Stacked Gold Nanodisks for Bimodal Photoacoustic and Optical

May 22, 2017 - More quantitative comparison of the average PAM and OCT intensities from the three nanoparticles is described in Supporting Information...
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Stacked Gold Nanodisks for Bimodal Photoacoustic and Optical Coherence Imaging Jung-Sub Wi,*,†,§ Jisoo Park,†,‡,§ Heesung Kang,†,§ Donggeun Jung,‡ Sang-Won Lee,† and Tae Geol Lee*,† †

Center for Nano-Bio Measurement, Korea Research Institute of Standards and Science, Daejeon 305-340, Republic of Korea Department of Physics, Sungkyunkwan University, Suwon 440-746, Republic of Korea

‡

S Supporting Information *

ABSTRACT: Herein, we report on biological imaging nanoprobes: physically synthesized gold nanodisks that have inherent optical advantagesa wide range of resonant wavelengths, tunable ratio of light absorption-to-scattering, and responsiveness to random incident lightdue to their two-dimensional circular nanostructure. Based on our proposed physical synthesis where gold is vacuum deposited onto a prepatterned polymer template and released from the substrate in the form of a nanodisk, monodisperse two-dimensional gold nanodisks were prepared with independent control of their diameter and thickness. The optical benefits of the Au nanodisk were successfully demonstrated by the measurement of light absorbance of the nanodisks and the application of stacked nanodisks, where a smaller sized Au nanodisk was laid atop a larger nanodisk, as bimodal contrast agents for photoacoustic microscopy and optical coherence tomography. KEYWORDS: gold nanoparticle, plasmonic, photoacoustic, OCT, contrast agent

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nanodisk, was used to avoid the kinetic or thermodynamic considerations necessary in typical colloidal syntheses of nanoparticles. Although 2D plate-like anisotropic shapes are preferred in a colloidal synthesis when the growth rate of a specific crystal plane is much slower than of others, Au nanospheres whose isotropic shape is thermodynamically preferred are usually synthesized together as byproducts.26−28 In addition, 2D nanoplates obtained from colloidal synthesis (typically trianglular nanoplates) have sharp corners and straight edges that require additional effort to smooth out in order to form circular nanodisks.29,30 Compared to chemical synthesis, 2D circular patterns are more easily formed using a lithographical method because a Gaussian beam of electrons or photons is more conducive to the circular shape. Lithographically defined 2D nanodisks, however, are usually substrate-bound and utilized for studies on their plasmonic sensing properties.2,3,7,31,32 In this work, substrate-released monodisperse 2D Au nanodisks were synthesized by our proposed physical synthesis. The diameters and thicknesses of the Au nanodisks were independently controlled, which allowed the resonant frequency tuning of the nanodisk as

ight absorption and scattering are greatly enhanced by the light-induced collective oscillation of free electrons in a nanostructured noble metal, namely a localized surface plasmon.1−8 This enhanced light−matter interaction allows plasmonic nanoparticles to be promising contrast agents for laser-based biological imaging such as photoacoustic tomography,9−16 optical coherence tomography,17−21 and surface enhanced Raman scattering-based imaging.22−25 Accordingly, much effort has been made to synthesize plasmonic nanoparticles that have well-controlled geometries, as these geometries strongly correlate to the plasmonic nanoparticles’ light-absorbing and light-scattering properties as well as the resonant wavelengths. In this report, we propose that two-dimensional (2D) Au nanodisks and their stacked form, resembling that of a fried egg sunny side up, as advanced nanoprobes for laser-based imaging because their 2D forms are intrinsically conducive to a wide range of resonant wavelengths, tunable ratio of light absorption-to-scattering, and responsiveness to random incident light. Here, we have judged the use of “2D” to most expeditiously convey the meaning of flatness and to differentiate these nanodisks from other, more obvious onedimensional (1D) or three-dimensional (3D) forms. To fabricate the nanodisks, a top-down physical synthesis, in which Au is vacuum-deposited onto a nanoimprinted polymer template and released from the substrate in the form of a 2D © 2017 American Chemical Society

Received: April 4, 2017 Accepted: May 22, 2017 Published: May 22, 2017 6225

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Figure 1. Schematic illustration of the overall process adopted in this study: Nanoimprint lithography (NIL) using a truncated Si nanocone array; O2 plasma etching for a controlled time to adjust the diameter of the PMMA opening; wet chemical dissolution of PMGI; vacuum deposition of Au with a surface normal or oblique angle. After Au lift-off, the Au nanodisks were released from the BCB surface and collected by centrifugation. PMMA, PMGI, and BCB are poly(methyl methacrylate), polymethylglutarimide, and bisbenzocyclobutene, respectively.

synthesized and used as contrast agents in laser-based biological imaging. In this process, the array of truncated Si nanocones shown in Figure S1 was used as the NIL mold and served to enable the synthesis of differently sized Au nanodisks. Since the sloped sidewall of the Si nanocone is transferred to the PMMA layer during the NIL step, the diameter of the cavity at the bottom of the PMMA and the diameters of the Au nanodisks could be increased from 65 to 166 nm by increasing the O2 plasma etching time from 4 to 20 s (Supporting Information, Figure S1). Independent control of the lateral and vertical dimensions of the Au nanodisk, then, is possible by varying the etching time of the PMMA and the deposition time of the Au, respectively. The SEM images shown in Figure 2a−d, observed after drying the aliquots of each nanodisk solution on the Si substrate, clearly demonstrate the role of the Si nanocone as a universal NIL mold that can offer various-sized nanodisks. The average diameters of the Au nanodisks and their deviations were evaluated according to the protocols proposed by NIST for measuring nanoparticle size using SEM35 and showed that the physically synthesized nanodisks had a narrow size distribution of approximately 3 nm (Supporting Information, Figure S2). The zeta potential of the Au nanodisks in deionized water was

well as its light absorption and scattering properties. In short, we show that by stacking two different-sized Au nanodisks it is possible to synthesize bimodal contrast agents that can interact with incident light at two different resonant wavelengths by two different interacting modes: light absorption for photoacoustic imaging and light scattering for optical coherence imaging.

RESULTS AND DISCUSSION As illustrated in Figure 1, the Au nanodisks were prepared using physical synthesis. The method includes steps for nanoimprint lithography (NIL); O2 plasma etching of the residual imprinting resist (poly(methyl methacrylate), PMMA); wet chemical development of an undercutting layer (polymethylglutarimide, PMGI); vacuum deposition of Au; Au lift-off; and final release of the nanodisks by dissolution of the sacrificial under-layer (benzocyclobutene, BCB). The released Au nanodisks were then redispersed in deionized water after centrifugation. The physical synthesis of artificially designed nanoparticles based on NIL and vacuum deposition has been highlighted in previous reports.33,34 In this work, by utilizing an array of truncated Si nanocones as the NIL mold and by applying an oblique-angle deposition of Au, differently sized two-dimensional Au nanodisks and their stacked forms were 6226

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Figure 2. Physically synthesized Au nanodisks. SEM images of (a−d) Au nanodisks and (e,f) fried egg-shaped Au nanodisks. Diameters of the 20 nm-thick Au nanodisks in (a−d) are 81, 105, 130, and 166 nm, respectively. The Au nanodisks in (a−e) were observed after drying the aliquots of each nanodisk solution on the Si substrate, and the cross-sectional image in (f) was observed before the nanodisk release step. The inset images in (f) show the Au nanodisks from three different deposition angles of Au. The scale bars are all 500 nm.

evaluated to be −23.4 ± 9.3 mV, which was suitable for dispersing the nanodisks in for several days and redispersing by gentle shaking due to the electrostatic repulsion between the nanodisks. As well as the water-dispersibility, the bare surface of the proposed Au nanodisk without toxic surfactant molecules serves its biocompatibility. As demonstrated in our previous study,36 the physically synthesized Au nanodisks show no noticeable influence to the cell viability (up to 104 nanodisks per cell) and also to the apoptotic activity (under 1 μL administration of 10 pM-concentation nanodisks in 6 week-old mice). As illustrated in Figure 1 and shown in Figure 2e,f, by tilting the deposition angle and rotating the sample during deposition, it was possible to synthesize a stacked Au nanodisk (SAN) composed of two differently sized nanodisks. Compared to the outer region of the disk where the Au flux is deposited at a specific angle of the sample rotation, the central region of the disk is exposed to the incident Au flux during the entire deposition time. This led to a natural formation of the central protrusion (i.e., upper disk) in the SAN, whose lateral size could be controlled by the incline angle of the Au flux. The three inset images in Figure 2f show that the sizes of the protrusions decreased as the deposition angle increased. In fact, at an extreme tilting angle of the Au flux, the central protrusion disappeared, and the Au films that were deposited at the bottom and sidewall surfaces of the polymer pores could be shaped into Au nanodishes.37,38 In the current study, the lateral size of the protrusion was defined as almost half of the overall lateral dimension of the SAN to ensure two different lightinteracting windows as discussed below. Figure 2e,f shows the SEM images of the SAN with an 80 nm-sized upper disk and 180 nm-sized lower disk. The overall height of the SAN was approximately 60 nm.

To assess the optical characteristics of the physically synthesized stacked Au nanodisks, the extinction spectra of the aqueous solutions of the nanodisks were examined. Figure 3a shows that the resonant wavelengths of the 20 nm-thick Au nanodisks increased from 670 to 830 nm when their diameters were increased from 81 to 166 nm. This spectral shift in plasmon resonance was attributed to the increased oscillation length of the surface plasmon as the geometrical size of the nanodisk increased, which aligns with our calculated results (Supporting Information, Figure S3). Further, by changing the thickness of the nanodisk, it is also possible to shift its resonant frequency while maintaining the lateral size of the nanodisk. Figure 3a,b shows that 81 nm-sized Au nanodisks with different thicknesses ranging from 10 to 30 nm can be excited in a broad spectral window, meaning that the two dimensions of the Au diskdiameter and thicknesscan be tuned independently to synthesize near-infrared (NIR)-active contrast agents. As tabulated in Figure 3b, another distinct benefit of using 2D Au nanodisks as contrast agents for light-based imaging is their large molar extinction coefficients. The experimentally averaged molar extinction coefficients of the 2D nanodisks in Figure 3b, ranging from 1010 to 1011 M−1 cm−1, clearly demonstrate their superior response to light, compared to 1D nanorods or their derivatives such as nanorices and nanostars, whose extinction coefficients have been reported to be about 109 M−1 cm−1.12 This is due to the responsiveness of 2D nanodisks to the random direction and polarization of incident light. To maximize the extinction cross-section of a nanorod, the light should be irradiated in a direction perpendicular to the long axis of the nanorod, while the polarization direction is parallel to it; without these conditions, the nanorods are not sufficiently activated (Supporting Information, Figure S4). For the 2D nanodisk, however, maximum extinction is assured with 6227

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Figure 3. Optical characteristics of physically synthesized Au nanodisks and the SANs. (a) Measured extinction curves of the aqueous solutions of the Au nanodisks. The diameters and thicknesses of the Au nanodisks are (black) 81 and 30 nm, (gray) 81 and 20 nm, (red) 105 and 20 nm, and (purple) 166 and 20 nm, respectively. (b) Measurements for the resonant wavelengths and molar extinction coefficients for the Au nanodisks synthesized in this study. (c) Measurements for the extinction curves of the aqueous solutions of the SANs. (d) Squared amplitude of the local electric field of the SAN. The wavelength of the incident light was (upper) 630 nm and (lower) 850 nm. Light directions (black arrows), polarization angles (blue arrows), and positions of electric field monitors (dish-dot lines) are noted in the levitating figures. The scale bars are all 100 nm.

our calculations on the substrate-released nanodisks by the FDTD simulation in this report (Figure S3) both show that Au nanodisks with relatively small diametersgenerally below 100 nm diameter for a 10−30 nm-thick nanodiskare effective for light-absorption, while nanodisks with diameters larger than 100 nm are effective for light-scattering. Therefore, the upper (i.e., smaller) and lower (i.e. larger) disks that make up the SAN allow interaction with incident light by two different modes of light-absorption and scattering at the two different resonant wavelengths of 630 and 850 nm. To utilize the two different light interaction modes of SANs, the SANs were applied as bimodal contrast agents for photoacoustic microscopy (PAM) and optical coherent tomography (OCT). The highly effective light absorption and scattering by the SANs fulfilled the principles of signal acquisition in PAM and OCT, respectively. Therefore, the SANs that were visible in both PAM and OCT functioned to enhance the image contrast in both PAM and OCT as well as to correlate the two different types of biological information obtained from PAM (by which vascular structures are imaged due to the strong light absorption by hemoglobin) and OCT (by which tissue morphologies are obtained due to their intrinsic scattering differences). As illustrated in Figure 4a, if a PAM-sensitive blood substitute flowed through one of the three tubes imbedded in a phantom tissue, it would be difficult to

random polarization angles if the incident direction of the light is perpendicular to the lateral plane of the nanodisk. Additionally, the incident light from a random direction can maximize the extinction probability if the light polarization is parallel to the lateral plane of the nanodisk (Supporting Information, Figure S4). The two optical benefits of the 2D nanodisks, namely, the wide range of resonant wavelengths and superior light responsiveness, are both embodied in our proposed nanodisk stack, i.e., SAN. The extinction spectrum in Figure 3c measured from the SAN aqueous solution can be fitted by the envelope curve of two Gaussian peaks (dotted lines in Figure 3c), meaning that the two different-sized disks inside the SAN interact with the light of two different wavelengths, as expected. The calculated local electric field contours in Figure 3d also show the two different interacting modes of SAN and that these two modes are not as sensitive to the direction of incident light as are 2D nanodisks. The locally amplified electric fields around the edges of the upper and lower disks visually demonstrate that two different geometrical lengths of SAN successfully function to host localized surface plasmon polaritons of two different oscillation lengths. It is notable that the relative ratio of absorption and scattering of the total extinction is sensitive to the lateral dimension of the nanodisk. Measurements taken of the substrate-bound nanodisks by Langhammer et al.32 and 6228

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of the SANs is better than the GNR under the PAM imaging conditions used (Supporting Information, Figure S6), and it would be another advantage of the SANs. Finally, the SANs were applied to in vivo imaging of a chick embryo. The images to the left in Figure 5a show the crosssectional and 3D-recontructed views of the OCT images of the chick embryo after partial removal of the eggshell. Because the scattering difference originated from structural differences makes the OCT signal, the inner and outer shell membranes in the chick embryo as well as the wall of the blood vessels underneath the inner membrane were clearly observed in the OCT images. These two membranes separate the outermost air cell, the thin intermediate albumin layer, and the thick inner albumin layer. Into the intermediate albumin layer was injected 1 μL of aqueous SANs solution (concentration = 7 × 109 mL−1) using a syringe. As shown in the images on the right in Figure 5a and Supporting Movie 1, the injected SANs diffused well between the two membranes and produced a bright OCT signal. The SAN-injected chick embryo was also imaged using PAM to demonstrate the potential of SANs as bimodal contrast agents for both PAM and OCT. The incident light of the wavelengths 650 and 532 nm was irradiated to observe the PA signals from the SANs and blood flow, respectively. Under the 650 nm laser irradiation, absorption coefficient of oxygenated whole blood is known to about 1 cm−1, 39 which is approximately 1011 orders of magnitude smaller than that of the SANs. This is why the PA signal of such a low dosage (12 pM, 1 μL) of SANs overwhelms the PA signal of blood in the left image of Figure 5b. This image of nanoparticle distribution could be overlapped with the PAM image of the vascular network obtained under the 532 nm laser irradiation, as shown in the right image in Figure 5b. Because the PA signals originate from wavelength-specific light absorption and its consequent conversion to ultrasound waves, the PAM images in Figure 5b show only the signals from light absorbers―the SANs and hemoglobins―without background signals from the surrounding environment. Therefore, as discussed previously, the contrast enhancing effect of the SANs in PAM and OCT is useful in isolating the location of the nanoparticle by PAM and correlating the nanoparticle distribution with their surrounding tissue structures by OCT. In our current study, the bare SANs move freely and become distributed randomly during imaging, which makes it challenging to correlate the information from PAM and OCT. However, target-specific distribution of the SANs, which can be made possible by introducing targetspecific ligands on the nanoparticle surface or by simply using the enhanced permeability and retention effects of the nanoparticle, is expected to become routine.

Figure 4. Phantom study of the SANs for OCT and PAM. (a) Schematic illustration of a cross-sectional OCT image and planeview PAM image of the tissue phantom where three silicone tubes are embedded. Two of the tubes are filled with (left) blood phantom and OCT contrast agents and (right) blood phantom and OCT-PAM bimodal contrast agents, respectively. (b) Crosssectional OCT image and plane-view PAM image of the tissue phantom where four silicone tubes are embedded. Black-colored ink, gold nanorods (GNRs), SANs, and gold nanospheres (GNSs) are contained in the tubes (from left to right: ink, GNRs, SANs, and GNSs). The scale bars are all 1 mm.

pinpoint the tube that contained the blood substitute, even with contrast agents for PAM or OCT flowing together in another tube. However, by utilizing bimodal contrast agents for PAM and OCT, we were able to correlate the two images obtained from PAM and OCT and to identify the blood-phantomcontaining tube in the OCT image. Figure 4b shows a crosssectional OCT image and a plane-view PAM image of the agarose tissue phantom in which four silicone tubes were embedded. The four tubes contained aqueous solutions of a black-colored ink (blood phantom), gold nanorods (GNRs) (PAM contrast agents), SANs (bimodal contrast agents), and gold nanospheres (GNSs) (OCT contrast agents). The concentrations of the three nanoparticles were all 140 ppm (GNRs: 2.4 × 1011 mL−1, SANs: 7 × 109 mL−1, GNSs: 1.7 × 109 mL−1). The GNRs and the GNSs were resonant with the excitation lights for PAM (wavelength = 650 nm) and OCT (wavelength = 850 nm), respectively. As demonstrated in Figure 4b, only the SANs were visible in both PAM and OCT, which made it possible to identify the ink-containing tube in the OCT image. More quantitative comparison of the average PAM and OCT intensities from the three nanoparticles is described in Supporting Information, Figure S5. Briefly, the average PAM intensity of a single SAN is 2 orders of magnitude larger than that of a GNR. The average OCT intensity of a single SAN is approximately four times smaller than that of a GNS, but the average OCT intensities normalized by the Au mass are similar in SAN and GNS. Moreover, the photostability

CONCLUSION In summary, we physically synthesized 2D Au nanodisks that have the intrinsic optical advantages of a wide range of resonant wavelengths, tunable ratio of light absorption-to-scattering, and responsiveness to random incident light. Based on our nanofabrication process with a controlled plasma etching time and vacuum deposition angle, we were able to synthesize variously sized 2D Au nanodisks with a narrow size distribution and SANs of a two-tiered form. The measured absorbance of the SANs and the calculated electromagnetic fields near the SANs clearly demonstrate that they combine the optical functionalities of the two nanodisks as well as their external geometries. The combined optical properties of the SANs were successfully utilized to improve the image contrast for PAM and 6229

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Figure 5. In vivo application of the SANs for bimodal imaging of OCT and PAM. (a) Cross-sectional and projective views of OCT images of a 5 day-old developed chick embryo (left) before and (right) after injection of SANs. The a.c., o.m., i.m., and b.v. represent the air cell, outer membrane, inner membrane, and blood vessels, respectively. (b) Plane-view PAM images of (left) the injected SANs only and (right) the injected-SANs overlapped with blood flows. The SANs and vasculature images were observed by light of wavelengths 650 and 532 nm, respectively. The colors in the right image are for clear visualization (red: blood flows, green: SANs). The hole indicated by the circular dashed line in the left image shows the entry point for the needle when injecting the SANs. The scale bars are all 500 μm. The color bars for OCT and PAM are logarithmic and linear scale, respectively. The intensity registered in the OCT image (Iimage) and the raw OCT signal (Iraw) have the following relation: Iimage = 20 log Iraw. profile. Then, a Au thin film was deposited by thermal evaporation. After the Au deposition, the PMMA and PMGI layers were removed with acetone and AZ 300 MIF, respectively, and the synthesized Au nanodisks were released from the sample surface by dissolving BCB with a commercial solution (Primary Stripper A, Dow Chemical). The Au nanodisks were then collected by centrifugation. After solvent exchange, the nanodisks were finally suspended in water. Optical Coherence Tomography Imaging. A superluminescent diode (SLD) with a center wavelength of 849 nm (BLM2-D-840-B-I10, Superlum, Ireland) and a −3 dB bandwidth of 100 nm was used as the broadband light source in the OCT system. The emitted light from the SLD was coupled to a 2 × 2 optical fiber coupler and split into reference and sample arms in a 50:50 ratio. In the sample arm, the collimated light was incident to the sample via a 2D galvanometer scanner and an objective lens. The light reflected from the reference and sample arms were recombined and directed to a linearwavenumber spectrometer. The interference signals generated by the path length differences between the reference and sample arms were detected by the spectrometer at the 125 kHz A-line rate. For 3D volume data, 800 cross-sectional images with 800 A-lines/image were acquired. 3D image was reconstructed by commercial software (Amira 6, FEI, USA). Photoacoustic Microscopy Imaging. A tunable wavelength nanosecond pulsed laser (NT242, EKSPLA, Lithuania) with a pulse

OCT. In light of these results, it is clear that the Au nanodisks and their stacked form can be applied as highly sensitive contrast agents for laser-based biological imaging. We expect that nanodisks containing magnetic elements or diseasetargeting ligands, which are incorporated by successive vacuum-deposition or by gold−thiol chemistry, would also be useful as multifunctional in vitro or in vivo imaging agents.

METHODS Synthesis of Gold Nanodisks. To fabricate the lithographically patterned polymer template, a 1.3 μm-thick benzocyclobutene (Cyclotene3022-35, Dow Chemical) layer was spin-coated on a Si substrate and baked at 230 °C for 5 min. Next, a 90 nm-thick polymethylglutarimide (PMGI-SF3, MicroChem) layer was spincoated on a Si substrate and baked at 200 °C for 5 min. Then, a 100 nm-thick nanoimprint resist (PMMA, Microresist Technology) was spin-coated on PMGI and baked at 100 °C for 2 min. After preparing the trilayered polymer stack, the wafers were subjected to thermal nanoimprinting at 200 °C under a pressure of 30 bar for 3 min using a commercial nanoimprint tool (ANT-4H, Exatech). After nanoimprinting, the PMMA was etched using O2 plasma, and the PMGI layer was dissolved by a commercial wet chemical developer (AZ 300 MIF, AZ electronic materials) for 3 s to form an undercut 6230

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ACS Nano width of 5 ns and repetition rate of 1 kHz was used to excite the nanoparticles. The collimated laser beam was focused through an objective lens and scanned across the sample using a 2D galvanometer scanner. For reflection mode PA signal detection, a customized module was used to confocally align the illuminated laser beam and the generated ultrasound.40 An unfocused ultrasonic transducer (V326-SU, Olympus-NDT, Japan) with a center frequency of 5 MHz and a −6 dB bandwidth of 76.2% was used to collect the PA signals. During chick embryo imaging, the light fluences were 552 and 780 nJ at 532 and 650 nm, respectively. The collected signals were amplified and converted using a high-speed digitizer to obtain crosssectional PA images (x−z plane), finally expressed as a maximum amplitude projection (MAP) image. The MAP image projected the maximum signal of each A-line onto the corresponding 2D plane (x−y plane). The GNRs and GNSs for PAM and OCT imaging were purchased from Nanopartz (product name: AC12-25-650) and BBI Solutions (product name: EM.GC200), respectively.

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ASSOCIATED CONTENT S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.7b02337. Additional data of FDTD calculations, SEM images (PDF) Movie S1: Spectral domain optical coherence tomography movie immediately after injection of 1 μL of aqueous SANs solution (concentration = 7 × 109 mL−1) using a syringe. Scan rate: 25 frames/s (averaged with 5 frames). Each frame of the movie shows the plane (x−y) view (AVI) Movie S2: Spectral domain optical coherence tomography movie before injection of aqueous SANs solution. Scan rate: 25 frames/s (averaged with 5 frames). Each frame of the movie shows the plane (x−y) view (AVI)

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jung-Sub Wi: 0000-0002-9531-2001 Tae Geol Lee: 0000-0002-6674-4147 Author Contributions §

These authors contributed equally. J.-S.W. and T.G.L. developed the idea and designed the experiments; J.-S.W. and J.P. fabricated the samples; H.K. carried out the optical measurements; S.-W.L. and D.J. contributed the data interpretation; J.-S.W. and T.G.L. prepared the manuscript, and all authors contributed to its revision. Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS This study was supported by Development of Platform Technology for Innovative Medical Measurements funded by Korea research Institute of Standards and Science (KRISS2017-GP2017-0020), the Pioneer Research Center Program (NRF-2012-0009541), the Global Frontier Project (HGUARD_2013M3A6B2078962), and the Bio & Medical Technology Development Program (2015M3A9D7029894) of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning. 6231

DOI: 10.1021/acsnano.7b02337 ACS Nano 2017, 11, 6225−6232

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DOI: 10.1021/acsnano.7b02337 ACS Nano 2017, 11, 6225−6232