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[Masanobu Iwanaga](https://orcid.org/0000-0002-8930-6940), [Qi Hu](https://orcid.org/0000-0003-4315-6665), [Youhong Tang](https://orcid.org/0000-0003-2718-544X)

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[Metasurface biosensors: Status and prospects](https://mdr.nims.go.jp/datasets/cd5a5931-931e-4d5d-99a0-0a890c94f976)

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Metasurface biosensors: Status and prospectsViewOnlineExportCitationREVIEW ARTICLE |  APRIL 04 2025Metasurface biosensors: Status and prospectsMasanobu Iwanaga   ; Qi Hu  ; Youhong Tang Appl. Phys. Rev. 12, 021305 (2025)https://doi.org/10.1063/5.0253333 04 April 2025 13:16:06https://pubs.aip.org/aip/apr/article/12/2/021305/3342510/Metasurface-biosensors-Status-and-prospectshttps://pubs.aip.org/aip/apr/article/12/2/021305/3342510/Metasurface-biosensors-Status-and-prospects?pdfCoverIconEvent=citejavascript:;https://orcid.org/0000-0002-8930-6940javascript:;https://orcid.org/0000-0003-4315-6665javascript:;https://orcid.org/0000-0003-2718-544Xhttps://crossmark.crossref.org/dialog/?doi=10.1063/5.0253333&domain=pdf&date_stamp=2025-04-04https://doi.org/10.1063/5.0253333https://e-11492.adzerk.net/r?e=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&s=hXZVRw-2ZD-aDgyxsYbphi1pf2AMetasurface biosensors: Status and prospectsCite as: Appl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333Submitted: 16 December 2024 . Accepted: 25 February 2025 .Published Online: 4 April 2025Masanobu Iwanaga,1,a) Qi Hu,2 and Youhong Tang2AFFILIATIONS1Research Centre for Electronic and Optical Materials, National Institute for Materials Science (NIMS), 1-1 Namiki,Tsukuba 305-0044, Japan2Institute for NanoScale Science and Technology, Flinders University, Bedford Park, South Australia 5042, Australiaa)Author to whom correspondence should be addressed: iwanaga.masanobu@nims.go.jpABSTRACTMetasurfaces have emerged as a rapidly evolving frontier in the fields of optics and photonics, with a growing emphasis on their potential forpractical applications. The considerable volume of contributions to the study on metasurfaces has expanded, creating challenges in trackingall the advancements within this dynamic field. In this review, we select practically useful metasurfaces among the diverse metasurfacesstudied so far. We refer to the selected hot research topics in metasurfaces at the beginning, succeedingly outline the status of severalapplications that are nearing practical applications, and then focus on biosensing applications, with particular attention to metasurfacefluorescence (FL) biosensors, because FL detection is a major approach in bioscience and biotechnology. However, the contributions to FLdetection by metasurface biosensors have not been reviewed in an extensive and comprehensive manner. Indeed, the metasurface FLbiosensors have demonstrated capability of detecting a wide range of biomolecules including nucleic acids and proteins, such as antigens andantibodies. Notably, they offer enhanced sensitivity assays and reduced assay time when compared to conventional commercial assays. Wehere provide a focused review on the current status and future directions of metasurface biosensors.VC 2025 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND) license (https://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1063/5.0253333TABLE OF CONTENTSI. INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1II. METASURFACES FOR VARIOUS APPLICATIONS . . . 4A. Light-wave manipulation . . . . . . . . . . . . . . . . . . . . . . 4B. Metalens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5C. IR absorbers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5D. IR emitters/detectors. . . . . . . . . . . . . . . . . . . . . . . . . . 6E. Biosensing techniques . . . . . . . . . . . . . . . . . . . . . . . . . 71. SERS—Surface-enhanced Raman scattering . . . 82. SPR—Surface plasmon resonance . . . . . . . . . . . 93. Mie resonance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94. BIC—Bound states in the continuum . . . . . . . . 95. SEIRA—Surface-enhanced infrared absorption 96. ELISA—Enzyme-linked immunosorbent assay 107. PCR—Polymerase chain reaction . . . . . . . . . . . . 108. Digital PCR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109. Electrochemical sensor . . . . . . . . . . . . . . . . . . . . . 1010. Metasurface FL biosensor . . . . . . . . . . . . . . . . . 1111. Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11III. METASURFACE FL BIOSENSORS . . . . . . . . . . . . . . . . . 11A. Outstanding FL enhancement . . . . . . . . . . . . . . . . . . 11B. Principle of FL enhancement. . . . . . . . . . . . . . . . . . . 13C. Detections with metasurface FL biosensors . . . . . . 14D. AIE—Aggregation-induced emission . . . . . . . . . . . . 17IV. FUTURE PROSPECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18I. INTRODUCTIONMetasurfaces are attracting great interest as a cutting-edge opticaland photonic technology and developing for various applications. Thepresent growing metasurface research and development (R&D) originin unconventional reflection using metallic metasurface with a compli-cated unit cell consisting of a set of different V-shaped structures.1 Theterm “metasurfaces” is presumably derived from metamaterials—aresearch field that has been the subject of extensive investigation fornearly 20 years, dating back to 1999.2–4 The conceptual framework ofmetasurfaces represents a significant departure from that of metamate-rials. To realize optical functions, complicated unit cells and nonperi-odic structures have been conceived and designed in metasurfaces,whereas metamaterials were characterized as uniformization of micro-structured/nanostructured materials using effective optical indices,such as effective permittivity and permeability. Historically, the termAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-1VC Author(s) 2025Applied Physics Reviews REVIEW pubs.aip.org/aip/are 04 April 2025 13:16:06https://doi.org/10.1063/5.0253333https://doi.org/10.1063/5.0253333https://www.pubs.aip.org/action/showCitFormats?type=show&doi=10.1063/5.0253333http://crossmark.crossref.org/dialog/?doi=10.1063/5.0253333&domain=pdf&date_stamp=2025-04-04https://orcid.org/0000-0002-8930-6940https://orcid.org/0000-0003-4315-6665https://orcid.org/0000-0003-2718-544Xmailto:iwanaga.masanobu@nims.go.jphttps://creativecommons.org/licenses/by-nc-nd/4.0/https://doi.org/10.1063/5.0253333pubs.aip.org/aip/are“metasurfaces” already appeared in 2004,5 yet its conceptualizationwas closely tied to that of metamaterials and did not catalyze diverseR&D across a wide range of optical and photonic applications.Contemporary R&D exploiting metasurfaces are being globallyconducted with huge efforts. Figure 1 presents representative metasur-faces that have been experimentally validated, showcasing their poten-tial for practical applications, such as light wave manipulation,1metalenses,6–8 infrared (IR) absorbers,9 emitters,10 and biosensors.11,12Prior to delving into the specific applications shown in Fig. 1, weaddress underlying key physics involved in metasurface studies. First,plasmonic and dielectric nanostructures were individually investigatedand found to exhibit pronounced optical resonances, termed Mie reso-nances.13 Around the year 2000, noble metal nanoparticles were syn-thesized chemically in various shapes, such as spheres, triangles, androds, and characterized as Mie resonators, owing to their strong lightscattering attributed to intrinsic optical resonances.14–16 In addition,dielectric nanostructures were are shown to function as electric dipole(ED) and magnetic dipole (MD) resonators, with theoretical analysesfor ideal spherical shapes.17 The analyses approximately account forthe prominent resonances observed in various configurations of dielec-tric nanostructures.18,19 Second, the concept of bound states in thecontinuum (BIC) in photonics was reported on a light-confined modewithin a photonic crystal in 2013.20 The photonic BIC modes arehidden in symmetric configurations, becoming observable only whenasymmetry is introduced. For example, by introducing structuralasymmetry in unit cell, the BIC modes can be observed even undernormal incidence that is a symmetric configuration regarding opticalexcitation. This property stimulated extensive studies on BIC in meta-surfaces,21–28 which pursued narrow linewidth resonant modes ofhigh-quality (Q) factors.Rapid progress in metasurfaces is based on high-precisionnumerical simulations and contemporary nanolithography. Regardingthe numerical simulations, finite-difference time-domain (FDTD)29–31finite element method (FEM)32 and rigorous coupled-wave analysis(RCWA) method33–35 are widely employed to design and evaluateoptical properties of metasurfaces. They were already established bynumerous publications on photonic crystals, metamaterials, and meta-surfaces, which showed good agreement of the simulated results withexperimentally measured results. In addition to independent develop-ment of the source codes for the numerical simulations, commercialFDTD, FEM, and RCWA packages are available, enabling manyresearchers to easily join the metasurface studies.Let us briefly describe several topics on metasurfaces that exhib-ited substantial progresses since the 2010s. Initially, the topic of raycontrol emerged, introducing the design and fabrication of a metasur-face of elaborate unit cell in 2011,1 as shown in Fig. 1(a) (yellow); theFIG. 1. Collection of representative metasurfaces for various applications. (a) Metasurface composed of a V-shaped unit cell (yellow).1 (b) 1D metalens working at telecommunica-tion wavelengths.6 (c) Metalens with nearly unity numerical aperture:7 low- and high-magnification scanning electron microscopy (SEM) images (upper and lower) with scale barsof 10lm and 500 nm, respectively. (d) Mass productive metalenses:8 Photograph of 2 cm diameter metalenses (upper) and SEM image with scale bar of 2lm, magnifying the cen-ter of the metalens (lower). (e) IR absorber:9 Design (upper) and SEM image of a fabricated sample (lower), where two different types are shown with blue and red. (f)Experimental absorptance (red) and emittance (blue) by the IR absorber.9 (g) Photograph of a packaged IR emitter.10 Scale bar indicates 5mm. (h) Metasurface fluorescence (FL)biosensors.11 (i) FL images of the metasurface biosensors employed in single cfDNA sensing.12 Target DNA numbers per test are shown together. (a) From Yu et al., Science 334,333 (2011). Reprinted with permission from American Association for the Advancement of Science (AAAS). (b) Adapted with permission from Khorasaninejad et al., Nano Lett. 15,5358 (2015). Copyright 2015 American Chemical Society (ACS). (c) Adapted with permission from Paniagua-Domínguez et al., Nano Lett. 18, 2124 (2018). Copyright 2018 ACS.(d) Adapted from She et al., Opt. Express 26, 1573 (2018). (e,f) Reproduced from [Miyazaki et al., Appl. Phys. Lett. 105, 121107 (2014)] with the permission of AIP Publishing. (g)Adapted from Miyazaki et al., Sci. Technol. Adv. Mater. 16, 035005 (2015); licensed under a Creative Commons Attribution (CC BY) license. (h) Adapted from Iwanaga, Biosensors13, 377 (2023); licensed under a CC BY license. (i) Adapted with permission from Iwanaga et al., Nano Lett. 23, 5755 (2023). Copyright 2023 ACS.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-2VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/areperiodicity in the horizontal was 11lm and the working wavelengthwas 8lm; the Au microstructures of 220nm width and 50nm heightwere fabricated on a Si wafer. The primary aim was to manipulatewavefront of refracted light through the design of subwavelength V-shaped structures, which reinforced a particular refraction componentdue to wavefront interference and traveled along one of the allowedreflective diffraction directions. This study strikingly stimulated manystudies on ray and wavefront control.36,37 As an extension of this study,phase and/or polarization control was also explored in various configu-rations for the visible and near infrared (IR) light,38,39 which were oftennonperiodic and non-uniform nanostructures, similar to the meta-lenses in Figs. 1(b) and 1(c).Furthermore, as a natural progression of the ray and wavefrontcontrol concepts, focus effects were examined through both numericalsimulations and experimental validations. The studies yielded metal-enses, sometime called flat lenses.6–8,36,40–46 Most of metalenses weredesigned at the height of sub micrometer, and the height was the samein each metalens. Thus, from a macroscopic view, the metalenses arecharacterized by their flat geometry. The principle for the focusingeffect is in common with conventional convex or concave opticallenses, made of glass or quartz. The key difference is that the ray isbent in the metasurface layer of subwavelength thickness, owing to theprecise alternation of the phase of light. Further improved designs ledexperimental demonstrations of achromatic or multiwavelength metal-enses.8,36,40–42,46Metalenses composed of subwavelength structures enable theintegration of multifunctional units. Indeed, this capability wasexploited to design color splitters,47–49 which effectively focus the indi-vidual red, green, and blue (RGB) components of light onto separatepixels. This advancement is beneficial to produce ultracompact CMOScameras, which will be found in smart phones and tablets soon. Theseoptical functions of metalenses are elaborated later (Sec. II). Althoughthe designs of the color splitters are more complex than those of metal-enses, the fundamental principle for design is in common with themetalenses, which means that the color splitters belong to a family ofmetalenses.Metagratings were also conceived along the concept of metasur-face.50–55 Conducting elaborate designs using computers enabled toobtain nearly 100% diffraction efficiency. The large degree of freedomin the structural designs yielded a diverse range of diffractionresponses. Historically, a similar notion to the metagratings wasreported in 1998,56 where a subwavelength grating was designed andfabricated to obtain superior diffraction efficiency compared to con-ventional �echlette gratings. The control of phase of refracted light wasanalyzed at the time. More elaborate and extensive designs for meta-gratings have significantly enriched the capabilities of subwavelengthgratings.Holography is a well-established optical technique that modulatesboth the amplitude and phase of light beam. Since metasurfaces cancontrol the amplitude and phase with large degree of freedom, meta-surfaces are suitable for holographic applications. Indeed, severalreports experimentally showed fine holographic images using plas-monic or all-dielectric metasurfaces.57–60 The designs of holographicmetasurfaces are also elaborate tasks; however, it is implementablewith help of current computational tools on personal computers.Nonlinear effects on metasurfaces have been also extensivelyexplored. There are two main directions: Lasing61–63 and higher-orderharmonic generation, specifically, second-order harmonic generation(SHG) and third-order harmonic generation (THG).64–69 The studieson lasing effect primarily focused on developing ultralow-thresholdlasing devices on BIC, which is a high-Q resonance and is consideredto make the lasing threshold lower. In reality, a low lasing threshold at55l W was observed under optical pumping.61 Regarding the higherharmonics generations, improvement of the conversion efficiency wasexpected. Such an improvement has been tested frequently using plas-monic nanostructures (i.e., metallic nanostructures) from the view-point of local electric-field enhancement; the highest SHG conversionefficiency of plasmonic systems was reported to be 7:5� 10�2% at amid-IR range.66 However, in 2016 and 2017, more efficient SHGs weredeveloped by exploiting dielectric nanostructures, which are Mie nano-resonators;70–72 the dielectric was AlGaAs, which enables lower opticalloss and a higher pumping threshold than the metallic nanostructuresmade of Au or Ag. Although optical metasurfaces optimized for SHGand THG remain unreported, the potential for designing such nonlin-ear metasurfaces is promising, based on efficient dielectric nanoresona-tors.70–73Very thin, artificially engineered structures with subwavelengththickness were found to function as perfect light absorbers,74–78 whenthey were designed incorporating light-harvesting metallic micro/nanostructures. The light absorption was attributed to plasmon-associated resonances. This principle has been adapted to the IR rangethrough the fabrication of elongated periodic structures and was vali-dated experimentally.79–81 Recently, all-dielectric metasurfaces werereported to act as effective light absorbers,82 in which Mie resonancesare origin of the light absorption.Furthermore, IR emitters were designed based on plasmonic reso-nators that comprised metal-insulator-metal (MIM) structures,9 asdepicted in the upper panel of Fig. 1(e). In this configuration, electro-magnetic (EM) fields can be resonantly confined within the narrowinsulating layer, which was confirmed conducting simulations and wasshown to be underlying mechanism of the efficient light absorp-tion.79,80 Au or Ag was chosen the metallic component because theyare good conductors and approximately behave as Drude metals in theIR range. The insulator was chosen from transparent dielectrics, suchas Al2O3 or SiO2. The MIM-based metasurface was fabricated throughelectron-beam (EB) lithography; a scanning-electron-microscopy(SEM) image is shown in the lower panel of Fig. 1(e), where blue andred are pseudocolors used to make the two types of MIM structuresclear to the eye.9 The MIM-based metasurface was optimized for tworesonances at k1 and k2 in the mid-IR range, as shown in Fig. 1(f). Thetwo resonant wavelengths correspond to the IR absorption of CO2 gasand a reference.Owing to reciprocity,83,84 light absorptance is equivalent to emit-tance. Therefore, perfect light absorbers at a wavelength can workas optimal emitters at the same wavelength. The reciprocal relationwas experimentally substantiated by fabricating membrane struc-tures that kept sufficient thermal insulation.10 Fig. 1(g) shows apackaged IR emitter that integrates the mm2-dimension metasurfacein Fig. 1(e) and is powered by dry cell batteries;10 the scale barindicates 5mm.The development of IR detectors has long history.85,86Metasurfaces engineered for large IR absorption have been fabricated,demonstrating high-frequency responsiveness and wavelength-selectivedetection,87–89 which are elaborated in more details later (Sec. II).Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-3VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/areBiosensors encompass a diverse range of devices sensing smallmolecules in environment to those sensing large biomolecules, such asDNA and antigen/antibody. Actually, many methodologies set theirgoals to biosensing. We here provide a concise overview of metasurfacebiosensors among various biosensing techniques, which are elaboratedlater (Sec. II). Metasurfaces often exhibit prominent optical resonances,some of which have been applied to the resonance-shift sensing of bio-molecules.90,91 Metasurface resonances at an IR range have been applyto molecular sensing to measure light absorption using a series of nar-row linewidth resonances.92 These types of metasurface sensors havebeen reviewed previously.93–95 In contrast, to the best of our knowl-edge, metasurface fluorescence (FL) biosensors have not been reviewedso far. As is widely known, FL sensing for biomolecules is a major tech-nique in the fields of bioscience and biotechnology,96 because it enablesto ensure specific detection of targets and to detect extremely weak sig-nals, thanks to the development of FL-probes for biomolecules and ofFL-detection methods, such as photon counting.Complicated structures for metasurfaces stimulated motives todesign novel functional nanostructures. Many trials have beenreported to date, using searching methods of inverse designs,97–100topological optimization,101–104 and generative algorithm.105,106 Inaddition to these approaches, nonempirical structural search canexplore the possibility to find functional metasurfaces.107–109 Thereports for design procedures has been already numerous and severalreviews were published.110–114In this review, we survey various metasurfaces developing towardpractical applications in Sec. II: Light-wave manipulations in Sec. IIA,metalenses in Sec. II B, IR absorbers in Sec. IIC, IR emitters/detectorsin Sec. IID, and biosensors in Sec. II E. Our primarily focus is on bio-sensor applications highlighted in Sec. III, with particular emphasis onthe FL-enhancing biosensors that ensure target-specific detections,favored in contemporary biotechnology. The basic characteristics andadvantages of metasurface FL biosensors are described in detail.Thereafter, the future prospects are addressed in Sec. IV.II. METASURFACES FOR VARIOUS APPLICATIONSPractical potential of metasurfaces are mainly two directions: (1)realization of compact optical devices and (2) highly functional opti-cal/photonic devices. For example, the former (1) is expected to realizeultrathin lenses of sub micrometer thickness, which are now known asmetalens. Although the focusing function is similar to the conventionaldiffraction-limited lenses, the thickness of metalenses is more than1000-time thinner than that of the conventional achromatic lenses,which enables to compact assemble/integration of optical devices andto lead tiny cameras as one of the applications. The latter (2) isexpected to go beyond the performance of conventional devices. Forexample, various biosensors are now commercially used; however, thecapability is almost the same for more than ten years and has notreached the ultimate level, such as one molecule detection discriminat-ing from zero molecule. Furthermore, the current high-precision bio-sensing techniques, called digital methods, are demanding in cost andhave not been used in daily medical tests. Highly FL enhancing meta-surfaces are expected to contribute to FL-detection biosensing in morepractical manners.The good candidates of metasurfaces for applications are pre-sented in Fig. 1, being briefly described above. This section aims not tomentions the diverse research topics but to provide descriptions forpractical metasurface applications in more details than Sec. I. Thefollowings are addressed: Light-wave manipulation (Sec. II A), metal-ens (Sec. II B), IR absorbers (Sec. IIC), IR emitters/detectors (Sec.IID), and biosensing techniques (Sec. II E) in comparison with theexisting ones to understand the status of biosensors from a wide pointof view.A. Light-wave manipulationWavefront control employing a metasurface composed of a seriesof Au V-shaped microstructures1 is visualized in Fig. 2(a). Each Aumicrostructure was assumed to be fabricated on a Si wafer and numer-ically designed to change the phase of a reflective component. Gradualchanges in the shapes correspond to the changes of the phase. By stra-tegically arranging the set of the V-shaped microstructures includingthe bars that look I shapes, the phase is able to be modulated from 0 to7p/4 in Fig. 2(a). Forming a periodic structure with the unit, therefraction beam in one of the reflective directions is reinforced due tothe interference, manifesting itself. This is the basic mechanism of theanomalous refraction induced by the metasurface.1 The exampleFIG. 2. Wavefront control, focusing, and color splitting by metasurfaces. (a)Wavefront modification by the V-shaped unit.1 (b) Diffraction-limited focusing by ametalens:7 focus image (left) and measured focal point under the diffraction limit(right). (c) Color splitting of white light into red, green, and blue (RGB) compo-nents.48 Upper inset: SEM image of the GaN metasurface. Lower inset: measuredRGB-separated focal points. (a) From Yu et al., Science 334, 333 (2011). Reprintedwith permission from AAAS. (b) Adapted with permission from Paniagua-Domínguez et al., Nano Lett. 18, 2124 (2018). Copyright 2018 ACS. (c) Adaptedwith permission from Chen et al., Nano Lett. 17, 6345 (2017). Copyright 2017 ACS.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-4VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/aresuggested that increasing the number of elements within the unit cellcan lead to a wide range of optical responses, thereby inspiring exten-sive studies on metasurfaces. Early-stage contributions to the metasur-face studies were collected in several review papers.115–118Along the design procedures similar to those for the wavefront-manipulating metasurface in Fig. 2(a), polarization and phase controlof light waves, which were often laser beams, were reported.38,39 Thefabricated subwavelength structures, i.e., metasurfaces, were often non-periodic and nonuniform, beam and vortex shapes were modulatedwith a large degree of freedom.B. MetalensOptical focusing using a metalens is illustrated on the left side ofFig. 2(b).7 The circular array of Si nanopillars, which are shown inFig. 1(c), serves as a lens with a nearly unity numerical aperture (NA).The measured focal spot is shown on the right side of Fig. 2(b). Thisfocus is diffraction-limited, meaning that the metalens functions asordinary optical lens whereas the primarily distinction is its planardesign. The height of the metalens was 250 nm and the designed arrayof Si nanopillars on an SiO2 substrate formed the metasurface. Theworking wavelength was set at 715nm. By adjusting the first-order dif-fractions in transmission and reflection components, the focal pointwas tuned in space. Essentially, the metalenses were designed to alignwith the Fresnel phase profile U for focusing, such that44Uðx; yÞ ¼ 2p� 2pnkffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffix2 þ y2 � f 2p� f� �; (1)where k is the working wavelength, f is the focal length, and n is therefractive index around the unit structure of nanopillars or nanorodsconstituting the metalens. Equation (1) was defined on the metasurfaceon the xy plane. After assessing the phase change by each unit struc-ture, the corresponding unit structures are configurated at the coordi-nate ðx; yÞ in accordance with the phase determined by Eq. (1).A more functional metalenses were explored, which are colorsplitters.47–49 An example of such a color splitter is shown inFig. 2(c).48 White light is separated into three color components ofRBG, and each separated color is focused onto different spot in a pixelof complemantary metal-oxide semiconductor camera. In other words,although the color splitter is a kind of metalens, each color componentwas designed to focus on a particularly designated position. Therefore,the design had more complicated than simple metalenses focusing ona in-plane position.48 Despite this complexity, the design and fabrica-tion were successfully executed. A GaN layer of 600 nm thickness wasgrown on a c-plane sapphire substrate, underwent EB-based nanoli-thography, and finally formed the patterned nanostructures, i.e., thecolor splitter; a part of it is shown in the inset of Fig. 2(c) with blueframe; the scale bar indicates 1lm; it is seen that subwavelengthmulti-components working for the three colors coexist. The focusingefficiencies of the RGB components were 50.6%, 91.6%, and 87%,respectively. The focal length was 110lm. The green component hadtwo focal positions, as shown in the inset of Fig. 2(c) with yellow frame.It is also seen that a small crosstalk appeared at the focal positions,which could be improved by additional adjustment in designs, nanoli-thographic procedures, and image-processing parameters.49At the end, we mention that, on the basis of these metalens R&D,metalens startup companies launched recently, aiming at the massproductive commercialization.119,120 The compact metalenses maybecome available for consumer use in the near future.C. IR absorbersFigures 3(a) and 3(b) show snapshots of resonant EM field distri-butions in the MIM metasurface [Fig. 1(e)], and correspond to the res-onant wavelengths k2 and k1, respectively; the xyz axes are in commonin these figures. The upper panels in Figs. 3(a) and 3(b) present anelectric field component, Ez , of the xy-section view in the middle of theinsulator layer, and the lower panels do a magnetic field component,Hy , of the xz-section view at the position indicated with dashed linesin the upper panels. Evidently, the EM fields are strongly enhanced inthe insulator layer between the metallic layers, exhibitingFIG. 3. IR detectors. (a) and (b) Electromagnetic (EM) distributions on large light-absorption resonance. (c) Schematic illustration of an infrared (IR) detector. Thefour patch cavities connected by synchronous wires. Yellow denotes Au and paleblue represents a semiconductor layer including a quantum well. (d) Simulatedabsorption spectrum. The horizontal axis covers a mid-IR range from 5.0 to 8.5 lm.(e) Measured responsivity spectra dependent on temperatures at 78–293 K. (a) and(b) Reproduced from [Miyazaki et al., Appl. Phys. Lett. 105, 121107 (2014)] with thepermission of AIP Publishing. (c)–(e) Adapted from Miyazaki et al., Nat. Commun.11, 565 (2020); licensed under a CC BY license.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-5VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/areapproximately 30-fold local enhancement, relative to the incident light.This resonance is often referred to as gap plasmons. From the resonantEM field distributions, it is confirmed that the resonant modes formstanding wave in the MIM structures. Note that the electric field is pre-dominantly z-polarized when the incidence is x-polarized. This obser-vation indicates that the incident polarization is converted to the otherdirection in the subwavelength MIM structures. The fundamentalproperties of the resonances—including the dispersion relationsbetween wavenumber and frequency—are ascribed to coupled eigenm-odes of surface plasmon polaritons in the configuration with twometal–insulator interfaces.121–124Light absorbers are not restricted to only IR range. Indeed, theywere explored in various artificially designed structures from micro-waves to the visible range.74–82D. IR emitters/detectorsApplying reciprocity to a planar object (e.g., a metasurface) at theequilibrium temperature, as drawn in Fig. 4, the Kirchhoff’s law wasderived in a general formalism,83 such thataðk;xÞ ¼ eð�k;xÞ; (2)where aðk;xÞ and eð�k;xÞ are directional light absorptance and thelight emittance to the corresponding direction, respectively. The vectork denotes wavevector of light. Equation (2) holds at the samefrequency x. This reciprocal relation is the guide for the exploration ofefficient light emitters.With respect to the Kirchhoff’s law in Eq. (2), we remark someextended configurations. The assumption to derive Eq. (2) was thermalequilibrium. If a dipole emission takes place on the metasurface at amoment, the emission minimally disturbs equilibrium because a singlephoton emission or a small number of photon emissions hardlychange the temperature. Therefore, in the case that the emission comesfrom sparse dipole radiations, Eq. (2) retains its validity. This meansthat Eq. (2) is also a good basis for the exploration of metasurfaceswith efficient FL-emission capability.In addition to the extended application of the Kirchhoff’s law, ageneral reciprocity holds in electromagnetics; that is, physical quanti-ties of current density ji (i ¼ 1; 2) and the induced electric field vectorsEi at positions ri are correlated such that125ðXj1ðr1Þ � E2ðr1ÞdR ¼ðXj2ðr2Þ � E1ðr2ÞdR; (3)where X denotes sphere with radius R. In the limit of R ! þ1, Eq.(3) holds exactly. When the current density is ED, expressed aspi � dðriÞ, Eq. (3) is modified such asp1 � E2ðr1Þ ¼ p2 � E1ðr2Þ: (4)Equation (4) is rewritten as jE1j=jp1j / jE2j=jp2j, which means that,when the p1 is the source of incident light and the p2 is an ED on themetasurface, the induced electric field E1 is proportional to the emittedfield E2 concerning the absolute values. From this relation, we canunderstand that the resonant-field intensity induced by the incidenceis proportional to the emitted field intensity from the metasurface.Therefore, one can assert that the FL emission from the metasurfacedirectly correlates with the resonant fields induced by the incidence.Generally, Eq. (4) connects an incoming wave to the reverselyoutgoing wave and leads reciprocity regarding transmittance andreflectance.84,126 This is called the Helmholtz’s reciprocity, which tellsus that reciprocal relation holds for reflectance and transmittance.Turning our attention to IR emitters, the reciprocal relation inEq. (2) describes blackbody radiation and implies that perfect lightabsorber is simultaneously perfect light emitter. This was the principleto design and fabricate highly efficient light emitters at IRranges.9,10,79,80 Actually, the metasurface IR emitters tailored for CO2detection have been produced in a compact, packaged format, asshown in Fig. 1(g); the IR emitters consumed 31% less power thanconventional thermal emitters.9,10Photodetectors were readily considered as another application ofmetasurface IR absorbers.87–89 The idea was akin to that for the IRemitters. However, the production of IR detectors is far more compli-cated than that of IR emitters, because the IR emitters go through aphoton-to-photon process intrinsically in the metasurfaces, whereasthe IR detectors need to transduce photon energy to electric power.The unit MIM structures need to be connected with wires, as theappearance is depicted in Fig. 3(c).88 Thus, the IR detectors requiremore elaborate design and fabrication than the IR emitters. In the pro-duction of the IR detectors, a typical fabrication procedure is as fol-lows:88 (i) a single quantum well (QW) of semiconductor, such as n-GaAs of 4 nm, were designed through computations for electronicenergy levels, especially subband levels, in the QW, in accordance withthe purpose; (ii) the designed QW was grown on a wafer, such as n-FIG. 4. Schematics of reciprocal configurations. (a) Light absorption (a) and emis-sion (e), which is usually referred to as Kirchhoff’s law [Eq. (2)]. Arrows indicatewavevectors k (black) and �k (red). (b) General configuration for Eq. (3), assum-ing two positions ri (i ¼ 1; 2). Red arrows denote current densities ji . Black arrowsstand for the induced electric field vectors Ei .Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-6VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/areGaAs (100), together with buffer GaAs, sacrificial AlxGa1�xAs, andcontacting Si-doped layers; (iii) after electronic characterization of thegrowth, the set of layers of QW IR photodetector (QWIP) was coatedwith Ti 5 nm/Au 150nm and bonded with another GaAs wafer; (iv)the original base wafer was removed via mechanically polishing andwet etching; (v) EB nanolithography was conducted on the wafer-removed QWIP layers, and the shapes of QWIP patches and electricwires were fabricated; (vi) Ti 5 nm and Au 150nm layers were depos-ited, and then liftoff of the metallic layers were conducted; (vii) wetetching for the uncoated QWIP regions was conducted, and patch-shape QWIP and wires were obtained. Overall, the fabrication of meta-surface QWIP has gone through several difficulties.The design for the IR detector was optimized for the absorptionpeak at 6.7lm. Figure 3(d) presents a simulated absorption spectra fora mid-IR range of 5.0–8.5lm; the corresponding photon energy inmeV is indicated at the top. Thus, a good design was prepared throughthe simulation.The responsivity of QWIP dependent on temperature is shownin Fig. 3(e). The temperature was varied from 78 to 293K. Obviously,the peak responsivity is located at 6.7lm, as designed. In addition, theresponsivity remains detectable even at 293K. The temperature depen-dence was similar to another study on QWIP.87 The decrease in theresponsivity over 100K was accounted for by thermal scattering of car-riers. The photocurrent spectra at approximately 150meV were hardlydependent on temperature.87 Furthermore, heterodyne measurementshowed that the metasurface QWIP is able to operate even at a highrepetition of 4GHz. The fast response is one of the advantages in theQWIP metasurfaces. Such high-repetition operations would requireoptimal current control, which can be realized by designing the wiresfor synchronous control of current.88 To achieve better performance,quantum ratchet detector was recently reported,89 in which the highresistance coming from potentials in multi-QW makes the thermal orbackground noise intrinsically smaller than that in the QWIPs.In addition to the aforementioned wavelength-selective IR emit-ters and detectors, metasurface filters present a viable alternative forthe development of IR detectors for gas sensing.127 In the device incor-porating the metasurface filters, other components, such as IR emitterand detectors, are chosen from conventional devices. In actual applica-tions, this type of IR detector directly competes with the commerciallyavailable IR sensors equipped with multilayer film filters on substratestransparent to IR radiation.E. Biosensing techniquesBiosensors represent a broad category of devices engineered forthe detection of various molecules, extending beyond the domain ofbiomolecules. Let us start arranging the types. Table I lists biosensingtechniques with respect to their working principles, target molecules,dynamic ranges in measurement, limits of detection (LODs), androbustness. In addition to commercially available techniques of surfaceplasmon resonance (SPR), enzyme-linked immunosorbent assay(ELISA), and polymerase chain reaction (PCR), nanostructure-basedbiosensing techniques are listed, such as Mie resonance, surface-enhanced IR absorption (SEIRA), electrochemical sensing, and meta-surface FL biosensing.Figure 5 shows the nanostructure-based biosensing andmolecular sensing techniques, addressed in this subsection.Schematics, biosensor images, and experimental results are shownin Fig. 5: (a) SPR using Au nanoparticle (upper) and Au thin film(lower) (b) Resonance-shift metasurface biosensors based on Mieresonance, (c) BIC-based IR metasurfaces, (d) IR spectra of refer-ence (upper) and SEIRA (lower), (e) metasurface FL biosensorsdetecting cfDNA, (f) metasurface FL biosensor detecting tumorTABLE I. Comparison of biosensing techniques in terms of principle, target molecule, limit of detection (LOD), dynamic range, and robustness. Each biosensing technique isreferred to, citing a representative reference. On biosensing techniques and the principles, SPR, ELISA, BIC, IR, PCR, SERS, and s-amp denotes surface plasmon resonance,enzyme-linked immunosorbent assay, bound-state in the continuum, infrared, polymerase chain reaction, surface-enhanced Raman scattering, and short-cycle amplification,respectively. A symbol of 1/0 denotes single-molecule sensing that can discriminate from zero molecules. Note that the quantities listed here are based on presented experimen-tal data in the references, which may be different from those claimed without experimental data or sufficient statistical analysis.Biosensing technique Principle Target molecule Dynamic range LOD Robustness ReferencesSERSenhanced Ramanscattering parathion unshown unshown unshown 128SPR resonance shift PSAa unshown �0:5l g/ml unshown 129Mie resonance resonance shift PSA 1–10 ng/ml 0.7 ng/ml good 90SEIRA IR absorption, BIC protein A/G unshown 2130 molecule/lm2 unshown 92ELISA enzyme reaction CEAb 1.25–50 ng/ml 1.25 ng/ml good 11PCR nucleic acid amplification COVID-19 102–105 copies/testc 406 10 copies/test good 130digital PCR nucleic acid amplification COVID-19 10–5000 copies/testd 10 copies/test good 131Electrochemical sensing current detection COVID-19 231–5:8� 107 copies/ll 231 copies/ll unshown 132Metasurface FL sensing enhanced FL CEA 2–25 000 pg/ml 2 pg/ml good 11Metasurface FL sensing s-amp & enhanced FL cfDNAe 1–5000 copies/testf 1/0 good 12aProstate specific antigen, a kind of tumor markers.bCarcinoembryonic antigen, a kind of tumor markers.cClinical RNA samples, 20ll per test.d10ll target per test.eCell-free DNA.f4ll target solution per test.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-7VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/aremarker, and (g) 3D illustration of plasmo-photonic metasurface(upper left), a section-view SEM image (upper right), and sche-matic of antibody detection.1. SERS—Surface-enhanced Raman scatteringAs a molecular sensing technique, surface-enhanced Raman scat-tering (SERS) was found in the 1970s,135–137 was explored as an opticalsensing technique since the 1980s,138 and became popular because twoappealing reports to claim single-molecule sensing were published in1997.139,140 In spite of the initial impact, it was found that large valida-tion significantly reduces reproducibility.141 This difficulty was tried tobe overcome using several structures that were less dependent on so-called hot spots, which are extremely enhanced electric-fieldspots.128,142,143 In spite of the appeal of the prominent SERS results,SERS has not been established as a commercial standard, probablybecause the reproducibility of the SERS signals has not attained. Acrucial criterion for practical applications is sufficient reproducibility.SERS is kept being studied144 after more than 20 years since the reportsin 1997.In Table I, a result of parathion molecule detection128 is summa-rized. The toxic molecules were identified as a residue on the peels offruits. The main claim was that a substantial reduction in the inhomo-geneity of SERS signals was attained using densely dispersed Au nano-particles that were coated SiO2 shell of a few nm thickness. However,the dynamic range of the target molecules and the LOD were notshown. Therefore, it is difficult to use SERS as a quantitative methodfor analysis. We note that single-molecule detection has been fre-quently claimed in the SERS reports;139,140 however, the concentrationof the target molecule solutions typically fell within the range of micro-molar (i.e., 10�6 mol/l); consequently, an extremely small fraction ofthe molecules was detected, which means that the overall detectionefficiency was extremely low. To our knowledge, this issue persists tothe present day.FIG. 5. Nanostructure-based biosensing and molecular sensing techniques. (a)–(d) Biosensing based on resonant wavelength shift. (a) Plasmon resonance sensing: surfaceplasmon polariton (SPP) configuration and reflection spectra (red curve) dependent on incident angle h at 633 nm (upper); local plasmon induced at an Au nanostructure andresonant electric-field intensity (lower). (b) Resonance-shift-type metasurface biosensors:90 Images of the biosensor (upper) and measured sensorgram dependent on time(lower). (c) and (d) Illustrations of BIC metasurfaces of asymmetric Si units and molecular absorption at an IR range, respectively.92 The horizontal axes in (f) represent wave-numbers and cover the range of 1350–1800 cm�1. (e)–(g) Metasurface FL biosensors, based on enhanced FL detection in common: all-dielectric ones applied for cfDNA andtumor marker CEA detections,12,133 and plasmon-photon hybrid one,134 respectively. (b) Adapted with permission from Yavas et al., Nano Lett. 17, 4421 (2017). Copyright 2017ACS. (c) and (d) From Tittl et al., Science 360, 1105 (2018). Reprinted with permission from AAAS. (e) Adapted with permission from Iwanaga et al., Nano Lett. 23, 5755(2023). Copyright 2023 ACS. (f) Adapted from Iwanaga, ACS Nano 14, 17458 (2020); licensed under a Creative Commons Noncommercial No Derivative Works license. (g)Adapted with permission from Iwanaga, Biosens. Bioelectron. 190, 113423 (2021). Copyright 2021 Elsevier.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-8VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/are2. SPR—Surface plasmon resonanceSPR is originally a surface plasmon polariton (SPP) excited at theflat interface of metal and dielectrics, such as air, glass, and water.145 Ina typical experimental configuration, SPP is detected using an Au thinfilm coupled with a prism and observed as a prominent dip at 46� inreflection spectrum (red curve) dependent on incident angle h, asshown in Fig. 5(a) (upper). SPP is known to be sensitive to the refrac-tive index of contacting medium and to exhibit definite resonance shiftdependent on the refractive index. Therefore, resonant shift wasapplied for biomolecule sensing.146 Another SPR, called local plas-mons, became popular owing to the synthesis of noble-metal nanopar-ticles in the era of nanotechnology around 2000.14 Local plasmons alsoenable the measurement of resonance shifts by immobilizing biomole-cules, such as antigens and antibodies, on the surface. An illustrationincluding an Au nanodisk is provided in Fig. 5(a) (lower). Resonantelectric-field intensity of the Au nanodisk with 152nm diameter and80nm height on an SiO2 substrate, simulated using RCWAmethod,124is shown in a section view of the nanodisk, exhibiting more than 50-fold enhanced intensity than that of incident plane wave at 633nm.The largely enhanced intensity distribution exists in 5 nm area fromthe outermost surface of the Au nanodisk.In Table I, a result on prostate-specific antigen (PSA) detection129is listed. In an optimal condition, the PSA solution at 0.5lg/ml wasflowed and detected as a signal of 74pg of proteins/mm2. Although thelimit of resolution for the measurement was not determined in the Ref.129, it is presumably located at approximately 10pg of proteins/mm2from the available data. Therefore, it is inferred that the LOD for PSAdetection is a few fold smaller than 0.5lg/ml but in the same order. Inthe same Ref. 129, cysteine-tagged protein G was detected at 2406 pgof proteins/mm2, being equivalent to 1.03� 105 molecules/lm2. Theseresults imply that the protein G was detectable by 100-fold dilution,i.e., at 1� 103 molecules/lm2, which is compared to a SEIRA resultlater (Sec. II E 5).The SPR reports129,146 hardly referred to robustness, whichensures selective detection of target molecules among various obstaclemolecules. The SPR technique is mainly used for high-concentrationtarget solutions and for evaluations of binding constant between par-ticular molecules, such as antigen and the antibody. Thus, the SPRtechnique is not suitable for low-concentration targets but for the basicanalysis within high-concentration ranges.3. Mie resonanceMie resonance is referred to in Sec. I. The main feature is thatboth metallic and dielectric nanostructures functions as opticallyprominent resonators.14–19 In this sense, plasmonic or dielectric nano-structures, including metasurfaces, were readily noticed as candidatesfor resonance-shift biosensors.90,91,147–151 Fig. 5(b) (upper) shows a setof images of all-dielectric metasurface biosensors composed of Si-nanodisk array. The metasurfaces and a PDMS microfluidic chip forma metasurface biosensors. A typical sensorgram is shown in Fig. 5(b)(lower).In Table I, a result of prostate specific antigen (PSA) detection90is listed; PSA is a tumor marker used in daily medical diagnoses. Theall-dielectric metasurfaces served as a biosensor, enabling the detectionin a dynamic range of 1–10 ng/ml. The LOD was estimated to be0.7 ng/ml. When the PSA was distributed in a human serum diluted to50%, the detection was performed in a similar precision on the meta-surfaces, yielding a dynamic range of 3–20 ng/ml and an LOD of1.6 ng/ml, as noted in the robustness column of Table I.4. BIC—Bound states in the continuumA BIC is a resonance that does not show prominent opticalresponses under forbidden conditions. For example, a symmetry-protected BIC does not show any optical signal under the normal inci-dence, as noted in Sec. I. However, once the symmetry is broken bysome ways, such as physical absorption of large molecules on nano-structures, a detectable optical signal appears. Further, increase in thedegree of symmetry breaking gives rise to increase in the optical signal,which was often observed as resonance shift. Thus, biosensing usingBIC was conducted,22,152 in a similar manner to that using Mie reso-nances in Sec. II E 3.To date, the reports on biosensing using BIC22,152 have not beenso many, compared with those using Mie resonances. The reportedtarget was limited to exosome and detected at hundreds of femtomolar(fM, i.e., 10�15mol/l). The detection level was inferior to the detectionlevel of � 0.22 fM, by colorimetric techniques using Aunanoparticles.153,1545. SEIRA—Surface-enhanced infrared absorptionIR absorption by molecular vibrations has been a well-knownproperty in molecular science. Trials for SEIRA were conducted usingplasmonic microstructures in the 2000s;155,156 the metallic rods of lmlength were prepared on substrates, in accordance with the IR workingwavelengths. The detected molecules were self-assembled monolayer(SAM) or silk proteins, which directly contacted with the metallicmicrostructures. The absorption spectra were Fano shapes,157,158 dueto the interaction of the narrow linewidth resonances of molecularvibrations with the plasmonic resonance with broad linewidth. Fromthe analyses of the experimental data, SEIRA signal enhancementsranged from 10000- to 100 000-fold for the reference signals. Theeffort to improve SEIRA kept being continued, based on plasmonicstructures;159 some of the studies incorporated nanofluidic or micro-fluidic paths to obtain better sensing efficiency.160–163In Table I, the BIC-based SEIRA using the all-dielectric metasur-faces92 is noted. The LOD in protein detection was reported to be 2130molecules/lm2, which is nearly equal to 1 molecule/(2.2� 2.2nm2).As noted in Sec. II E 2, the protein G was detected at the order of1� 103 molecules/lm2 via the SPR; the in-plane density is a littlesmaller than the LOD evaluated by the BIC-based metasurfaces. Asanother comparison, the in-plane density is comparable to the denselyimmobilized density of proteins using a 200l g/ml solution, or 1 mole-cule/(2.24� 2.24 nm2), which was evaluated using the SPR instru-ment.134 Thus, it is most likely that the BIC-based SEIRA is valid onlyfor molecular detections at high concentrations.SEIRA was recently measured on another BIC metasurface.164 Athin film of polymethyl methacrylate (PMMA) of 111 nm thicknesscontacted with the metasurface, and the coupled systems of thePMMA and metasurface exhibited strong coupling of the BIC with amolecular vibration mode in a mid-IR range of 5.7–5.9lmwith tuningthe asymmetry of the BICmetasurfaces. The interaction of the molecu-lar vibration mode with the EM resonance in the IR range was shownApplied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-9VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/areto cover both weak and strong coupling regimes. Thus, BIC metasurfa-ces are a new platform to explore light–matter interplay.6. ELISA—Enzyme-linked immunosorbent assayELISA is a commercially standard assay for proteins, such as anti-gen and antibody. When medical examinations for protein targetsrequire precision, ELISAs are mostly conducted by inspection compa-nies. Although typical detection ranges of ELISA depend on the com-mercial kits, they are mostly in a range of 0.5–5000ng/ml. Althoughsome of commercial ELISA kits claim better detection capability thanthe above, it is often unclear whether the capability is reproduced byusers when the kits are applied to actual samples, such as serum andblood plasma.In Table I, a result of detection for carcinoembryonic antigen(CEA), which is a kind of tumor markers, is listed. In user detections,the dynamic range was 1.25–50 ng/ml and the LOD was 1.25ng/ml,11which was slightly different from the product sheet.165 The medical cri-terion for CEA is 5 ng/ml. Therefore, the commercial kit showed thatit serves as a diagnosis kit. It also turned out that the working rangewas optimized only around the medical criteron and did not guaranteehigh-sensitivity detection at the range of pg/ml. This result is com-pared with a result by the metasurface FL biosensor later (Sec. II E 10).As a related development, great efforts were devoted to pursue ahigh-sensitivity assay based on the ELISA. Incorporating a fractioncounting method into the conventional ELISA, digital ELISA wasintroduced.166,167 At the expense of the extremely high sensitivity atpg/ml or lower, the overall cost was significantly raised in the digitalELISA. Consequently, the digital ELISA is not used for the daily medi-cal examinations and the conventional ELISA noted above remains tobe the commercial standard for protein assay.7. PCR—Polymerase chain reactionPCR is a standard technique for detection of nucleic acids ofDNA and RNA. The amplification technique was invented in 1983and reported in 1985.168,169 Going through the extensive R&D, it iswidely known that the PCR technique became a commercial standardfor detection of nucleic acids in 1990s.As a typical result using ordinary quantitative PCR (qPCR),Table I lists a result for COVID-19 detection.130 As is widely recog-nized during the COVID-19 pandemic (2019–2022), numerous testsfor COVID-19 using the qPCR were conducted worldwide. The RNAof COVID-19 was reversely transcribed to complementary DNA(cDNA), which was amplified and recorded as qPCR signals. A seriesof tests for actual samples showed the dynamic range of 102–105 cop-ies/test and the LOD estimated at 40610 copies/test. The actual sam-ples were swabs of patients and uninfected persons, and containedvarious obstacle molecules in reality. The detection through the reversetranscription and qPCR is robust in the practical tests. In the era ofCOVID-19, many trials to detect the RNA of COVID-19 werereported. Nevertheless, the qPCR was kept being the standard becausethe era was short and it took time for the new methods to be estab-lished in society. For providing against the future pandemic, usefulnew methods seem to establish their practical performance and valuesin advance.Throughout the COVID-19 pandemic, numerous contributionswere published and several review papers were already published.170–175Readers seeking further in-depth insights can consult the review liter-ature. Regarding the COVID-19 detection, a comparison of the qPCRwith the metasurface FL biosensors is discussed later (Sec. III C).8. Digital PCRDigital PCR (dPCR) is an improved technique of the ordinaryPCR, i.e., qPCR.176–178 The incorporation of a fraction countingmethod minimized background noise, thereby enhancing the precisionand lowering the LOD. In reality, the LOD was improved, at most, byone order. Instead of the higher detection capability, the measurementrequired elaborate statistic analysis and became complicated. Theinstrument itself also became complicated, requiring higher cost thanthat for qPCR. Consequently, the dPCR is not used for the daily medi-cal diagnoses.As a typical result using the dPCR, a result of COVID-10 detec-tion employing droplet dPCR131 is listed in Table I. In comparisonwith the result of qPCR in Sec. II E 7, the detected signals at 10 copies/test was observed with an improved statistical confidence. The LODwas 10 copies/test. Although LOD of 5 copies/test was claimed,131 thedata of 10 and 5 copies/test overlapped with each other within one r(r: standard deviation), thereby being statistically indistinguishable.Generally, it is difficult to state how much the dPCR was improved forthe qPCR because the process including reagents and data acquisitionare different. However, fivefold–tenfold better LOD is often obtainedin the dPCR. Therefore, the dPCR is currently ranked at a gold stan-dard in the techniques for nucleic-acid detection, while it is demandingin cost.9. Electrochemical sensorIn parallel to the biosensing techniques addressed above, electro-chemical sensors have been extensively studied for various targetsfrom gas to biomolecules. The studies are conducted more numerouslythan those on optical sensors, probably because the measurement isimplemented by use only of current and voltage meters. Since the elec-trochemical sensors were reviewed frequently,179 we here specify onlythe status of biosensing. A key element in electrochemical biosensing ismagnetic beads that collect antibodies efficiently.180,181 Although widedynamic ranges for target concentrations were often claimed, theytend to be exaggerated;182–186 indeed, the dynamic range and LODwere claimed without data or beyond the statistical limit. The electro-chemical signals were heavily reduced by abundant obstacle moleculesin human serums.182,184 Thus, it is not easy to find quantitatively reli-able references concerning the electrochemical biosensing.In Table I, an electrochemical result of detection of COVID-19RNA is listed.132 In the experimental configuration, the RNA ofCOVID-19 was first extracted in viral; second, the extracted RNAs ofCOVID-19 were directly placed on an Au-nanoparticle-dispersed gra-phene; third, single-strand DNAs (ssDNAs) were added and incu-bated, which combined with the Au nanoparticles and served as probefor the RNAs; finally, RNAs hybridized with the ssDNA probes outputelectric signals. Thus, the electrochemical signals of the RNAs weredetected, which were voltages and presented for the RNA concentra-tions of 231–5:8� 107 copies/ll. When the concentration was 231copies/ll, the voltage signal was substantially zero. However, the LODwas claimed to be 6.9 copies/ll,132 which is an inconsistent, uncon-vincing jump from the measured data, because any justification is notApplied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-10VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/areprovided. Therefore, the LOD is noted as 231 copies/ll in Table I.From the comparison with the qPCR and dPCR, which areamplification-based techniques, it is reasonable that the electrochemi-cal sensing is ranked as a technique, at least, one-order less sensitivethan the qPCR.10. Metasurface FL biosensorImages (specifically, a photograph and a micrograph) and the FLimages of the all-dielectric metasurface FL biosensors are shown inFigs. 1(h) and 1(i), respectively. The biosensing images for cell-freeDNA (cfDNA) and tumor-marker protein are illustrated in Figs. 5(e)and 5(f), respectively. The FL-detection biosensors based on the all-dielectric metasurfaces were validated, based on the finding of out-standing FL-enhancing capability.187 A few years before the report,187plasmon-photon hybrid metasurfaces demonstrated an exceptionaland highly uniform FL enhancement exceeding 2600-fold.188,189 Theunderlying mechanism responsible for this prominent FL enhance-ment is detailed later (Sec. III).In Table I, the results of CEA and cfDNA detection by the all-dielectric metasurface FL biosensors are listed. The CEA is a kind oftumor markers for cancers in lung, colon, and so on, and is widelyused in medical diagnostics. The dynamic detection range was 2–25 000pg/ml, which was over four-order of target concentrations, andthe LOD was 2 pg/ml, which was more than 600-times lower than theLOD of 1250pg/ml evaluated by a commercial ELISA kit,11 as listed inTable I. In addition, the CEA detection was conducted for the CEA inhuman serum, and it was shown that the detection curve remainedlargely unaffected, indicating that the metasurface FL biosensors arerobust for interfering molecules in the human serum.Regarding the cfDNA detection by the metasurface FL biosen-sors, the dynamic range was 1–5000 copies/test, and the LOD wasexpressed using a symbol, 1/0, which means that one cfDNA was dis-criminated from zero. The LOD represents the ultimately high sensi-tivity because no better sensitivity is expected in bio- and molecularsensing. Even the dPCR has never attained this sensitivity, to ourknowledge. The cfDNA detection was a combination of short-cycleDNA amplification and enhanced FL sensing, both of which are robustmethods for obstacle molecules and support robust sensing forcfDNA.11. MiscellaneousLateral flow technique emerges as a valuable approach for themanagement of liquid samples within constrained environments,thus, promoting efficient and cost-effective point-of-care biosensingsolutions.173,174,190,191 Nanostructure-based biosensors, including themetasurface biosensors, typically feature dimensions of 1mm2 orsmaller. Therefore, they do not need to large liquid samples. Instead,it becomes important to handle small volume liquid samples, suchas 50ll. Thus, microfluidic/nanofluidic systems should be effec-tively incorporated with the nanostructure-based and metasurfacebiosensors.90,94,160–163,192We mention trials for micro-/nano-optical sensors, which weresurveyed from a viewpoint of miniaturization of optical sensors andefficiency improvement.193 Metasurface optical sensors are one of themicro-/nano-sensors. In addition to the biosensing techniquesaddressed in this section, other candidates for circular dichroic sensorsand a frequency-shift sensor were discussed.193 Nevertheless, the con-cept of the micro-/nano-sensors has not been established as biosensorsin terms of sensitivity, selectivity, and robustness, compared with thebiosensors listed in Table I.III. METASURFACE FL BIOSENSORSAs listed in Table I and described in Sec. II E, the metasurface FLbiosensors show excellent performance among the various conven-tional biosensors. However, the metasurface FL biosensors have notbeen widely understood because they are a new type of biosensors.In this section, we provide a comprehensive descriptions for thefundamentals of FL enhancement on the metasurfaces (Secs. IIIA andIII B) and for the outstanding achievement using the metasurface FLbiosensors, covering a diverse range of target molecules from proteins,such as antigens and antibodies, to nucleic acids, such as cfDNA andRNA-transcribed DNA (Sec. IIIC). Notably, an ultimate high-sensitivity was attained for the cfDNA. These were demonstrated usingordinary FL probes.Furthermore, we address a new approach integrating the meta-surface FL biosensors with functional FL probes, called aggregation-induced emission (AIE) molecules, for detection of human serumalbumin (HSA) in noninvasive liquid biopsy (Sec. IIID). The AIE mol-ecules are shown to function as a new kind of FL sources on the meta-surface FL biosensors, expanding the use cases toward practical biopsy.A. Outstanding FL enhancementThe pursuit of enhanced FL intensity has been an interestingissue across the fields of optical physics and photochemistry. Since the1980s,203 plasmonic resonances induced at metallic nanostructures,especially nanogaps, were a plausible candidate for achieving thisenhancement.204,205 Further numerous studies were stimulated afterthe effective synthesis of metallic nanoparticles.14A nanogap between Au bowtie-shaped nanoantennas exhibited aprominent FL enhancement in 2009;194 the pairs of nanoantennaswere fabricated through EB-based nanolithography and aligned pre-cisely, which was different from the chemically synthesized nanopar-ticles. The nanogap structures shown in Fig. 6 was a realization of ideafor FL enhancement on a plasmonic resonance, being favored widely.However, nanogap structures had a definite drawback, i.e., inhomoge-neous FL enhancement, which was evident from the structure and theresonant EM field distribution called hotspot. While the strong FLenhancement was attained only at the nanogap, it was not observed atthe nearly 99% area surrounding the nanogap. Starting from thisresult, we delve into the outstanding FL enhancement in thissubsection.Regarding FL-intensity enhancement, the top ten experimentalresults,187–189,194–200 which reported FL-intensity enhancement factor(EF) exceeding 1000-fold, are shown in Fig. 6; the horizontal axis rep-resents the EF in a logarithmic scale. The EF is defined as ratio of theFL intensity measured on the metasurfaces (or nanostructures) to thaton a relevant reference (or flat glass or Si wafer) that does not have anyenhancing effect. FL enhancement was reported in numerous reports,and it is unrealistic for us to refer to all the them that presumablyexceed one thousand reports; instead, we here focus only on the top 10results. We notice that some other references, which are not cited here,claimed over 1000-fold FL enhancement and note that the reportswith substantial experimental data are selectively cited. Also, we noteApplied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-11VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/arethat the cited results in Fig. 6 are limited to experimental data, and donot include purely theoretical claims or expectations based onsimulations.In Fig. 6(a), the vertical axis represents reproducibility in %,which means the percentage to observe the best EF. For instance, 50%denotes that the best EF is observed by 50% in experiment; in otherwords, 100 measurements result in 50 results showing the best EF and50 results differ from the best EF, implying substantial an inhomoge-neous FL-enhancement effect. We estimated the reproducibility basedon the available data. The reproducibility is crucial when the enhancedFL is applied to FL sensing, because, in general, low reproducibilitymethods cannot deserve practical applications. We point out that thenanostructures featuring nanogaps or nanoridges exhibited low repro-ducibility. As far as we surveyed the related references, tens of reportsshowed 100- to 999-fold FL enhancement, and the other mass ofreports, presumably over 500, addressed 1- to 99-fold FL enhance-ment. Thus, the top 10 results are exceptional; moreover, among them,the highly reproducible metasurfaces are limited only to the plasmo-photonic metasurfaces188,189 and the all-dielectric metasurfaces of Sinanocolumn array.187,200A 3D-view illustration of a plasmo-photonic metasurface is pro-vided in Fig. 6(b). The structure includes complementary stacked Aunanostructures; there is a perforated Au film at the top and Au disksare located at the bottom; the top and bottom layers are complemen-tary in structure to each other. Experimentally, the stacked comple-mentary structures were formed by a normal deposition of Au. Themiddle layer is perforated Si slab, which is a photonic crystal. Thus,plasmonic resonances at the top and bottom layers couple with eachother via photonic modes in the Si photonic crystal, which have hugephotonic density of states. This unique coupled system form theplasmon-photon hybrid eigenmodes, some of which exhibit large lightabsorption.206 This plasmo-photonic metasurfaces do not rely on so-called nanogaps; instead, it exhibits a macroscopic feature of large lightemittance, equivalent to the large light absorption.The plasmo-photonic metasurfaces in Fig. 6(b) were tested as aplatform for FL enhancement. After a few trials and improvements,effects of excellent FL enhancement of 2600-fold at the maximumwere attained.188,189 Not only the prominent EF but also high repro-ducibility was obtained, which was not realized in any other platforms.The underlying mechanism is specified later (Sec. III B).An SEM image of an all-dielectric metasurface consisting of Sinanocolumn array187 is shown in Fig. 6(c). Whtie scale bar indicates1lm. The Si nanocolumns are rectangular shapes; the widths alongthe x and y axes are 220nm, and the height is 200nm. The periodicityof the array is 330 nm along the x and y axes. The metasurface was fab-ricated using a silicon-on-insulator (SOI) wafer. The FL enhancementcorresponds to the closed purple circle in Fig. 6(a), exceeding 1000-fold. We note that the FL-enhancing capability is similar to the meta-surface of circular Si-nanocolumn array. The key for the prominent FLenhancement is a higher-order magnetic resonance, specified later(Sec. III B). Both rectangular and circular Si nanocolumns have themagnetic resonance.Another SEM image of mushroom-shaped Au structures isshown in Fig. 6(d), which was formed by Au deposition on an SiO2FIG. 6. Top 10 FL enhancement on metasurfaces and other nanostructures. (a) Plot of the FL enhancement for enhancement factor (EF) and reproducibility. Marks indicatedata taken from literature.187–189,194–200 Labels (b)–(f) correspond to the followings. (b) Illustration of plasmo-photonic metasurface.201 (c) SEM image of the all-dielectric meta-surface comprising an array of Si nanocolumns.187 (d) SEM image of mushroom-shaped Au nanostructures.198 Scale bar indicates 50 nm. (e) Nanopetal Au/Ag nanostruc-tures:196 schematic (left) and SEM images with a scale bar of 10 lm (right), whose inset magnifies the structure with a scale bar of 2lm. (f) Au bowtie nanoanntena:202illustration for the unit (top) and simulated resonant electric fields (bottom). (b) Adapted from Iwanaga et al., J. Nanomater. 2015, 507656 (2015); licensed under a CC BYlicense. (c) Adapted from Iwanaga, Appl. Sci. 8, 1328 (2018); licensed under a CC BY license. (d) Adapted with permission from Zhou et al., Anal. Chem. 84, 4489 (2012).Copyright 2012 ACS. (e) Reproduced from [Fu et al., Appl. Phys. Lett. 97, 203101 (2010)] with the permission of AIP Publishing. (f) Adapted from Sederberg and Elezzabi Opt.Express 19, 10456 (2011).Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-12VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/arenanopillar array of 300 nm periodicity. The Au was located on the topand around the nanopillars. The strongest electric fields were identifiedto appear around the nanopillars because Au nanodots were formed inthe deposition process. The FL EF was evaluated to be approximately2000-fold whereas the EF was not uniform; accordingly, the reproduc-ibility in Fig. 6(a) is estimated to be 5% from the shown experimentaldata. The mushroom structure is in common with that shown with anopen orange triangle in Fig. 6(a). The same structure was applied toSERS measurement, and prominent Raman-scattering enhancementwas reported,142 as referred to in Sec. II E 1.Figure 6(e) shows a schematic of nanopetal structures of Au/Ag(left) and the SEM images (right). The nanopetal structures wereformed by heating of prestressed polystyrene (PS). The productionprocess is lithography-free and a kind of bottom-up approach, whilethe nanogaps of Au/Ag are not controllable. The hot spots inducinglocally strong electric fields are restricted to a small portion in the unitarea estimated to the order of 1%. Consequently, the FL enhancementexhibits significant inhomogeneity. Considering these points, thereproducibility was assessed at 1%, shown with an open black rectan-gular in Fig. 6(a).Au bowtie antenna is shown in Fig. 6(f):202 a schematic (top) andsimulated resonant electric field distribution with an indicator (bot-tom). In the case of gap g ¼ 30 and length L ¼ 475 nm, the simula-tions showed that the locally enhanced electric-field intensity reached3500 at the maximum for the input of unity. Nanogap structures, suchas the bowtie antenna, are widely favored in plasmonics, probablybecause the feature to enhance electric fields looks comprehensive formany researchers. FL molecules were dispersed around the bowtieantennas and the FL was measured. Obviously, the probability for themolecules to be at the center of the bowtie antenna (i.e., hotspot) isinevitably small. Therefore, the most enhanced FL signals are obtained,only when the FL molecules are located at the nanogap with a smallprobability. From the available measured data,194 the reproducibility isestimated to be 1%, as shown with open green circle in Fig. 6(a).Although the other structures in the top ten results are not shownin Fig. 6(a), they are similar to the structures that appears in thisreview. As shown with an open red square in Fig. 6(a), a MIM struc-ture was reported to show 2000-fold FL enhancement;195 the hot spotswere sparsely dispersed; therefore, the reproducibility was approxi-mately 10% from the measured data. Another Au bowtie antenna wasreported to show over 1000-fold EF together with approximately 2%reproducible data.199 Lately, an all-dielectric metasurface of an array ofSi nanopellets with 50nm height was reported as a platform with1200-fold EF,200 which is structurally similar to the all-dielectric meta-surface in Fig. 6(c), except for the low height and the unit cell com-prised the four elements.Among the top ten results, the plasmo-photonic metasurfacesand the all-dielectric metasurface of Si nanocolumn array are highlyreproducible, and therefore, are good candidates for practical FL bio-sensors. The underlying mechanism of the reproducible, high-efficiency FL enhancement is detailed in the Sec. III B.B. Principle of FL enhancementThe whole process from photoexcitation to FL emission isillustrated in Fig. 7. This diagram depicts the outstanding FL-enhancing process on the plasmo-photonic metasurface, described inSec. III A. Except for the energy band peculiar to the plasmo-photonicmetasurface, this framework of photoexcited dynamics is in commonwith that on the all-dielectric metasurfaces and nanostructures inFig. 6. In this context, the diagram is generally accountable for theFL-enhancing process.The EF equation for a particular direction has been addressed fre-quently,124,187,188,200,205,207,208 being phenomenologically expressed as aproduct of three factors as follows:EF ¼ NenhN0� genhg0� cenhðkÞc0ðkÞ; (5)where Nenh and N0 denote excited populations per unit time underenhanced and reference conditions, respectively, and FL quantum yieldgi and radiative decay rate ci are expressed using similar subscripts tothe Ni. Note that the decay rate c depends on wavevector k of radia-tion. The ratio of cenh=c0 is known as Purcell factor.209 In Eq. (5), thePurcell factor is anisotropic and directional along the wavevector k.Normally, the direction dependent on k is determined by the positionof FL-signal detection. The FL quantum yield is defined such thatg ¼ ccþ cNR; (6)where c and cNR denote radiative and nonradiative decay rates, respec-tively. The rates cenh and c0 in Eq. (5) are radiative components.Equation (6) indicates that the nonradiative decay can significantlyreduce the FL yield and becomes close to 0, when cNR � c. Thus, sup-pression of the nonradiative rate is one of the crucial factors to attainlarge EF.The ratios of Nenh=N0 and cenh=c0 in Eq. (5) are proportional toelectric field intensity.124 Therefore, the electric fields at the excitationand FL emission are also crucial to realize effective photoexcitationand efficient FL emission. This is the reason why various metallic anddielectric nanostructures were tested for large FL enhancement.Another key factor is the ratio of FL quantum yield genh=g0. Thisfactor is often neglected in the descriptions and analyses for FL-enhancement effects. However, it is evident that a substantial reductionof this factor significantly reduces the value of EF in Eq. (5). In the con-figurations that were expected to induce large FL enhancement,FIG. 7. Schematic of the principle of FL enhancement, describing the energy dia-gram involved in the FL-enhancing effect on a plasmon–photon (PlasPh) hybridmetasurface.188 Reproduced with permission from Choi et al., Chem. Commun. 51,11470 (2015). Copyright 2015 Royal Society of Chemistry.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-13VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/aresignificant quenching of FL or photoluminescence (PL) was oftenobserved;141,210 such phenomena are called metal-induced quenchingwhen metallic micro- or nanostructures are used. Not only metals butalso dielectrics can induce FL or PL quenching even on the flat sur-face,211 which is sometimes referred to as F€oster resonant energy trans-fer. Thus, the excitation-state transfer to the contacting metals ordielectrics needs to be suppressed to obtain the large FL-intensity EF.We first address the FL-enhancing mechanism on the plasmo-photonic metasurfaces in Fig. 6(b). The whole optical excitation-to-relaxation diagram is schematically illustrated in Fig. 7. Photoexcitationat 532nm, indicated by a green arrow, corresponds to an excited stateje; 0i of the FL molecule on the metasurface. The excitation energy isthe same with that of plasmon–photon (PlasPh) hybrid mode j0; pni,which has large light absorptance. In reality, the mixed state of je; 0iand j0; pni is excited, which has larger transition probability than theoriginal je; 0i and enhances excitation efficiency, leading to the increasein Nenh=N0. Following the photoexcitation, the excitation transfer takesplace on an ultrafast timescale. The FL molecules located on bare Ausurface could be affected by the metal-induced quenching. To avoid it,self-assembled monolayer (SAM) was introduced.188 The SAM pre-vented the excited state from transferring to the Au and assisted thetransition to the lowest unoccupied molecular orbital (LUMO), which isinitial state of FL. Thus, the SAM contributed to the increase in the ratiogenh=g0. FL emission is induced via the transition from the LUMO tothe highest occupied molecular orbital (HOMO) in the FL molecules.Some of the HOMO overlap in energy with the PlasPh modes of highlight emittance and exhibit enhanced FL intensity. These total processescontribute to the FL EF, being expressed in Eq. (5). For the plasmo-photonic metasurfaces,188 the experimental EF took the maximum of2610 at 676nm; the excitation efficiency Nenh=N0 was estimated to be50 from the resonant electric fields and the k-dependent Purcell factorcenh=c0 was experimentally determined to be 11; finally, the increase inthe quantum yield genh=g0 was estimated to be 47. Thus, the SAM func-tioned well as a block to prevent the nonradiative decay. It is crucial thatthe total management of the FL process led to the large EF. We stressthat the large EF did not rely only on the local intense electric fieldenhancement, i.e., hotspot, and therefore, did exhibit high uniformity,i.e., high reproducibility.Second, we describe the FL enhancement on the all-dielectric meta-surface in Fig. 6(c). The entire process, from photoexcitation toenhanced FL emission, is similar to that in Fig. 7. The differences arethat the PlasPh modes should be replaced with the resonant modes inthe all-dielectric metasurface and that the SAM is unnecessary becauseof being free from the metal-induced quenching in the all-dielectric con-figuration. The design strategy for the all-dielectric metasurface to obtainthe large FL enhancement was optimizing the resonance at the FL-emission wavelength.187 When the resonances matched with the FL-emission wavelength, large FL-enhancement effects of almost 1000-foldwere observed. One of the resonant modes contributing to the large FLenhancement is shown in Fig. 8. Numerically computed reflectancespectrum at the normal incidence is shown in Fig. 8(a); a red arrow indi-cates an FL-emission wavelength. The resonant electric- and magnetic-field distributions, jEj and jHj, are presented in Figs. 8(b) and 8(c),respectively. One of the features in the resonant EM fields is that themagnetic fields are strongly localized inside the Si nanocolumn, whoseboundary is drawn with white lines. The maximum of jHj is 11.1, com-pared to the incidence, meaning that the intensity jHj2 is 123.2 at themaximum. The multinode magnetic-field distributions indicates thatthe mode is a higher-order magnetic resonance. As Mie resonances, themagnetic dipole resonance has been frequently referred to.17–19However, the higher-order modes are rarely addressed, except for asmall number of literature.133,187 As an effect of the higher-order mag-netic mode, the corresponding electric-field distributions appear on theoutmost surface of Si nanocolumn, as shown in Fig. 8(b). The electricfields can contribute to the FL enhancement on the outermost surface.From the resonant electric-field distributions, the enhancement factorswere estimated as follows:187 the excitation efficiency Nenh=N0 wasapproximately 20 and the FL-emission efficiency cenhðkÞ=c0ðkÞ wasapproximately 50 for the total EF ¼ 1000 in Eq. (5), under the assump-tion that the ratio of quantum yield was constant, i.e., genh=g0 ¼ 1.The principle for the EL enhancement is considered applicablefor combined systems composed of the metasurfaces and other FL/PLmaterials. Indeed, the plasmo-photonic and all-dielectric metasurfacesin this subsection were recently tested using an atomic monolayermaterial of WS2.212,213 Regarding the PL EF, 1030- and 300-foldenhancements were observed employing the plasmo-photonic and all-dielectric metasurfaces, respectively. Thus, the framework to describethe entire photoexcitation dynamics in Fig. 7 is widely accountable forFL/PL-enhancing effects.C. Detections with metasurface FL biosensorsIn this subsection, we examine the advancements and current sta-tus of the all-dielectric metasurface FL biosensors, which are heredefined as a combined pair of a metasurface substrate and a microflui-dic chip made of PDMS. An appearance of the metasurface FL biosen-sor is seen in Fig. 5(e).FIG. 8. FL-enhancing resonance in the all-dielectric metasurface of the Si nanocol-umn array.187 (a) Reflectance spectrum at the normal incidence. Red arrow indi-cates an FL-enhancing wavelength. (b) and (c) Resonant electric- and magnetic-field distributions, respectively. Adapted from Iwanaga, Appl. Sci. 8, 1328 (2018);licensed under a CC BY license.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-14VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/areFigure 9 shows representative FL-detection results attained by themetasurface FL biosensors. The target biomolecules, detected ranges oftarget concentrations, and used buffers are listed in Table II. TheLODs correspond to the lowest concentrations of the detection ranges.We mention that the detection ranges are potentially extended tohigher concentrations.As an antigen target, a tumor marker CEA was detected using themetasurface FL biosensors. Figure 9(a) illustrates two configurations inexperiment:11 one is a phosphate-buffer saline (PBS)-based diluentbuffer suitable for proteins (left) and the other is a human serum(right). The target CEA was sandwiched using a pair of biotin-labeledand FL-labeled antibodies. Using the microfluidic paths, the metasur-face FL biosensors were first coated using cysteine-tagged streptavidin(Cys-SA), and then the sandwich CEA complexes were immobilizedvia biotin–streptavidin coupling, which is known to be the mosteffective coupling between biomolecules. Thus, an effective immobili-zation protocol was implemented.In Figs. 9(b) and 9(c), the results in the two configuration areshown; orange dots with error bars indicate experimental data anddashed curves represent fitted curves using the Hill equation,216,217which is mathematically equivalent to the four-parameter equationused widely in analysis of protein detection. The Hill equationdescribes immobilization reaction of the target molecules on the meta-surface, being expressed asy ¼ y0 þ ðS� y0Þ xnxn þ KnD; (7)where y represents the FL intensity, y0 the background level in the FLmeasurement, S the saturated signal intensity, x the concentration oftarget molecules, n the degree of cooperative reaction, and KD theFIG. 9. Proof-of-performance of the all-dielectric metasurface FL biosensors. (a)–(c) Tumor marker CEA detection.11 Illustrations of captured CEA in a phosphate-buffer saline(PBS) buffer with bovine serum albumin (BSA) (left) and human serum (right) are shown in (a). Detection profiles in the PBS buffer and human serum are presented in (b) and(c), respectively. Measured data are plotted with closed orange circles and dashed curves are fitted curves using the Hill equation [Eq. (7)]. (d)–(g) Detection of COVID-19 spikeprotein and the antibody.214 (h)–(j) cfDNA detection.12 A scheme from the collection of cfDNAs to the determination of the target sequence by a next-generation sequencer isshown in (h). FL images of the metasurface biosensors and the detection profile are shown in (i) and (j), respectively. (k)–(n) Detection of COVID-19 cDNA detection.215Photographs of the metasurface biosensors and the FL-detection configuration using a microfluidic system are shown in (k) and (l), respectively. Illustration of FL detection onthe metasurface is presented in (m). The detection profile is shown in (n); closed black circles represent measured data and red curve represents the fitted profile by the Hillequation. (a)–(c) Adapted from Iwanaga, Biosensors 13, 377 (2023); licensed under a CC BY license. (d)–(g) Adapted from Iwanaga et al., Biosensors 12, 981 (2022); licensedunder a CC BY license. (h)–(j) Adapted with permission from Iwanaga et al., Nano Lett. 23, 5755 (2023). Copyright 2023 ACS. (k)–(n) Adapted from Iwanaga, Biosensors 12,987 (2022); licensed under a CC BY license.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-15VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/aredissociation constant of molecular interaction. The Hill equationdescribes a quasi-static chemical reaction, such as Aþ B ! C, whichis applicable for the immobilization reaction in microfluidic paths.When we consider a simple reaction of antigen capture, the A is theantibody, the B is the antigen, and the C is the product after the reac-tion of A and B. The amount of reaction products is described by theHill equation in Eq. (7).The dynamic range of the CEA detection was 2–25000 pg/ml,which is listed in Table I and is shown again in Table II for explicitcomparison with other results using the metasurface FL biosensors.The LOD was 2pg/ml, which was determined by evaluating the crosspoint of the Hill curve and 3r (r: standard deviation) level from thezero concentration (i.e., negative control), as shown in Fig. 9(b). Themedical criterion for CEA is 5000 pg/ml; therefore, the detection capa-bility of the metasurface biosensors is sufficient in practice.Importantly, as shown in Figs. 9(b) and 9(c), the detection profileswere hardly affected in the case of the human serum, which has abun-dant obstacle biomolecules, as illustrated in Fig. 9(a). Note that thecomparison with the commercially standard ELISA is already dis-cussed in Sec. II E 10.PSA is a widely used tumor marker for men. The detections wereconducted in a similar manner to the CEA.11 The detection range ofthe PSA was 0.16–1000 ng/ml, even when a buffer composed of ahuman serum was used, as listed in Table II. The LOD was 0.16 ng/ml,which was mainly affected by the capture and detection antibodies. Asis widely known, the performance of antibodies depends on produc-tion companies; therefore, the LOD could be improved just as that ofCEA. The medical criterion of PSA is now set to 4ng/ml. Thus, themetasurface FL biosensors are practically suitable for the diagnosticpurpose.COVID-19 spike glycoproteins were detected using the metasur-face FL biosensors.214 The detection protocol was similar to that forthe CEA and PSA. The configuration after immobilization on a meta-surface of the Si nanocolumn array is illustrated in Fig. 9(d).Experimental data for the COVID-19 spike protein (SP) are shownwith red dots with error bars in Fig. 9(e); the detection range was aswide as 0.64–100 000pg/ml over five-order of concentrations, and theLOD was 0.64pg/ml, evaluated based on the 3r level. Table II lists thequantitative results. The detection was conducted using a PBS-baseddiluent buffer including BSA, which is symbolically expressed asPBSþBSA in Table II.The results concerning the detection of the antibodies against theCOVID-19 spike glycoproteins are shown in Figs. 9(f) and 9(g). It waswidely recognized that the antibodies functioned as a neutralizing anti-body and there was a social demand to measure the concentrations inthe COVID-19 pandemic. The detection configuration is similar tothat in Fig. 9(d). In this case, since the target is the antibody, the spikeproteins were immobilized in advance at a high concentration and theconcentration-varied antibodies were detected using a FL lable.214Obviously, the FL images of the metasurfaces in Fig. 9(f) change thebrightness in proportional to the target antibody concentrations. TheFL intensities are plotted with red dots with error bars in Fig. 9(g); theinset magnifies the data near 0 ng/ml. The profile is almost lineardown to 1.56ng/ml, which was the LOD for the antibodies.Other antibodies, such as IgG and anti-p53 antibody, weredetected in ranges of pg/ml on the metasurface FL biosensors.133 Thedetection procedures were similar to those for the CEA, PSA, andCOVID-19 antibody. Immunoglobulin G (IgG) is the most abundantantibody in human body. The anti-p53 antibody is a tumor marker forearly stage.219–221 As listed in Table II, the detection ranges of the IgGand anti-p53 antibody were 5–2000pg/ml and 50–5000 pg/ml, respec-tively, and the LODs were 5 pg/ml for the IgG and 50pg/ml for theanti-p53 antibody. The medical criterion for the anti-p53 antibody isset to a few ng/ml. Therefore, the metasurface FL biosensors can meetthe diagnostic range.The IgG and anti-p53 antibody were also detected in the rangesof pg/ml on the plasmo-photonic metasurface biosensors.134 Thedetection ranges of IgG and of anti-p53 antibody were 5–10 000pg/mland 50–5000pg/ml, respectively. The detection capability was similarto that of the all-dielectric metasurface FL biosensors in Fig. 9 andTable II. From a practical and economic standpoint, the plasmo-photonic metasurfaces requires Au deposition and have a slight disad-vantage, compared to the all-dielectric metasurfaces, though the FL-enhancement capability is twofold better [Fig. 6(a)].As a nucleic acid target, cfDNA was detected, which is consideredto be a next-generation diagnosis marker in the near future.222,223However, the concentration in liquid biopsies, such as blood, is knownto be extremely low; therefore, ideally high sensitivity is required forthe accurate detection. Figure 9(h) presents a schematic of cfDNA gen-eration, collection, and sequence analysis using a next-generationsequencer;224 the target sequence for detection was determined as dis-played in Fig. 9(h). A set of the FL images on the metasurface FL bio-sensors is shown in Fig. 9(i), and the detection profiles are shown inFig. 9(j)12 where the horizontal axis represents target cfDNA concen-trations in the units of copies/test and the corresponding concentra-tions in attomolar (aM, i.e., 10�18mol/l) is indicated at the top; theinset magnifies the data near 0 copies/test, represented in linear scales.The detected signals at 1 copy/test were discriminated from 0. Thisdemonstrates an ultimate high-sensitivity detection of DNA, whichhas not been realized, to the best of our knowledge, in any other bio-sensing techniques.At the level of a single-target molecule, the sampling processbecomes probabilistic and follows the Poisson distribution; this statisti-cal analysis was implemented in the demonstration of the singlecfDNA detection.12 Table II lists a set of the cfDNA results, which areTABLE II. Summary of targets detected by the all-dielectric metasurface FL biosen-sors. The detection range is presented, based only on the reported experimentaldata. SP and Ab denote spike protein and antibody, respectively.Target Detection range Buffer ReferencesCEA 2–25 000 pg/ml Serum 11PSA 0.16–1000 ng/ml Serum 11COVID-19 SP 0.64–100 000 pg/ml PBS þ BSA 214COVID-19 Ab 1.56–100 ng/ml PBS þ BSA 214IgGa 5–2000 pg/ml PBS þ BSA 133anti-p53 Ab 50–5000 pg/ml PBS þ BSA 133cfDNA 0.488–2000 aM Tris-HCl 12COVID-19 cDNAb 5.86–4000 aM Tris-HCl 215HSAc 18.75–160 000 ng/ml Urine 218aImmunogloblin G.bComplementary DNA.cHuman serum albumin.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-16VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/arealso referred to in Sec. II E 10. As a buffer for cfDNA, a standard bufferfor DNA, Tris-HCl 10mM, was used to conduct the short-cycle ampli-fication procedure that suppresses falsely positive reactions and rein-forces the robustness of the detection.The COVID-19 complementary DNAs (cDNAs) were detectedusing the metasurface FL biosensors,215 one of which is shown inFig. 9(k). The FL signals were measured under illumination of greenlight-emitting diode (LED) light, as shown in Fig. 9(l). A schematic ofFL detection of the amplicons of the COVID-19 cDNA is shown inFig. 9(m). The experimental data (black dots with error bars) areshown in Fig. 9(n); the horizontal axis is the target concentration inaM, and the data are shown in the log-log scale. A fitted curve usingthe Hill equation [Eq. (7)] is shown with a red curve. As listed in TableII, the LOD was evaluated to be 5.86 aM (or 14 copies/test). Notably,this LOD was achieved through only 35 thermal cycles for nucleic-acidamplification. This LOD meets the criterion that was officiallyannounced for reliable infection tests.225 As we refer to in Secs. II E 7and II E 8, typical LODs for COVID-19 were approximately 40 and 10copies/test in the qPCR and dPCR, respectively, under the conditionthat the PCR cycling was conducted at more than 40 cycles, whichmeans that more than 32-fold amplicons were produced in the qPCRand dPCR, compared to the metasurface FL biosensors. Thus, themetasurface FL biosensors exhibit a substantially better detection capa-bility than the dPCR that is considered to be the present gold standard.Other comparisons and discussions are found in the literature.215In a different approach, HSA was detected using a methodologydistinct from the previously mentioned cases using the ordinary FLprobes. For HSA, specific fluorogen molecules inducing AIE wereincorporated. Further details are described in the Sec. IIID.D. AIE—Aggregation-induced emissionAIE is a unique optical phenomenon that molecules exhibitbright FL in their aggregated state, whereas they exhibit weak or negli-gible FL in their dispersed state.227 The restriction of intramolecularmotion (RIM) is currently the most widespread and acceptedmechanism to explain the AIE phenomena,228 as illustrated inFig. 10(a). The molecular rotors, such as rotatable aromatic rings, inAIE molecules persistently consume energy from the excited statewhen they are completely dissolved in benign solvents, thereby leadingto a fast energy decay without being released.229 When AIE moleculesaggregate, intermolecular interactions limit the spinning rotors, whichcauses molecules to decay through the radiation channel.230 Based onthis background, the strong hydrophobic luminous cores of AIE FLmolecules are typical properties that allow them to readily form aggre-gates in physiological settings or aqueous media.231 Furthermore, natu-ral spatial restricted environment is produced by the significant sterichindrance of reactive substances especially posed by biological macro-molecules, which further results in FL emission upon photoexcitationby continuous accumulation into the macromolecular structure.232Significantly, efficient radiative transition and photosensitization in theaggregate state promote outstanding FL emission with the characteris-tics of fast response, high sensitivity, “on-off” switch ability and goodstability.233In the past few decades, numerous researchers have successfullydeveloped plenty of AIE FL bioprobes with high emissions and largeStroke shifts to achieve FL detection of simple and cost efficiency inbiosensing.234–237 For instance, it was reported that an AIE probe, atetraphenylethylene (TPE) derivative sodium 1,2-bis[4–(3-sulfonato-propoxyl)phenyl]-1,2-diphenylethene (BSPOTPE) for quantitativedetection of HSA.238 This probe is non-fluorescent in PBS buffers butbecomes emissive in the presence of HSA. The established FL methodshowed a broad linear dynamic range (LDR) of 0.0676–6.76mg/l,LOD of 0.0676mg/l, and an excellent selectivity to HSA. Additionally,the sensing process was also demonstrated in artificial urine, showinggreat potential in practical application. However, the performance ofAIE probes may be interfered by autofluorescence or impurity compo-nents in actual complex biosamples.239 Moreover, extremely low con-centrations of analytes also make AIE bioprobes difficult to detect theFL signal because of the tiny amplitude of light absorption. To addressthose issues, a feasible expectation is to integrate AIE bioprobes intoFIG. 10. (a) Mechanism of AIE phenomena.226 (b) Schematic of AIE fluorogens incorporated with an all-dielectric metasurface FL biosensor for HSA detection.218 (a) Adaptedfrom Zhang et al., Regen. Biomater. 10, rbad044 (2023); licensed under a CC BY license. (b) Hu et al., Adv. Opt. Mater. 12, 2400868 (2024); licensed under a CC BY license.Applied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-17VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/arecompatible optical biosensors to further amplify sensitivity or reducelight loss and background noise. The all-dielectric metasurface biosen-sor is most likely to satisfy such requirements of AIE bioprobes.The first study on the combination of an AIE-based fluorogen,TPE-4TA, and the all-dielectric FL metasurface FL biosensor has beenconducted recently to achieve quantitative detection of trace HSA.218The experimental configuration is illustrated in Fig. 10(b). This meta-surface FL biosensor have six independent microfluidic channels,which can be controlled to deliver different analytes simultaneously. Inthe meanwhile, the TPE-4TA with typical AIE characteristics can beimmobilized on the metasurfaces through the flexible biofunctionaliza-tion of Si nanostructures. First, the binding molecules of Cys-SA pro-vide a robust and durable physical adsorption layer240 when flowingacross Si nanocolumns. Second, the biotin-labeled HSA (Biotin-HSA)antibodies can establish a dense biological network via the non-covalent protein-ligand interactions between streptavidin and biotin,where HSA are captured efficiently and specifically. Third, when thetetrazolate nitrogens of TPE-4TA reacts to the polar dominant-contacting lysine residue in the HSA binding conformation throughhydrogen bonding and electrostatic interactions,241 the restriction ofintramolecular motion triggers the strong FL signal.Furthermore, the optical properties of this metasurface are suitedto the excitation and emission wavelengths of the TPE-4TA.218 Thereflectance spectrum of the metasurface shows two definite reflectancebands of 30% and 70% at 360 and 530nm, respectively. The corre-sponding distributions of resonant EM fields accounted for the under-lying mechanism of FL enhancements.218 The electric field distributionat 360 nm excitation wavelength predominantly appears at the upperoutermost surface of Si nanocolumns, which is the most favorablezone for HSA immobilizations. This electric field distribution at theFL-emission wavelength of 530nm qualitatively resembled with thatin Fig. 8, facilitating the ED transition in the AIE molecules. Theprinciple for the AIE enhancement is in common with that describedin Sec. III B.The FL kinetic behaviors of TPE-4TA used in the metasurface FLbiosensor exhibited excellent FL stability within 2 h and a good LDR inthe microalbuminuria range of 0.0188–160l g/ml, especially high sen-sitivity to the traces of HSA less than 20l g/ml.218 More significantly,the FL regulation of the metasurface was superior to that of the othertwo conventional platforms; indeed, the metasurface FL biosensorsshowed a significant 25.6-fold FL enhancement for HSA detection,compared to enhancements of onefold and 3.48-fold observed in themicroplate and microfluidic platforms, respectively. In the applicationscenarios involving human urine samples, the metasurface platformalso showed the highest HSA recovery of 95.6% while the microplateand microfluidic platforms did 88.9% and 91.5% recovery, respectively.Moreover, the LOD for metasurface platform was as low as 18.75 ng/ml whereas those of microplate and microfluidic platforms were 300and 150ng/ml, respectively. Even when an urine sample was diluted2560 times, the metasurface FL biosensors still possessed 10% FLretention rate of HSA. These results fully demonstrate that the meta-surface FL biosensors function very efficiently for the HSA detection,which is most likely to come from the following three factors: (i) Sinanocolumns that enable HSA to immobilize is the primary factor forthe effect of FL enhancement, (ii) FL amplification is determined bythe local enrichment of AIE molecules, and (iii) the FL-enhancementeffect of resonant EM fields. The scope of FL activities is furthercompressed by the spatial constraints of microfluidic pathways, whileSi nanocolumns facilitate the local enrichment of FL molecules withina non-uniform stacking in a minuscule area, contributing to the FLoutput. Furthermore, the resonant EM fields further reinforce the FLemission of HSA and TPE-4TA conjugates, immobilized at the outer-most surface of Si nanocolumns.Summing up the HSA results, this AIE-based fluorogens incorpo-rating with the all-dielectric metasurface FL biosensors successfullyachieves FL enhancement for HSA detection. In the realistic configura-tion in the urine, the AIR fluorogens functioned with the metasurfaceFL biosensors, exhibiting high sensitivity and robustness.IV. FUTURE PROSPECTSIn summary, we have conducted a comprehensive survey withfocusing on practical applications of metasurfaces. Concretely, themetalens, metasurface IR absorber/emitter/detector, and metasurfacebiosensors have been addressed together with the key concepts. With aparticular emphasis, the biosensing techniques are further addressedfor comparison with the metasurface biosensors. Moreover, we havedelineated the current status of the metasurface FL biosensors. Theproof-of-concept has covered a broad range of target biomoleculesacross nucleic acids and proteins, such as antigens and antibodies, andhas reached an ultimate sensitivity that can discriminate one targetDNA from zero, which has not been attained in any other biosensors.One of the advantages in the metasurface FL biosensors is thatthey are mass productive, similarly to the metalenses through high-precision, high-throughput nanolithography. Thanks to their excep-tional and reproducible FL enhancement, the metasurface FL biosen-sors enable high-sensitivity biosensing in a simple, compact, cost-effective, and automated manner,12 which is another practical advan-tage. The existing high-sensitivity methods, such as digital ELISA anddigital PCR, require complicated and elaborate statistical analysis, andare demanding in cost, due to the complex instruments; these draw-backs have not been overcome for more than ten years. Consideringthese points, the metasurface FL biosensors are one of the good candi-dates for the next-generation biosensors that are applicable for diversetargets.One of the trends in the next-generation diagnoses is to detectlow-concentration targets in an aM range, such as cfDNA andmicroRNA. At present, the biosensing methods that can conduct alarge number of short-time biosensing for the low-concentration tar-gets have not yet been established. This is one of the most suitableissues that the metasurface FL biosensors can contribute to. Asdescribed in Sec. III, the high sensitivity, high throughput, and robust-ness of the metasurface FL biosensors have been substantiated for thefuture practical biosensing. Thus, the basic requirements for the next-generation diagnoses are satisfied.Regarding the emerging technology, artificial intelligence (AI), itis often discussed that AI makes complicated responses by biosensorsmore comprehensive and feasible. However, this means that the bio-sensors themselves are generally hard to use and/or understand, imply-ing that they are originally impractical. In contrast, simply speaking,the metasurface FL biosensors transduce the target biomolecule con-centrations to the FL intensity, which is feasible to understand.As one of the best scenarios in the near future, the metasurfaceFL biosensors will contribute to high-precision, high-throughput, andmassive data-acquisition biosensing services that combine with big-data life science and data-handling AI. Although the aspect of massiveApplied Physics Reviews REVIEW pubs.aip.org/aip/areAppl. Phys. Rev. 12, 021305 (2025); doi: 10.1063/5.0253333 12, 021305-18VC Author(s) 2025 04 April 2025 13:16:06pubs.aip.org/aip/aredata acquisition has hardly discussed regarding biosensors, one of themost significant roles of scientific devices, such as biosensors, will be totake scientifically reliable big data. This role can be efficiently con-ducted by the metasurface FL biosensors.242 This role is similar to thefirst-principle calculations for molecular dynamics in chemistry, whichyielded big data to make use of AI in the field of protein design.243 Thescientific firm ground built by quantitative biosensing data, a part ofwhich can be acquired by the metasurface FL biosensors, will be cou-pled with generative AI to enable the individual to enjoy the maxi-mized healthful life.ACKNOWLEDGMENTSM.I. acknowledges Takashi Hironaka, Wanida Tangkawsakul,and Saki Ishihara for their contributions to the daily measurementsusing metasurface FL biosensors. This study was partially supportedby JSPS KAKENHI Grant Nos. JP17H01066 and JP24K01389,NIMS Priority Research Project “Biomaterials,” and AdvancedResearch Infrastructure for Materials and Nanotechnology (ARIM)of the Ministry of Education, Culture, Sports, Science andTechnology (MEXT), Japan, Proposal No. JPMXP1223NM5163.AUTHOR DECLARATIONSConflict of InterestThe authors have no conflicts to disclose.Author ContributionsMasanobu Iwanaga: Conceptualization (lead); Project administration(lead); Supervision (lead); Visualization (lead); Writing – original draft(lead). Qi Hu: Conceptualization (supporting); Validation (support-ing); Writing – original draft (supporting). Youhong Tang:Conceptualization (supporting); Project administration (supporting);Supervision (supporting); Writing – original draft (supporting).DATA AVAILABILITYData sharing is not applicable to this article as no new data werecreated or analyzed in this study.REFERENCES1N. Yu, P. Genevet, M. A. Kats, F. Aieta, J.-P. Tetienne, F. 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