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