nanomaterials

Review A Review of Graphene-Based Surface Plasmon Resonance and Surface-Enhanced Raman Scattering Biosensors: Current Status and Future Prospects

Devi Taufiq Nurrohman 1,2 and Nan-Fu Chiu 1,3,*

1 Laboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, Taipei 11677, Taiwan; devi.taufi[email protected] 2 Department of Electronics Engineering, State Polytechnic of Cilacap, Cilacap 53211, Indonesia 3 Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan * Correspondence: [email protected]

Abstract: The surface plasmon resonance (SPR) biosensor has become a powerful analytical tool for investigating biomolecular interactions. There are several methods to excite surface plasmon, such as coupling with prisms, fiber optics, grating, nanoparticles, etc. The challenge in developing this type of biosensor is to increase its sensitivity. In relation to this, graphene is one of the materials that is widely studied because of its unique properties. In several studies, this material has been proven theoretically and experimentally to increase the sensitivity of SPR. This paper discusses the current development of a graphene-based SPR biosensor for various excitation methods. The discussion begins with a discussion regarding the properties of graphene in general and its use in biosensors. Simulation and experimental results of several excitation methods are presented. Furthermore, the discussion regarding the SPR biosensor is expanded by providing a review regarding graphene-based



 Surface-Enhanced Raman Scattering (SERS) biosensor to provide an overview of the development of materials in the biosensor in the future. Citation: Nurrohman, D.T.; Chiu, N.-F. A Review of Graphene-Based Keywords: biosensors; surface plasmon resonance; graphene Surface Plasmon Resonance and Surface-Enhanced Raman Scattering Biosensors: Current Status and Future Prospects. Nanomaterials 2021, 11, 216. https://doi.org/10.3390/ 1. Introduction nano11010216 Graphene, the mother of all carbon materials, has opened a new era in technological development because of its unique properties. Graphene is a single layer of carbon atoms Received: 30 December 2020 with a 2D hexagonal crystal lattice and is the thinnest and strongest material that has Accepted: 12 January 2021 existed to date [1]. Various and unique new properties can be generated by shaping the Published: 15 January 2021 graphene layer into 0D buckyballs, 1D nanotubes, and 3D graphite [2]. This property makes graphene suitable for applications in various fields, including drug delivery [3], Publisher’s Note: MDPI stays neutral energy storage [4], bioimaging [5], and biosensors [6]. with regard to jurisdictional claims in The Surface Plasmon Resonance (SPR) biosensor is a type of biosensor which is very published maps and institutional affil- powerful for detecting and determining the specificity, affinity, and kinetic parameters iations. of macromolecular bonds. The working principle of this biosensor uses metals such as gold (Au), silver (Ag), and aluminum (Al) to excite surface plasmon waves which are very sensitive to changes in the refractive index on their surface [7]. Various macromolecular bonds have been detected such as protein–protein, protein–DNA, enzyme–substrate or Copyright: © 2021 by the authors. inhibitor, receptor drug, membrane lipids–proteins, proteins–polysaccharides, and cell—or Licensee MDPI, Basel, Switzerland. virus—proteins [8]. This article is an open access article The sensitivity of the SPR biosensor is simply defined as the ratio between the shift in distributed under the terms and wavelength or angle and the change in the refractive index on the sensing surface. This conditions of the Creative Commons sensitivity is influenced by many factors depending on the excitation method chosen. For Attribution (CC BY) license (https:// the prism coupled SPR biosensor, the sensitivity of the SPR is influenced by the type of creativecommons.org/licenses/by/ prism, metal and wavelength used. Islam et al. reported that for the angle investigation 4.0/).

Nanomaterials 2021, 11, 216. https://doi.org/10.3390/nano11010216 https://www.mdpi.com/journal/nanomaterials Nanomaterials 2021, 11, x FOR PEER REVIEW 2 of 30

Nanomaterials 2021, 11, 216 2 of 29 prism, metal and wavelength used. Islam et al. reported that for the angle investigation mode, the SPR structure has the best sensitivity with a gold metal with a thickness of 50 nm [9]. For the fiber coupled SPR biosensor with an investigation mode in the form of mode,wavelength, the SPR of the structure four types has theof metals best sensitivity investigated, with the a goldhighest metal sensitivity with a thicknessis gold (Au), of 50silver nm (Ag), [9]. For copper the fiber (Cu) coupled and aluminum SPR biosensor (Al), respectively with an investigation [10]. For grating mode in coupled the form SPR of wavelength,biosensor, the of sensitivity the four types is influenced of metals by investigated, the shape of the the highest grating, sensitivity the period is of gold the (Au),grat- silvering, the (Ag), height copper of the (Cu) grating, and aluminum and the wave (Al),length. respectively Cao et[ 10al.]. reported For grating that coupledin the wave- SPR biosensor,length range the of sensitivity 600–1000 is nm influenced for the angular by the shape investigation of the grating, mode, the the period best sensitivity of the grating, be- thelongs height to the of first the grating,diffraction and order the wavelength.[11]. Cao et al. reported that in the wavelength range of 600–1000 nm for the angular investigation mode, the best sensitivity belongs to The challenge in biosensor development is to detect analytes with small molecular the first diffraction order [11]. weight and extremely diluted concentrations [12]. At this molecular weight and concen- The challenge in biosensor development is to detect analytes with small molecular tration, conventional biosensors are not able to detect it. Therefore, the development di- weight and extremely diluted concentrations [12]. At this molecular weight and concen- rection of the SPR biosensor is increasing the sensitivity to reach this limit. Several ways tration, conventional biosensors are not able to detect it. Therefore, the development have been done and one of the most popular is by exploiting the unique properties of direction of the SPR biosensor is increasing the sensitivity to reach this limit. Several ways graphene [13]. In this review, the authors summarize the latest developments regarding have been done and one of the most popular is by exploiting the unique properties of the graphene-based SPR biosensors. There are several sensing methods discussed in this graphene [13]. In this review, the authors summarize the latest developments regarding review, including prism-based, fiber-optic-based, grating-based, nanoparticle-based, and the graphene-based SPR biosensors. There are several sensing methods discussed in this SERS-based SPR biosensors. The discussion was started by presenting a brief theory and review, including prism-based, fiber-optic-based, grating-based, nanoparticle-based, and continued by presenting the results obtained regarding the graphene-based biosensor, SERS-based SPR biosensors. The discussion was started by presenting a brief theory and continuedboth simulation, by presenting and experiment. the results These obtained result regardings include the the graphene-based sensitivity and biosensor,detection accu- both simulation,racy obtained and due experiment. to the presence These of results graphene include in the the SPR sensitivity biosensor. and detection accuracy obtained due to the presence of graphene in the SPR biosensor. 2. Graphene and Its Properties 2. GrapheneGraphene and is Itsan Propertiesallotrope of carbon and is intrinsically a zero-gap semiconductor (semimetal).Graphene Graphene is an allotrope band structure of carbon hasand a lin isear intrinsically energy dispersion a zero-gap and gives semiconductor rise to two (semimetal).cones crossing Graphene at the Dirac band point structure [14]. There has are a linear three energycommon dispersion forms of graphene, and gives namely rise to twographene cones oxide crossing (GO), at thereduced Dirac graphene point [14 ].oxi Therede (rGO), are three pure common graphene, forms and ofcarboxyl-GO graphene, namely(Figure graphene1). These three oxide forms (GO), of reduced graphene graphene exhibit oxide different (rGO), properties pure graphene, due to their and carboxyl-different GOmolecular (Figure structural1). These arrangements three forms of [15]. graphene GO is composed exhibit different of a graphene properties layer due with to theirfunc- differenttional groups molecular containing structural active arrangements oxygen on its[ 15surface]. GO such is composed as carboxyl of a(–COOH), graphene alkoxy layer with(C–O–C), functional hydroxyl groups (–OH), containing and carbonyl active oxygen(C–O) groups. on its surface The presence such as of carboxyl functional (–COOH), groups alkoxyin GO (C–O–C),makes it hydroxylhydrophilic (–OH), and andhighly carbonyl dispersible (C–O) in groups. water. The Howe presencever, the of functionalfunctional groupsgroup breaks in GO makesthe sp it2 bond hydrophilic in the crystal and highly plane dispersible which will in water.make GO However, non-conductive the functional and grouphas lower breaks mechanical the sp2 bond properties in the crystalthan graphe planene which [16]. willrGO makecan be GO produced non-conductive by removing and hasthe lowerfunctional mechanical groups properties from the GO than and graphene will restore [16]. rGOthe mechanical can be produced and electrical by removing conduc- the functionaltivity properties groups of from the thegraphene GO and layer will restore[17]. The the presence mechanical of andfunctional electrical groups conductivity in rGO propertiesmakes it quite of the dispersible graphene in layer water. [17 Briefly,]. The presence the physical of functional properties groups of graphene in rGO are makes shown it quitein Table dispersible 1. in water. Briefly, the physical properties of graphene are shown in Table1.

FigureFigure 1.1. GrapheneGraphene andand itsits derivatives.derivatives.

Some of the special properties of graphene which make this material very promising to be developed in biosensors in the future, among others, are due to its high electron mobility and high surface to volume ratio. The electron mobility in graphene is ~200,000

Nanomaterials 2021, 11, 216 3 of 29

Table 1. Physical properties of graphene [15].

Graphene Oxide Reduced Graphene Physical Properties Pure Graphene (GO) Oxide (rGO) Tensile strength ∼ 0.13 GPa Unknown ∼ 130 GPa Elastic modulus 23 − 24 GPa 250 ± 150 GPa 1000 GPa Elongation at break 0.6% unknown 0.8% Electrical Nanomaterials 2021, 11, x FOR PEER REVIEW Non conductive ∼667 S/m 3∼ of1000 30 S/m conductivity Dispersibility in Moderately Highly dispersible Not dispersible cm2/Vs.water This mobility can still be triggered by applying adispersible gate voltage, making it possible to build graphene-based biosensor with high response speeds. The detection capability of Somethe graphene-based of the special biosensor properties is still of possible graphene to increase which to makea single this molecule material by utilizing very promising to be developedthe surface in atoms biosensors in the graphene in the future, layer [18,19]. among Specifically, others, are in duethe SPR to itsbiosensor, high electron the mobility number of graphene layers in plasmonic metal can be controlled so that it is possible to 2 and highcontrol surface the SPR to response volume and ratio. sensitivity The [20]. electron The presence mobility of graphene in graphene can also is serve ~200,000 to cm /Vs. This mobilityprotect plasmonic can still metals be triggered from oxidation by applying so that their a performance gate voltage, is more making stable it[21,22]. possible to build graphene-based biosensor with high response speeds. The detection capability of the graphene-basedTable 1. Physical biosensor properties of is graphene still possible [15]. to increase to a single molecule by utilizing the surface atoms in the grapheneGraphene layer Oxide [18,19 ].Reduced Specifically, Graphene in theOx- SPR biosensor, the number Physical Properties Pure Graphene of graphene layers in plasmonic(GO) metal can be controlledide (rGO) so that it is possible to control the SPR responseTensile strength and sensitivity~0.13 [20 GPa]. The presenceUnknown of graphene can~130 also GPa serve to protect 23 24 GPa 250 150 GPa 1000 GPa plasmonicElastic metals modulus from oxidation so that their performance is more stable [21,22]. Elongation at break 0.6% unknown 0.8% Electrical conductivity Non conductive ~667 S/m ~1000 S/m 3. Graphene-Based Prism Coupled SPR Biosensor Dispersibility in water Highly dispersible Moderately dispersible Not dispersible The history of the prism-coupled SPR biosensor dates back to the results of Ritchie’s research3. Graphene-Based in the 1950s. Prism At that Coupled time, SPR Ritchie Biosensor introduced the surface plasmon in detail [23]. From theseThe results, history of finally the prism-coupled Otto in 1968 SPR biosensor studied dates a prism back combinedto the results withof Ritchie’s SPR which was basedresearch on attenuated in the 1950s. total At that reflection time, Ritchie (ATR) introduced [24]. This the surface sensing plasmon configuration in detail [23]. developed by From these results, finally Otto in 1968 studied a prism combined with SPR which was Otto isbased known on attenuated as the Otto total configuration reflection (ATR) and [24]. is This shown sensing in Figureconfiguration2a. In developed the Otto by configuration, the prismOtto is and known the as plasmonic the Otto configuration metal are and separated is shown by in Figure a gap 2a. in In the the order Otto configura- of micrometers. The performancetion, the prism of the and SPR the biosensor plasmonic metal in this are configuration separated by a gap is influenced in the order byof microme- the air-gap distance betweenters.the The plasmonicperformance metal of the SPR and biosensor the prism in this [25 ].configuration Due to the is difficulty influenced ofby controllingthe air- the gap gap distance between the plasmonic metal and the prism [25]. Due to the difficulty of betweencontrolling the prism the gap and between the plasmonic the prism and metal, the plasmonic Kretschmann metal, upgradedKretschmann the upgraded Otto configuration as shownthe Otto in Figureconfiguration2b. The as shown plasmonic in Figure metal 2b. The is betweenplasmonic themetal analyte is between and the the analyte prism [ 26]. Due to theand ease the of prism fabrication [26]. Due ofto the SPR ease structures, of fabrication the of KretchmannSPR structures, configurationthe Kretchmann con- is currently the most commonfiguration is and currently widely the usedmost common configuration and widely for used SPR configuration sensing applications for SPR sensing [27 ]. applications [27].

Figure 2. ConfigurationsFigure 2. Configurations of the of attenuated the attenuated total total reflection reflection (ATR) method: method: (a) Otto (a) Ottoconfiguration configuration and (b) Kretschmann and (b) Kretschmann configuration. (c) The dispersion curve for a surface plasmon mode shows the momentum mismatch problem between configuration.the (freec) The space dispersion photon (kphoton curve, gree forline) a and surface surface plasmon plasmon modes mode (k showsSP, red line). the momentum(d) Dispersion relation mismatch of surface problem plas- between the free space photonmon with (k photonphoton., ( greee) The line) same and effect surface of momentum-supply plasmon modes can be (k achievedSP, red by line). corrugating (d) Dispersion the metallic relation surface in of the surface so- plasmon with photon.called (e) Theprism-coupled same effect SPR. of The momentum-supply resonance is by using evanesce can bent achieved wave produced by corrugating in attenuated the total metallic reflection surface (ATR). in the so-called prism-coupled SPR. The resonance is by using evanescent wave produced in attenuated total reflection (ATR).

Nanomaterials 2021, 11, 216 4 of 29

The surface plasmon is a quantum plasmonic oscillation produced by the interaction between photons and free electrons possessed by metals. Resonance occurs when the sur- face plasmon (SP) wave vector matches the incident light wave vector [1,27]. Theoretically, the SP wave vector can be obtained from Maxwell’s theory. Applying the appropriate boundary conditions, the wave vectors of the surface plasmon are: r ω εmεd Ksp = (1) c εm + εd

and the wave vector of incident light is: ω √ K = ε sin θ (2) x c p i

where ε p, εm, and εd indicate the dielectric constant of the prism, metal, and dielectric, respectively, while θi indicates the incident angle. Resonance can be achieved by changing the incidence angle and it can be predicted mathematically by the following equation [28]:

r ! −1 1 εmεd θres = sin √ (3) ε p εm + εd

where θres indicates the resonance angle and in some literature it is called the SPR angle. The dispersion relation of the SPR biosensor coupled with the prism is shown in Figure2. It can be seen that by using the refractive index material np, the incident light propagation constant k is capable of coupling the SP wave vector at the intersection point representing the resonance conditions. A number of studies, both simulations and experiments, have been carried out to obtain a good performance SPR biosensor. In a simulation study, the Fresnel equation and the transfer matrix method (TMM) can be used to determine reflectance in multilayer SPR structures [29]. From the resulting SPR spectrum, the performance of the SPR biosensor coupled with a prism can be evaluated through the value of sensitivity (S), detection accuracy (DA), and quality factor (QF). These three values must be as high as possible to get the best performing biosensor. Sensitivity (S), detection accuracy (DA), and quality factor (QF) can be determined by the following equation:

∆θ S = SPR (4) ∆nBio ∆θ DA = SPR (5) FWHM S QF = (6) FWHM

In the above equation, ∆θSPR shows the shift in the SPR angle, ∆nBio shows the change in the refractive index of the sensing medium, and FWHM shows the full width at half maximum [30]. The effect of adding a graphene layer to the prism-based SPR on its performance was described by Wu et al. in 2010 and Choi et al. in 2011. Wu et al. investigated the effect of adding a graphene layer to the gold surface (Figure3a). At the same refractive index change (∆nBio = 0.005), the SPR angle shifts in conventional biosensors and graphene monolayer-based biosensors were 0.26 and 0.266, respectively. The results of calculations by Wu et al. also show that the graphene on gold SPR biosensor with a graphene (L) layer is (1 + 0.025 L) × γ (where γ > 1) times more sensitive than conventional gold SPR biosensors. However, adding more layers of graphene to the gold will widen the SPR curve. This will result in difficult reading of the SPR angle during the experiment so that there will be potential for reading errors [31]. Nanomaterials 2021, 11, 216 5 of 29 Nanomaterials 2021, 11, x FOR PEER REVIEW 5 of 30

Nanomaterials 2021, 11, x FOR PEER REVIEW 5 of 30

(a) (b)

FigureFigure 3. The 3. SPRThe SPRstructure structure investigated investigated by: (a by:) Wu (a) et Wu al. et (left) al. (left) and ( andb) Choi (b) Choi et al. et (right) al. (right) (adapt (adapteded with withpermission permission from from ReferenceReferences [31,32] [31 ©, 32The] © Optical The Optical Society). Society).

ChoiChoi et al. et investigated al. investigated the effect the effect of the of graphene the graphene layer layer on a ondifferent a different metal, metal, namely namely (a) (b) silversilver (Figure (Figure 3b).3 Increasingb). Increasing the number the number of gr ofaphene graphene layers layers results results in a inhigher a higher reflectance reflectance Figure 3. Theat SPR the atstructure SPR the SPRangle investigated angle and by: anda shallower(a) aWu shallower et al. (left) SPR and SPRcurve. (b) Choi curve. In et addition,al. In (right) addition, (adapt a decreaseed awith decrease permission in sensitivity in from sensitivity due dueto to Reference [31,32] © The Optical Society). an increasean increase in the in number the number of graphene of graphene layers layers cannot cannot be avoided. be avoided. However, However, it should it should be be notednoted that thatthe presenceChoi the presenceet al. investigatedof a graphene of a graphene the effect monolayer of monolayer the graphene and andbilayer layer bilayer on ina different the in SPR the metal, SPRbiosensor namely biosensor results results in a remarkablein a remarkablesilver (Figureincrease increase 3b). inIncreasing SPR in SPRsensitivity. the sensitivity. number Inof grthisaphene In thisstructure, layers structure, results the SPRin the a higher SPRsensitivity sensitivityreflectance is 3.5 is and 3.5 and at the SPR angle and a shallower SPR curve. In addition, a decrease in sensitivity due to 2.5 times2.5 times higher higher than than that thatof conventional of conventional gold-based gold-based SPR SPRbiosensors biosensors [32]. [ 32]. Thean increase results in of the Wu number et al. of and graphene Choi layers et al.’s cannot research be avoided. inspired However, other it should researchers be in the The resultsnoted that of theWu presence et al. andof a graphene Choi et monolayer al.’s research and bilayer inspired in the SPRother biosensor researchers results in the fieldfield of SPR ofin SPRbiosensors.a remarkable biosensors. increaseMaharana Maharana in SPR et sensitivity. al. compared et al. In compared this structure,chalcogenide chalcogenide the SPR and sensitivity silicon and is silicon3.5prisms and prismsin an in SPR anbiosensor SPR2.5 biosensor times composed higher composed than of thatgold of ofconventionaland gold a graphene and gold-based a graphene monolayer SPR biosensors monolayer (Figure [32]. (Figure4a). The4 a).results The ob- results The results of Wu et al. and Choi et al.’s research inspired other researchers in the tainedobtained show that show the that biosensor the biosensor accuracy accuracy is up isto up100% to 100%compared compared to the to silica-based the silica-based SPR SPR biosensorfield[ of33 SPR]. In biosensors. the same Maharana year, Verma et al. compared et al. added chalcogenide a material and withsilicon a prisms high refractivein an index, biosensor [33].SPR biosensorIn the same composed year, ofVerma gold and et al.a graphene added amonolayer material (Figure with a4a). high The refractive results ob- index, namely silicon (Si), to the graphene-based SPR structure (Figure4b). The results obtained namely silicontained (Si), show to that the the gr aphene-basedbiosensor accuracy SPR is up structure to 100% compared (Figure to 4b). the Thesilica-based results SPR obtained show that the best performance is owned by the SPR biosensor with gold (40 nm)/Si show that biosensorthe best [33].performance In the same year, is owned Verma et by al. addedthe SPR a material biosensor with a highwith refractive gold (40 index, nm)/Si (7 (7 nm)/bilayernamely silicon graphene. (Si), to the Ingraphene-based this structure, SPR thestructure shift (Fig inure the 4b). SPR The angle results isobtained more than twice nm)/bilayer graphene. In this structure, the shift in the SPR angle is more than twice that that reportedshow that by the Wu best etperformance al. [34]. Inis owned 2014, by Ryu the et SPR al. biosensor also investigated with gold (40 the nm)/Si effect (7 of GO on reported by Wu et al. [34]. In 2014, Ryu et al. also investigated the effect of GO on SPR SPR sensitivitynm)/bilayer throughgraphene. In simulations this structure, and the shift experiments in the SPR angle on structuresis more than twice composed that of gold, sensitivity throughreported by simulations Wu et al. [34]. and In 2014, experiment Ryu et al.s alsoon structuresinvestigated composedthe effect of ofGO gold, on SPR GO, and GO, andsensitivity SiO2 asthrough a spacer simulations layer and between experiment golds on andstructures GO. composed The results of gold, obtained GO, and show that SiO2 as a spacer layer between gold and GO. The results obtained show that the SPR bio- the SPRSiO biosensor2 as a spacer coupled layer between with gold GO and has GO. an Th SPRe results angle obtained shift show of 13% that than the SPR the bio- conventional sensor coupled with GO has an SPR angle shift of 13% than the conventional structure structuresensor [35 coupled]. with GO has an SPR angle shift of 13% than the conventional structure [35]. [35].

Figure 4. The SPR structure investigated by (a) Maharana et al. (left) and (b) Verma et al. (right) (adapted with permission Figure 4. Thefrom SPR Reference structure [33,34], investigated copyright Elsevier). by (a) Maharana et al. (left) and (b) Verma et al. (right) (adapted with permission from References [33,34], copyright Elsevier). Figure 4. The SPR structure investigated by (a) Maharana et al. (left) and (b) Verma et al. (right) (adapted with permission Another method that can be used to improve the performance of the SPR biosensor is from Reference [33,34], copyright Elsevier). long-range surface plasmon resonance (LRSPR). LRSPR is a development of conventional

Nanomaterials 2021, 11, 216 6 of 29 Nanomaterials 2021, 11, x FOR PEER REVIEW 6 of 30

SPR biosensorAnother method by adding that acan dielectric be used bufferto impr layerove the (DBL) performance with a lowof the refractive SPR biosensor index such asis Fluoride, long-range Cytop, surface and plasmon Teflon. resonance When applied (LRSPR). for LRSPR sensing is a purposes, development LRSPR of conven- will exhibit a narrowertional SPR andbiosensor deeper by adding resonance a dielectric dip and buffer allow layer it to(DBL) penetrate with a low deeper refractive into index the analyte duesuch to lessas Fluoride, loss than Cytop, conventional and Teflon. SPR When biosensor. applied Therefor sensing are two purposes, types ofLRSPR LRSPR will structures, ex- namelyhibit a thenarrower common and LRSPRdeeper resonance (DBL is between dip and theallow prism it to penetrate and the metal) deeper and into thethe symmetricana- LRSPRlyte due (the to metalless loss is than sandwiched conventional between SPR biosensor. two DBLs) There [36 are]. two types of LRSPR struc- tures, namely the common LRSPR (DBL is between the prism and the metal) and the sym- Wu et al. investigated LRSPR on graphene in 2016. They investigated three different metric LRSPR (the metal is sandwiched between two DBLs)[36]. metalsWu (Al, et Ag, al. andinvestigated Cu) with LRSPR Cytop on as graphene their DBL. in 2016. The structureThey investigated of the SPR three investigated different was commonmetals (Al, LRSPR, Ag, and which Cu) waswith composedCytop as their of 2S2GDBL. prism/Cytop/metal/graphene/analyte.The structure of the SPR investigated Figurewas 5common is the SPR LRSPR, spectrum which forwas the composed standard of SPR 2S2G and prism/Cytop/metal/graphene/ana- LRSPR structures. Figure5a shows thelyte. spectrum Figure 5 in is Al the metal, SPR spectrum Figure5 bfor shows the standard the spectrum SPR and in LRSPR Cu metal, structures. and Figure Figure5c 5a shows theshows spectrum the spectrum in Ag metal. in Al Inmetal, the threeFigure different 5b shows metals, the spectrum the LRSPR in Cu spectrum metal, and shows Figure a shape with5c shows a very the small spectrum FWHM in comparedAg metal. In to the the three standard different structure. metals, Thethe LRSPR FWHM spectrum of the LRSPR andshows SPR a biosensors shape with area very 0.0115 small◦ and FWHM 0.1408 compared◦ for Al-graphene to the standard based structure. configurations, The FWHM 0.0099 ◦ andof 0.1869the LRSPR◦ for and Cu-graphene SPR biosensors based are configurations,0.0115° and 0.1408° 0.0123 for Al-graphene◦ and 0.3854 based◦, respectively, configu- for Ag-graphenerations, 0.0099° based and configurations.0.1869° for Cu-graphene This shows based thatconfigurations, LRSPR has 0.0123° succeeded and 0.3854°, in reducing FWHMrespectively, and enhancing for Ag-graphene the accuracy based ofconfigurations. the SPR biosensor This shows [37]. that LRSPR has suc- ceeded in reducing FWHM and enhancing the accuracy of the SPR biosensor [37].

FigureFigure 5. Reflectance 5. Reflectance and and sensitivity sensitivity on standard and and long-ran long-rangege surface surface plasmon plasmon resonance resonance (LRSPR) (LRSPR) structure structurefor (a) for (a) Al+graphene,Al+graphene, ( b(b)) Cu+graphene,Cu+graphene, and and (c () cAg+graphene) Ag+graphene (adapted (adapted with withpermission permission from Reference from Reference [37], copyright [37], copyright IEEE). IEEE).

ApartApart from from simulation simulation studies, studies, experimental experimental studies studies on graphene on graphene for SPR for biosensors SPR biosensors havehave also also shown shown veryvery fast progress and and development. development. In a In group a group led by led prof. by prof.Chiu, Chiu,the the experimentexperiment was was started started in in 2012. 2012. The The research research waswas startedstarted byby investigatinginvestigating the perfor- performance ofmance the SPR of biosensorthe SPR biosensor integrated integrated with loop-mediated with loop-mediated isothermal isothermal amplification amplification (LAMP) on single-layer(LAMP) on GO single-layer and rGO GO with and cystamine rGO with cystamine (Cys) as a (Cys) linker as toa linker detect to tuberculosis detect tubercu- bacterial losis bacterial DNA (TB DNA) (Figure 6a). To determine the resulting performance, three DNA (TB DNA) (Figure6a). To determine the resulting performance, three different sensing different sensing surfaces were fabricated, namely Cys-linker, Cys-GO, and Cys-rGO. Fig- surfacesure 6b shows were fabricated,the SPR response namely after Cys-linker, the TB DNA Cys-GO, was injected and Cys-rGO. into each sensing Figure 6surface.b shows the SPRIf we response look at the after SPR the respon TB DNAse, two was important injected results into eachare obtained sensing from surface. this experiment. If we look at the SPRFirst, response, the Cys-GO two sensing important layer results has the are best obtained sensitivity from because this experiment. it has a higher First, SPR theangle Cys-GO sensingshift. Second, layer has the theCys-GO best sensing sensitivity layer because has excellent it has stability. a higher After SPR the angle sensing shift. layer Second, was the Cys-GOregenerated sensing with layer NaOH, has the excellent baseline stability. did not decrease. After the The sensing presence layer of the was -COOH regenerated group with NaOH,on GO the results baseline in a very did notstrong decrease. covalent Thebond presence between ofthe the develo -COOHped substrate group on and GO TB results inDNA a very [38]. strong The covalenteffect of the bond number between of GO the and developed rGO layers substrate on SPR sensitivity and TB DNAwas also [38 ]. The effectinvestigated of the number by Chung of et GO al. andGO with rGO differen layerst onnumber SPR sensitivityof layers was was fabricated also investigated by alter- by Chungnative et dipping al. GO of with gold different substrate numberin positive of and layers negatively was fabricated charged GO by alternativesolutions. Mean- dipping of goldwhile, substrate the rGO in layer positive was andobtained negatively by reducing charged GO GOusing solutions. hydrazine. Meanwhile, From several the struc- rGO layer tures investigated, the three-layer GO based chip showed the best performance. The re- was obtained by reducing GO using hydrazine. From several structures investigated, the sulting SPR sensitivity for this structure was 150.38 °/RIU which was 3.45% higher than three-layer GO based chip showed the best performance. The resulting SPR sensitivity for the bare gold substrate [39]. this structure was 150.38 ◦/RIU which was 3.45% higher than the bare gold substrate [39].

Nanomaterials 2021, 11, 216 7 of 29 Nanomaterials 2021, 11, x FOR PEER REVIEW 7 of 30 Nanomaterials 2021, 11, x FOR PEER REVIEW 7 of 30

FigureFigure 6.6. (aa) Experimental scheme of the SPR biosensor integrated with loop-mediated isothermal amplification (LAMP) Figure 6. (a) Experimental (scheme) Experimental of the SPR scheme biosensor of the integrated SPR biosensor with integratedloop-mediated with loop-mediatedisothermal amplification isothermal (LAMP) amplification (LAMP) for for detection of tuberculosis bacterial DNA (TB DNA). (b) SPR response on Cys-GO, Cys-rGO, and Cys-linker sensing sur- for detection of tuberculosisdetection of bacterial tuberculosis DNA bacterial (TB DNA). DNA (b (TB) SPR DNA). response (b) SPR on Cys-GO, response Cys-rGO, on Cys-GO, and Cys-rGO, Cys-linker and sensing Cys-linker sur- sensing surface face (adapted with permission from Reference [38], copyright SPIE). face (adapted with(adapted permission with from permission Reference from [38], Reference copyright [38 ],SPIE). copyright SPIE). Chiu et al. (2014) used a previously studied to study the interaction between antibody Chiu et al. (2014)Chiu used et a al.previously (2014) used studied a previously to study studied the interaction to study between the interaction antibody between antibody (BSA) and antigen (anti-BSA). Figure 7a shows the biomolecular bonding mechanism be- (BSA) and antigen(BSA) (anti-BSA). and antigen Figure (anti-BSA). 7a shows Figurethe biomolecular7a shows thebonding biomolecular mechanism bonding be- mechanism tween BSA and anti-BSA and Figure 7b shows the response of the SPR biosensor. At all tween BSA andbetween anti-BSA BSA and andFigure anti-BSA 7b shows and the Figure response7b shows of the the SPR response biosensor. of the At SPR all biosensor. At detected anti-BSA concentrations (75.75 nM, 151.51 nM, and 378.78 nM), the GO-based detected anti-BSAall detectedconcentrations anti-BSA (75.75 concentrations nM, 151.51 (75.75 nM, and nM, 378.78 151.51 nM), nM, andthe 378.78GO-based nM), the GO-based SPR biosensor showed a higherhigher response.response. Specifically,Specifically, atat thethe anti-BSAanti-BSA concentrationconcentration ofof SPR biosensor showed a higher response. Specifically, at the anti-BSA concentration of 75.75 nM,nM, thethe SPR SPR angle angle shift shift in in the the GO-based GO-based SPR SPR structure structure was was 1.4 times1.4 times higher higher than than that 75.75 nM, the SPR angle shift in the GO-based SPR structure was 1.4 times higher than ofthat the of conventional the conventional structure; structure; whereas whereas at the at highest the highest concentration concentration (378.78 (378.78 nM), nM), the SPR the that of the conventional structure; whereas at the highest concentration (378.78 nM), the angleSPR angle shift wasshift upwas to up two to times two highertimes higher than that than of that conventional of conventional structure. structure. These results These SPR angle shift was up to two times higher than that of conventional structure. These indicateresults indicate that the that GO-based the GO-based SPR structure SPR structure has a betterhas a better performance performance than conventionalthan conven- results indicate that the GO-based SPR structure has a better performance than conven- structurestional structures [40]. [40]. tional structures [40].

Figure 7. (a) GOS based SPR structure. (b) The response of the SPR biosensor at different anti-BSA Figure 7. (a) GOS based SPR structure. (b) The response of the SPR biosensor at different anti-BSA Figure 7. (a) GOS based SPRconcentrations structure. (b) The (adapted response with of permission the SPR biosensor from Reference at different [40], anti-BSA copyright concentrations Springer Nature). (adapted with permissionconcentrations from Reference (adapted [40 with], copyright permission Springer from Nature). Reference [40], copyright Springer Nature). Chiu et al. also conducted an experimental study of other structures, namely GO- Chiu et al. alsoChiu conducted et al. alsoan experiment conductedal an study experimental of other st studyructures, of other namely structures, GO- namely GO- based structures that functionalized with –COOH (GO–COOH chip) as an immunosensor based structuresbased that functionalized structures that with functionalized –COOH (GO–COOH with –COOH chip) (GO–COOH as an immunosensor chip) as an immunosensor to detect non-small cell lung carcinoma via cytolerayin 19 (CK19) (Figure 8a). Biomolecu- to detect non-smallto detect cell lung non-small carcinoma cell lung via cytolerayin carcinoma via 19 cytolerayin(CK19) (Figure 19 (CK19) 8a). Biomolecu- (Figure8a). Biomolecular lar interactions between CK19 and anti CK19 at different concentrations were measured lar interactions interactionsbetween CK19 between and anti CK19 CK19 and at anti different CK19 at concentrations different concentrations were measured were measured in real in real time to obtain sensorgram data for each fabricated chip. Based on sensorgram data, in real time to obtaintime tosensorgram obtain sensorgram data for each data fabricated for each fabricatedchip. Based chip. on sensorgram Based on sensorgram data, data, the the GO–COOH-based SPR chip has a shorter response time than conventional chip. In the GO–COOH-basedGO–COOH-based SPR chip has SPR a chip shorter has aresponse shorter response time than time conventional than conventional chip. In chip. In addition, addition, functionalization of –COOH on GO resulted in a better detection limit of 0.001– addition, functionalizationfunctionalization of –COOH of –COOH on GO on re GOsulted resulted in a better in a better detection detection limit limit of 0.001– of 0.001–100 pg/mL 100 pg/mL (Figure 8b). 100 pg/mL (Figure(Figure 8b).8 b).

Nanomaterials 2021, 11, 216 8 of 29 Nanomaterials 2021, 11, x FOR PEER REVIEW 8 of 30

Figure 8. (a) Carboxyl-functionalized graphene oxide (GO)-based SPR structure as immunosensor to detect CK19. (b) Figure 8. (a) Carboxyl-functionalized graphene oxide (GO)-based SPR structure as immunosensor to detect CK19. (b) Re- Response of SPR biosensor at different CK19 concentrations and their linear ranges (adapted with permission from Refer- sponse of SPR biosensor at different CK19 concentrations and their linear ranges (adapted with permission from Refer- ence [41], copyright Elsevier). ence [41], copyright Elsevier). The use of graphene for biomolecule detection has also been carried out by other The use of graphene for biomolecule detection has also been carried out by other research groups. He et al. used a fabrication method for the growth of graphene layers on research groups. He et al. used a fabrication method for the growth of graphene layers on coopercooper foil foil developed developed by by Li Li et et al. al. to to construct construct an an SPR SPR biosensor biosensor for for the the purpose purpose of detecting of detect- seruming serum folate folate biomarkers biomarkers [42]. [42]. The specificThe specific recognition recognition of FAP of FAP is based is based on the on interactionthe interac- betweention between the integrated the integrated folicacid folic receptors acid receptors via the via buildup the buildup of π on of the π graphene-coatedon the graphene- SPRcoated chip SPR and chip the FAPand analytethe FAP in analyte serum. in To serum. block non-specificTo block non-specific interactions interactions on the SPR on chip, the humanSPR chip, serum human (HS) serum is mixed (HS) with is mixed bovine with serum bovine albumin serum (BSA). albumin Figure (BSA).9a showsFigure the9a shows SPR responsethe SPR response at different at FPAdifferent concentrations FPA concentratio rangingns from ranging 10 fM from to 1 10 pM. fM Based to 1 pM. on thisBased SPR on response,this SPR aresponse, linear range a linear was range obtained was up obtained to a concentration up to a concentration of 500 fM. Inof this500 range,fM. In thethis correlationrange, the coefficientcorrelation Rcoefficient2 is 0.999 andR2 is the 0.999 relationship and the relationship between the between FPA concentration the FPA concen- and thetration SPR responseand the SPR can beresponse determined can be as determined 1.62 + 25.85 as× [FAP].1.62 + In25.85 addition, × [FAP]. the In manufactured addition, the chipsmanufactured also have chips excellent also reproducibility.have excellent reproducibility. Over the twenty-day Over the time twenty-day span, there time was span, no significantthere was changeno significant in the SPRchange signal. in the A sensorSPR signal. interface A sensor with ainterface long lifetime with a was long obtained lifetime inwas this obtained experiment in this (Figure experiment9b) [43]. (Figure 9b) [43].

Figure 9. (a) SPR response at different FAP concentrations from 10 fM to 1 µm. (b) Repeatability of FAP detection for 20 days using the same sensor (adapted with permission from Reference [43], Figure 9. (a) SPR response at different FAP concentrations from 10 fM to 1 µm. (b) Repeatability of FAP detection for copyright Elsevier). 20 days using the same sensor (adapted with permission from Reference [43], copyright Elsevier). Omar et al. developed an SPR biosensor based on the rGO–Polyamidoamine (rGO- Omar et al. developed an SPR biosensor based on the rGO–Polyamidoamine (rGO- PAMAM)PAMAM) composite composite that that functioned functioned with with amines amines to to detect detect and and measure measure the thedengue denguevirus. virus. GoldGold film film is is inserted inserted into into succinimidyl succinimidyl undecanoate undecanoate (DSU) (DSU) solution solution to form to aform self-assamble a self-as- monolayersamble monolayer (SAM) which(SAM) functionswhich functions for chemisorption for chemisorption of biomolecules of biomolecules through through amide am- relations.ide relations. After After SAM SAM was formed,was formed, rGO-PAMAM rGO-PAMAM was deposited was deposited on the on gold the surface gold surface using using the spin coating method and followed by immobilization of specific antibodies for

Nanomaterials 2021, 11, 216 9 of 29

the spin coating method and followed by immobilization of specific antibodies for DENV 2 E-Protein via EDC/NHS using the same method. From this experimental scheme, the SPR chip formed is called the Au/DSU/rGO-PAMAM/Ab chip. Figure 10 shows the calibration curve and selectivity of a fabricated SPR chip. The cali- bration curve was obtained based on the shift in the SPR angle at different concentrations of DENV 2 E-Proteins from 0.08 pM to 1 pM. The linear range is obtained in this concentration range with the correlation coefficient R2 is 0.92577. The selectivity of the SPR chip was also tested by detecting other types of antigens, namely DENV E-proteins and ZIKV E-proteins. Based on Figure 10b, the shift of SPR angle in a solution of DENV E-proteins and ZIKV E-proteins is very much smaller when compared to DENV 2 E-Proteins; whereas in both antigens the sample concentration was 10 pM and in the DENV 2 E-Proteins solution was 0.1 pM. From this experiment, it can be concluded that the sensitivity and selectivity of the sensor are very good with a detection limit of 0.08 pM [44].

Figure 10. (a) Calibration curve or SPR angle shift at different DENV 2 E-Protein concentrations, (b) The response of the SPR chip to different antigens (DENV 2 E-Protein, DENV E-protein, and ZIKV E-protein) (adapted with permission from Reference [44], copyright MDPI).

The prism-coupled SPR biosensor is a popular platform and is used in many detection cases. The preceding discussion describes several approaches that have been investigated to improve the performance of SPR biosensor. Table2 below shows the resulting performance of the various types and structures of analytes. Nanomaterials 2021, 11, 216 10 of 29

Table 2. Comparison of the sensitivity of graphene-based prism coupled SPR biosensor with relevant work based on experiment results.

SPR Structure Target Linear Range Sensitivity Ref. ◦ BK7/Au/WSe2/Graphene - 1.3–1.38 178.87 /RIU [45] BK7/ZnO/Au/Graphene Bacteria 1.33–1.4 187.43◦/RIU [46] ◦ Prism/TiO2/ZnO/Au/MoS2/GO - 1.3–1.38 210.75 /RIU [47] ◦ BK7/Ag/BaTiO3/Graphene - 1.338–1.353 257 /RIU [48] N-FK51A/Au/Graphene Glucosa 1.338–1.405 275.15◦/RIU [49] Au/graphene Anticholera toxin 0.004–4 ng/mL - [50] Au/graphene Folic acid protein 5 fM 25.85/M [43] Au/GO/COOH Anti-BSA 0.01 pg/mL 450.67 m/[µg/mL] [51] Au/GO hCG protein 0.065–250 nM 38.34 m/nM [52] Au/GO/COOH CK19 protein 0.001–100 pg/mL 4.83 m/[pg/mL] [41] Au/GO/COOH Anti-PAPP-A2 0.01–104 pg/mL 8.34 m/[pg/mL] [53] Au/graphene Glycerol 1.33–1.36 179.79◦/RIU [54]

4. Graphene-Based Fiber Coupled SPR Biosensor The propagation of light in optical fiber also works based on total internal reflection (TIR). The prism in the prism-based SPR biosensor functions to produce TIR on the metal– prism surface. For this reason, the prism can be replaced with a core from an optical fiber to form a fiber-optic-based SPR biosensor [55]. The sensing surface of an optical fiber can be formed by removing a small portion of the fiber to be coated with a thin layer of metal. A polychromatic light source is launched from one end of the optical fiber and the other end measures the transmitted light [56]. Resonances occur at specific wavelengths and biomolecular interactions can be identified by shifting the resonant wavelengths. Several parameters that affect the performance of the SPR biosensor for this platform are the length of the sensing region and the diameter of the fiber core. Simulation of the effect of graphene on conventional optical fiber SPR biosensors carried out by Fu et al. in 2012. Fu et al. investigated the sensitivity changes in fiber clading with sensing medium N = 5 mm, gold thickness 40 nm, number of graphene layers N = 5, diameter of fiber cores. D = 50 micrometers, and the refractive index of fiber core and clading are 1.451 and 1.45, respectively. The complete experimental scheme is shown in Figure 11a. Figure 11b shows the SPR spectrum of the simulation results which shows the relationship between the sensing surface refractive index and the SPR wavelength shift. At three different refractive indexes (1.33, 1.35, and 1.37), the SPR biosensor with graphene showed a higher wavelength shift than without graphene. This suggests that the presence of graphene in fiber-optic-based biosensors can also increase SPR sensitivity [57].

Figure 11. (a) Experimental scheme of the SPR biosensor coupled with fiber optic. (b) SPR spectrum at the refractive index of 1.33, 1.35, and 1.37 (top: without graphene, bottom: with graphene) (adapted with permission from Reference [57], copyright IEEE). Nanomaterials 2021, 11, 216 11 of 29

Another research group, Zhou et al. investigated the effect of single layer graphene on SPR sensitivity in end reflection optical fibers with a coroless fiber diameter of 600 microm- eters and a silver thickness of 40 nm (Figure 12a). The results showed that in the refractive index range from 1.3411 to 1.3737, the SPR sensitivity without and with graphene was 2657 nm/RIU and 3091 nm/RIU, respectively [58]. The simulation results reaffirm that graphene in conventional optical fibers is proven to increase sensor sensitivity.

Figure 12. (a) Schematic diagram of an end reflection optical fiber with graphene. (b) SPR reflectance and sensitivity spectra were generated in structures without (left) and with graphene (right) (adapted with permission from Reference [58], copyright Elsevier). Zhuo et al. have also succeeded in confirming the simulation results obtained through experiments. The sensing part (about 10 mm) of the probe was immersed in acetone to soften the clading layer so that the clading layer on the sensing part could be removed easily. After that, the sensing part was coated with Ag film by chemical method and followed by transferring graphene on the optical fiber. Briefly, the transferring process begins by immersing the PMMA/graphene/Cu film in ferric chloride (FeCl3) to etch the Cu foil, placing the PMMA/graphene film on the sensing surface, heating the graphene and removing PMMA by immersing the sensing probe in acetone. The fabricated probes are then tested by detecting NaCl with different concentrations. At the same concentration change, the shift in the SPR wavelength for graphene-based optical fibers shows a higher shift (Figure 13). Based on the fitting curve data, the sensitivity for probes without and with graphene were 4.05 nm/% (2487.7 nm/RIU) and 6.417 nm/% (3936.8 nm/RIU), respectively [58]. Nanomaterials 2021, 11, 216 12 of 29

Figure 13. The SPR reflection spectrum at different concentrations of NaCl solution on sensing probes: (a) without graphene and (b) with graphene (adapted with permission from Reference [58], copyright Elsevier).

Another optical fiber type for SPR biosensor applications is photonic crystal fiber (PCF). Li et al. investigated an H-formed photonic crystal fiber SPR biosensor with U- shaped grooves open structure for refractive index sensing. PCF biosensors are composed of two layers of air holes in a hexagonal layout. The center air outlet can lower the effective RI from core guiding mode to in phase with plasmon mode. There are two large air holes in the first layer, leading to the phenomenon of strong birefringence and a highly polarized light connection with the metal dielectric interface. In this investigation, the designed structure has a gap between two air holes Λ = 2 µm, dc/ Λ = 0.5, d1/ Λ = 0.5, d2/ Λ = 0.9, d3/ Λ = 0.8, tAg = 40 nm, and tgraphene = 4.08 nm, where dc, d1, d2, d3 are the diameter of the air holes in PCF, and the tAg and tgraphene show the thickness of the silver and graphene layers, respectively. In simple terms, the schematic of the investigated PCF biosensor is shown in Figure 14a. Figure 14b shows the biosensor response at different refractive indications from 1.33 to 1.41. Based on the results of the fitting curve, in this refractive index range there are two slopes which indicate the sensitivity of the biosensor. The first sensitivity was 2770 nm/RIU in the refractive index range from 1.33 to 1.36, and the second sensitivity was 6057 nm/RIU in the refractive index range from 1.36 to 1.41 [59].

Figure 14. (a) Schematic of the designed Ag–Graphene coated photonic crystal fiber (PCF)–SPR sensor. (b) The relationship between the resonant wavelength and the analyte’s refractive index varies from 1.33 to 1.41 (adapted with permission from Reference [59], copyright MDPI).

The last configuration is optical fiber with a nano-structured coating to produce the localized surface plasmon. One of the studies using this configuration was carried out by Huang et al. in 2019. Huang et al. used a multimode fiber-single mode–multimode (MMF– Nanomaterials 2021, 11, 216 13 of 29

SMF–MMF) structure coated with a graphene-metal hybrid for temperature sensor. The sen- sor sensitivity was further enhanced by the addition of core-shell gold–silver nanoparticles (Au@AgNPs) modified with polydimethylsiloxane (PDMS) as a material for temperature sensing. PDMS is a material with a high thermo-optical coefficient (−4.5 × 10−4/◦C) and its refractive index decreases with increasing temperature [60]. Briefly the probe fabrication process is shown in Figure 15a. Figure 15b shows the biosensor response at different tem- peratures. As the temperature increases, the SPR wavelength shifts to a smaller wavelength. The SPR wavelength shifted from 871.41 nm to 798.60 nm when the temperature changed from 30 ◦C to 110 ◦C. The repeatability of the biosensor was also tested through heating and cooling processes. Based on the fitting curve in Figure 14c, the correlation coefficient R2 is 0.993 which indicates the biosensor has good repeatability. From the slope obtained from the fitting process, the sensitivity of the MMF–SMF–MMF structure with graphene- gold-Au@Ag NPs-PDMS is −1.02 nm/◦C[61]. The sensitivity of this structure is higher than PDMS-long period fiber gratings coated with PDMS (0.2554 nm/◦C) [62], graphene Nanomaterials 2021, 11, x FOR PEER REVIEW quantum dots-coated hollow core fiber (0.1237 nm/◦C) [63], and Multimode13 of 30 Fiber—Fiber

Bragg Grating—Multimode Fiber (MMF-FBG-MMF) structure (0.172 nm/◦C) [64].

Figure 15. (aFigure) SPR probe15. (a) fabricationSPR probe fabrication process. (b process.) SPR transmittance (b) SPR transmittance spectrum spectrum at different at different temperatures tempera- from 40 ◦C to 110 ◦C. (c) SPRtures response from 40 and °C fittingto 110 curve°C. (c) after SPR heatingresponse and and cooling fitting process curve after (adapted heating with and permission cooling process from Reference [61], copyright IEEE).(adapted with permission from Reference [61], copyright IEEE).

The previous Thediscussion previous describes discussion four describes configurations four configurations in the SPR fiber-optic-based in the SPR fiber-optic-based biosensor andbiosensor papers relating and papers to the relating use of graphene to the use in of each graphene configuration. in each configuration. Table 3 below Table3 below shows a summaryshows of a research summary results of research related results to the related SPR biosensor to the SPR which biosensor is coupled which with is coupled with a a graphene-basedgraphene-based optical fiber. optical fiber.

Nanomaterials 2021, 11, x FOR PEER REVIEW 14 of 30

Table 3. A summary of selected papers regarding graphene-based optical fiber coupled SPR biosensor.

Sensitivity and Limit of Fiber optic Type Structure Target Ref. Detection (LOD) Side polished optical fiber Au/graphene ssDNA 1039.8 nm/RIU and 10−12 M [65] Plastic clad silica fiber Au/graphene BSA 6500 nm/RIU [66] Nanomaterials 2021, 11, 216 14 of 29 Plastic clad silica fiber Au/graphene BSA 7.01 nm/(mg/mL) [66] End reflection optical fiber Ag/graphene NaCl solutions 3936.8 nm/RIU [58] U-bent plastic optical fiber Graphene + Ag nanoparticles Glucosa solutions 700.3 nm/RIU [67] MMF-PCF-MMFTable 3. sensorA summary of selected Au+graphene+ papers regardingSPA graphene-basedanti-human optical IgG fiber coupled4649.8 SPR biosensor. nm/RIU [68] D-shaped fiber Cr/Au/MoS2/graphene Glucosa 6708.87 nm/RIU [69] Sensitivity and Limit Fiber optic Type Structure Target Ref. Note: SPA: The staphylococcal protein A. of Detection (LOD) 1039.8 nm/RIU and Side polished optical fiber5. Graphene Au/graphene Based Grating Coupled ssDNA SPR Biosensor [65] 10−12 M Plastic clad silica fiberThe Au/graphene SPR biosensor coupled with BSA a grating as shown 6500 in nm/RIU Figure 16 has been [66 ]an im- Plastic clad silica fiberportant Au/graphenepioneer in the SPR configuration. BSA This grating 7.01 configuration nm/(mg/mL) was first introduced [66] End reflection optical fiberby Wood Ag/graphene in 1902 [70]. To obtain NaCl plasmon solutions and photon resonance, 3936.8 nm/RIU both the wave vector [58] and Graphene + Ag U-bent plastic optical fiber the effective refractive index ofGlucosa the guided solutions wave must meet 700.3 the nm/RIU following equation [67 ][71,72]: nanoparticles MMF-PCF-MMF sensor Au+graphene+SPA anti-human IgG 4649.82𝜋 nm/RIU2𝜋 [68] 𝑘 =𝑘 sin 𝜃 𝑚 𝑘 = 𝑛 sin 𝜃 𝑚 (7) D-shaped fiber Cr/Au/MoS2/graphene ,Glucosa 6708.87𝜆 nm/RIU 𝑃 [69] and Note: SPA: The staphylococcal protein A. 𝜆 5. Graphene Based Grating Coupled𝑛 SPR=𝑛 Biosensorsin 𝜃 𝑚 (8) 𝑃 The SPR biosensor coupled with a grating as shown in Figure 16 has been an important pioneerIn the in the above SPR equation, configuration. 𝑘, This, grating𝑘 configuration, and 𝑘 show was the first wave introduced vector of by incident Wood inlight, 1902 grating, [70]. Toand obtain surface plasmon plasmon, and respectively. photon resonance, Next, 𝑛, both 𝑚, theand wave P show vector the refractive and the effectiveindex of refractivethe medium, index the of diffraction the guided order wave and must the meet grating the following period, respectively. equation [71 For,72]: the sub wavelength grating-mediated interactions between surface plasmon and analytes, the (m) 2π 2π following momentumk = matchingk sinrelationθ ± m is kpreserved:= n sin θ ± m (7) sp x,photon i grating λ p i P 2𝜋 2𝜋 2𝜋 𝜀𝜀, and 𝑘 = 𝑛 sin 𝜃 𝑚 = (9) 𝜆 𝑃 λ𝜆 𝜀 +𝜀 n = n sin θ ± m , (8) e f f b res P

FigureFigure 16.16. Schematic diagram of the grating-based grating-based SPR SPR biosensor biosensor (adapted (adapted with with permission permission from from ReferenceReference [[73],73], copyrightcopyright MDPI).MDPI).

InThe the performance above equation, of the kSPR-basedx,photon, kgrating grating, and biosensorksp show is influenced the wave vectorby several of incident factors, light,including grating, the andshape surface of the plasmon, grating, respectively.the operating Next, wavelength,nb, mth, andthe period P show of the the refractive grating, indexthe type of theof metal, medium, and thethe diffractionrefractive index order of and the the analyte grating [71]. period, Sadeghi respectively. and Shirani For inves- the subtigated wavelength the performance grating-mediated of the graphene–gold interactions between ellipse grating surface SPR plasmon biosensor and analytes, in the mid- the followinginfrared region. momentum The schematic matching diagram relation isof preserved:the investigated biosensor is shown in Figure s (m) 2π 2π 2π εmεD,e f f ksp = np sin θres ± m = (9) λ P λ εm + εD,e f f

The performance of the SPR-based grating biosensor is influenced by several factors, including the shape of the grating, the operating wavelength, the period of the grating, the type of metal, and the refractive index of the analyte [71]. Sadeghi and Shirani investigated the performance of the graphene–gold ellipse grating SPR biosensor in the mid-infrared region. The schematic diagram of the investigated biosensor is shown in Figure 17a. The Nanomaterials 2021, 11, 216 15 of 29

initial parameters of the SPR biosensor are as follows: grating period (p) = 1500 nm, Nanomaterials 2021, 11, x FOR PEER REVIEW 15 of 30 perpendicular radius (T1) = 56 nm, gold thickness (h) = 10 nm, horizontal diameter (T2) = 46 nm, and the height of the sensing medium (Ds) = 600 nm. Based on the profile of the extinction17a. The initial curve parameters at wavelengths of the SPR biosensor from 1500 are as nm follows: to 2500 grating nm, period the peak(p) = 1500 extinction is at a wavelengthnm, perpendicular of 2001.2 radius nm. (T1)Figure = 56 nm, 17 goldb shows thickness the (h) electromagnetic= 10 nm, horizontal distributiondiameter profile at this(T wavelength.2) = 46 nm, and the The height intensity of the sensing of the medium magnetic (Ds) = field 600 nm. increases Based onexponentially the profile of with the closerthe to extinction the interface curve inat wavelengths the metal medium. from 1500 nm However, to 2500 nm, the the magnetic peak extinction field is decreases at a slowly wavelength of 2001.2 nm. Figure 17b shows the electromagnetic distribution profile at this in thewavelength. dielectric The medium. intensity Furthermore,of the magnetic fiel thed increases sensitivity exponentially of the biosensor with the closer is obtained to from the shiftthe interface in peak in extinctionthe metal medium. wavelength However, to the changes magnetic field in a decreases certain slowly refractive in the index (S = ∆λpeakdielectric/∆n). Inmedium. the refractive Furthermore, index the sensitivity change of∆ nthe= biosensor 0.001 from is obtained 1.333 from to 1.334, the shift the resulting SPR biosensorin peak extinction sensitivity wavelength is 1450 to changes nm/RIU. in a certain After refractive the optimization index (𝑆=∆𝜆 process,/Δ𝑛). In the best SPR the refractive index change Δ𝑛 = 0.001 from 1.333 to 1.334, the resulting SPR biosensor sensitivity generated in this structure is 1782 nm/RIU [74]. Sadeghi and Shirani also sensitivity is 1450 nm/RIU. After the optimization process, the best SPR sensitivity gener- investigatedated in this the structure performance is 1782 nm/RIU of the [74]. SPR Sadeghi biosensor and Shirani on rectangular also investigated gratings. the per- The resulting sensitivityformance for of this the structureSPR biosensor is 1180 on rectangular nm/RIU gratings. [75]. The resulting sensitivity for this structure is 1180 nm/RIU[75].

Figure 17. (a) A schematic diagram of graphene–gold grating. (b) The intensity distribution of the electromagnetic field at Figure 17. (amaximum) A schematic wavelength diagram of SPR ofmode. graphene–gold (c) SPR sensitivity grating. investigations (b) The based intensity on the shift distribution in peak wavelength of the electromagnetic on the ex- field at maximumtinction wavelength curve (adapted of SPR with mode. permission (c) SPRfrom Reference sensitivity [74], investigations copyright Elsevier). based on the shift in peak wavelength on the extinction curve (adapted with permission from Reference [74], copyright Elsevier). In the mid infrared range, noble metal exhibits large ohmic losses due to its low Incharge-carrier the mid infraredmobility and range, large permittivity noble metal [76]. exhibits Wei et al. largesimulated ohmic a conformal losses gra- due to its low phene-decorated nanofluidic channel (CGDNC) based on surface plasmons at infrared charge-carrierfrequencies.mobility The CGDNC and schematic large and permittivity transmittance [76 spectrum]. Wei at etdifferent al. simulated refractive in- a conformal graphene-decorateddices are shown in nanofluidicFigure 18 below. channel The sensitivity (CGDNC) at different based period on surface ∧, width plasmons W, height at infrared frequencies.H, and Fermi The level CGDNC 𝐸 is determined schematic by and the transmittanceequation 𝑆=𝛿𝜆 spectrum/ 𝛿𝑛 . The at results different ob- refractive indicestained are show shown that at in a Figureperiod of 18 100 below. nm to 300 The nm and sensitivity a height of at20 nm different to 100 nm, period the best∧ , width W, sensitivity is owned by the structure with the highest period and height, namely 300 nm height H, and Fermi level Ef is determined by the equation S = δλGSP/ δnd. The results obtained show that at a period of 100 nm to 300 nm and a height of 20 nm to 100 nm, the best sensitivity is owned by the structure with the highest period and height, namely 300 nm and 100 nm. The sensor sensitivities in these dimensions are 4356 nm/RIU and 3693 nm/RIU, respectively. On the other hand, if the sensitivity is investigated at different Fermi width and energy, the best sensitivity is the structure with the smallest fermi width and energy. At a width of 20 nm and a fermi energy of 0.1 eV, the sensitivity obtained Nanomaterials 2021, 11, x FOR PEER REVIEW 16 of 30

Nanomaterials 2021, 11, 216 and 100 nm. The sensor sensitivities in these dimensions are 4356 nm/RIU and 369316 of 29 Nanomaterials 2021, 11, x FOR PEERnm/RIU, REVIEW respectively. On the other hand, if the sensitivity is investigated at 16different of 30

Fermi width and energy, the best sensitivity is the structure with the smallest fermi width and energy. At a width of 20 nm and a fermi energy of 0.1 eV, the sensitivity obtained was was 6050 nm/RIU and 8004 nm/RIU, respectively [77]. The most important result of this 6050and nm/RIU100 nm. andThe 8004sensor nm/RIU, sensitivities respectively[77]. in these dimensions The most are important 4356 nm/RIU result ofand this 3693 simu- simulation shows that the sensor sensitivity can be actively increased by lowering the lationnm/RIU, shows respectively. that the sensor On the sensitivity other hand, can if bethe actively sensitivity increased is investigated by lowering at different the Fermi FermienergyFermi energy widthlevel levelofand graphene energy, of graphene thewhich best which can sensitivity be can done be is bythe done adjusting structure by adjusting withthe external the the smallest external voltage fermi voltage [77,78]. width [ 77,78]. and energy. At a width of 20 nm and a fermi energy of 0.1 eV, the sensitivity obtained was 6050 nm/RIU and 8004 nm/RIU, respectively[77]. The most important result of this simu- lation shows that the sensor sensitivity can be actively increased by lowering the Fermi energy level of graphene which can be done by adjusting the external voltage [77,78].

FigureFigure 18. 18. (a) (Schematica) Schematic of the of theconformal conformal grap graphene-decoratedhene-decorated nanofluidic nanofluidic channel channel (CGDNC) (CGDNC) infrared infrared sensor. ( sensor.b) Investigation (b) Investi- of sensor sensitivity based on data on the transmittance spectrum (adapted with permission from Reference [77], copyright MDPI). gation of sensor sensitivity based on data on the transmittance spectrum (adapted with permission from Reference [77],

copyright MDPI). Figure 18. (a) Schematic of the conformalIn 2013, graphene-decorated Reckinger et nanofluidical. fabricated channel holey (CGDNC) gold films infrared with sensor. colloid (b) Investigationnanosphere of lithog- sensor sensitivity based on dataraphy on the transmittancewith grating spectrum parameter (adapted of 980 with nm permission and holes from diameter Reference of [77],405 copyrightnm for ethanol MDPI). detec- In 2013, Reckinger et al. fabricated holey gold films with colloid nanosphere lithogra- tion. The fabricated film was then confirmed based on a Scanning Electron Microscope phy with grating parameter of 980 nm and holes diameter of 405 nm for ethanol detection. imageIn (Figure 2013, Reckinger 19a). Graphene et al. fabricated is then grown holey on gold the filmsgold surfacewith colloid to improve nanosphere the biosensor’s lithog- The fabricated film was then confirmed based on a Scanning Electron Microscope image performance.raphy with grating To determine parameter the of resulting980 nm and perf holesormance, diameter ethanol of 405 isnm exposed for ethanol to the detec- sensor (Figure 19a). Graphene is then grown on the gold surface to improve the biosensor’s interfacetion. The coated fabricated and filmwithout was graphene.then confirme Thed et basedhanol on level a Scanning detected Electron was determined Microscope based performance.image (Figure To 19a). determine Graphene the is then resulting grown on performance, the gold surface ethanol to improve is exposed the biosensor’s to the sensor on the transmission peak shift as shown in Figure 19b. The transmission peaks shifted by performance. To determine the resulting performance, ethanol is exposed to the sensor interface105 from coated 1460 nm and to without1565 nm graphene. for bare metal The and ethanol by 140 level nm detected from 1475 was nm determined to 1615 nm basedfor interface coated and without graphene. The ethanol level detected was determined based ongraphene-coated the transmission gold. peak The shift sensitivity as shown of inthe Figure graphene-coated 19b. The transmission sensor is improved peaks shifted with a by on the transmission peak shift as shown in Figure 19b. The transmission peaks shifted by 105transmission from 1460 peak nm to shift 1565 33% nm higher for bare than metal that of and bare by gold 140 nm[79]. from 1475 nm to 1615 nm for graphene-coated105 from 1460 nm gold. to 1565 The nm sensitivity for bare metal of the and graphene-coated by 140 nm from 1475 sensor nm to is 1615 improved nm for with a graphene-coated gold. The sensitivity of the graphene-coated sensor is improved with a transmission peak shift 33% higher than that of bare gold [79]. transmission peak shift 33% higher than that of bare gold [79].

Figure 19. (a) Sketch of the developed SPR biosensor and SEM image results. (b) The response of the biosensor with bare gold and graphene coated gold after exposure to ethanol (Reproduced from [79], with the permission of AIP Publishing). Figure 19. (a) Sketch of the developed SPR biosensor and SEM image results. (b) The response of the biosensor with bare Figure 19. (a) Sketch of the developed SPR biosensor and SEM image results. (b) The response of the biosensor with bare gold and graphene coated gold after exposure to ethanol (Reproduced from [79], with the permission of AIP Publishing). gold and graphene coated gold after exposure to ethanol (Reproduced from [79], with the permission of AIP Publishing).

Wei et al. investigated the effect of graphene on LPG to detect methane. Long period fiber grating (LPFG) with a grating period of 600 micrometers was fabricated by the writing method of high frequency CO2 laser pulses. The dimensions of the sensing medium (L), Nanomaterials 2021, 11, x FOR PEER REVIEW 17 of 30

Nanomaterials 2021, 11, 216 17 of 29 Wei et al. investigated the effect of graphene on LPG to detect methane. Long period fiber grating (LPFG) with a grating period of 600 micrometers was fabricated by the writ- ing method of high frequency CO2 laser pulses. The dimensions of the sensing medium fiber core diameter (D), and metal thickness (T) are shown in Figure 20a. Figure 20b (L), fiber core diameter (D), and metal thickness (T) are shown in Figure 20a. Figure 20b shows the relationship between methane concentration and resonance wavelength shift in shows the relationship between methane concentration and resonance wavelength shift three different structures, namely LPFG, LPFG + Au, and LPFG + Au + graphene. In the in three different structures, namely LPFG, LPFG + Au, and LPFG + Au + graphene. In the methane concentration range below 3.5%, the three structures have good linearity with the methane concentration range2 below 3.5%, the three structures have good linearity with correlationthe correlation coefficients coefficients R of R LPFG,2 of LPFG, LPFG LPFG + Ag, + Ag, LPFG LPFG + Ag + +Ag graphene + graphene being being 0.975, 0.975, 0.995, and0.995, 0.995. and The 0.995. sensitivity The sensitivity and detection and detection limits obtained limits obtained were 0.116 were nm 0.116 /% andnm 0.086%/% and for LPFG,0.086% 0.262 for LPFG, nm /% 0.262 and nm 0.038% /% and for 0.038% LPFG +for Ag, LPFG and + 0.34 Ag, nm and /% 0.34 and nm 0.029% /% and for 0.029% LPFG. for The presenceLPFG. The of graphenepresence of on graphene the silver on surface the silver of LPFGsurface can of increaseLPFG can sensor increase sensitivity sensor sensi- by 1.31 timestivity that by 1.31 of bare times silver that LPFGof bare [ 80silver]. LPFG [80].

FigureFigure 20. 20.(a )(a Longitudinal) Longitudinal section section of of the the graphene-based graphene-based longlong period fiber fiber grating grating (LPFG) (LPFG) SPR SPR sensor. sensor. (b) ( bResonance) Resonance wavelength shift versus concentration of methane (adapted with permission from Reference [80], copyright MDPI). wavelength shift versus concentration of methane (adapted with permission from Reference [80], copyright MDPI).

AlthoughAlthough SPR biosensors biosensors coupled coupled with with gratings gratings are pioneers are pioneers in the infield the of field SPR ofbio- SPR sensors, experimental studies related to the use of graphene for this platform are still rare. biosensors, experimental studies related to the use of graphene for this platform are still rare. Table 4 below shows some of the applications of this platform and the resulting sensitivity. Table4 below shows some of the applications of this platform and the resulting sensitivity. Table 4. A summary of selected papers regarding graphene-based grating coupled SPR biosensor. Table 4. A summary of selected papers regarding graphene-based grating coupled SPR biosensor. Grating shape Structure Analyte Sensitivity Ref. Grating shape Structure Analyte Sensitivity Ref. Rectangular Au/graphene dangerous gases 1180 nm/RIU [75] RectangularEllipse Au/graphene Au/graphene dangerous Biological gases cells 1180 nm/RIU 1782 nm/RIU [75 [74]] Ellipse Au/graphene Biological cells 1782 nm/RIU [74] Rectangular SiO2/graphene ssDNA 8004 nm/RIU [77] Rectangular SiO /graphene ssDNA 8004 nm/RIU [77] Holey Au/graphene2 Ethanol - [79] Holey Au/graphene Ethanol - [79] LongLong period period fiber fiber Ag/grapheneAg/graphene MethaneMethane 0.344 nm/%0.344 nm/% [80[80]] gratinggrating (LPFG) (LPFG) Rectangular Ag grating/Ag/grapheneAg grat- - 220°/RIU [81] Rectangular - 220◦/RIU [81] ing/Ag/graphene 6. Graphene-Based Nanoparticle Coupled SPR Biosensor 6. Graphene-BasedAnother type of Nanoparticle SPR biosensor Coupled is the SPR SPR biosensor Biosensor which uses nanoparticles as a signalAnother amplifier. type Of of the SPR various biosensor types is of the na SPRnoparticles, biosensor plasmonic which usesnanoparticles nanoparticles are the as a signalmost amplifier.preferred Ofbecause the various of their types properties of nanoparticles, that can produce plasmonic localized nanoparticles surface areplasmon the most preferredresonance because (LSPR) of which their can properties increase that local can el produceectromagnetic localized fields surface [82] and plasmon increase resonance SPR (LSPR) which can increase local electromagnetic fields [82] and increase SPR response [83]. Gold nanoparticles (AuNPs) are recognized as the best material for immunoassay because of their extraordinary properties such as easy reductive preparation, exceptional optical property, water solubility, and significant bicompability. For silver nanoparticles (Ag NPs), this material produces a sharper peak and can be used to increase the sensitivity of the biosensor. Nanomaterials 2021, 11, x FOR PEER REVIEW 18 of 30

Nanomaterials 2021, 11, 216 response [83]. Gold nanoparticles (AuNPs) are recognized as the best material for immu- 18 of 29 noassay because of their extraordinary properties such as easy reductive preparation, ex- ceptional optical property, water solubility, and significant bicompability. For silver na- noparticles (Ag NPs), this material produces a sharper peak and can be used to increase Takingthe sensitivity advantage of the biosensor. of the unique properties of gold, silver and graphene, Zhang et al. decoratedTaking gold advantage or silver of nanoparticles the unique properties with of graphene gold, silver toand detect graphene, mouse Zhang IgG. et al. To be able to decorated gold or silver nanoparticles with graphene to detect mouse IgG. To be able to capturecapture the the IgG IgG mouse, mouse, thethe hybrid hybrid nanoparticle nanoparticless are functionalized are functionalized with goat anti with human goat anti human IgG. Next,IgG. Next, solutions solutions containing containing different different conc concentrationsentrations of target of human target IgG human are flushed IgG are flushed onto theonto sensingthe sensing surface surface to toevaluate evaluate the the perf performanceormance and detection and detection limits of limits the system. of the system. Of the threeOf the fabricated three fabricated systems, systems, Ag-graphene Ag-graphene hybridhybrid nanoparticles nanoparticles showed showed the best the re- best response sponse compared to Au-graphene hybrid nanoparticles and unmodified biosensors (Fig- compared to Au-graphene hybrid nanoparticles and unmodified biosensors (Figure 21a). ure 21a). The detection limits of Ag-Graphene and Au-Graphene are 0.15 µg/mL and 0.30 The detectionµg/mL, respectively. limits of The Ag-Graphene selectivity of the and biosensor Au-Graphene was also tested are 0.15by detectingµg/mL human and 0.30 µg/mL, respectively.IgG and bovine Theselectivity IgG. There is of nothe observable biosensor shift in was the alsoresonant tested wavelength by detecting (Figure 21b). human IgG and bovineThis IgG. demonstrates There is the no selective observable binding shiftof the system in the that resonant was created wavelength with the IgG (Figure mouse 21b). This demonstrates[84]. the selective binding of the system that was created with the IgG mouse [84].

Figure 21. (a) SPR response at three different nanoparticles (Au film, Au-Gra, Ag-Gra). (b) The selectivity of the SPR on Figure 21. (threea) SPR different response analytes at (human three IgG, different bovine IgG, nanoparticles and mouse IgG) (Au (adapted film, with Au-Gra, permission Ag-Gra). from Refere (b)nce The [84], selectivity copyright of the SPR on three differentElsevier). analytes (human IgG, bovine IgG, and mouse IgG) (adapted with permission from Reference [84], copyright Elsevier). Chiu et al. proposed a colorimetric LSPR immunoassay based on the AuNPs-GO hy- Chiubrid to et detect al. proposed disease biomarkers a colorimetric and rapidly LSPR diagnose immunoassay infectious diseases. based The on thebinding AuNPs-GO hy- of AuNPs-GO- anti-BSA to GO-BSA is detected by monitoring changes in optical absorb- brid toance detect at a specific disease wavelength. biomarkers Figure and 22a rapidly shows the diagnose absorbance infectious spectra at diseases.different anti- The binding of AuNPs-GO-BSA concentrations anti-BSA from to GO-BSA 145 fM to 1.45 is detected nM. There by are monitoring two absorbance changes peaks at inthe optical wave- absorbance at a specificlengths of wavelength. 540 nm and 760Figure nm. From 22 thisa shows absorbance the peak, absorbance a calibration spectra curve is at obtained different anti-BSA concentrationswhich states from the relationship 145 fM to between 1.45 nM. the Thereanti-BSA are concentration two absorbance and the peaksshift in atthe the ab- wavelengths sorbance peak at the two peaks (Figure 22b). The detection limit for this sensor is 145 fM of 540with nm a andlinear 760 range nm. from From 145 fM this to 1.45 absorbance nM [85]. peak, a calibration curve is obtained which states the relationship between the anti-BSA concentration and the shift in the absorbance Nanomaterials 2021, 11, x FOR PEER REVIEW 19 of 30 peak at the two peaks (Figure 22b). The detection limit for this sensor is 145 fM with a linear range from 145 fM to 1.45 nM [85].

Figure 22. (aFigure) The 22. relationship (a) The relationship between between optical optical absorbance absorbance and wavele wavelengthngth at different at different anti BSA anti concentrations BSA concentrations (145 fM- (145 fM– 1.45 nM). (b) Calibration curves obtained from shifts in absorbance peaks (A and B) due to detection of anti-BSA with 1.45 nM). (bdifferent) Calibration concentrations curves (adapted obtained with frompermission shifts from in Reference absorbance [85], copyright peaks (A Springer and B) Nature). due to detection of anti-BSA with different concentrations (adapted with permission from Reference [85], copyright Springer Nature). The same structure was also applied to gas detection by Cittadini et al. They devel- oped gas sensor based on LSPR using rGO coupled with a gold monolayer. Gold mono- layer was fabricated by spinning gold colloids with a concentration of 15 and 30 mM at a speed of 3000 rpm for 30 s. The gold monolayer produced from gold colloids for a con- centration of 15 mM was indicated by L (AuL) and for a concentration of 30 mM indicated by H (AuH). The two monolayers of gold are then coated with rGO by the spin method and produce a sensing layer called AuL-rGO and AuH-rGO. The sensing layer was then tested by exposing different gas types, namely H2 (10,000 ppm and 100 ppm), CO (10,000 ppm), and NO2 (1 ppm). The results obtained indicate that the sensor shows a good and reversible response with fast kinetics to H2 and NO2, while no response was detected to CO [86]. A summary of the SPR biosensor coupled nanoparticles based-graphene is shown in Table 5.

Table 5. A summary of selected papers regarding graphene-based nanoparticle coupled SPR biosensor.

Technique Structure Analyte Sensitivity LOD Ref. SPR two layers of GO-Au NPs composite miRNA-141 - 0.1 fM [87] LSPR Au NPs-GO-anti BSA hCG - 145 fM [85] SPR Au-(Au NPs-Graphene nanohybrids)-anti human IgG mouse IgG 0.15 µg/mL [84] LSPR Au NPs coupled with GO NO2 - - [86] SPR Graphene-coated SPR with Au nanostars carrying ssDNA ssDNA - 500 aM [88] LSPR Au NPs/GO/uricase Uric acid 0.0082 nm/µM 206 µM [89]

7. Graphene-Based Plasmon Coupled Emission Biosensor In 2003, Lakowicz et al. developed the SPR biosensor with a fluorescence technique called surface plasmon coupled emission (SPCE) [90]. The working principle of this biosen- sor is based on the fluorescence and plasmonic properties of the nanostructures. Fluores- cence molecules are placed on a metal surface with a thickness of 20–50 nm [91]. Next, a light source of a specific wavelength is directed through the prism (Figure 23a) or from the sample side (Figure 23b) to excite the SP wave and high directional emission [91,92]. When the analyte binds to the fluorescence molecule, an energy shift occurs in the fluorescence spectrum. This shift is the basis for the application of SPCE for biosensor applications.

Nanomaterials 2021, 11, 216 19 of 29

The same structure was also applied to gas detection by Cittadini et al. They developed gas sensor based on LSPR using rGO coupled with a gold monolayer. Gold monolayer was fabricated by spinning gold colloids with a concentration of 15 and 30 mM at a speed of 3000 rpm for 30 s. The gold monolayer produced from gold colloids for a concentration of 15 mM was indicated by L (AuL) and for a concentration of 30 mM indicated by H (AuH). The two monolayers of gold are then coated with rGO by the spin method and produce a sensing layer called AuL-rGO and AuH-rGO. The sensing layer was then tested by exposing different gas types, namely H2 (10,000 ppm and 100 ppm), CO (10,000 ppm), and NO2 (1 ppm). The results obtained indicate that the sensor shows a good and reversible response with fast kinetics to H2 and NO2, while no response was detected to CO [86]. A summary of the SPR biosensor coupled nanoparticles based-graphene is shown in Table5. Table 5. A summary of selected papers regarding graphene-based nanoparticle coupled SPR biosensor.

Technique Structure Analyte Sensitivity LOD Ref. two layers of GO-Au SPR miRNA-141 - 0.1 fM [87] NPs composite LSPR Au NPs-GO-anti BSA hCG - 145 fM [85] Au-(Au NPs-Graphene SPR nanohybrids)-anti mouse IgG 0.15 µg/mL [84] human IgG Au NPs coupled with LSPR NO --[86] GO 2 Graphene-coated SPR SPR with Au nanostars ssDNA - 500 aM [88] carrying ssDNA LSPR Au NPs/GO/uricase Uric acid 0.0082 nm/µM 206 µM[89]

7. Graphene-Based Plasmon Coupled Emission Biosensor In 2003, Lakowicz et al. developed the SPR biosensor with a fluorescence technique called surface plasmon coupled emission (SPCE) [90]. The working principle of this biosensor is based on the fluorescence and plasmonic properties of the nanostructures. Flu- orescence molecules are placed on a metal surface with a thickness of 20–50 nm [91]. Next, a light source of a specific wavelength is directed through the prism (Figure 23a) or from the sample side (Figure 23b) to excite the SP wave and high directional emission [91,92]. When

Nanomaterials 2021, 11, x FOR PEERthe REVIEW analyte binds to the fluorescence molecule, an energy shift occurs in the fluorescence20 of 30 spectrum. This shift is the basis for the application of SPCE for biosensor applications.

FigureFigure 23. The 23. excitationThe excitation and and emission emission of of surface surface plasmonplasmon coupled coupled emission emission (SPCE) (SPCE) in (a in) Kretschmann (a) Kretschmann (KR) configuration, (KR) configuration, (b) reverse(b) reverse Kretschmann Kretschmann (RK) (RK) configuration configuration (adapted (adapted with with permissionpermission from from Reference Reference [93], [93 copyright], copyright Elsevier). Elsevier).

MulpurMulpur et et al. al. engineeredengineered and and investigated investigated the the SPCE SPCE properties properties of the of graphene–silver the graphene–silver thinthin film film stack stack as a a function function of the of thegraphene graphene thickness. thickness. Different Different types of graphene, types of both graphene, single both layer and multilayer, are fabricated by the CVD method compared to graphene which is fab- single layer and multilayer, are fabricated by the CVD method compared to graphene ricated by the chemical exfoliation method. The resulting graphene is then grown on a silver surface using the spin coating method. Flourescence measurements were carried out at a wavelength of 532 nm with a reverse Kretschmann (RK) configuration (Figure 24a). Figure 24b shows the fluorescence intensity in different structures where the exfoliated graphene- based substrate has the highest intensity. The fluorescence intensity at EG is forty times that of the free space structure [94].

Figure 24. (a) Schematic depicting the graphene–fluorophore (π–π stacking) and graphene–silver (plasmon–plasmon cou- pling) interactions. (b) Enhancement plot displaying intensity of the SPCE of the different Ag–graphene (Single layer gra- phene (SLG), bilayer graphene (BLG), few layered graphene (FLG), and exfoliated graphene (EG)) versus the intensity of the free space emission (adapted with permission from Reference [94], copyright American Chemical Society).

Nanocubes (NCs) have a special edge structure and tip effect that can induce strong localization and increased localized surface plasmons resonance fields. Therefore, Xie et al. performed an enhanced fluorescence signal using silver nanocubes (Ag NCs) and GO on a gold film. The SPCE signal is measured in the reverse kretschmann (RK) configura- tion at a wavelength of 532 nm (Figure 25a). The results obtained showed that the fluores- cence intensity of the SPCE structure with AgNCs and GO had a signal intensity thirty times higher than the structures without GO and NCs (Figure 25b) [95].

Nanomaterials 2021, 11, x FOR PEER REVIEW 20 of 30

Figure 23. The excitation and emission of surface plasmon coupled emission (SPCE) in (a) Kretschmann (KR) configuration, Nanomaterials(b2021) reverse, 11, 216 Kretschmann (RK) configuration (adapted with permission from Reference [93], copyright Elsevier). 20 of 29

Mulpur et al. engineered and investigated the SPCE properties of the graphene–silver thin film stack as a function of the graphene thickness. Different types of graphene, both single whichlayeris and fabricated multilayer, by are the fabric chemicalated by the exfoliation CVD method method. compared The to resulting graphene which graphene is fab- is then grownricated on by a silverthe chemical surface exfoliation using the method. spin coating The resulting method. graphene Flourescence is then grown measurements on a silver were carriedsurface out using at athe wavelength spin coating of method. 532 nm Flourescence with a reverse measurements Kretschmann were carried (RK) configurationout at a (Figurewavelength 24a). Figureof 532 nm 24 bwith shows a reverse the fluorescence Kretschmannintensity (RK) configuration in different (Figure structures 24a). Figure where the exfoliated24b shows graphene-based the fluorescence substrateintensity in has differe thent highest structures intensity. where Thethe exfoliated fluorescence graphene- intensity at EGbased is forty substrate times thathas the of thehighest free intensity. space structure The fluorescence [94]. intensity at EG is forty times that of the free space structure [94].

FigureFigure 24. ( 24.a) Schematic(a) Schematic depicting depicting thethe graphene–fluorophore graphene–fluorophore (π–π (π stacking)–π stacking) and graphene–silv and graphene–silverer (plasmon–plasmon (plasmon–plasmon cou- pling) interactions. (b) Enhancement plot displaying intensity of the SPCE of the different Ag–graphene (Single layer gra- coupling) interactions. (b) Enhancement plot displaying intensity of the SPCE of the different Ag–graphene (Single layer phene (SLG), bilayer graphene (BLG), few layered graphene (FLG), and exfoliated graphene (EG)) versus the intensity of graphenethe free (SLG), space bilayer emission graphene (adapted (BLG), with permission few layered from graphene Reference (FLG), [94], andcopyright exfoliated American graphene Chemical (EG)) Society). versus the intensity of the free space emission (adapted with permission from Reference [94], copyright American Chemical Society). NanocubesNanocubes (NCs) (NCs) havehave a special special edge edge structur structuree and and tip tipeffect effect that thatcan induce can induce strong strong localizationlocalization and and increased increased localized localized surface pl plasmonsasmons resonance resonance fields. fields. Therefore, Therefore, Xie Xieet et al. al. performed an enhanced fluorescence signal using silver nanocubes (Ag NCs) and GO performed an enhanced fluorescence signal using silver nanocubes (Ag NCs) and GO on a on a gold film. The SPCE signal is measured in the reverse kretschmann (RK) configura- goldtion film. at a wavelength The SPCE signalof 532 nm is measured (Figure 25a). in The the results reverse obtained kretschmann showed (RK) that the configuration fluores- at a wavelength of 532 nm (Figure 25a). The results obtained showed that the fluorescence Nanomaterials 2021, 11, x FOR PEER REVIEWcence intensity of the SPCE structure with AgNCs and GO had a signal intensity21 thirty of 30 intensitytimes higher of the than SPCE the structurestructures without with AgNCs GO and and NCs GO (Figure had 25b) a signal [95]. intensity thirty times higher than the structures without GO and NCs (Figure 25b) [95].

Figure 25. (a) AgNCs and GO enhanced SPCE structure. (b) The resulting fluorescence spectrum (right) (adapted with permission Figure 25. (a) AgNCs and GO enhanced SPCE structure. (b) The resulting fluorescence spectrum (right) (adapted with from Reference [95], copyright Elsevier). permission from Reference [95], copyright Elsevier). Xie et al. amplified the SPCE signal in gold using GO and applied it to detect human IgG.Xie The et fluorescence al. amplified signal the from SPCE SPCE signal was in measured gold using with GO a Reverse and applied Kretschmann it to detect (RK) human IgG.configuration The fluorescence at a wavelength signal from of 532 SPCE nm. wasThe results measured obtained with indicate a Reverse that Kretschmann GO can in- (RK) configurationcrease the fluorescence at a wavelength intensity of up 532 to nm.seven The times results that obtainedof the SPCE indicate structure that without GO can GO increase the(SPCE fluorescence (Au)) or twenty-five intensity up times to seven that of times the free that space of the emission SPCE (FSE). structure Furthermore, without GOdif- (SPCE ferent human IgG concentrations were measured by SPCE (Au + GO) and SPCE (Au) and the fluorescence intensity at each concentration was then measured. The results obtained indicate that the linear relationship is shown in SPCE (Au + GO) with a wider range com- pared to SPCE (Au) (Figure 26). At semilogarithmic coordinates, the linear relationship and correlation coefficient R2 are 0.01–800 ng/mL and 0.993 for SPCE (Au + GO) and 1–100 ng/mL and 0.926 for SPCE (Au), respectively. The detection limits for SPCE (Au + GO) and SPCE (Au) were 0.006 ng/mL and 0.15 ng/mL [96].

Figure 26. Dependences of the fluorescence intensities of (a) SPCE (Au+GO) and (b) SPCE (Au) on the concentration of human IgG (adapted with permission from Reference [96], copyright Elsevier).

The previous discussion describes the working principle of SPCE and the use of gra- phene for this platform of biosensor. Until now, graphene has not been widely applied to this platform. Table 6 below is a summary of the results of research related to graphene- based SPCE.

Nanomaterials 2021, 11, x FOR PEER REVIEW 21 of 30

Figure 25. (a) AgNCs and GO enhanced SPCE structure. (b) The resulting fluorescence spectrum (right) (adapted with permission from Reference [95], copyright Elsevier).

Xie et al. amplified the SPCE signal in gold using GO and applied it to detect human Nanomaterials 2021, 11, 216 21 of 29 IgG. The fluorescence signal from SPCE was measured with a Reverse Kretschmann (RK) configuration at a wavelength of 532 nm. The results obtained indicate that GO can in- crease the fluorescence intensity up to seven times that of the SPCE structure without GO (SPCE(Au)) or(Au)) twenty-five or twenty-five times times that of that the of free the space free space emission emission (FSE). (FSE). Furthermore, Furthermore, different dif- ferenthuman human IgG concentrations IgG concentrations were were measured measured by SPCE by SPCE (Au (Au + GO) + GO) and and SPCE SPCE (Au) (Au) and and the thefluorescence fluorescence intensity intensity at at each each concentration concentration was was then then measured. measured. The results obtained obtained indicateindicate that that the the linear linear relationship relationship is shown is shown in SPCE in SPCE (Au (Au+ GO) + GO)with witha wider a wider range rangecom- paredcompared to SPCE to SPCE (Au) (Au) (Figure (Figure 26). 26 At). Atsemiloga semilogarithmicrithmic coordinates, coordinates, the the linear linear relationship relationship andand correlation correlation coefficient coefficient R2 R are2 are 0.01–800 0.01–800 ng/mL ng/mL and and0.993 0.993 for SPCE for SPCE (Au + (AuGO) +and GO) 1–100 and ng/mL1–100 ng/mLand 0.926 and for 0.926 SPCE for (Au), SPCE respectively. (Au), respectively. The detection The detection limits limitsfor SPCE for SPCE(Au + (AuGO) + andGO) SPCE and SPCE(Au) were (Au) 0.006 were 0.006ng/mL ng/mL and 0.15 and ng/mL 0.15 ng/mL [96]. [96].

Figure 26. Dependences of the fluorescence intensities of (a) SPCE (Au+GO) and (b) SPCE (Au) on the concentration of Figure 26. Dependences of the fluorescence intensities of (a) SPCE (Au+GO) and (b) SPCE (Au) on the concentration of human IgG (adapted with permission from Reference [96], copyright Elsevier). human IgG (adapted with permission from Reference [96], copyright Elsevier).

TheThe previous previous discussion discussion describes describes the the work workinging principle principle of SPCE of SPCE and andthe use the of use gra- of phenegraphene for this for thisplatform platform of biosensor. of biosensor. Until Until now, now, graphene graphene has hasnot notbeen been widely widely applied applied to thisto this platform. platform. Table Table 6 below6 below is isa summary a summary of of the the results results of of research research related related to to graphene- graphene- basedbased SPCE. SPCE.

Table 6. A summary of selected papers regarding graphene-based plasmon coupled emission biosensor.

Structure Enhancement Factor Fluorophore Ref.

Ag/graphene 40 RhB–PVA [94] Au/GO 25 RhB–PVA [96] Ag/single layer GO 112 R6G [97] Au/Ag NCs/GO 30 AgNCs [95] Ag/Gallium 4.772 - [98] arsenide/Ag/graphene/MoS2

8. Graphene-Based SERS Biosensor Raman spectroscopy is a vibration spectroscopy technique that measures the inelastic scattering of light. The resulting Raman spectrum provides a specific fingerprint regarding the molecular structure and material composition [99]. In biosensors, this fingerprint can be used to directly identify an analyte and determine its level [100]. However, Raman scattering is very weak and will not be seen especially when identifying organic molecules which have high fluorescence. The presence of fluorescence can inhibit the identification of molecules especially at very low concentration levels [101,102]. The latest development in analyte detection which utilizes Raman signals is the surface-enhanced Raman scattering (SERS) technique. This technique, first introduced by Fleischmann, Hendra, and McQuillan in 1973 [103], was accomplished by adding metal nanostructures to increase the weak signal and reduce the risk of fluorescence interference as illustrated in Figure 27[ 104]. The increase in the Raman signal in this technique occurs due to SPR, which is when the laser excitation energy is close the surface plasmon energy of the metal substrate. This technique is called electromagnetic enhancement [105]. There is Nanomaterials 2021, 11, x FOR PEER REVIEW 22 of 30

Table 6. A summary of selected papers regarding graphene-based plasmon coupled emission bio- sensor.

Structure Enhancement Factor Fluorophore Ref. Ag/graphene 40 RhB–PVA [94] Au/GO 25 RhB–PVA [96] Ag/single layer GO 112 R6G [97] Au/Ag NCs/GO 30 AgNCs [95] Ag/Gallium arsenide/Ag/graphene/MoS2 4.772 - [98]

8. Graphene-Based SERS Biosensor Raman spectroscopy is a vibration spectroscopy technique that measures the inelastic scattering of light. The resulting Raman spectrum provides a specific fingerprint regard- ing the molecular structure and material composition [99]. In biosensors, this fingerprint can be used to directly identify an analyte and determine its level [100]. However, Raman scattering is very weak and will not be seen especially when identifying organic molecules which have high fluorescence. The presence of fluorescence can inhibit the identification of molecules especially at very low concentration levels [101,102]. The latest development in analyte detection which utilizes Raman signals is the sur- face-enhanced Raman scattering (SERS) technique. This technique, first introduced by Fleischmann, Hendra, and McQuillan in 1973 [103], was accomplished by adding metal Nanomaterials 2021, 11, 216 nanostructures to increase the weak signal and reduce the risk of fluorescence interference 22 of 29 as illustrated in Figure 27 [104]. The increase in the Raman signal in this technique occurs due to SPR, which is when the laser excitation energy is close the surface plasmon energy of the metal substrate. This technique is called electromagnetic enhancement [105]. There is anotheranother technique technique inin whichwhich the the Raman Raman signal signal do doeses not not depend depend on the on substrate the substrate but on but the on the molecularmolecular analyte. analyte. ByBy taking advantage advantage of of th thee increased increased probability probability of the of Raman the Raman transition transition whenwhen the the analyte analyte is is absorbed,absorbed, this this techniqu techniquee is known is known as chemical as chemical enhancement enhancement [104–106]. [104 –106].

FigureFigure 27. The27. The principles principles behind behind RamanRaman and and Surf Surface-Enhancedace-Enhanced Raman Raman Scattering Scattering (SERS) (SERS)techniques techniques (adapted with (adapted per- with mission from Reference [107], copyright Institute of Food Technologists). permission from Reference [107], copyright Institute of Food Technologists). GrapheneGraphene hashas been shown shown to tobe bea very a very outs outstandingtanding SERS SERSactive substrate active substrate due to its due to itsadvantages advantages over over other other traditional traditional materials. materials. By utilizing By its utilizing large surface its large area and surface superior area and adsorption capabilities, graphene can be utilized to extinguish photoluminescence of flu- superior adsorption capabilities, graphene can be utilized to extinguish photoluminescence orescent dyes and drastically eliminate the fluorescence background [108]. Xie et al. de- of fluorescent dyes and drastically eliminate the fluorescence background [108]. Xie et al. veloped a graphene substrate grown on SiO2/Si surfaces to suppress photoluminescence. developedGraphene a is graphene fabricated substrate by mechanical grown oxfoliation on SiO2/Si from surfaces graphite. to Figure suppress 28b photoluminescence.shows the Ra- Grapheneman spectrum is fabricated of rhodamine by mechanical 6G (R6G) in oxfoliation aqueous solution from graphite. (10 µM) and Figure R6G 28in bsingle shows the Ramanlayer graphene. spectrum From of rhodamine the two spectra 6G (R6G) obtained in aqueous, the graphene solution substrate (10 µ showedM) and a R6G clearer in single layerRaman graphene. signal without From the fluorescence two spectra backgrou obtained,nd than the the graphene R6G solution. substrate The showedphotolumi- a clearer Ramannescence signal suppression without effect fluorescence is due to backgroundelectron transfer than and the energy R6G solution.transfer between The photolumi- the Nanomaterials 2021, 11, x FOR PEERgraphene REVIEW and the R6G dye molecule [109]. In 2010, Ling et al. compared SERS23 ofsubstrate 30 nescence suppression effect is due to electron transfer and energy transfer between the graphene and the R6G dye molecule [109]. In 2010, Ling et al. compared SERS substrate based on graphene and SiO2/Si. To determine the performance of the two substrates, R6G wasbased deposited on graphene on and the SiO two2/Si. substratesTo determineusing the performa a solution-soakingnce of the two substrates, method. R6G As shown in was deposited on the two substrates using a solution-soaking method. As shown in Figure Figure28c, 28 afterc, after solution-soaking, solution-soaking, the Raman the signal Raman intensity signal of R6G intensity on single layer of R6G graphene on single layer graphenewas much was stronger much stronger than on SiO than2/Si substrate. on SiO2 In/Si addition, substrate. the Raman In addition, signal in single theRaman layer signal in singlegraphene layer graphene can still be can detected still be clearly detected even th clearlyough the even R6G thoughconcentration the R6Gis as low concentration as 1 is as low asnM 1 nM[110]. [110 ].

Figure 28. (aFigure) Schematic 28. (a) Schematic illustration illustration of graphene of graphene as as a substratea substrate for suppressing suppressing the phot theoluminescence photoluminescence of R6G. (b of) Raman R6G. (b) Raman spectrum of R6G in water (blue line) and R6G in single layer graphene (red line). (c) Raman spectra of R6G on SiO2/Si and spectrum of R6Ggraphene in watersubstrate, (blue respectively line) and (adapted R6G with in single permission layer from graphene Reference (red [109,110], line). copyright (c) Raman American spectra Chemical of R6G Society). on SiO 2/Si and graphene substrate, respectively (adapted with permission from References [109,110], copyright American Chemical Society). Graphene only supports chemical enhancement and does not support electromag- netic enhancement due to its smooth surface and high optical transmission over the visible range [111]. To overcome this shortcoming, one approach to obtain high performance SERS substrates with chemical and electromagnetic enhancement is by fabricating the substrate which is composed of graphene and metal nanoparticles [112]. Lin et al. studied DNA hybridization by utilizing self-assembly of Ag NPs and SERS substrate based on Ag NPs and graphene (Ag NPs–graphene) nanocomposites. AgNPs are modified with non- fluorescent 4-mercaptobenzoic acid (4-MBA) which is a very efficient Raman probe for DNA hybridization. Furthermore, automatic assembly can occur by functionalization of Ag NPs-GO with DNA probes and Ag NPs with DNA targets. The experimental sche- matic is shown in Figure 29a. As shown in Figure 29b, the detection limit of the SERS- based DNA sensor was determined by measuring the SERS intensity with a variation of the target DNA concentration up to a concentration of 1 pM. The characteristic peak at 1078 cm−1 can be clearly observed. More importantly, the SERS intensity at 1078 cm−1 in- creases linearly with the logarithm of the target DNA concentration in the range 10−6–10−12 M. The detection limit obtained from this experiment is 10−14 M[113]. In addition to DNA hybridization applications, the SERS substrate based on Ag and graphene nanocompo- sites has also been utilized for sensing inorganic ions, dye molecules, and pesticides [114].

Nanomaterials 2021, 11, 216 23 of 29

Graphene only supports chemical enhancement and does not support electromagnetic enhancement due to its smooth surface and high optical transmission over the visible range [111]. To overcome this shortcoming, one approach to obtain high performance SERS substrates with chemical and electromagnetic enhancement is by fabricating the substrate which is composed of graphene and metal nanoparticles [112]. Lin et al. studied DNA hybridization by utilizing self-assembly of Ag NPs and SERS substrate based on Ag NPs and graphene (Ag NPs–graphene) nanocomposites. AgNPs are modified with non-fluorescent 4-mercaptobenzoic acid (4-MBA) which is a very efficient Raman probe for DNA hybridization. Furthermore, automatic assembly can occur by functionalization of Ag NPs-GO with DNA probes and Ag NPs with DNA targets. The experimental schematic is shown in Figure 29a. As shown in Figure 29b, the detection limit of the SERS-based DNA sensor was determined by measuring the SERS intensity with a variation of the target DNA concentration up to a concentration of 1 pM. The characteristic peak at 1078 cm−1 can be clearly observed. More importantly, the SERS intensity at 1078 cm−1 increases linearly with the logarithm of the target DNA concentration in the range 10−6–10−12 M. The detection limit obtained from this experiment is 10−14 M[113]. In addition to DNA hybridization Nanomaterials 2021, 11, x FOR PEERapplications, REVIEW the SERS substrate based on Ag and graphene nanocomposites has24 of also 30 been utilized for sensing inorganic ions, dye molecules, and pesticides [114].

FigureFigure 29. (a 29.) Illustration (a) Illustration of detectionof detection of of DNA DNA targetstargets with with Ag Ag NPs-Ag NPs-Ag NPs-GO. NPs-GO. (b) The (b) SERS The SERSspectrum spectrum was obtained was obtained at different complement DNA target concentrations (Reproduced from Reference [113] with permission from the PCCP at different complement DNA target concentrations (Reproduced from Reference [113] with permission from the PCCP Owner Societies). Owner Societies). The second metal type that is widely used as a SERS substrate is gold. One of the advantagesThe second of this metal material type is that its ishigher widely stability used than as a Ag SERS NP. substrate Possible interactions is gold. One be- of the advantagestween graphene of this and material gold can is its occur higher in severa stabilityl ways than including Ag NP. covalent Possible bonds interactions when gra- between graphenephene, gold, and or gold both can are occur functionalized in several [115], ways non-covalent including attachments covalent bonds in the whenform of graphene, 𝜋– gold,𝜋 interactions or both are [116], functionalized and van der [115 walls], non-covalent forces which attachmentsmay occur in inunmodified the form graphene of π–π interac- tions[117]. [116 Until], and now, van the der SERS walls substrate forces whichbased mayon graphene occur in and unmodified gold has been graphene successfully [117]. Until now,fabricated the SERS using substrate self-assembly[116], based on graphene electrochemical and gold deposition has been successfully[118], or in situ fabricated growth using self-assemblyprocesses [119] [116 and], electrochemical has employed for deposition biosensing [cancer118], orand in cancer situ growth steam cells processes [120], mul- [119] and 2+ hastiplex employed DNA detection for biosensing [121], or canceras Hg andsensors cancer [122,123]. steam Table cells 7 [below120], shows multiplex a summary DNA detec- tionof [some121], of or the as literature Hg2+ sensors related [122 to graphene-based,123]. Table7 below SERS biosensors. shows a summary of some of the Table 7. A summary of selectedliterature papers related regarding to graphene-based the graphene-based SERS Surface-Enhanced biosensors. Raman Scattering (SERS) biosen- sor.

SERS Platform Probe Molecule Enhancement Factors (EF) LOD Ref. Graphene-encapsulated Ag NPs decorated silicon nan- R6G 107 - [124] owire GO-Au NPs composites R6G 4.9 × 106 10−9 M [125] GO-based Au hybrids R6G 1.2 × 107 10−7 M [126] Graphene-Au nano-pyramid (tip) hybrid structure R6G - - [127] Au NPs arranged on GO R6G - 10−9 M [106] Self assembly of Ag NPs into Ag NPs-GO nanocompo- R6G - 10−14 M [113] sites Au NPs/graphene/epoxy resin nanosheet - 6.2 × 106 3.3 μM [128] Graphene functionalized with polyamidoamine den- - 8.3 × 104 1.43 pM [129] drimers decorated Ag NPs

9. Conclusions Graphene and its derivatives have proven to be one of the best materials to enhance the performance of SPR biosensors in many platforms. The simulation study of the gra- phene-based SPR biosensor has been proven experimentally. To date, experimental stud- ies have reported that the graphene-based SPR biosensor is capable of detecting analytes up to nM or ng/mL levels. Some researchers have also claimed that they were able to detect analyte to smaller levels (fM or fg/mL and aM or ag/mL). This shows that graphene is a superior material and is very promising in the development of SPR biosensors in the future. One of the challenges in developing graphene-based biosensors is to reduce noise in the detection process of very complex human samples such as in the form serum, plasma, urine, and stool. Modification of the sensing surface is needed to reduce noise so that the detection process is very selective and accurate. For the commercialization of graphene-

Nanomaterials 2021, 11, 216 24 of 29

Table 7. A summary of selected papers regarding the graphene-based Surface-Enhanced Raman Scattering (SERS) biosensor.

Enhancement Factors SERS Platform Probe Molecule LOD Ref. (EF) Graphene-encapsulated Ag NPs R6G 107 -[124] decorated silicon nanowire GO-Au NPs composites R6G 4.9 × 106 10−9 M [125] GO-based Au hybrids R6G 1.2 × 107 10−7 M [126] Graphene-Au nano-pyramid (tip) R6G - - [127] hybrid structure Au NPs arranged on GO R6G - 10−9 M [106] Self assembly of Ag NPs into Ag R6G - 10−14 M [113] NPs-GO nanocomposites Au NPs/graphene/epoxy resin - 6.2 × 106 3.3 µM[128] nanosheet Graphene functionalized with polyamidoamine dendrimers - 8.3 × 104 1.43 pM [129] decorated Ag NPs

9. Conclusions Graphene and its derivatives have proven to be one of the best materials to enhance the performance of SPR biosensors in many platforms. The simulation study of the graphene- based SPR biosensor has been proven experimentally. To date, experimental studies have reported that the graphene-based SPR biosensor is capable of detecting analytes up to nM or ng/mL levels. Some researchers have also claimed that they were able to detect analyte to smaller levels (fM or fg/mL and aM or ag/mL). This shows that graphene is a superior material and is very promising in the development of SPR biosensors in the future. One of the challenges in developing graphene-based biosensors is to reduce noise in the detection process of very complex human samples such as in the form serum, plasma, urine, and stool. Modification of the sensing surface is needed to reduce noise so that the detection process is very selective and accurate. For the commercialization of graphene- based SPR biosensors, a simple SPR chip fabrication method, which can control the chip dimensions precisely and accurately in large quantities, is required. This is very important to ensure the resulting performance is as desired.

Author Contributions: D.T.N.: investigation, data curation, writing—original draft. N.-F.C.: con- ceptualization, methodology, data curation, supervision, data curation, investigation, resources, methodology. All the authors contributed equally and have given approval to the final version of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This study was supported by the Ministry of Science and Technology of the Republic of China (ROC), Taiwan, for financially supporting this research under Contract No. MOST 105-2221- E-003-027, MOST 106-2221-E-003-020, MOST 107-2221-E-003-009, MOST 108-2221-E-003-020-MY3, MOST 109-2314-B-195-012-MY3, MOST 109-2221-E-003-028-MY3. Acknowledgments: The authors would like to thank the Mackay Hospital, Taipei, Taiwan; this work was approved by the Institutional Review Board (IRB) of Mackay Hospital for Human Clinical Trials (Permit Numbers: 15MMHIS020, 15MMHIS115, and 17MMHIS185). We thank the National Synchrotron Radiation Research Center (NSRRC, Taiwan Light Source) for their help in analyzing XPS and FTIR spectra (Beamline 09A2, 24A1 and 14A1). Conflicts of Interest: The authors declare no conflict of interest.

References 1. Li, Z.; Zhang, W.; Xing, F. Graphene Optical Biosensors. Int. J. Mol. Sci. 2019, 20, 2461. [CrossRef][PubMed] 2. Papageorgiou, D.G.; Kinloch, I.A.; Young, R.J. Graphene/elastomer nanocomposites. Carbon 2015, 95, 460–484. [CrossRef] 3. Liu, J.; Cui, L.; Losic, D. Graphene and graphene oxide as new nanocarriers for drug delivery applications. Acta Biomater. 2013, 9, 9243–9257. [CrossRef][PubMed] Nanomaterials 2021, 11, 216 25 of 29

4. Bai, L.; Zhang, Y.; Tong, W.; Sun, L.; Huang, H.; An, Q.; Tian, N.; Chu, P.K. Graphene for Energy Storage and Conversion: Synthesis and Interdisciplinary Applications. Electrochem. Energy Rev. 2020, 3, 395–430. [CrossRef] 5. Lin, J.; Huang, Y.; Huang, P. Graphene-Based Nanomaterials in Bioimaging. In Biomedical Applications of Functionalized Nanomateri- als; Elsevier: Amsterdam, The Netherlands, 2018; pp. 247–287. ISBN 9780323508797. 6. Bai, Y.; Xu, T.; Zhang, X. Graphene-based biosensors for detection of biomarkers. Micromachines 2020, 11, 60. [CrossRef][PubMed] 7. Oliveira, L.C.; Herbster, A.; da Silva Moreira, C.; Neff, F.H.; Lima, A.M.N. Surface Plasmon Resonance Sensing Characteristics of Thin Aluminum Films in Aqueous Solution. IEEE Sens. J. 2017, 17, 6258–6267. [CrossRef] 8. Nguyen, H.H.; Park, J.; Kang, S.; Kim, M. Surface Plasmon Resonance: A Versatile Technique for Biosensor Applications. Sensors 2015, 15, 10481–10510. [CrossRef] 9. Islam, M.S.; Kouzani, A.Z.; Dai, X.J.; Michalski, W.P. Parameter sensitivity analysis of surface plasmon resonance biosensor through numerical simulation. In Proceedings of the 2010 IEEE/ICME International Conference on Complex Medical Engineering, Gold Coast, Australia, 13–15 July 2010; Volume 1, pp. 171–176. [CrossRef] 10. Sharma, N.K. Performances of different metals in optical fibre-based surface plasmon resonance sensor. Pramana J. Phys. 2012, 78, 417–427. [CrossRef] 11. Cao, J.; Sun, Y.; Kong, Y.; Qian, W. The sensitivity of grating-based SPR sensors with wavelength interrogation. Sensors 2019, 19, 405. [CrossRef] 12. Jia, Y.; Peng, Y.; Bai, J.; Zhang, X.; Cui, Y.; Ning, B.; Cui, J.; Gao, Z. Magnetic nanoparticle enhanced surface plasmon resonance sensor for estradiol analysis. Sens. Actuators B Chem. 2018, 254, 629–635. [CrossRef] 13. Suvarnaphaet, P.; Pechprasarn, S. Graphene-based materials for biosensors: A review. Sensors 2017, 17, 2161. [CrossRef][PubMed] 14. Paquin, F.; Rivnay, J.; Salleo, A.; Stingelin, N.; Silva, C. Multi-phase semicrystalline microstructures drive exciton dissociation in neat plastic semiconductors. J. Mater. Chem. C 2015, 3, 10715–10722. [CrossRef] 15. Qureshi, T.S.; Panesar, D.K. A comparison of graphene oxide, reduced graphene oxide and pure graphene: Early age properties of cement composites. In Proceedings of the 2nd RILEM Spring Convention & International Conference on Sustainable Materials, Systems and Structures, Rovinj, Croatia, 18–22 March 2019; pp. 318–325. 16. Chu, H.; Jiang, J.; Sun, W.; Zhang, M. Effects of graphene sulfonate nanosheets on mechanical and thermal properties of sacrificial concrete during high temperature exposure. Cem. Concr. Compos. 2017, 82, 252–264. [CrossRef] 17. Gholampour, A.; Valizadeh Kiamahalleh, M.; Tran, D.N.H.; Ozbakkaloglu, T.; Losic, D. From Graphene Oxide to Reduced Graphene Oxide: Impact on the Physiochemical and Mechanical Properties of Graphene-Cement Composites. ACS Appl. Mater. Interfaces 2017, 9, 43275–43286. [CrossRef][PubMed] 18. Basu, S.; Bhattacharyya, P. Recent developments on graphene and graphene oxide based solid state gas sensors. Sens. Actuators B Chem. 2012, 173, 1–21. [CrossRef] 19. Guy, O.J.; Walker, K.A.D. Graphene Functionalization for Biosensor Applications, 2nd ed.; Elsevier Inc.: Amsterdam, The Netherlands, 2016; ISBN 9780128029930. 20. Szunerits, S.; Maalouli, N.; Wijaya, E.; Vilcot, J.P.; Boukherroub, R. Recent advances in the development of graphene-based surface plasmon resonance (SPR) interfaces. Anal. Bioanal. Chem. 2013, 405, 1435–1443. [CrossRef] 21. Kravets, V.G.; Jalil, R.; Kim, Y.J.; Ansell, D.; Aznakayeva, D.E.; Thackray, B.; Britnell, L.; Belle, B.D.; Withers, F.; Radko, I.P.; et al. Graphene-protected copper and silver plasmonics. Sci. Rep. 2014, 4, 1–8. [CrossRef] 22. Wu, F.; Thomas, P.A.; Kravets, V.G.; Arola, H.O.; Soikkeli, M.; Iljin, K.; Kim, G.; Kim, M.; Shin, H.S.; Andreeva, D.V.; et al. Layered material platform for surface plasmon resonance biosensing. Sci. Rep. 2019, 9, 1–10. [CrossRef] 23. Ritchie, R.H. Plasma Losses by Fast Electrons in Thin Films. Phys. Rev. 1957, 106, 874–881. [CrossRef] 24. Otto, A. Excitation of nonradiative surface plasma waves in silver by the method of frustrated total reflection. Z. Phys. 1968, 216, 398–410. [CrossRef] 25. Lee, Y.; Sim, S.M.; Kim, J.M. Otto configuration based surface plasmon resonance with tunable air-gap using piezoactuator. In Proceedings of the 2019 International Conference on Optical MEMS and Nanophotonics (OMN), Daejeon, Korea, 29 July–2 August 2019; pp. 64–65. [CrossRef] 26. Schasfoort, R. Handbook of Surface Plasmon Resonance; Schasfoort, R.B.M., Tudos, A.J., Eds.; Royal Society of Chemistry: Cambridge, UK, 2008; ISBN 978-0-85404-267-8. 27. Hlubina, P.; Ciprian, D. Spectral Phase Shift of Surface Plasmon Resonance in the Kretschmann Configuration: Theory and Experiment. Plasmonics 2017, 12, 1071–1078. [CrossRef] 28. Islam, M.S.; Kouzani, A.Z.; Dai, X.J.; Michalski, W.P.; Gholamhosseini, H. Comparison of performance parameters for conventional and localized surface plasmon resonance graphene biosensors. In Proceedings of the 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Boston, MA, USA, 30 August–3 September 2011; pp. 1851–1854. [CrossRef] 29. Ouyang, Q.; Zeng, S.; Jiang, L.; Hong, L.; Xu, G.; Dinh, X.Q.; Qian, J.; He, S.; Qu, J.; Coquet, P.; et al. Sensitivity Enhancement of Transition Metal Dichalcogenides/Silicon Nanostructure-based Surface Plasmon Resonance Biosensor. Sci. Rep. 2016, 6, 1–13. [CrossRef][PubMed] 30. Basak, C.; Hosain, M.K.; Sazzad, A.A. Design and Simulation of a High Sensitive Surface Plasmon Resonance Biosensor for Detection of Biomolecules. Sens. Imaging 2020, 21, 1–19. [CrossRef] 31. Wu, L.; Chu, H.S.; Koh, W.S.; Li, E.P. Highly sensitive graphene biosensors based on surface plasmon resonance. Opt. Express 2010, 18, 14395. [CrossRef][PubMed] Nanomaterials 2021, 11, 216 26 of 29

32. Choi, S.H.; Kim, Y.L.; Byun, K.M. Graphene-on-silver substrates for sensitive surface plasmon resonance imaging biosensors. Opt. Express 2011, 19, 458. [CrossRef] 33. Maharana, P.K.; Jha, R. Chalcogenide prism and graphene multilayer based surface plasmon resonance affinity biosensor for high performance. Sens. Actuators B Chem. 2012, 169, 161–166. [CrossRef] 34. Verma, R.; Gupta, B.D.; Jha, R. Sensitivity enhancement of a surface plasmon resonance based biomolecules sensor using graphene and silicon layers. Sens. Actuators B Chem. 2011, 160, 623–631. [CrossRef] 35. Ryu, Y.; Moon, S.; Oh, Y.; Kim, Y.; Lee, T.; Kim, D.H.; Kim, D. Effect of coupled graphene oxide on the sensitivity of surface plasmon resonance detection. Appl. Opt. 2014, 53, 1419. [CrossRef] 36. Jing, J.Y.; Wang, Q.; Zhao, W.M.; Wang, B.T. Long-range surface plasmon resonance and its sensing applications: A review. Opt. Lasers Eng. 2019, 112, 103–118. [CrossRef] 37. Wu, L.; Ling, Z.; Jiang, L.; Guo, J.; Dai, X.; Xiang, Y.; Fan, D. Long-Range Surface Plasmon with Graphene for Enhancing the Sensitivity and Detection Accuracy of Biosensor. IEEE Photonics J. 2016, 8, 1–9. [CrossRef] 38. Chiu, N.-F.; Huang, T.-Y.; Kuo, C.-C.; Lee, W.-C.; Hsieh, M.-H.; Lai, H.-C. Single-layer graphene based SPR biochips for tuberculosis bacillus detection. In Biophotonics: Photonic Solutions for Better Health Care III; SPIE: Bellingham, WA, USA, 2012; Volume 8427, p. 84273M. [CrossRef] 39. Chung, K.; Rani, A.; Lee, J.E.; Kim, J.E.; Kim, Y.; Yang, H.; Kim, S.O.; Kim, D.; Kim, D.H. Systematic study on the sensitivity enhancement in graphene plasmonic sensors based on layer-by-layer self-assembled graphene oxide multilayers and their reduced analogues. ACS Appl. Mater. Interfaces 2015, 7, 144–151. [CrossRef][PubMed] 40. Chiu, N.F.; Huang, T.Y.; Lai, H.C.; Liu, K.C. Graphene oxide-based SPR biosensor chip for immunoassay applications. Nanoscale Res. Lett. 2014, 9, 1–7. [CrossRef][PubMed] 41. Chiu, N.F.; Lin, T.L.; Kuo, C.T. Highly sensitive carboxyl-graphene oxide-based surface plasmon resonance immunosensor for the detection of lung cancer for cytokeratin 19 biomarker in human plasma. Sens. Actuators B Chem. 2018, 265, 264–272. [CrossRef] 42. Li, X.; Cai, W.; An, J.; Kim, S.; Nah, J.; Yang, D.; Piner, R.; Velamakanni, A.; Jung, I.; Tutuc, E.; et al. Large-area synthesis of high-quality and uniform graphene films on copper foils. Science 2009, 324, 1312–1314. [CrossRef] 43. He, L.; Pagneux, Q.; Larroulet, I.; Serrano, A.Y.; Pesquera, A.; Zurutuza, A.; Mandler, D.; Boukherroub, R.; Szunerits, S. Label-free femtomolar cancer biomarker detection in human serum using graphene-coated surface plasmon resonance chips. Biosens. Bioelectron. 2016, 89, 606–611. [CrossRef] 44. Omar, N.A.S.; Fen, Y.W.; Abdullah, J.; Sadrolhosseini, A.R.; Kamil, Y.M.; Fauzi, N.I.M.; Hashim, H.S.; Mahdi, M.A. Quantitative and selective surface plasmon resonance response based on a reduced graphene oxide–polyamidoamine nanocomposite for detection of dengue virus E-proteins. Nanomaterials 2020, 10, 569. [CrossRef][PubMed] 45. Nurrohman, D.T.; Chiu, N.-F. Surface Plasmon Resonance Biosensor Performance Analysis on 2D Material Based on Graphene and Transition Metal Dichalcogenides. ECS J. Solid State Sci. Technol. 2020, 9, 115023. [CrossRef] 46. Kushwaha, A.S.; Kumar, A.; Kumar, R.; Srivastava, M.; Srivastava, S.K. Zinc Oxide, Gold and Graphene-Based Surface Plasmon Resonance (SPR) Biosensor for Detection of Pseudomonas Like Bacteria: A Comparative Study; Elsevier GmbH: Amsterdam, The Netherlands, 2018; Volume 172, ISBN 0060006986. 47. Guo, S.; Wu, X.; Li, Z.; Tong, K. High-Sensitivity Biosensor-Based Enhanced SPR by ZnO/MoS2 Nanowires Array Layer with Graphene Oxide Nanosheet. Int. J. Opt. 2020, 2020, 1–6. [CrossRef] 48. Sun, P.; Wang, M.; Liu, L.; Jiao, L.; Du, W.; Xia, F.; Liu, M.; Kong, W.; Dong, L.; Yun, M. Sensitivity enhancement of surface plasmon resonance biosensor based on graphene and barium titanate layers. Appl. Surf. Sci. 2019, 475, 342–347. [CrossRef] 49. Panda, A.; Pukhrambam, P.D.; Keiser, G. Performance analysis of graphene-based surface plasmon resonance biosensor for blood glucose and gas detection. Appl. Phys. A 2020, 126, 153. [CrossRef] 50. Singh, M.; Holzinger, M.; Tabrizian, M.; Winters, S.; Berner, N.C.; Cosnier, S.; Duesberg, G.S. Noncovalently functionalized monolayer graphene for sensitivity enhancement of surface plasmon resonance immunosensors. J. Am. Chem. Soc. 2015, 137, 2800–2803. [CrossRef][PubMed] 51. Chiu, N.F.; Fan, S.Y.; Yang, C.D.; Huang, T.Y. Carboxyl-functionalized graphene oxide composites as SPR biosensors with enhanced sensitivity for immunoaffinity detection. Biosens. Bioelectron. 2017, 89, 370–376. [CrossRef][PubMed] 52. Chiu, N.F.; Kuo, C.T.; Lin, T.L.; Chang, C.C.; Chen, C.Y. Ultra-high sensitivity of the non-immunological affinity of graphene oxide-peptide-based surface plasmon resonance biosensors to detect human chorionic gonadotropin. Biosens. Bioelectron. 2017, 94, 351–357. [CrossRef][PubMed] 53. Chiu, N.F.; Tai, M.J.; Wu, H.P.; Lin, T.L.; Chen, C.Y. Development of a bioaffinity SPR immunosensor based on functionalized graphene oxide for the detection of pregnancy-associated plasma protein A2 in human plasma. Int. J. Nanomed. 2019, 14, 6735–6748. [CrossRef] 54. Chung, K.; Lee, J.S.; Kim, E.; Lee, K.E.; Kim, K.; Lee, J.; Kim, D.; Kim, S.O.; Jeon, S.; Park, H.; et al. Enhancing the Performance of Surface Plasmon Resonance Biosensor via Modulation of Electron Density at the Graphene–Gold Interface. Adv. Mater. Interfaces 2018, 5, 1–8. [CrossRef] 55. Sharma, A.K.; Jha, R.; Gupta, B.D. Fiber-Optic Sensors Based on Surface Plasmon Resonance: A Comprehensive Review. IEEE Sens. J. 2007, 7, 1118–1129. [CrossRef] 56. Gupta, B.D.; Pathak, A.; Semwal, V. Carbon-based nanomaterials for plasmonic sensors: A review. Sensors 2019, 19, 3536. [CrossRef] Nanomaterials 2021, 11, 216 27 of 29

57. Fu, H.; Zhang, S.; Chen, H.; Weng, J. Graphene enhances the sensitivity of fiber-optic surface plasmon resonance biosensor. IEEE Sens. J. 2015, 15, 5478–5482. [CrossRef] 58. Zhou, X.; Li, X.; Cheng, T.L.; Li, S.; An, G. Graphene enhanced optical fiber SPR sensor for liquid concentration measurement. Opt. Fiber Technol. 2018, 43, 62–66. [CrossRef] 59. Li, T.; Zhu, L.; Yang, X.; Lou, X.; Yu, L. A refractive index sensor based on h-shaped photonic crystal fibers coated with ag-graphene layers. Sensors 2020, 20, 741. [CrossRef] 60. Zhu, Z.; Liu, L.; Liu, Z.; Zhang, Y.; Zhang, Y. Surface-plasmon-resonance-based optical-fiber temperature sensor with high sensitivity and high figure of merit. Opt. Lett. 2017, 42, 2948–2951. [CrossRef][PubMed] 61. Huang, Q.; Wang, Y.; Zhu, W.; Lai, T.; Peng, J.; Lyu, D.; Guo, D.; Yuan, Y.; Lewis, E.; Yang, M. Graphene-Gold-Au@Ag NPs-PDMS Films Coated Fiber Optic for Refractive Index and Temperature Sensing. IEEE Photonics Technol. Lett. 2019, 31, 1205–1208. [CrossRef] 62. Wang, Q.; Du, C.; Zhang, J.; Lv, R.; Zhao, Y. Sensitivity-enhanced temperature sensor based on PDMS-coated long period fiber grating. Opt. Commun. 2016, 377, 89–93. [CrossRef] 63. Zhao, Y.; Tong, R.J.; Chen, M.Q.; Xia, F. Fluorescence temperature sensor based on GQDs solution encapsulated in hollow core fiber. IEEE Photonics Technol. Lett. 2017, 29, 1544–1547. [CrossRef] 64. Hu, T.; Zhao, Y.; Song, A. Ning Fiber optic SPR sensor for refractive index and temperature measurement based on MMF-FBG- MMF structure. Sens. Actuators B Chem. 2016, 237, 521–525. [CrossRef] 65. Zhang, N.M.Y.; Li, K.; Shum, P.P.; Yu, X.; Zeng, S.; Wu, Z.; Wang, Q.J.; Yong, K.T.; Wei, L. Hybrid Graphene/Gold Plasmonic Fiber-Optic Biosensor. Adv. Mater. Technol. 2017, 2, 1600185. [CrossRef] 66. Wei, W.; Nong, J.; Zhu, Y.; Zhang, G.; Wang, N.; Luo, S.; Chen, N.; Lan, G.; Chuang, C.J.; Huang, Y. Graphene/Au-Enhanced Plastic Clad Silica Fiber Optic Surface Plasmon Resonance Sensor. Plasmonics 2018, 13, 483–491. [CrossRef] 67. Jiang, S.; Li, Z.; Zhang, C.; Gao, S.; Li, Z.; Qiu, H.; Li, C.; Yang, C.; Liu, M.; Liu, Y. A novel U-bent plastic optical fibre local surface plasmon resonance sensor based on a graphene and silver nanoparticle hybrid structure. J. Phys. D Appl. Phys. 2017, 50, 165105. [CrossRef] 68. Wang, Q.; Wang, B. Sensitivity enhanced SPR immunosensor based on graphene oxide and SPA co-modified photonic crystal fiber. Opt. Laser Technol. 2018, 107, 210–215. [CrossRef] 69. Yu, H.; Chong, Y.; Zhang, P.; Ma, J.; Li, D. A D-shaped fiber SPR sensor with a composite nanostructure of MoS2-graphene for glucose detection. Talanta 2020, 219, 121324. [CrossRef] 70. Homola, J. Springer Series on Chemical Sensors and Biosensors 4. In Surface Plasmon Resonance Based Sensors; Springer: Berlin/Heidelberg, Germany, 2006. 71. Islam, M.S.; Kouzani, A.Z. Variable incidence angle subwavelegth grating SPR graphene biosensor. In Proceedings of the 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Osaka, Japan, 3–7 July 2013; pp. 3024–3027. [CrossRef] 72. Lin, C.-Y.; Chien, F.-C.; Yu, L.-Y.; Chang, C.-W.; Chiu, K.-C.; Chen, S.-J. Surface plasmon resonance biosensors with subwavelength grating waveguide. Plasmon. Biol. Med. IV 2007, 6450, 64500L. [CrossRef] 73. Prabowo, B.A.; Purwidyantri, A.; Liu, K.C. Surface plasmon resonance optical sensor: A review on light source technology. Biosensors 2018, 8, 80. [CrossRef][PubMed] 74. Sadeghi, Z.; Shirkani, H. Highly sensitive mid-infrared SPR biosensor for a wide range of biomolecules and biological cells based on graphene-gold grating. Phys. E Low-Dimens. Syst. Nanostruct. 2020, 119, 114005. [CrossRef] 75. Sadeghi, Z.; Shirkani, H. High-Performance Label-Free Near-Infrared SPR Sensor for Wide Range of Gases and Biomolecules Based on Graphene-Gold Grating. Plasmonics 2019, 14, 1179–1188. [CrossRef] 76. Law, S.; Yu, L.; Rosenberg, A.; Wasserman, D. All-semiconductor plasmonic nanoantennas for infrared sensing. Nano Lett. 2013, 13, 4569–4574. [CrossRef][PubMed] 77. Wei, W.; Nong, J.; Tang, L.; Zhang, G.; Yang, J.; Luo, W. Conformal graphene-decorated nanofluidic sensors based on surface plasmons at infrared frequencies. Sensors 2016, 16, 899. [CrossRef][PubMed] 78. Lu, H.; Zeng, C.; Zhang, Q.; Liu, X.; Hossain, M.M.; Reineck, P.; Gu, M. Graphene-based active slow surface plasmon polaritons. Sci. Rep. 2015, 5.[CrossRef] 79. Reckinger, N.; Vlad, A.; Melinte, S.; Colomer, J.F.; Sarrazin, M. Graphene-coated holey metal films: Tunable molecular sensing by surface plasmon resonance. Appl. Phys. Lett. 2013, 102, 1–5. [CrossRef] 80. Wei, W.; Nong, J.; Zhang, G.; Tang, L.; Jiang, X.; Chen, N.; Luo, S.; Lan, G.; Zhu, Y. Graphene-based long-period fiber grating surface plasmon resonance sensor for high-sensitivity gas sensing. Sensors 2017, 17, 2. [CrossRef] 81. Kong, L.; Lv, J.; Gu, Q.; Ying, Y.; Jiang, X.; Si, G. Sensitivity-enhanced spr sensor based on graphene and subwavelength silver gratings. Nanomaterials 2020, 10, 2125. [CrossRef] 82. Chen, N.; Chang, M.; Lu, X.; Zhou, J.; Zhang, X. Numerical analysis of midinfrared D-shaped photonic-crystal-fiber sensor based on surface-plasmon-resonance effect for environmental monitoring. Appl. Sci. 2020, 10, 3897. [CrossRef] 83. Singla, S.; Singal, P. Photonic Crystal Fiber: Construction, Properties, Developments and Applications. Int. J. Electron. Eng. 2017, 9, 1–8. 84. Zhang, H.; Song, D.; Gao, S.; Zhang, J.; Zhang, H.; Sun, Y. Novel SPR biosensors based on metal nanoparticles decorated with graphene for immunoassay. Sens. Actuators B Chem. 2013, 188, 548–554. [CrossRef] Nanomaterials 2021, 11, 216 28 of 29

85. Chiu, N.-F.; Chen, C.-C.; Yang, C.-D.; Kao, Y.-S.; Wu, W.-R. Enhanced Plasmonic Biosensors of Hybrid Gold Nanoparticle- Graphene Oxide-Based Label-Free Immunoassay. Nanoscale Res. Lett. 2018, 13, 152. [CrossRef][PubMed] 86. Cittadini, M.; Bersani, M.; Perrozzi, F.; Ottaviano, L.; Wlodarski, W.; Martucci, A. Graphene oxide coupled with gold nanoparticles for localized surface plasmon resonance based gas sensor. Carbon 2014, 69, 452–459. [CrossRef] 87. Li, Q.; Wang, Q.; Yang, X.; Wang, K.; Zhang, H.; Nie, W. High sensitivity surface plasmon resonance biosensor for detection of microRNA and small molecule based on graphene oxide-gold nanoparticles composites. Talanta 2017, 174, 521–526. [CrossRef] [PubMed] 88. Zagorodko, O.; Spadavecchia, J.; Serrano, A.Y.; Larroulet, I.; Pesquera, A.; Zurutuza, A.; Boukherroub, R.; Szunerits, S. Highly sensitive detection of dna hybridization on commercialized graphene-coated surface plasmon resonance interfaces. Anal. Chem. 2014, 86, 11211–11216. [CrossRef] 89. Singh, L.; Singh, R.; Zhang, B.; Cheng, S.; Kumar Kaushik, B.; Kumar, S. LSPR based uric acid sensor using graphene oxide and gold nanoparticles functionalized tapered fiber. Opt. Fiber Technol. 2019, 53, 102043. [CrossRef] 90. Lakowicz, J.R.; Malicka, J.; Gryczynski, I.; Gryczynski, Z. Directional surface plasmon-coupled emission: A new method for high sensitivity detection. Biochem. Biophys. Res. Commun. 2003, 307, 435–439. [CrossRef] 91. Cao, S.-H.; Cai, W.-P.; Liu, Q.; Li, Y.-Q. Surface Plasmon–Coupled Emission: What Can Directional Fluorescence Bring to the Analytical Sciences? Annu. Rev. Anal. Chem. 2012, 5, 317–336. [CrossRef] 92. Sadrolhosseini, A.R.; Shafie, S.; Fen, Y.W. Nanoplasmonic sensor based on surface plasmon-coupled emission: Review. Appl. Sci. 2019, 9, 1497. [CrossRef] 93. Gryczynski, Z.; Gryczynski, I.; Matveeva, E.; Malicka, J.; Nowaczyk, K.; Lakowicz, J.R. Surface-plasmon-coupled emission: New technology for studying molecular processes. Methods Cell Biol. 2004, 2004, 73–104. [CrossRef] 94. Mulpur, P.; Podila, R.; Lingam, K.; Vemula, S.K.; Ramamurthy, S.S.; Kamisetti, V.; Rao, A.M. Amplification of Surface Plasmon Coupled Emission from Graphene–Ag Hybrid Films. J. Phys. Chem. C 2013, 117, 17205–17210. [CrossRef] 95. Xie, K.X.; Xu, L.T.; Zhai, Y.Y.; Wang, Z.C.; Chen, M.; Pan, X.H.; Cao, S.H.; Li, Y.Q. The synergistic enhancement of silver nanocubes and graphene oxide on surface plasmon-coupled emission. Talanta 2019, 195, 752–756. [CrossRef][PubMed] 96. Xie, K.X.; Cao, S.H.; Wang, Z.C.; Weng, Y.H.; Huo, S.X.; Zhai, Y.Y.; Chen, M.; Pan, X.H.; Li, Y.Q. Graphene oxide-assisted surface plasmon coupled emission for amplified fluorescence immunoassay. Sens. Actuators B Chem. 2017, 253, 804–808. [CrossRef] 97. Badiya, P.K.; Srinivasan, V.; Ramamurthy, S.S. Silver-graphene oxide based plasmonic spacer for surface plasmon-coupled fluorescence emission enhancements. Mater. Res. Express 2017, 4.[CrossRef] 98. Masnad, M.M.; Mominuzzaman, S.M. Graphene-MoS2 spacer on metal-insulator-metal structure for enhanced surface plasmon coupled emission. AIP Adv. 2018, 8.[CrossRef] 99. Yuen, C.; Zheng, W.; Huang, Z. Surface-enhanced raman scattering: Principles, nanostructures, fabrications, and biomedical applications. J. Innov. Opt. Health Sci. 2008, 1, 267–284. [CrossRef] 100. Chisanga, M.; Muhamadali, H.; Ellis, D.I.; Goodacre, R. Surface-Enhanced Raman Scattering (SERS) in Microbiology: Illumination and Enhancement of the Microbial World. Appl. Spectrosc. 2018, 72, 987–1000. [CrossRef] 101. Boujday, S.; Chapelle, M.; Srajer, J.; Knoll, W. Enhanced Vibrational Spectroscopies as Tools for Small Molecule Biosensing. Sensors 2015, 15, 21239–21264. [CrossRef] 102. Sole, M.; Agostinelli, I.; Karimian, N.; Ugo, P.; Misericordia, M. Ag-Nanostars for the Sensitive SERS Detection of Dyes in Artistic Cross-Sections—Madonna della Misericordia of the National Gallery of Parma: A Case Study. Heritage 2020, 3, 1344–1359. 103. Fleischmann, M.; Hendra, P.J.; McQuillan, A.J. Raman spectra of pyridine adsorbed at a silver electrode. Chem. Phys. Lett. 1974, 26, 163–166. [CrossRef] 104. Mungroo, N.; Neethirajan, S. Biosensors for the Detection of Antibiotics in Poultry Industry—A Review. Biosensors 2014, 4, 472–493. [CrossRef][PubMed] 105. Kim, J.; Jang, Y.; Kim, N.J.; Kim, H.; Yi, G.C.; Shin, Y.; Kim, M.H.; Yoon, S. Study of Chemical Enhancement Mechanism in Non-plasmonic Surface Enhanced Raman Spectroscopy (SERS). Front. Chem. 2019, 7, 1–7. [CrossRef] 106. Lee, D.J.; Kim, D.Y. Hydrophobic paper-based SERS sensor using gold nanoparticles arranged on graphene oxide flakes. Sensors 2019, 19, 5471. [CrossRef] 107. Zheng, J.; He, L. Surface-Enhanced Raman Spectroscopy for the Chemical Analysis of Food. Compr. Rev. Food Sci. Food Saf. 2014, 13, 317–328. [CrossRef] 108. Dalfovo, M.C.; Lacconi, G.I.; Moreno, M.; Yappert, M.C.; Sumanasekera, G.U.; Salvarezza, R.C.; Ibañez, F.J. Synergy between graphene and au nanoparticles (heterojunction) towards quenching, improving raman signal, and UV light sensing. ACS Appl. Mater. Interfaces 2014, 6, 6384–6391. [CrossRef] 109. Xie, L.; Ling, X.; Fang, Y.; Zhang, J.; Liu, Z. Graphene as a substrate to suppress fluorescence in resonance raman spectroscopy. J. Am. Chem. Soc. 2009, 131, 9890–9891. [CrossRef] 110. Ling, X.; Xie, L.; Fang, Y.; Xu, H.; Zhang, H.; Kong, J.; Dresselhaus, M.S.; Zhang, J.; Liu, Z. Can graphene be used as a substrate for Raman enhancement? Nano Lett. 2010, 10, 553–561. [CrossRef] 111. Xu, W.; Mao, N.; Zhang, J. Graphene: A platform for surface-enhanced Raman spectroscopy. Small 2013, 9, 1206–1224. [CrossRef] 112. Lai, H.; Xu, F.; Zhang, Y.; Wang, L. Recent progress on graphene-based substrates for surface-enhanced Raman scattering applications. J. Mater. Chem. B 2018, 6, 4008–4028. [CrossRef][PubMed] Nanomaterials 2021, 11, 216 29 of 29

113. Lin, T.W.; Wu, H.Y.; Tasi, T.T.; Lai, Y.H.; Shen, H.H. Surface-enhanced Raman spectroscopy for DNA detection by the self-assembly of Ag nanoparticles onto Ag nanoparticle-graphene oxide nanocomposites. Phys. Chem. Chem. Phys. 2015, 17, 18443–18448. [CrossRef][PubMed] 114. Wang, Z.; Wu, S.; Colombi Ciacchi, L.; Wei, G. Graphene-based nanoplatforms for surface-enhanced Raman scattering sensing. Analyst 2018, 143, 5074–5089. [CrossRef][PubMed] 115. Neri, G.; Fazio, E.; Mineo, P.G.; Scala, A.; Piperno, A. SERS sensing properties of new graphene/gold nanocomposite. Nanomateri- als 2019, 9, 1236. [CrossRef][PubMed] 116. Huang, J.; Zhang, L.; Chen, B.; Ji, N.; Chen, F.; Zhang, Y.; Zhang, Z. Nanocomposites of size-controlled gold nanoparticles and graphene oxide: Formation and applications in SERS and catalysis. Nanoscale 2010, 2, 2733–2738. [CrossRef][PubMed] 117. Kim, N.; Oh, M.K.; Park, S.; Kim, S.K.; Hong, B.H. Effect of gold substrates on the raman spectra of graphene. Bull. Korean Chem. Soc. 2010, 31, 999–1003. [CrossRef] 118. Zhu, X.; Shi, L.; Schmidt, M.S.; Boisen, A.; Hansen, O.; Zi, J.; Xiao, S.; Mortensen, N.A. Enhanced light-matter interactions in graphene-covered gold nanovoid arrays. Nano Lett. 2013, 13, 4690–4696. [CrossRef][PubMed] 119. Tao, G.Q.; Wang, J. Gold nanorod@nanoparticle seed-SERSnanotags/graphene oxide plasmonic superstructured nanocomposities as an “on-off” SERS aptasensor. Carbon 2018, 133, 209–217. [CrossRef] 120. Manikandan, M.; Nasser Abdelhamid, H.; Talib, A.; Wu, H.F. Facile synthesis of gold nanohexagons on graphene templates in Raman spectroscopy for biosensing cancer and cancer stem cells. Biosens. Bioelectron. 2014, 55, 180–186. [CrossRef] 121. He, S.; Liu, K.K.; Su, S.; Yan, J.; Mao, X.; Wang, D.; He, Y.; Li, L.J.; Song, S.; Fan, C. Graphene-based high-efficiency surface- enhanced Raman scattering-active platform for sensitive and multiplex DNA detection. Anal. Chem. 2012, 84, 4622–4627. [CrossRef][PubMed] 122. Ding, X.; Kong, L.; Wang, J.; Fang, F.; Li, D.; Liu, J. Highly sensitive SERS detection of Hg2+ ions in aqueous media using gold nanoparticles/graphene heterojunctions. ACS Appl. Mater. Interfaces 2013, 5, 7072–7078. [CrossRef][PubMed] 123. Benítez-Martínez, S.; López-Lorente, Á.I.; Valcárcel, M. Multilayer graphene-gold nanoparticle hybrid substrate for the SERS determination of metronidazole. Microchem. J. 2015, 121, 6–13. [CrossRef] 124. Li, Y.; Dykes, J.; Gilliam, T.; Chopra, N. A new heterostructured SERS substrate: Free-standing silicon nanowires decorated with graphene-encapsulated gold nanoparticles. Nanoscale 2017, 9, 5263–5272. [CrossRef][PubMed] 125. Jiang, Y.; Wang, J.; Malfatti, L.; Carboni, D.; Senes, N.; Innocenzi, P. Highly durable graphene-mediated surface enhanced Raman scattering (G-SERS) nanocomposites for molecular detection. Appl. Surf. Sci. 2018, 450, 451–460. [CrossRef] 126. Liang, X.; Liang, B.; Pan, Z.; Lang, X.; Zhang, Y.; Wang, G.; Yin, P.; Guo, L. Tuning plasmonic and chemical enhancement for SERS detection on graphene-based Au hybrids. Nanoscale 2015, 7, 20188–20196. [CrossRef][PubMed] 127. Wang, P.; Liang, O.; Zhang, W.; Schroeder, T.; Xie, Y.H. Ultra-sensitive graphene-plasmonic hybrid platform for label-free detection. Adv. Mater. 2013, 25, 4918–4924. [CrossRef][PubMed] 128. Hussein, M.A.; El-Said, W.A.; Abu-Zied, B.M.; Choi, J.W. Nanosheet composed of gold nanoparticle/graphene/epoxy resin based on ultrasonic fabrication for flexible dopamine biosensor using surface-enhanced Raman spectroscopy. Nano Converg. 2020, 7. [CrossRef] 129. Saleh, T.A.; Al-Shalalfeh, M.M.; Al-Saadi, A.A. Graphene Dendrimer-stabilized silver nanoparticles for detection of methimazole using Surface-enhanced Raman scattering with computational assignment. Sci. Rep. 2016, 6.[CrossRef]