Ultrasensitive Sensing Material Based on Opal Photonic Crystal for

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Ultrasensitive Sensing Material Based on Opal Photonic Crystal for Label-Free Monitoring of Transferrin Enqi Wu,†,‡,# Yuan Peng,†,# Xihao Zhang,† Jialei Bai,† Yanqiu Song,† Houluo He,† Longxing Fan,†,‡ Xiaochen Qu,‡ Zhixian Gao,*,† Ying Liu,*,‡ and Baoan Ning*,†,‡ †

Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, China ‡ College of Public Health, Inner Mongolia Medical University, Hohhot, 010059, China ABSTRACT: A new opal photonic crystal (PC) sensing material, allowing label-free detection of transferrin (TRF), is proposed in the current study. This photonic crystal was prepared via a vertical convective self-assembly method with monodisperse microspheres polymerized by methyl methacrylate (MMA) and 3-acrylamidophenylboronic acid (AAPBA). FTIR, TG, and DLS were used to characterize the components and particle size of the monodisperse microspheres. SEM was used to observe the morphology of the PC. The diffraction peak intensity decreases as the TRF concentration increase. This was due to the combination of TRF to the boronic acid group of the photonic crystal. After condition optimization, a standard curve was obtained and the linear range of TRF concentration was from 2 × 10−3 ng/mL to 200 ng/mL. Measurement of TRF concentration in simulated urine sample was also investigated using the sensing material. The results indicated that the PC provided a cheap, label-free, and easy-to-use alternative for TRF determination in clinical diagnostics. KEYWORDS: opal photonic crystal, soap-free emulsion polymerization, sensing material, label-free detection, transferrin

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and clinical curative effect. TRF is a kind of glycoprotein.14 In the early stage of renal injury, TRF is more likely to be filtered from glomerula than albumin,15 indicating that TRF is more sensitive to reflect the glomerular filtration membrane damage. When early renal injury happens without clinical symptoms, TRF has appeared in urine significantly, but the detection result of urine protein is still negative. Accordingly, TRF in the urine can be used as an indicator of early diagnosis and treatment monitoring of renal injury. Therefore, it is urgent to develop sensitive and efficient methods to facilitate the regular monitoring of TRF levels. At present, there have been some methods for determination of TRF, such as rocket immunoelectrophoresis (RIEP), radioimmunoassay (RIA), enzyme linked immunosorbent assay (ELISA), and turbidimetric inhibition immunoassay. However, these methods are time-consuming and the detection process is complicated, and the fluorescence or absorbance labels are usually unavoidable in target analysis.16,17 The labels may impede the interactions of bimolecules, which will generate false-negative detection results. Furthermore, the storage and usage condition of an antibody is rigorous. As a result, there has been considerable interest in the development of an easy-to-operate and economic analytical technique to detect TRF levels efficiently and rapidly.

INTRODUCTION Photonic crystals (PCs) are optical materials which contain regularly repeating regions of high and low dielectric constant. According to the Bragg diffraction, the light either propagates through the PCs or not, depending on the wavelength. Thus, these materials can modulate the light to a wanted wavelength through the formation of photonic band gap which is fabricated by diverse materials. Currently, PCs have attracted much interest due to their promising applications in various fields, such as laser, light beam bending, light-emitting diode, sensing material, and solar cell.1−5 Optical sensing materials are known for their simplicity, low cost, and efficiency. Much of the outstanding contributions to the application of hydrogel PC sensing material were due to Asher’s group. They prepared highly charged polystyrene (PS) colloids and fixed these colloids in a cross-linkable hydrogel to form a crystalline array. When the crystalline array was exposed to the targets, such as pH, metal ions, glucose, and biological molecules,6−13 the PC structure was changed leading to a variation of the diffraction wavelength. PCs can self-response to the target, which does not need labeling, and it has a good prospect in clinical detection and in vitro diagnosis. As a special kind of protein, the level of transferrin (TRF) as the early diagnostic index of glomerular damage is of great value for disease diagnosis. In most types of anemia and acute inflammation, TRF concentration was significantly lower than the normal control group. The detection of TRF was applied to observe the degree of liver damage and estimate the prognosis © XXXX American Chemical Society

Received: November 12, 2016 Accepted: January 27, 2017 Published: January 27, 2017 A

DOI: 10.1021/acsami.6b14498 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Research Article

ACS Applied Materials & Interfaces

reflection spectra were obtained using a fiber optic spectrometer. The fiber probe of the spectrometer was fixed vertically above the PA PC surface. The concentrations of the added TRF were gradually increased from 10−3 ng/mL to 10 μg/mL, and the PC responses were recorded. The temperature was controlled at 20 °C during the measurement. Considering the effect of the urine matrix to the PC, a standard curve for mimicking urine was constructed. The mimicking urine was prepared by 3.8 mM CaCl2·2H2O, 3.0 mM MgCl2·6H2O, 72.1 mM NaCl, 14.5 mM Na2SO4, 2.2 mM Na3C6H5O7·2H2O, 0.15 mM Na2C2O4, 18.7 mM KH2PO4, 19.3 mM KCl, 17.2 mM NH4Cl, and 41.6 mM urea and saved in 4 °C. Then, TRF was dissolved into the mimicking urine. After the PA PC was soaked in CHES buffer to stabilization, the optical response to TRF at a serial concentration was recorded. The simulating urine without TRF was used as the control group. Specificity of the Photonic Crystal. In order to study the response of PA PC to other proteins, HSA, OVA, and BSA were dissolved into the mimicking urine sample for detection, respectively. The PA PC was immersed into CHES buffer for 1 h, and the responses to the mentioned protein at different concentration were recorded. Analysis of Mimicking Urine Sample Containing TRF. TRF was spiked to the mimicking urine to form the final concentration at 0.01, 0.2, and 1 ng/mL. Subsequently, these TRF-spiked samples were detected using the same method without further pretreatment, and the recoveries were investigated.

In this work, we proposed a simple method to prepare a PC sensing material for label-free detection of TRF. 3-Acrylamidophenylboronic acid (AAPBA) and methyl methacrylate (MMA) were used as monomers, and they were copolymerized by soap-free emulsion polymerization to produce monodisperse microspheres. Then, the monodisperse microspheres were piled up to form opal PC by vertical convective self-assembly. After stabilization in the buffer, this PC was used to detect TRF. TRF could be captured by the boronic acid group of the PC, which caused the refractive index change leading to a decrease of the PC diffraction peak intensity. The boronic acid group, as the recognition elements, had many advantages, especially that they could bind to the targets rapidly, resulting in fast response signals.18−20 PC technologies were employed in detection based on their self-response to the changes in refractive index and volume.21−23 Compared with the inverse opal photonic crystal, the preparation process of this PC was easy-to-operate and cost-efficient, and only needed self-assembly.24

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MATERIALS AND METHODS

Reagents and Materials. Methyl methacrylate (MMA) and potassium persulfate (KPS) were purchased from Aladdin (Shanghai, China) and treated with activated carbon for 24 h prior to use. 3Acrylamidophenylboronic acid (AAPBA), transferrin (TRF), human serum albumin (HSA), ovalbumin (OVA), bovine serum albumin (BSA), and 2-(cyclohexylamino) ethanesulfonic acid (CHES) were purchased from Sigma (Shanghai, China). CaCl2·2H2O, MgCl2·6H2O, NaCl, Na2SO4, Na3C6H5O7·2H2O, Na2C2O4, KH2PO4, KCl, NH4Cl, and urea were purchased from Tianjin Chemical Reagent Company (Tianjin, China). All solvents and chemicals were of analytical purity and used without further purification. Deionized water was used throughout the study. Common glass slides were pretreated according to the reported method24 prior to use. Apparatus. The reflection spectra were obtained using an Ocean Optics Maya 2000 PRO fiber optic spectrometer (Ocean Optics, Dunedin, FL, USA). The SEM images were obtained from an S-3500N SEM (Hitachi Limited). Dynamic light scattering (DLS) images were obtained from ZETAPALS/BI-200SM (Brookhaven). FTIR spectra were recorded by Tensor 27 (Bruker, Germany) spectrophotometer. Thermogravimetric Analysis result (TG) was obtained from TG209DSC204 DMA242 TMA202 (NETZSCH, Germany). The constant temperature and humidity chamber was purchased from Ningbo HaishuSaifu Experimental Instrument Co., Ltd. Fabrication of the PMMA-AAPBA PC. The monodisperse PMMA-AAPBA (PA) microspheres were prepared according to the previously reported method18 with some modification. The prepolymerized solution MMA-AAPBA (17 mg AAPBA dissolved in 3 mL MMA) was mixed with 25.5 mL deionized water and degassed for 15 min. Then this mixture was stirred at 370 rpm under nitrogen atmosphere in the water bath. After the mixture reached 80 °C, the initiator, KPS (60 mg KPS dissolved in 1.5 mL deionized water), was added and the reaction system was continuously stirred at 370 rpm. Nitrogen was bubbled to remove oxygen throughout the polymerization. PA colloidal particles were obtained after 45 min, followed by centrifugation and washing. Subsequently the uniform PA microspheres were collected by centrifugation separation method. The PA PC was fabricated by vertical convective self-assembly which was a common and simple method.18 Monodisperse PA microsphere suspensions were placed in the glass beakers and then put in a constant temperature and humidity chamber at 30 °C with humidity of 40%. After 5 to 7 days, the highly ordered PA PC was formed. A PMMA PC (without AAPBA) was prepared using the same method. Response to TRF. The PA PC was immersed into 30 mL CHES buffer (pH 8.0 to 8.5) for 1 h until the PC reached a state of equilibrium in CHES buffer. The detection of TRF was carried out following the sequence from low to high concentrations. The

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RESULTS AND DISCUSSION Detection Principle. The design of PA PC was shown in Scheme 1. In alkaline aqueous solutions (pH 8.0 to 8.5), Scheme 1. Experimental Procedure for the TRF Detection Used a PA PC

phenylboronic acid group combined with the cis-form adjacent hydroxyl alcohol, and TRF is equipped with the cis-form adjacent hydroxyl structures. According to this principle, MMA and AAPBA were polymerized to form monodisperse PA microspheres, which were used to fabricate the PA PC by vertical convective self-assembly. The phenylboronic acid groups, as the recognition elements, were attached on the PC through this convenient process. In this system, the dissociated state of phenylboronic acid could form covalent complexes with TRF. Thus, the PC could be used to recognize TRF effectively in the weak alkaline solution, and this recognition of TRF caused the refractive index change of the PC resulting in a corresponding change in the Bragg diffraction peak intensity. This peak intensity change could be use for quantitatively determination of the number of bound biomolecules. B

DOI: 10.1021/acsami.6b14498 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Research Article

ACS Applied Materials & Interfaces Effect of Mass Fraction on the PA PC. The influence of mass fraction on our PA PC was examined. A series of PA monodisperse microsphere suspensions (0.6, 0.5, and 0.3 wt % PA in deionized water) were placed in the glass beakers, and then these glass beakers were put inside a constant temperature and humidity chamber at 30 °C with humidity of 40%. After 5 to 7 days, the highly ordered PA PC was formed. These PA PCs were used to detect TRF. Figure 1 showed the detection

the PC affected the diffusion and combination of TRF. In order to obtain a better detection range, the PC prepared with PA (0.3 wt %) was chosen as the optimum due to its excellent stability and sensitivity in the detection of the TRF. PC Structure Characterization. Scanning electron microscopy (SEM) was used to scrutinize the morphology of the PA PC, and the results were shown in Figure 2. It showed a highly ordered, closest-packing sphere arrangement, and the 111 plane of the FCC lattice of the PC was observed. The PA microsphere diameter was about 300 nm.

Figure 2. SEM images of the PA PC.

Dynamic Light Scattering (DLS). The effective diameters of PA microspheres in aqueous solution were shown in Figure 3. The DLS results indicated that the mean particle size of PA

Figure 3. DLS image of PA microspheres in aqueous solution.

was 340 nm ± 30 nm. These implied that the microsphere had a narrow size distribution and good uniformity, which could satisfy the requirements for the preparation of photonic crystals. These laid a foundation for further experiments. Fourier Transform Infrared Spectroscopy (FTIR) Characterization. The FTIR spectra of PMMA and PA microspheres were shown in Figure 4. In the PA, the band at 1539 cm−1 was attributed to the N−H bending vibration. The Figure 1. Optical response of different mass fraction of PA PC: (A) 0.6 wt %; (B) 0.5 wt %; (C) 0.3 wt %.

results from different PA PCs. With an increase in the concentration of TRF, the intensity of diffraction peaks decreased. However, the result clearly showed that the PCs prepared with PA (0.6 or 0.5 wt %) did not respond to the lower concentration of TRF, while the PC prepared with PA (0.3 wt %) exhibited a strong decline in the peak intensity at 10−3 ng/mL TRF. The reason might be that the thickness of

Figure 4. FTIR spectra of PMMA and PMMA-AAPBA microspheres. C

DOI: 10.1021/acsami.6b14498 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Research Article

ACS Applied Materials & Interfaces small band at 710 cm−1 was the absorption band of the metaaromatic compounds, which was the typical absorption band in AAPBA. These results confirmed that AAPBA was successfully polymerized in the PA microspheres. Thermogravimetric Analysis (TG). The thermogravimetric analysis curve of PA was shown in Figure 5. About 7%

Figure 5. Thermogravimetric analysis of PMMA-AAPBA.

weight loss was observed on the curve of PA corresponding to the decomposition of AAPBA. In addition, it also showed that AAPBA was successfully polymerized in the PA microspheres. Response of the PA PC. Figure 6 showed the response time of the PA PC when detecting TRF. After 2 × 10−3 ng/mL Figure 7. Optical responses of PA PC (A) and PMMA PC (B) with a series of concentrations of TRF.

the TRF bound to the phenylboronic acid groups of PA PC under the condition of weak alkaline solution, which caused the refractive index change of the PA PC. To further clarify the recognition properties of the PA PC, experiments were conducted on a PMMA fabricated PC under the same prepared conditions. Then, the PMMA PC was used to detect TRF through the same procedures as mentioned earlier. Figure 7B showed that the diffraction peak intensity of PMMA PC had a slight change with the increase of the TRF concentration, which was quite different from the response exhibited by the PA PC. As a result, AAPBA played an important role in the detection of TRF, because it could provide phenylboronic acid groups which could combine with the cis-form adjacent hydroxyl groups of TRF in alkaline aqueous solutions. Detection in the Simulating Urine. Considering the effect of the urine matrix to the PC, a standard curve in mimicking urine was constructed. TRF was dissolved into the mimicking urine, and then detected by the PA PC. Meanwhile, the mimicking urine without TRF was used as the control group. After the PA PC was stabilized in CHES buffer, mimicking urine containing different concentration of TRF was added gradually. It was found in Figure 8 that the diffraction peaks of the mimicking urine scarcely changed (Figure 8A) and the decrease of peak intensity was linearly correlated to the concentration of TRF (Figure 8B). Therefore, the working curve (Figure 9) was obtained, and R2 was 0.9995. The limited of detection (LOD) was 3 × 10−4 ng/mL and the detection range was from 2 × 10−3 ng/mL to 200 ng/mL. Compared with the ELISA kit,25 the PC method showed lower detection

Figure 6. Kinetic response of the PA PC to TRF (2 × 10−3 ng/mL).

of TRF was added, the response process occurred rapidly and became stable within 15 min. This phenomenon could be a result of the following two situations. On one hand, the large surface area made the TRF diffuse into the PA PC smoothly and occupy the binding sites easily. On the other hand, the binding sites were distributed widely in the PA PC. From the above, the materials could be used to detect TRF in a short period of time. This advantage promoted its application in sensing. Optical Response of the PA PC to Analytes. Figure 7A showed the response of the PA PC to a series of concentrations of TRF. TRF dissolved in CHES buffer was added gradually. With the increase in the concentration of the targets, the intensity of diffraction peaks decreased, accompanied by a slight wavelength red-shift. The reasonable explanation for this was D

DOI: 10.1021/acsami.6b14498 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Research Article

ACS Applied Materials & Interfaces

Figure 8. Optical response of PA PC to (A) mimicking urine and (B) a series of concentrations of TRF in mimicking urine.

Figure 10. Optical response of the PA PC to other protein: (A) HSA; (B) OVA; (C) BSA.

response of PA PC caused by OVA was smaller, which only showed a slight decrease in peak intensity. Analysis of Mimicking Urine Sample Containing TRF. In order to investigate the applicability of this PA PC in detecting real samples, TRF was spiked to the mimicking urine to form the simulating samples, and subsequently detected using the same method without further pretreatment. The results were listed in Table 1. It could be seen that the recoveries were from 89.82% to 100.3%, which indicated that this PA PC was suitable for the determination of TRF.

Figure 9. Standard curve of TRF in mimicking urine.

limit (LOD of the ELISA kit was 4.6 ng/mL) and shorter assay time within 15 min (assay time of the ELISA kit was 2 h). Specificity of the Photonic Crystal to TRF. The responses of the PA PC to other proteins were also investigated. HSA, OVA, and BSA were dissolved into the mimicking urine for detection, respectively. Test results were shown as below. However, the PA PC showed no response to HSA (Figure 10A) and BSA (Figure 10C). OVA could cause slight decrease of diffraction intensity under the same measurement conditions (Figure 10B), because OVA was a kind of glycoprotein, which was similar to TRF. Compared to TRF, the molecular weight of OVA was smaller, and thus the

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CONCLUSIONS An opal PC sensing material that allowed label-free detection of TRF was successfully prepared. The preparation of PA PC was simple, which did not need to be colloid padded or polymerized like the inverse opal photonic crystal. The PA E

DOI: 10.1021/acsami.6b14498 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Research Article

ACS Applied Materials & Interfaces

(8) Walker, J. P.; Kimble, K. W.; Asher, S. A. Photonic crystal sensor for organophosphate nerve agents utilizing the organophosphorus hydrolase enzyme. Anal. Bioanal. Chem. 2007, 389 (7−8), 2115−2124. (9) Kimble, K. W.; Walker, J. P.; Finegold, D. N.; Asher, S. A. Progress toward the development of a point-of-care photonic crystal ammonia sensor. Anal. Bioanal. Chem. 2006, 385 (4), 678−685. (10) Ben-Moshe, M.; Alexeev, V. L.; Asher, S. A. Fast responsive crystalline colloidal array photonic crystal glucose sensors. Anal. Chem. 2006, 78 (14), 5149−5157. (11) Asher, S. A.; Alexeev, V. L.; Goponenko, A. V.; Sharma, A. C.; Lednev, I. K.; Wilcox, C. S.; Finegold, D. N. Photonic crystal carbohydrate sensors: low ionic strength sugar sensing. J. Am. Chem. Soc. 2003, 125 (11), 3322−3329. (12) Xu, X.; Goponenko, A. V.; Asher, S. A. Polymerized polyHEMA photonic crystals: pH and ethanol sensor materials. J. Am. Chem. Soc. 2008, 130 (10), 3113−3119. (13) Lee, K.; Asher, S. A. Photonic crystal chemical sensors: pH and ionic strength. J. Am. Chem. Soc. 2000, 122 (39), 9534−9537. (14) Gomme, P. T.; McCann, K. B.; Bertolini, J. Transferrin: structure, function and potential therapeutic actions. Drug Discovery Today 2005, 10 (4), 267−273. (15) Narita, T.; Sasaki, H.; Hosoba, M.; Miura, T.; Yoshioka, N.; Morii, T.; Shimotomai, T.; Koshimura, J.; Fujita, H.; Kakei, M. Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin, transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients. Diabetes Care 2004, 27 (5), 1176−1181. (16) Kuang, M.; Wang, D.; Bao, H.; Gao, M.; Möhwald, H.; Jiang, M. Fabrication of Multicolor-Encoded Microspheres by Tagging Semiconductor Nanocrystals to Hydrogel Spheres. Adv. Mater. 2005, 17 (3), 267−270. (17) Gao, X.; Nie, S. Quantum dot-encoded mesoporous beads with high brightness and uniformity: rapid readout using flow cytometry. Anal. Chem. 2004, 76 (8), 2406−2410. (18) Hong, X.; Peng, Y.; Bai, J.; Ning, B.; Liu, Y.; Zhou, Z.; Gao, Z. A Novel Opal Closest-Packing Photonic Crystal for Naked-Eye Glucose Detection. Small 2014, 10 (7), 1308−1313. (19) Li, L.; Lu, Y.; Bie, Z.; Chen, H. Y.; Liu, Z. Photolithographic boronate affinity molecular imprinting: a general and facile approach for glycoprotein imprinting. Angew. Chem., Int. Ed. 2013, 52 (29), 7451−7454. (20) Ye, J.; Chen, Y.; Liu, Z. A boronate affinity sandwich assay: an appealing alternative to immunoassays for the determination of glycoproteins. Angew. Chem., Int. Ed. 2014, 53 (39), 10386−10389. (21) Hou, J.; Zhang, H.; Yang, Q.; Li, M.; Jiang, L.; Song, Y. Hydrophilic−Hydrophobic Patterned Molecularly Imprinted Photonic Crystal Sensors for High-Sensitive Colorimetric Detection of Tetracycline. Small 2015, 11 (23), 2738−2742. (22) Zhang, Y.; Qiu, J.; Gao, M.; Li, P.; Gao, L.; Heng, L.; Tang, B. Z.; Jiang, L. A visual film sensor based on silole-infiltrated SiO 2 inverse opal photonic crystal for detecting organic vapors. J. Mater. Chem. C 2014, 2 (42), 8865−8872. (23) Chen, W.; Ma, Y.; Pan, J.; Meng, Z.; Pan, G.; Sellergren, B. Molecularly Imprinted Polymers with Stimuli-Responsive Affinity: Progress and Perspectives. Polymers 2015, 7 (9), 1689−1715. (24) Guo, C.; Zhou, C.; Sai, N.; Ning, B.; Liu, M.; Chen, H.; Gao, Z. Detection of bisphenol A using an opal photonic crystal sensor. Sens. Actuators, B 2012, 166, 17−23. (25) Transferrin ELISA kit. (n. d.). Retrieved June 15, 2016, fromhttp://www.enzolifesciences.com/ENZ-KIT143/transferrin-elisakit/.

Table 1. Results for the determination of the TRF in mimicking urine

a

amount spiked (ng/mL)

amount measureda (ng/mL)

recoverya (%)

RSD (%)

0.01 0.2 1

0.01003 0.1796 0.9852

100.3 89.82 98.52

16.65 3.090 9.636

Mean values of three measurements.

PC realized the ultrasensitive detection of TRF, which could be used in the diagnosis of early renal injury. It could also be used for therapeutic effect evaluation or routine monitoring. The developed method exhibited high sensitivity and was relatively easy and cheap to perform. Furthermore, the urine sample could be directly detected without pretreatment. This PC was anticipated to open new horizons in medical diagnostics.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel/fax: +86-22-84655191. *E-mail: [email protected]. Tel/fax: +86-471-6653334. *E-mail: [email protected]. Tel/fax: +86-22-84655403. ORCID

Enqi Wu: 0000-0001-9282-5656 Author Contributions

# Enqi Wu and Yuan Peng contributed equally. All authors have given approval to the final version of the manuscript.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the National Natural Science Foundation of China (Grant No. 81472985, 81502847, AWS15J006) and the Tianjin Research Program of Application Foundation and Advanced Technology (Grant No. 15JCYBJC51200) for funding this research project.

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REFERENCES

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DOI: 10.1021/acsami.6b14498 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX