection(asshowninFig.1.1d).Thespectral characteristics of reflection, such as its resonance wavelength, peak reflection effi- ciency,andlinewidth,aredeterminedbythematerialsandgeometryofthe2DPhC slab [16]. The resonance mode supported by the out-of-plane coupled PhC can be exploitedforbothrefractiveindex-basedbiosensorandnearfield-enhancedsensing. TheexamplesoftheGMR-basedsensorareshowninSect.1.3ofthischapter. 1.2.2 Fabrication Processed for PhCs For the PhCs that operate in the visible wavelength region, the critical feature size could be as small as 100 nm. The subwavelength feature size presents a great challengeforPhCfabrication,inparticular,thelithographystep.Nanoscalepatterns ofthe2DPhCslabshavebeensuccessfullyfabricatedusingconventionallithogra- phy approaches, such as deep UV (DUV) lithography, electron beam lithography (EBL),focusedionbeamlithography(FIB),andheliumionbeamlithography(HIL) [17]. Following the lithography process, the pattern can be transferred into the substrate layer using dry etching, such as ion milling or reactive ion etching. These methods can provide excellent resolution but also have constrains of low throughputandhighcost.Fabricationof3DPhCsisparticularlydifficultusingthese conventional approaches because of the requirement of patterning and alignment betweenmultiplelayers.Unconventionalapproaches,includinginterferencelithog- raphy, nanoimprint lithography (NIL), and self-assembly method, have been suc- cessfullyexploitedtofabricatesubwavelengthgratingsforthePhCslabswithhigh 1 PhotonicCrystalsforBiomoleculeSensingApplications 5 throughput,highfidelity,uniformity,andlowcost[18].Detailsoftheself-assembly, NIL, and interference lithography processes for the PhC fabrication are reviewed below. Self-AssemblyMethod Theself-assemblymethodusescolloidalsolutionstoforma variety of PhCs through the ordered arrangement of nanobeads. Using self- assembly, large-area and high-quality PhC can be fabricated on a substrate with lowcostandhighthroughput.Many3DPhCstructureshavebeensuccessfullyself- assembledusingcolloidalsolutionsofsilica,polymer,orhydrogelnanobeads.The simplest self-assembly method is to naturally precipitate the nanobeads using a diluted colloidal solution, followed by a sintering process to improve the PhC’s stability(Fig.1.2a)[19,20].Alternatively,inverticaldeposition,whichisthemost widely used method upon evaporation of the solution, the nanobeads are forced to line up on the substrate, as shown in Fig. 1.2b. The Langmuir-Blodgett method is another alternative, where a single-layer film of nanobeads can be formed at the interface between air and liquid surface [21]. The single layers can be built up to form2Dand3DPhCpatterns. ImprintLithography For2DPhCslabs,itispossibletoformlarge-areaandsingle- layerperiodicstructuresusingnanoimprintlithography(NIL).TheNILprocessisa contact patterning method, which is not limited by the diffraction limit and can produceafeaturesizebelow25nm.Figure1.2cillustratesthebasicstepsofaNIL process[22]. Inthe first step, a stamp (also knownas mold or template)ispressed againstathinlayerofimprintresist.Afterthe1Dor2Dgratingpatterncarriedbythe moldistransferredtotheresistlayer,themoldiscarefullydetached.Inthesecond step, the residual resist is removed and the pattern is transferred onto the substrate material using a dry-etching process. Both thermal and UV light-based NIL pro- cesseshavebeenexploitedtofabricated2DPhCslabs. Interference Lithography The principle of laser interference lithography is based ontheinterferencepatternproducedbytwoormorelaserbeams,whichistranslated asphysicalpatternsonalayerofphotoresist.ThesetupshowninFig.1.2discalled Lloyd’s mirror interferometer [23]. The angle between the Lloyd’s mirror can be adjustedtochangetheperiodoftheinterferencepatternandthuscontrolstheperiod of the grating pattern. A two-dimensional grating pattern of a PhC slab can be produced by interfering with three laser beams. Moreover, a variety of 3D PhC structurescanbeformedwithinterferenceofatleastfourlaserbeams[24]. 1.3 Detection of Biomolecules Using PhC Sensors The PhC structures can be implemented for sensing applications in a few different ways.Themostuniqueoneisthelabel-freedetections,whichrepresentthedetection ofchemicalsandbiomoleculesbasedontheirintrinsicphysicalproperties.Both3D PhCs and 2D PhC slabs have been successfully demonstrated as label-free

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