sensors Article
Design and Performance of a Portable and Multichannel SPR Device Xiao-ling Zhang 1,† , Yan Liu 2,† , Ting Fan 1,2 , Ning Hu 1,2, *, Zhong Yang 3 , Xi Chen 1 , Zhen-yu Wang 4 and Jun Yang 1, * 1
2 3 4
* †
Key Laboratory of Biorheological Science and Technology, Chongqing University, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400030, China;
[email protected] (X.Z.);
[email protected] (T.F.);
[email protected] (X.C.) Chongqing Engineering Research Center of Medical Electronics Technology, Chongqing University, Bioengineering College, Chongqing University, Chongqing 400030, China;
[email protected] Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, China;
[email protected] Department of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China;
[email protected] Correspondence:
[email protected] (N.H.);
[email protected] (J.Y.); Tel.: +86-23-6511-1954 (N.H.) These authors contributed equally in this study.
Received: 20 April 2017; Accepted: 16 June 2017; Published: 19 June 2017
Abstract: A portable multichannel surface plasmon resonance (SPR) biosensor device is presented in this study. As an optical biosensor device, the core component of its light path is a semi-cylindrical prism, which is used as the coupling unit for the excitation of the SPR phenomena. Based on this prism, a wedge-shaped incident light beam including a continuous angle range (10◦ ) is chosen to replace the commonly-used parallel light beam in traditional SPR devices, in which the incident angle is adjusted by a sophisticated mechanical system. Thus, complicated, cumbersome, and costly mechanical structures can be avoided in this design. Furthermore, the selection of a small and high-stability semiconductor laser and matrix CCD detector as well as a microfluidic system aids in the realization of a miniaturized and multichannel device. Several different samples were used to test the performance of this new device. For ethanol with different concentrations, the sensing response was of good linear relativity with the concentration (Y = 3.17143X + 2.81518, R2 = 0.97661). Mouse IgG and goat anti-mouse IgG were used as biological samples for immunological analysis, and BSA as the control group. Good specific recognition between mouse IgG and goat anti-mouse IgG has been achieved. The detection limit of antibody to antigen coated on the sensing surface was about 25 mg/L without surface modification. Keywords: surface plasmon resonance; sensor; portability; microfluidic
1. Introduction Surface plasmon resonance (SPR) biosensors are a widely-used optical sensor, capable of rapidly monitoring the interaction between two kinds of biomolecules in real-time, with no requirement for a label. Since Liedeberg and Nylander [1] set up a gas sensor based on the SPR phenomenon in 1983, SPR technology has been applied not only in gas detection [2], but also in biomacromolecular interaction (e.g., protein and protein [3,4], DNA and DNA [5], aptamer and ligand [6]) analysis, food safety [7], environmental monitoring [8–10], drug screening [11], and so on. Owing to its outstanding advantages compared with some other traditional methods such as enzyme-linked immune sorbent assay (ELISA) and radioimmunoassay (RIA), SPR biosensors have high value and huge potential use in biomedical
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analysis. However, some bottlenecks, such as cumbersome and complicated structure as well as high cost, must be overcome. The research and development of miniaturized and high-throughput SPR sensors are attracting wide Sensors attention. For example, an SPR sensing device (Spreeta SPR2000) developed by Texas Instruments 2017, 17, 1435 2 of 7 (USA) integrated a delicate optical structure in a miniaturized system [12]. Compared with traditional The research and development of miniaturized and high-throughput SPR sensors SPR biosensors with single or dual channels, multichannel design cannot only excludeare theattracting temperature wide attention. For example, an SPR sensing device (Spreeta SPR2000) developed by Texas fluctuation, non-specific binding, and background noise, but also detect more samples simultaneously Instruments (USA) integrated a delicate optical structure in a miniaturized system [12]. Compared to achieve high efficiency [13,14]. Increasing efforts have been made to realize the miniaturization and with traditional SPR biosensors with single or dual channels, multichannel design cannot only multichannel detection of SPR devices [11]. exclude the temperature fluctuation, non-specific binding, and background noise, but also detect In this study,simultaneously a miniaturized and portable SPR biosensor was developed. Tobeen realize more samples to achieve high efficiency [13,14]. Increasing efforts have madethe to aim of miniaturization and portability, the complicated turntable structure realize the miniaturization and multichannel detection of SPR devices [11].which is used in traditional devices toInachieve variable incidentand angles was SPR replaced withwas a wedge-shaped incident this study, a miniaturized portable biosensor developed. To realize the light aim ofbeam miniaturization and portability, the complicated which usedfocal in traditional formed by a focusing lens. Meanwhile, a focusing turntable lens withstructure small size and isshort distance was devices to achieve variable angles was replaced with a wedge-shaped incident beamwere adopted. Additionally, a smallincident and high-stability semiconductor laser and matrix CCDlight detector formed by a focusing lens. Meanwhile, a focusing lens with small size and short focal distance was chosen. Aiming at multichannel monitoring and low sample consumption, a few micro-channels adopted. Additionally, a small and high-stability semiconductor laser and matrix CCD detector were were fabricated and integrated with the sensing surface to realize the detection of multiple samples chosen. Aiming at multichannel monitoring and low sample consumption, a few micro-channels simultaneously. Finally, several samples were used to calibrate and test this new device. were fabricated and integrated with the sensing surface to realize the detection of multiple samples simultaneously. Finally, several samples were used to calibrate and test this new device.
2. Experimental
2. Experimental
2.1. SPR Device
2.1. SPR SPR Device An biosensor is an optical sensor device, in which the optical path is the most important unit. This device based on anisangle-modulated mode,inand thethe reflectivity of different angles Anis SPR biosensor an optical sensor device, which optical path is the mostincident important is detected to achieve SPRonangle (the angle of the lowest In of thedifferent optical incident path design unit. This device isthe based an angle-modulated mode, andreflectivity). the reflectivity angles is detected to achieveisthe SPR angle (the angle of the reflectivity). Infrom the optical path will (Figure 1), the core component a semi-cylindrical prism. A lowest parallel light beam the source design (Figure 1), the core componentincident is a semi-cylindrical parallel light beam from the of be converged to form a wedge-shaped light beam, prism. which Awill be focused on the bottom sourceA will be converged to form a wedge-shaped incident light beam, which will of be the focused on the the prism. sensor chip with a 50 nm-thick gold film is bound on the bottom prism, and the bottom of the prism. A sensor chip with a 50 nm-thick gold film is bound on the bottom of the prism, SPR phenomenon on the gold film will change the reflectivity of incident light. Biological reaction and the SPR phenomenon on the gold film will change the reflectivity of incident light. Biological may influence the SPR phenomenon, and hence change the SPR angle. The wedge-shaped incident reaction may influence the SPR phenomenon, and hence change the SPR angle. The wedge-shaped light incident beam includes a series of continuous incident angles, so the reflectivity of these angles can be light beam includes a series of continuous incident angles, so the reflectivity of these angles monitored using aby photoelectric detector,detector, and complicated mechanical rotation structures can be can be by monitored using a photoelectric and complicated mechanical rotation structures omitted. This optical system is integrated with a microfluidic system as well as a controlling can be omitted. This optical system is integrated with a microfluidic system as well as a controlling and processing module module to formtothe sensor devicedevice (Figure 1). 1). and processing form the sensor (Figure
Figure 1. Sketch map of the optical system of the surface plasmon resonance (SPR) sensor device Figure 1. Sketch map of the optical system of the surface plasmon resonance (SPR) sensor device (Channel: CH).CH). (Channel:
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The thickness of the protein film l on the surface of the gold film is constant, and the refractive index of the protein film on the surface of the gold film increases with the adsorption of protein molecules. Assuming that the protein concentration of the layer of protein film on the surface of the gold film is C after a period of time t, the surface concentration of the protein on the surface of the gold film is Γ = Cl. With the adsorption of protein molecules on the surface of the gold film, the change of protein concentration in the membrane leads to the change of the surface concentration, which also increases the refractive index of the protein membrane: ∆Γ = ∆C · l =
∂C ∂C ∆n · l = ∆(nl ) ∂n ∂n
(1)
Using the linear relationship between the effective optical path difference and the resonance angle, the relationship between the SPR pixel shift and the protein surface concentration adsorbed on the surface of the gold film was obtained as follows [15]: ∆P = A
∂n ∆Γ ∂c
(2)
∆P is pixel shift, and A is constant. When the light source chosen is red light with a wavelength of about 650 nm, ∂n/∂c ≈ 0.18 [16], the relationship between SPR pixel changes and the biofilm concentration in the gold film surface is: ∆P = 0.18A∆Γ (3) 2.1.1. Optical System A small semiconductor laser (77 L × 30 W × 30 H mm3 , 0.2 kg, PRL-FS-637, New Industries Optoelectronics, Changchun, China) was chosen as the light source. A monochromatic laser beam (637 nm, 0.1 mW) of 3 mm diameter passes through a polarizer to form p-polarized light. It is converged by using a plano-convex cylinder lens to form a wedge-shaped light beam. By choosing a shading plate with a suitable rectangular orifice, the angle range of the wedge-shaped light beam can be adjusted to 10◦ . This light beam enters the K9 glass semi-cylindrical prism from one side of the cylindrical surface and is focused on a line at the bottom plane. The reflective light beam, which passes through another side of the cylindrical surface of the prism, is detected by using a CCD camera (Seek, CSK-802B, GlenSeek Electronics, Shenzhen, China). The sensing area of this monochrome CCD camera is 582 pixels (W) × 512 pixels (H), and the distance between two neighboring pixels is 8.3 µm, which corresponds to a 0.015◦ variation of the reflective angle in our devices. 2.1.2. Microfluidic System The microfluidic system is another important part in this SPR device for sample control. There are four micro-channels flowing through the sensing surface, so four reactions can be monitored simultaneously. The microfluidic network is fabricated on a polydimethylsiloxane (PDMS) slab, and each microchannel is 1000 µm (L) × 100 µm (W) × 180 µm (D). The fabrication of the PDMS chip was based on a traditional replica molding method, in which the master was fabricated by using SU 8 photoresist on a silicon wafer by the photography method [17]. Input and output tubes were bonded on the microfluidic chip. After the oxygen plasma treatment of the gold surface and the PDMS slab, the PDMS slab was covered on the gold surface to form a closed microfluidic network (Figure 2). 2.2. Materials Ethanol was purchased from Dongfang Chemical (Chongqing, China). Phosphate-buffered saline (PBS, pH 7.4), bovine serum albumin (BSA), mouse immune globulin G (IgG) and goat anti-mouse immune globulin G (anti-IgG) were purchased from Jianglai Biological (Shanghai, China). Deionized water was used for the preparation of all solutions.
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Figure 2. Sensor chip with integrated microchannels. (a) A polydimethylsiloxane (PDMS) slab with Figure 2. 2. Sensor Sensor chip chip with with integrated microchannels. (a) (a) A A polydimethylsiloxane polydimethylsiloxane (PDMS) (PDMS) slab slab with with Figure integrated microchannels was bonded on the goldmicrochannels. surface to form a closed microfluidic network (Channel: CH); microchannels was bonded on the gold surface to form a closed microfluidic network (Channel: CH); microchannels was on the gold surface form the a closed microfluidic (Channel: CH); (b) CCD image ofbonded the reflective light beamtofrom sensor chip; (c) network Microscopic image of (b) CCD image of the reflective light beam from the sensor chip; (c) Microscopic image of microchannels (b) CCD image of the light beam the sensor chip; (c) Microscopic image of microchannels (a. the end reflective of microchannel, b. the from middle of microchannel). (a. the end of microchannel, b. the middle of microchannel). microchannels (a. the end of microchannel, b. the middle of microchannel).
3. Results and Discussion 3. Results Results and and Discussion Discussion 3. 3.1. Ethanol Calibration 3.1. Ethanol Calibration 3.1. Ethanol Calibration For calibration of the sensor device, ethanol solutions with concentration 5–20% were detected. For calibration of the sensor device, ethanol solutions with concentration 5–20% were detected. For calibration of the sensor device, ethanol solutions with 5–20% were Before sample loading, deionized water was loaded to rinse theconcentration microfluidic network anddetected. then the Before sample loading, deionized water was loaded to rinse the microfluidic network and then the Before sample loading, deionizedInwater was loaded to rinse solutions, the microfluidic network the detection baseline was achieved. the detection of ethanol the flow rate of and eachthen sample detection baseline was achieved. In the detection of ethanol solutions, the flow rate of each sample was detection baseline In the detection ethanol thetoflow of each was 50 μL/min. Forwas thisachieved. SPR device, change of of SPR angle solutions, corresponds the rate location shiftsample of the 50 µL/min. For this SPR device, the change of SPR angle corresponds to the location shift of the pixel was 50with μL/min. this reflectivity. SPR device, Thus, the change of SPR angle corresponds to the location of the pixel the For lowest the SPR response of each ethanol solutionshift could be with the lowest reflectivity. Thus, the SPR response of each ethanol solution could be represented as pixel with the lowest reflectivity. Thus, SPR of each ethanol solution could be represented as the location shift of the pixelthe (with theresponse lowest reflectivity) from that of the deionized the location shift of the pixel (with the lowest reflectivity) from that of the deionized water (baseline). represented as theFor location shift of the pixel the lowest reflectivity) of the deionized water (baseline). each concentration, the(with test was repeated 10 times.from The that experimental results For each concentration, the test was repeated 10 times. The experimental results (Figure 3) showed 2 water (baseline). each concentration, was repeated 10 times. The experimental results (Figure 3) showedFor good linear relationshipthe (Y =test 3.17143X + 2.81518, R = 0.97661, n = 10) between the good linear relationship (Y = 3.17143X + 2.81518, R2 = 0.97661, n = 10)2between the SPR response and (Figure 3) showed good linear relationship (Y =Response 3.17143X unit + 2.81518, = 0.97661, n =pixels, 10) between the SPR response and the concentration of ethanol. refers R to CCD camera and pixel the concentration of ethanol. Response unit refers to CCD camera pixels, and pixel number means SPR response and the concentration of ethanol. Response unit refers to CCD camera pixels, and pixel number means CCD camera pixels increment. CCD camera pixels increment. number means CCD camera pixels increment.
Figure 3. Ethanol detection in the SPR device. (a) SPR response of variable ethanol concentrations from Figure 3. Ethanol detection in the SPR device. (a) SPR response of variable ethanol concentrations from 5% 5% to 15% (Ethanol: ET); After the SPR response curvevariable almost returned to the baseline; (b) 5% the Figure Ethanol detection thewashing, SPR device. (a)response SPR response ethanol to concentrations to 15% 3.(Ethanol: ET); Afterinwashing, the SPR curveofalmost returned the baseline,from (b) the calibration curve of variable ethanol concentrations. The fitting relationship is Y = 3.17143X + 2.81518, to 15% (Ethanol: After washing, the SPR response returned to=the baseline, (b) the calibration curve ET); of variable ethanol concentrations. Thecurve fittingalmost relationship is Y 3.17143X + 2.81518, 2 = 0.97661 (repeat times n = 10). the goodness of fit R 2 calibration curve ethanol concentrations. the goodness of fitofRvariable = 0.97661 (repeat times n = 10). The fitting relationship is Y = 3.17143X + 2.81518, the goodness of fit R2 = 0.97661 (repeat times n = 10).
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3.2. BSA Adsorption 3.2. BSA Adsorption BSA (molecular weight ~66 kDa) is commonly used to block out the redundant binding sites on BSA (molecular weight ~66 kDa) is commonly used to block out the redundant binding sites the sensor chip, and was used as a protein sample to test the on-chip protein adsorption. In this on the sensor chip, and was used as a protein sample to test the on-chip protein adsorption. In this experiment, PBS solution was used to prepare BSA solution (76–606 mmol/L) and as the running experiment, PBS solution was used to prepare BSA solution (76–606 mmol/L) and as the running buffer. buffer. For each sample, the flow rate was 50 μL/min. For BSA with different concentrations, the For each sample, the flow rate was 50 µL/min. For BSA with different concentrations, the detected detected results showed that the adsorption was basically stable after 30 min. The adsorption of four results showed that the adsorption was basically stable after 30 min. The adsorption of four different different samples could be monitored simultaneously. One channel was used as a reference channel samples could be monitored simultaneously. One channel was used as a reference channel to eliminate to eliminate the background noise including temperature fluctuation, non-specific adsorption, and the background noise including temperature fluctuation, non-specific adsorption, and so on (Figure 4). so on (Figure 4). The difference of the SPR response of 30 min was just about 5% less than that of 60 The difference of the SPR response of 30 min was just about 5% less than that of 60 min, and 20% larger min, and 20% larger than that just loading the sample. This means that the full adsorption of BSA on than that just loading the sample. This means that the full adsorption of BSA on the sensing surface the sensing surface required nearly 30 min. For BSA adsorption, the fitted curve of the detection required nearly 30 min. For BSA adsorption, the fitted curve of the detection results was also of good results was also of good linearity (R2 = 0.99007), which indicates that there is a good liner relationship linearity (R2 = 0.99007), which indicates that there is a good liner relationship between pixel numbers between pixel numbers and BSA concentration for this home-made sensor. and BSA concentration for this home-made sensor.
Figure albumin (BSA) (BSA)adsorption. adsorption.(a) (a)The Thedifference differenceofof Figure4.4.SPR SPRdetection detectionresults resultsof ofthe the bovine bovine serum serum albumin the the SPR response of 30 min was just about 5% less than that of 60 min, and 20% larger than that just SPR response of 30 min was just about 5% less than that of 60 min, and 20% larger than that just loading loading the sample. Thefitting linear relationship fitting relationship BSA of different concentrations (76–606 the sample; (b) The(b) linear of BSA of different concentrations (76–606 mmol/L), mmol/L), R2 = 0.99007 (repeat n = 3). PBS: phosphate-buffered R2 = 0.99007 (repeat times n times = 3). PBS: phosphate-buffered saline. saline.
3.3. Immunological 3.3.IgG IgG ImmunologicalReaction Reaction IgG IgGisisthe themain mainingredient ingredientofofthe theserum serumimmunoglobulin immunoglobulin(up (uptoto75% 75%ofoftotal). total).It Itplays playsa avery very important role in the immune response, and hence is regularly used in immunological analysis. important role in the immune and hence is regularly used in immunological analysis. In In this this device, analyte was coated the sensor by physical adsorption based on the SPRSPR device, analyte was coated on theon sensor chip bychip physical adsorption [18] based[18] on the electrostatic electrostatic and hydrophobic so that the of disturbance of chemical could modification couldIf be and hydrophobic interaction, interaction, so that the disturbance chemical modification be avoided. IgG avoided. If IgG was adsorbed onsurface, the sensing surface, the physical may adsorption may binding hide some binding was adsorbed on the sensing the physical adsorption hide some sites on the sites on the “Y”-shape [19,20]and structure and the interaction betweenand antigen and antibody. “Y”-shape [19,20] structure disturb thedisturb interaction between antigen antibody. However, However, free antibody in the solution may expose sufficient bonding sites, and antigen free antibody in the solution may expose sufficient bonding sites, and antigen is immobilized on is the immobilized chip here. on the chip here. Before Beforethe theimmunological immunologicalanalysis analysisexperiment, experiment,the thesensor sensorchip chipwas wasimmersed immersedand andwashed washedinin ethanol, followed by being dipped into DI water and dried by nitrogen. Both mouse IgG, BSA, ethanol, followed by being dipped into DI water and dried by nitrogen. Both mouse IgG, and BSA, goat IgG were in PBS in solution. In orderIntoorder guarantee that thethat mouse could andanti-mouse goat anti-mouse IgGdissolved were dissolved PBS solution. to guarantee the IgG mouse IgG cover most of the gold surface, a high concentration (1 g/L) was adopted to decrease the nonspecific could cover most of the gold surface, a high concentration (1 g/L) was adopted to decrease the adsorption between the sensing and antibody. After the antigen on adsorbed the surface nonspecific adsorption betweensurface the sensing surface and antibody. Afteradsorbed the antigen onfor the 30surface min followed PBS flowing to remove looselyloosely boundbound molecules, BSABSA solution of ofhigh for 30 minby followed by PBS flowing to remove molecules, solution high concentration was loaded loadedtotooccupy occupy blank onsurface. the surface. Antibodies with concentration(152 (152 mmol/L) mmol/L) was blank sitessites on the Antibodies with different different concentrations mg/L)loaded. were loaded. concentrations (25–500 (25–500 mg/L) were The TheIgG IgGimmunological immunologicalreaction reactionresult resultisisshown shownininFigure Figure5.5.AsAsthe theconcentration concentrationofofanti-IgG anti-IgG increases between 25 mg/L and 200 mg/L, the sensing response increases gradually (Figure 5a). increases between 25 mg/L and 200 mg/L, the sensing response increases gradually (Figure 5a). However, when the concentration exceeds 200 mg/L (e.g., 200–500 mg/L), the response has little
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However, when the concentration exceeds 200 mg/L (e.g., 200–500 mg/L), the response has little increase. The Thesaturation saturationofofthe the response signal be induced bylimited the limited binding of the increase. response signal maymay be induced by the binding sites ofsites the coated coated IgGsurface. on the When surface. When BSA usedthe toblank blocksites the on blank on surface, the sensing surface, the IgG on the BSA is used to is block the sites sensing the infinitesimal infinitesimal (shiftindicates of the pixel) indicates that theofconcentration 1 g/L IgG is SPR responseSPR (shiftresponse of the pixel) that the concentration 1 g/L IgG is of high enough to high coat enough to coat most of the Below sensingthe surface. Below the saturation concentration (25–200 mg/L), the most of the sensing surface. saturation concentration (25–200 mg/L), the interrelationship interrelationship between and response is linear (R2 5b). = 0.99773, Figure 5b). between concentration andconcentration response is linear (R2 = 0.99773, Figure
Figure of the IgGIgG immunological reaction. (a) Shift the pixel increment for different Figure 5.5.Detection Detectionresults results of the immunological reaction. (a)ofShift of the pixel increment for concentrations of anti-IgG; (b) Below the saturation concentration (25–200 mg/L), the interrelationship different concentrations of anti-IgG; (b) Below the saturation concentration (25–200 mg/L), the 2 = 0.99773 (repeat times n = 3). between the concentration andconcentration response is linear interrelationship between the and R response is linear R2 = 0.99773 (repeat times n = 3).
In this this device, device, BSA BSA was was used used as aa control control group group in in order order to to verify verify the the specific specific binding binding between between In mouse IgG and goat anti-Mouse IgG. BSA with the same concentration as IgG was coated the mouse and goat anti-Mouse same concentration coated on the sensing surface at at first. first. Experimental results (not shown here) indicated that little response response could could be be sensing detected when goat anti-IgG was loaded on the BSA-coated surface. detected when goat anti-IgG was loaded on the BSA-coated surface. 4. 4. Conclusions In this paper, paper,we we aimed to develop a lightweight and multi-channel SPR device. sensor Adevice. In this aimed to develop a lightweight and multi-channel SPR sensor semiA semi-cylindrical prism as aunit coupling the SPRThe excitation. adoption of a cylindrical prism was usedwas as a used coupling for theunit SPR for excitation. adoption The of a wedge-shaped wedge-shaped incident lightavoid beamthe could the use of a complicated, and costly incident light beam could useavoid of a complicated, cumbersome,cumbersome, and costly mechanical mechanical structure. Some other carefully-chosen components such as a small semiconductor laser structure. Some other carefully-chosen components such as a small semiconductor laser light source light lighthelped stabilitythe helped the realization the portability of this device. addition, with source good with light good stability realization of the of portability of this device. In In addition, a amicrofluidic microfluidicchip chip was used core of the sample manipulation system for more channels was used as as thethe core of the sample manipulation system for more channels and and low low consumption. Several experiments were carried thisnew newdevice, device,and and good good precision and consumption. Several experiments were carried outout in in this and linearity linearity of the the response response could could be be achieved. achieved. The The home-made home-made multichannel multichannel SPR sensors had a good good performance performance in in detecting detecting the the biomolecule biomolecule interactions. interactions. Acknowledgments: was supported by the Natural ScienceScience Foundation of China of (Nos. 81371691, Acknowledgments:This Thiswork work was supported byNational the National Natural Foundation China (Nos. 31571005, 81501617), the Fundamental Research Funds for the Central Universities (No. 106112016CDJZR238807) 81371691, 31571005, 81501617), the Fundamental Research Funds for the Central Universities (No. and the Program of International S&T Cooperation (No. 2014DFG31380). 106112016CDJZR238807) and the Program of International S&T Cooperation (No. 2014DFG31380). Author Contributions: N.H. and J.Y. conceived and designed the experiments; Y.L. built up the device; Author Contributions: N.H. and J.Y. conceived and designed the fabrication; experiments; Y.L. built the device; X.Z. X.Z. performed the experiments; T.F. and X.C. contributed microchip Z.Y. and Z.W.up analyzed the data; X.Z. wrote the N.H. and J.Y.and revised the paper. microchip fabrication; Z.Y. and Z.W. analyzed the data; performed thepaper; experiments; T.F. X.C. contributed X.Z. wroteofthe paper;The N.H.authors and J.Y. revised paper.of interest. Conflicts Interest: declare nothe conflict
Conflicts of Interest: The authors declare no conflict of interest.
References References 1. Liedberg, B.; Nylander, C.; Lunström, I. Surface plasmon resonance for gas detection and biosensing. 1. 2.
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