Nitride-based Microarray Biochips: A New Route of Plasmonic Imaging

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Functional Inorganic Materials and Devices

Nitride-based Microarray Biochips: A New Route of Plasmonic Imaging Fan-Ching Chien, Jen-Long Lo, Xingwang Zhang, Ertugrul Cubukcu, Yu-Tang Luo, KaiLin Huang, Xiaofang Tang, Chien-Sheng Chen, Chii-Chang Chen, and Kun-Yu Lai ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b14962 • Publication Date (Web): 29 Oct 2018 Downloaded from http://pubs.acs.org on October 31, 2018

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ACS Applied Materials & Interfaces

Nitride-based Microarray Biochips: A New Route of Plasmonic Imaging Fan-Ching Chien†, Jen-Long Lo†, Xingwang Zhang‡, Ertugrul Cubukcu‡,§, Yu-Tang Luo†, Kai-Lin Huang†, Xiaofang Tang||,⊥, Chien-Sheng Chen#,⊥, Chii-Chang Chen†, and Kun-Yu Lai*,†

†

Department of Optics and Photonics, National Central University, Chung-Li 320, Taiwan.

‡

Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.

§

Department of Electrical and Computer Engineering, University of California, San Diego, La Jolla, CA 92093, USA.

||Research

⊥Department

Center for Applied Sciences, Academia Sinica, Taipei 11529, Taiwan.

of Biomedical Science and Engineering, National Central University, Chung-Li 320, Taiwan.

#

Department of Food Safety/Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Keywords: surface plasmon resonance, biosensors, InGaN, quantum wells, local density of states

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ABSTRACT:

The desire to improve human lives has led to striking development in biosensing technologies. While the ongoing research efforts are mostly dedicated to enhance speed and sensitivity of the sensor, a third consideration has become increasingly important: compactness, which is strongly desired in emergency situations and personal health management. Surface plasmon resonance imaging (SPRi) is one of the few techniques that can potentially fulfill all the three goals, considering its multiplexed assay capability. However, miniaturizing SPRi biosensors remains elusive as it entails complicated optical gears. Here we significantly slim the architecturing of SPRi devices by visualizing the varied local density of states around analytes. The unusual detection scheme is realized by building a gain-assisted SPRi with InGaN quantum wells (QWs), where the QW-plasmon coupling efficiency hinges on localized refractive-index variation. This new modality abolishes the prism, the polarizer and beam-tracking components in the most used Kretschmann configuration, without compromising the performances.


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Surface plasmon resonance imaging (SPRi) is one of the most promising high-throughput biosensing techniques. Comparing with their fluorescent counterpart, SPRi biosensors not only render the label-free process,1 but further expedite the assay by simultaneously visualizing numerous biomolecular interactions with a multi-array format.2-4 Most of current SPRi instruments are realized through the Kretschmann arrangement, wherein a prism coupler is adopted to increase the momenta of incident photons so that SP polaritons can be launched along the metal/dielectric interface.3,4 In order to record the resonance signals (intensity or wavelength), precise optical tracking components have to be implemented,2-4 plus the indispensable refractive-index-matching oil to ensure efficient coupling between the prism and the metal-coated glass slide.5 These onerous designs/procedures make on-site and personal diagnoses exceedingly difficult. Although the prism coupler can be replaced with diffraction gratings or metal nanoparticles,3 the necessitated submicron patterns and demanding nano-fabrication prohibit these technologies from scalable and reproducible applications. SPR effect in InGaN quantum wells (QWs) has been extensively studied since late 90’s.6-8 The very efficient QW-SP coupling is often evidenced by the large Purcell factor,6,7 which quantifies the boosted spontaneous emission rate of the QW adjacent to a resonant SP mode. The phenomenon is attributed to the fast energy transfer from carrier recombination in the QWs to electron oscillations in the metal within a near-field distance.6,7 Essentially, the interaction between the QW and the SP is dictated by the photonic local density of states (LDOS), being enclosed in the Purcell factor and closely related to the local electrical fields surrounding the QW-SP companion.9 Since the intensity 3 ACS Paragon Plus Environment


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of SP waves propagating along the metal/dielectric interface is extremely sensitive to the change of surface refractive index (and thus the local field), the concomitant change of LDOS leads to a varied QW-SP energy transfer rate, serving as an ideal instrument for the detection of biomolecular bonding events. With specifically designed microscopic methods, superresolution images can be achieved by mapping the localized optical intensities due to LDOS variation,9,10 but such notion is rarely exploited in SPRi biosensing. In this study, InGaN QWs are demonstrated as an exceptional tool for LDOS-sensitive SPRi biosensors. The device is built with a much simplified configuration, which is made possible by many distinct properties of the QW wafer, including the chemical inertness, the transparent waveguide structure, the inherent polarized emission, and most importantly, the gain-medium-like behavior. These characteristics are not collected by other semiconductors, making nitride QWs one of the scarce materials that are exclusively suitable for SPRi biosensing. RESULTS AND DISCUSSION Figure 1a shows the layer structure of the nitride biosensing platform. The 3-nm InGaN QW is sandwiched by a 6-nm GaN spacer and a 3-μm GaN base layer. The 6-nm spacer acts as a protection cap of the QW, as well as an important factor in the coupling between the QW and the plasmons created at the Ag/GaN interface. Since the plasmonic intensity decays exponentially away from the interface, the electron-hole recombination must take place in close proximity to the metal in order to facilitate energy transfer to the SP mode.6 The band gaps (Eg’s) and refractive indices (RI’s) of GaN 4 ACS Paragon Plus Environment

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and InN are:11 Eg_GaN = 3.4 eV; Eg_InN =0.7 eV and RI_GaN = 2.5; RI_InN = 3.1, readily providing the SP evanescent wave via the multi-angled spontaneous emission from the GaN/InGaN/GaN waveguide structure. The QW emits blue light (~ 446 nm), being close to the plasmon resonance wavelength of Ag/GaN,7 Ag is therefore employed as the metal layer. The inertness of Ga-polar GaN and sapphire allows them to survive in most chemical solutions.12 That is to say, the SPRi wafer can be recycled by etching/re-depositing the Ag layer, obviating the index-matching oil in the prism-based systems. The stability of GaN-based biosensors in chemical solutions has been reported by researchers.13,14 Although the index-matching oil can also be avoided in Kretschmann-based systems by directly depositing metal layers on the prism, such method is rarely applied considering the vulnerability of glass in strong etchants. Another important feature of the nitride wafer lies in the fact that InGaN/GaN/sapphire is transparent at the plasmon resonance wavelengths (400-600 nm) of Au and Ag,7 the mostly used metals for SPRi devices. This allows the favored back-side optical pumping, leaving the biomolecules undisturbed on the front (metal) side. Such arrangement is not possible with other QW semiconductors (GaAs, GaP, InP and other related compounds), considering their opaqueness or substrate absorption of the incident light. For example, the room-temperature band gap of GaP is 2.26 eV, showing strong optical absorption for the photon energy above 2.2 eV (λ < 564 nm),15 which would not allow the operation wavelengths in the blue regime. Figure 1b compares the dispersion curves of Ag/GaN and Au/N-SF5 glass. The latter is often seen in typical Kretschmann-based SPR sensors.16 The presented curves are obtained with the well-known 5 ACS Paragon Plus Environment


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surface plasmon dispersion relation, ksp = (ω/c)[εdεm/(εd + εm)]1/2, where ksp is the wavenumber of the surface plasmon wave, ω is the angular frequency, c is the light speed in vacuum, and εd (or εm) is the relative permittivity of the dielectric material (or metal). Calculations were performed with reported dielectric functions (Table S1, Supporting Information). It can be seen that the larger RI of GaN contributes to the greater plasmonic momentum of Ag/GaN, which is expected to improve the detection sensitivity through the longer SP propagating length.17 The RI-sensing mechanism on the Ag surface can be understood by Figure 1c, where the distribution of electrical field is visualized by the finite-difference time-domain (FDTD) analyses considering a dipole placed within the QW structure described in Figure 1a. Boundaries of the QW and the Ag layer are delineated by dotted lines in the figure. The inset shows an enlarged view enclosed by the green dashed circle. In order to see the effect of RI-change on the metal, a 10-nm analyte layer with varied RI is added on the Ag surface, followed by a semi-infinite layer of water (RI = 1.33). The displayed field intensities are normalized to the maxima within the QW. Additional calculation details can be found in Supporting Information. In the figure, two intensity peaks are clearly seen at the interfaces of the Ag layer, indicating the formation of plasmonic waves. As the analyte RI is increased from 1.33 (the blue line) to 1.54 (the red line), the electric field shifts toward the analyte layer, enhancing the plasmon intensity at the interface (viewed by the inset). In other words, the increased surface index leads to larger photon momenta, facilitating the collective electron oscillation in metal and thus intensifying the plasmonic wave.18 6 ACS Paragon Plus Environment

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Nevertheless, the enhanced plasmonic intensity with a larger RI can be compromised by the reduced energy transfer rate from the QW to the polaritons, as depicted by Fermi’s golden rule:6 Γ(ω) = (2π/ℏ)〈d∙EQW〉2ρ(ω)

(1)

where Γ(ω) is the spontaneous recombination rate of the QW emitting to the plasmon continuum, d is the electron-hole dipole moment, EQW quantifies the spatial confinement of the electrical field within the QW, and ρ(ω) is the mode density of plasmons. It can be shown that the product of 〈d∙EQW 〉2ρ(ω) is proportional to LDOS.9 Since increasing RI on the metal leads to increased

evanescent penetration away from the nitride layer, i.e. less field confinement within the QW, Γ(ω) is reduced through the weakened EQW.

More importantly, the competing dynamics between the increased plasmon momentum and the decreased Γ(ω) can be manipulated by the number of QW. It has been shown that including a gain medium in the SPR structure can effectively compensate the intrinsic ohmic loss due to metal absorption.19,20 As the QW acts like a gain medium by pumping energy into the plasmonic resonance, increasing the QW number brings in additional plasmon intensity, effectively prolonging the propagation length along the metal/dielectric interface, and therefore enhancing the sensitivity of RI.17 It should be mentioned that the InGaN QW functions with merits of the larger gain coefficient and the immunity to photobleaching,8,21 in comparison with the commonly used dye molecules. Figure 2a shows photoluminescence (PL) spectra of the InGaN/GaN QW with different surface conditions. With the contribution of Ag reflection (20 % at 446 nm) deducted, one can still see that 7 ACS Paragon Plus Environment


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the emission intensity is increased after the coverage of the 10-nm Ag layer, signifying the occurrence of QW-SP coupling.7 The enhanced PL intensities also indicate that the spontaneous rate in QW is increased and the propagating plasmonic waves are extracted by the scattering due to the inherent Ag/GaN interface roughness, as discussed in literatures.7 The response to RI changes on the wafer is confirmed by the further enhanced emission intensities observed on water (RI = 1.33) and ethylene glycol (C2H6O2, RI = 1.43). The spectra in Figure 2a and the following SPR intensities/images were attained with the apparatus displayed in Figure 2b. This optical setup not merely discards the bulky prism and the reflection tracking system, but also excludes the polarizers that are often obligated in the Kretschmann configuration. Although some particular materials, such as epsilon-near-zero conducting oxides,22,23 can also produce SP polaritons without prisms or grating couplers, the exclusion of polarizers (and the short detecting wavelength) make the nitride-based SPRi device distinct from these competitors. In SPR biosensing, transverse-magnetic (TM) polarized (or p-polarized) light is required to induce the plasmonic effect along the metal interface.3 The essential TM light is intrinsically created in InGaN QWs thanks to the extraordinary band structure of III-nitrides. The lack of inversion symmetry in wurtzite nitride compounds gives rise to the presence of a crystal filed along the c-axis, which

splits

the

valence

bands

and

results

in

isotropic

emission

of

TM-

and

TE(transverse-electric)-light from the c-plane surface.24 The naturally produced TM light further saves the space for SPRi acquisition, greatly increasing the potential in device portability. 8 ACS Paragon Plus Environment

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Performances of the QW-based biosensor can be evaluated by the detecting resolution (Δn), which is the minimum detectable index change on the metal surface. To demonstrate the tunability and the effect of the gain-medium QW, the structures with one-repeat (1×) and six-repeat (6×) QWs were analyzed. The multiple QWs, separated by 12-nm GaN barriers, emit much intenser radiation than the single QW (see Figure S1 in Supporting Information for PL spectra and the layer structure). Figure 2c presents the relative SPR intensities as a function of RI measured with varied concentrations of ethylene glycol. It is clear that the intensity increases with a steeper slope on the QW×6 wafer, validating the benefit of the enlarged gain coefficient. The detecting resolution is calculated by the equation: Δn = Δd/s, where Δd is the noise level (0.03 % in our case, see Figures S2 in Supporting Information) and s (in %/RIU, as % per RI unit) is the slope of dotted linear fitting lines shown in the figure. With s = 465 %/RIU and 1340 %/RIU, the corresponding Δn’s are 6.5×10-5 RIU and 2.2×10-5 RIU for the QW×1 and the QW×6, respectively. These results demonstrate that the QW structure offers an important dimension in optimizing the detection capability of the biosensor. In order to estimate the limit of detection (LOD), i.e. the lowest detectable biomolecular concentration, human immunoglobulin G (hIgG) was immobilized on the sensing surface. The immobilization process started with a drop coating of thiolate monolayer on the Ag layer, followed by a protein G layer, and finally the hIgG with varied concentrations was applied. The thiolate monolayer not only provides anchors to immobilize protein G, but also serves as a passivation layer to prevent the interaction between Ag and the biomolecules.25 Figure 3a presents the PL spectra 9 ACS Paragon Plus Environment


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recorded after the coverage of the thiolate monolayer (dashed lines) and the subsequent protein G (solid lines) on the QW×1 and the QW×6 samples. Echoing the result in Figure 2a, the PL signals are intensified on the protein G layer, owing to the increased thickness and RI on the thiolate.26,27 The effect of gain enlargement is again manifested by the fact that the integrated PL intensity of the QW×6 sample is enhanced by 43 % upon the application of protein G, comparing to the 25 % enhancement seen on the QW×1 sample. The characterization with hIgG reveals a similar fashion (Fig. 3b). Both of the samples exhibit increased emission intensities as the hIgG concentration goes from 0.2 μM to 1.0 μM. Dividing the noise level (0.03 %) by the sensitivity (determined from the slope of the dotted fitting line), LOD of the QW×6 sample is 1.9 nM, being 27 % improved from that (2.6 nM) of the QW×1. Comparing to the results in Figure 2c, the less distinctive improvement with the QW×6 can be due to inhomogeneous distribution of the biomolecules, leading to non-identical RI’s of the same hIgG concentration. It should be noticed that the sensing performances can be further pushed through the optimization of QW number and growth conditions. Specifically, although the multiple QWs lead to enhanced emission intensity, the intensified QW emission will not wholly contribute to the ultimate detecting sensitivity/resolution. This is because the QW toward the bottom (i.e. substrate) become less contributive to the SPR effect as the QW-SP coupling deteriorates exponentially with the distance from the metal surface.7 In other words, the well/barrier thicknesses should be properly selected to maximize the QW-SP coupling efficiency, while ensuring sufficient quantum confinement for 10 ACS Paragon Plus Environment

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photon generation. In laboratories, the LOD can be easily reduced via a lock-in detection scheme to stabilize the excitation power. As depicted in the Supporting Information (Figs. S2), the LOD as low as 0.089 nM is achieved with a 3 kHz lock-in amplifier. Table 1 summarizes the resolutions and LOD’s presented in this work. These performances are superior to many other SPRi devices,28-32 particularly the portable ones.29-32 The characterization of resolutions and LOD’s was performed within 48 hours after the deposition of Ag in order to avoid the issues of Ag deterioration. Frankly, the oxidation of silver can lead to a decreased plasmonic wave intensity (and thus lower detection sensitivity), owing to the decreased number of collectively oscillating electrons on the oxidized surface. Silver oxidation may also affect biocompatibility because of the toxicity induced by the oxidative stress.33 However, recent research efforts have overcome the problem with various passivating materials, such as graphene,34 thiol,25 and gold,35 which are currently under investigation in our group. High-throughput assay process of the QW-based SPRi platform was presented with the antibody microarray shown in Figure 4, obtained by an automatic array printer. After the immobilization of protein G (1 μM) on the QW×6 sample, the hIgG with concentrations of 0.2 μM, 0.6 μM, and 1.0 μM was spotted in a 3×3 array on the Ag surface. Figure 4a illustrates the differentiability and the repeatability of the microarray biochips. The diameter of each circular spot is around 380 μm, and the average image intensities (arbitrary unit) within a spot are listed (in yellow numbers) at the lower-right corner. With these results, the average intensities for the three hIgG concentrations of 0.2 11 ACS Paragon Plus Environment


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μM, 0.6 μM, and 1.0 μM are 7.40±0.34, 8.63±0.17, and 9.18±0.14, respectively. The assay precision can be improved with specific strategies for signal sampling and data management.36 Note that the detecting wavelength (~ 446 nm) is in the blue regime, being shorter than those used in most current SPRi biosensors.2-5 As the minimum resolvable length is proportional to the detecting wavelength,17 the nitride-based SPRi system can deliver the images with superior resolutions. Figure 4b shows the microarray of 9×8 spots prepared on a 0.8×0.8 cm2 wafer. The biochip was cut from on a 2-inch wafer, and thus the number of spots can be facilely increased with a scalable biochip size. CONCLUSIONS A QW-based SPRi microarray biochip is introduced with new operation modality, in which biomolecular interactions are visualized via the varied LDOS. The novel biosensing tactic is realized with a much simplified architecture, featuring four distinctive traits: i) Chemical inertness, enabling biochip reusability. ii) Transparent waveguide-like QW structure, rendering the prism-free SPR effect. iii) Inherent polarized emission, eliminating the external polarizer. iv) Gain-medium function, enhancing the detection sensitivity. The SPRi biosensor presented here opens a new landscape for the development of compact and high-throughput diagnostic devices.


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METHODS Crystal Growth of the InGaN QWs: The Ga-polar InGaN QW wafers were grown on double-side-polished sapphire substrates by commercial MOCVD (AIXTRON 200/4 RF). Ammonia (NH3), trimethylgallium (TMG, for the 3-μm GaN base), triethylgallium (TEG, for QWs), and trimethylindium (TMI) were used as the precursors. Growth temperature was 1120 ºC for the GaN base, and 785 ºC for the QWs. V/III ratios for the 1120-ºC GaN base, the 785-ºC InGaN wells, and the 785-ºC GaN barriers were 2400, 9028 and 11416, respectively. The reactor pressure was kept at 200 mbar. Reagent

Preparations:

16-Mercaptohexadecanoic

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide

hydrochloride

acid (EDC

(MHDA), hydrochloride),

N-hydroxysuccinimide (NHS), protein G, and IgG from human serum were purchased from Sigma-Aldrich. Phosphate buffered saline (PBS) buffer with pH 7.4 was procured form Bioman. The orientated immobilization of hIgG was implemented as previously described.37 An ethanol solution containing MHDA (0.5 mM) was used for the MHDA functionalization on the surface of Ag film. The chip was soaked in the MHDA solution for 30 min. After rinsed with ethanol, the self-assembled monolayer of MHDA with the carboxyl group on the Ag surface was fabricated. The chip was then soaked for 30 min in a 2 mM EDC and 5 mM NHS solution and rinsed twice. The carboxyl-modified chip was drop-coated by the 1-μM protein G in 1× PBS buffer solution for 30 min. After washing, the protein G was covalently immobilized on the self-assembled MHDA monolayer. Since protein G has Fc domains for hIgG immobilization, orientated hIgG molecules are obtained via the binding in the Fc region. Imaging Acquisition: SPR images were acquired by an inverted optical microscope (Olympus) with a scientific CMOS (sCMOS) camera (Andor). A diode laser (CNI) with a wavelength of 405 nm was used to excite the QW emission. The microarray were spotted on the QW wafer with a SmartArray TM136 printer (Capitalbio). In the characterization of RI resolution and LOD, each presented SPR 13 ACS Paragon Plus Environment


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intensity was the average of 2000-repeat automatic measurements with the sampling interval of 0.2 sec (total acquisition time: 400 sec).


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Figure 1. (a) Layer structure of the silver-coated nitride compound used for the proposed SPRi biosensor. (b) Dispersion relations for the SPR structures of Ag/GaN and Au/Glass(N-SF5), showing the larger SP momentum of the nitride combination. (c) The distribution of normalized absolute electric fields attained by FDTD analyses, with a dipole placed in the center of the InGaN QW shown in (a). Boundaries of the QW, the Ag layer, and the 10-nm analyte layer with the RI of 1.33 or 1.54 are indicated by black dotted lines. The inset enlarges the area enclosed by the green dashed line, displaying the enhanced field intensity with the analyte of the larger RI.



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Figure 2. (a) PL spectra of the InGaN/GaN QWs with different surface conditions. The refractive indices (RI) of water (H2O) and ethylene glycol (C2H6O2) are 1.33 and 1.43, respectively. (b) The optical path employed to record the PL spectra/images presented in this study. (c) Relative SPR intensities as a function of RI, which are linearly fitted with dotted lines. Error bars indicate standard deviation of the repeated measurements. The QW×6 sample (in red) exhibits improved detecting resolution (Δn) because of the increased plasmonic intensity and thus the prolonged propagation length along the GaN/Ag interface.


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Figure 3. (a) PL spectra recorded on the QW×1 and QW×6 samples, both of which were firstly measured with the surface covered by a thiolate monolayer, followed by a repeated measurement with the immobilized protein G on top of the thiolate layer. (b) Relative SPR intensities attained with hIgG at the concentrations varied from 0.2 μM to 1.0 μM. Error bars indicate standard deviation of the repeated measurements. The slopes of dotted fitting lines were used to calculate the limit of detection (LOD) for the QW×1 and QW×6 samples.



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Figure 4. (a) Images of the microarray spots with varied hIgG concentrations on the QW×6 sample captured by a CCD camera. The yellow numbers at the lower-right corner of every spot are averaged relative SPR intensities within the circular area. (b) Photograph of a 0.8×0.8 cm2 QW-based SPRi biochip, cut from a 2-inch epitaxial wafer. The microarray of 9×8 spots are fabricated on the sensing surface.


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Table 1. Resolutions & LOD’s of the QW-based biosensors characterized with the DC (direct current) condition and the lock-in amplifier.

DC

Lock-in

QW x 1

QW x 6

Resolution (RIU)

6.5 x 10-5

2.2 x 10-5

LOD (nM)

2.6

1.9

Resolution (RIU)

9.7 x 10-6

4.4 x 10-6

LOD (nM)

1.7 x 10-1

8.9 x 10-2



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ASSOCIATED CONTENT Supporting Information Information includes simulations, PL spectra of the QW×1 and QW×6 samples, and the lock-in characterizations. These materials are available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes The authors declare no competing ﬁnancial interest.


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ToC Graphic

Cover Art Caption:

0.4-mm-thick plasmonic microarray biochips built with InGaN quantum wells, pumping blue photons, like a gain medium, into the surface plasmon resonance. Biomolecular interactions are sensed via varied local density of states. This new modality abolishes the prism and many other components in the conventional Kretschmann configuration, without compromising the performances.


Nitride-based Microarray Biochips: A New Route of Plasmonic Imaging

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