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Abstract
In order to perform microfluidic detection of cytokines with low concentration, such as growth differentiation factor 11 (GDF11), the most common method is to construct microfluidic channels and integrate them with SPR sensing units. In this paper, we proposed a novel all-fiber SPR microfluidic chip for GDF11 detection. The method was to construct the SPR sensing area on a designed D-shaped multimode fiber, which was nested inside a quartz tube to form a semi-cylindrical microfluidic channel. The surface of the SPR sensing area experienced sensitization and specifically modification to achieve the specific detection of GDF11. When the sensitivity of detection was 1.38 nm/lg(g/mL) and the limit of detection was 0.52 pg/mL, the sample consumption was only 0.4 µL for a single detection. The novel all-fiber SPR microfluidic detection chip has the advantages of flexible design, compact structure and low sample consumption, which is expected to be used in wearable biosensing devices for real-time online monitoring of trace cytokines in vivo.
© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement
1. Introduction
Growth differentiation factor 11 (GDF11), as a member of transforming growth factor β (TGF-β) protein, is reported to improve the aging of the heart and other organs [1]. The quantitative analysis of cytokine GDF11 is of great importance in the field of basic research and clinical diagnosis [2,3].However, the content of GDF11 and other cytokines is less and the test samples are often very precious, and the quantitative analysis of GDF11 is difficult. The methods commonly used for GDF11 detection include Western Blot and enzyme-linked immunosorbent assay (ELISA), which require large amounts of reagents, a complicated labeling process, and are susceptible to external environmental influences [4,5]. Surface plasmon resonance (SPR) has the advantages of no biomarker and real-time detection, and fiber-optic SPR sensors have been used for GDF11 detection [6]. However, its detection still requires a certain amount of reagents and can be affected by the external environment. In order to improve the detection sensitivity and avoid environmental interference, the detection of such substances can be performed by SPR detection microfluidic chip [7]. However, the process of constructing a microfluidic channel to match the sensing unit is very cumbersome [8–10].
Depending on the type of SPR sensing module integrated with the microfluidic channel, SPR detection microfluidic chips can be divided into two categories [11,12]: one is the integration of the microfluidic channel made of polymer with the spatial prism type SPR sensing module [13–16]. The polymer material is molded in a corresponding mold to build a polymer microfluidic channel [17–21]. The polymer microfluidic channel is then bound with a spatial prism type SPR sensing module to achieve precise flow control and detection of the cytokine to be measured on the surface of the sensing metal film of the SPR module. Such type of sensing microfluidic chips has the following disadvantages: large size, inflexible operation, spatial alignment systems for light injection and light collection, mold-dependence for microfluidic channel construction, long fabrication cycles and uneasy change of channels [22–25].
The other type is the integration of microfluidic channels made of polymer with fiber optic SPR sensing modules [26,27]. After the polymer microfluidic channel is made by the mold, the fiber-optic SPR sensor is integrated in the microfluidic channel [28,29]. The analytes containing cytokine flow in the microfluidic channel to the gold film of the fiber optic SPR sensing area embedded in the channel to achieve SPR detection. These sensing microfluidic chips have a small size and are integrated with fiber optic SPR sensors, which have no need of spatial optical alignment system. However, this kind of sensing microfluidic chips still have complex operation process. It needs to construct the microfluidic channel by patterning the polymer material through a mold. Then it is integrated with the fiber optic SPR sensor by bonding [30,31]. The mold needs to be redesigned and fabricated if you want to change the style of the microfluidic channel.
To further develop the microfluidic chip for cytokine SPR detection, it has become a research trend to integrate SPR sensing module and microfluidic channels into an all-fiber structure. It will eliminate the processes of fabrication of polymeric microfluidic channels and bonding integration, which will further reduce the size of the SPR microfluidic chip and improve the chip fabrication efficiency, flexibility and stability of the chip. In this paper, we designed and fabricated a multimode D-shaped fiber with semicircular cross-section. It was nested in a quartz tube, and the upper half of the fiber formed a semi-cylindrical microfluidic channel. The flat surface of the D-shaped multimode fiber core was exposed, and the SPR sensing area was fabricated on the flat surface. It directly realized the contact between the cytokine to be measured and the sensing metal film. The D-shaped fiber core was large core multimode fiber, and its higher-order mode realized the SPR resonance angle matching. The SPR sensing gold film was sensitized and specifically modified. The method achieved a rapidly fabricated all-fiber SPR microfluidic chip for GDF11 and other trace cytokine detection.
2. Design and fabrication of all-fiber SPR microfluidic chip
2.1 Structure design of D-shaped fiber SPR microfluidic chip
In order to realize an all-fiber SPR microfluidic detection chip, a D-shaped multimode fiber was designed and fabricated to realize the SPR sensing structure and provide microfluidic channels.. After peeling the coating layer with a blade, the cross-section was semi-circular with straight side length of the cladding was 110 µm. The distance between the straight side and the lower end of the semicircle was 74 µm. The fiber core was also semicircular (straight side length of 24 µm), located on the straight side of the D-shaped multimode fiber. The flat surface of the fiber core was exposed to the air. A 50 nm metal film was coated on the straight side of the D-shaped multimode fiber to form the SPR sensing area. The D-shaped multimode fiber was embedded in a quartz tube with an inner diameter of 130 µm to form a semi-cylindrical microfluidic channel. Figure 1(A-A) showed a cross-sectional micrograph of the D-shaped fiber in the quartz tube to form a microfluidic channel.
Figure 1 showed the structure of the D-shaped fiber SPR microfluidic detection chip. The left side of the D-shaped multimode fiber with SPR sensing function was a single-mode fiber, and the right side was a multimode fiber with a core diameter of 105 µm. 20 mm long D-shaped multimode fiber was nested in 18 mm long quartz tube. There was a 1 mm gap at the connection points between both ends of the quartz tube and both sides of D-shaped multimode fiber, forming a liquid inflow and outflow for the inlet and outlet ports. The inlet and outlet were encapsulated by a T-junction. A capillary hose was connected to the outside of the T-junction, which was connected to the inlet and outlet, respectively. The sample can flow into the microfluidic channel from the left inlet for SPR detection and then flow out from the right outlet capillary hose, which realized the all-fiber structure of SPR sensing module and microfluidic channel.
2.2 D-shaped fiber SPR microfluidic chip fabrication
The fabrication flow of the D-shaped fiber SPR microfluidic chip was shown in Fig. 2.
- (a) We took a section of D-shaped multimode fiber (custom design, JiangSu Fasten), peeled off one end of the coating layer by 5 cm with a razor blade, wiped it with alcohol, and cut the cross-section flat with a fiber stress cutter (FL-500, Fiberlink). Then we took another section of single-mode fiber (SMF-28e, Corning), peeled off the coating layer at one end with Miller pliers for 5 cm, and cut the cross-section flat with a fiber cutter. We put the single-mode fiber and D-shaped multimode fiber into the rotating fixture of the polarization-maintaining fiber splicer (FL-4000, Fiberlink), observed the two kinds of fibers in the display screen of the polarization-maintaining fusion splicer. The D-shaped multimode fiber was adjusted in manual mode to coincide with the lower semicircle of the single-mode fiber cross-section and then experienced fusion splicing. After the fusion was completed, the fiber stress cutter (FL-500, Fiberlink) was used to cut 2 cm from the fusion point on the D-shaped multimode fiber to obtain a probe that was fused with a single-mode fiber and a D-shaped fiber.
- (b) We took a section of quartz tube fiber (custom designed, XYAT) with an inner diameter of 130 µm, an outer diameter of 200 µm, and a coating layer diameter of 250 µm. We peeled one side of its coating layer by 5 cm long with a blade, cut the cross-section flat using a fiber stress cutter (FL-500, Fiberlink), and then cut the quartz tube at a distance of 18 mm from the cutting point to obtain a quartz tube with a length of 18 mm. The quartz tube was threaded into the probe from the D-shaped fiber side until the quartz tube coverd the left single-mode fiber area.
- (c) We took a section of thick core multimode fiber (SI105/125-22/250, YOFC) with 105 µm core diameter, and peeled off its end coating layer 2 cm long with Miller pliers. We used a fiber cutting knife to cut the fiber cross-section flat, which was put into the rotating fixture of the polarization-maintaining fiber fusion splicer together with the D-shaped fiber probe. We adjusted the D-shaped multimode fiber to coincide with the lower semicircle of the multimode fiber cross-section and then fused it.
- (d) The fused probe was rotated under the microscope, adjusted to the flat side of the D-shaped fiber facing upward, and fixed on the substrate. We placed the substrate and probe directly under the gold target of the magnetron sputterer (ETD-650MS, YLBT), plated a 50 nm gold film and then removed it.
- (e) We moved the quartz tube in the left single-mode fiber area to locate it in the middle of the D-shaped multimode fiber. There is a 1 mm gap from both ends of the quartz tube to fusion points of the D-shaped multimode fiber on both sides.
- (f) We took two polypropylene (PP) T-junctions (1.6mm, YISAI) with 1.6 mm inner diameter of the joint, made the probe body pass through the horizontal channels of the two T-junctions, and adjusted the position of the two T-junctions to wrap around the 1 mm gap at the two ends of the quartz tube. The vertical branch of the T-junction was connected to the gap on both sides of the quartz tube. We used UV-curable adhesive (9307, LEAFTOP) to seal the two ends of the horizontal main tube of the left T-junction with single-mode fiber and quartz tube fiber, and sealed the two ends of the horizontal main tube of the right T-junction with quartz tube fiber and multimode fiber. We took two sections of capillary hose matching the outer diameter of the vertical branch of the T-junction, inserted them into the vertical branch of the T-junction and sealed them. The sample can flow in from the left inlet tube, through the semi-cylindrical microfluidic channel surrounded by D-shaped fiber and capillary fiber. After SPR detection, The sample flowed out through the outlet tube.
2.3 Construction of testing experimental installation
The experimental installation of D-shaped fiber optic SPR microfluidic chip was shown in Fig. 3. The single-mode fiber on the left side of the chip was connected to a broad-spectrum light source (HL1000, WY Optics). The light source was injected into the D-shaped multimode fiber core from the single-mode fiber and interacted with the 50 nm gold film coated on the outside of the D-shaped multimode fiber core to excite the SPR effect. The light in the D shaped multimode fiber core continued to travel to the right and was collected by the large core multimode fiber, which was then injected into a spectrometer (USB2000+, Ocean Optics). The spectral data was processed by a computer. The syringe on the microfluidic pump (LSP01-1A, Longer Pump) was loaded with the solution to be measured and connected to the inlet capillary on the left side of the chip. The microfluidic pump controlled the solution to be measured from the inlet tube into the microfluidic channel formed by the D-shaped fiber and quartz tube. The solution to be measured passed through the SPR sensing area on the surface of the D-shaped fiber, and then was discharged into the waste pool by the right outlet capillary. When the refractive index of the liquid passing into the microfluidic channel changed (or when cytokines such as GDF11 were passed in after the gold film modification of specific antibodies in the sensing area, the antigen-antibody combination caused the change of refractive index), it will cause the SPR resonance valley wavelength to shift to realize SPR detection.
3. Probe surface modification
To achieve specific detection of cytokines such as GDF11, it needed to modify the surface of the SPR sensing area of the D-shaped fiber optic SPR detection microfluidic chip. Due to the low concentration of GDF11 in the human body and the small molecular weight, it was high for the sensitivity of the SPR detection module, and it needed the sensitization modification. In order to realize the directional recognition of GDF11 molecules, it was also necessary to specifically modify the surface of the sensing area. The modification process of the SPR sensing area surface was shown in Fig. 4.
3.1 Sensitization modification
The content of GDF11 is less in the human body. A high-sensitivity sensor is required for its detection, which requires compound sensitization modification on the surface of the sensing area of the fiber-optic SPR microfluidic chip. In this paper, a strong cationic polyelectrolyte PolyDADMAC (PDDA) was used to realize the connection between the gold film and the sensitization modified film. Gold nanoparticles and Metal Organic Frameworks (MOFs) were sequentially modified to jointly sensitize the sensing area.
Firstly, gold nanoparticles with a diameter of 20 nm were selected as the first layer of sensitization material. This is due to the fact that gold nanoparticles of different sizes have a certain modulating effect on the resonance range of SPR. These gold nanoparticles can modulate the sensitivity of SPR detection, where gold nanospheres with a diameter of 20 nm have a significant sensitizing effect on SPR [32,33]. MOF-74 was chosen as the second layer of sensitization material, which is due to the good electron mobility of MOF-74. The absorbed light energy can be used for the transfer of electrons, and electrons are continuously transferred from MOF-74 material to the gold film, thus increasing the surface electric field strength and enhancing the sensitivity; meanwhile MOF-74 material has high porosity and large specific surface area, which can provide more binding sites and can bind more antigenic antibodies and improve the sensitivity of detection [34,35].
Sensitization modification was first applied to the surface of the sensing area. To test the refractive index sensing sensitivity of the unmodified microfluidic chip, a refractive index standard solution with refractive indices of 1.333-1.385 was sequentially passed into the microfluidic channel by a microfluidic pump, and its SPR transmission spectrum was shown in Fig. 6(a), with the working range of the SPR resonance valley as 631.5-715.8 nm and an average sensitivity of 1621.2 nm/RIU.
The sensing area was rinsed by deionized water and blew dry with nitrogen gas. 0.2 mg/mL of PDDA solution was passed and kept for 10 min, and the sensing area was cleaned by deionized water and blew dry with nitrogen gas. We passed 0.05 mg/mL of 20 nm gold nanoparticle solution (XFJ60, XFNANO) into the sensing area and kept it for 1 h. We used deionized water to clean the gold nanoparticles not attached on the surface of the gold film, and then used nitrogen gas to blow dry it. In the meantime, the gold nanoparticles have been successfully modified on the surface of the gold film, as shown in Fig. 5(a). The refractive index sensing test was carried out, and the SPR transmission spectrum was shown in Fig. 6(b). The working range of SPR resonance valley redshifted 637.6-765.9 nm, and sensitivity increased to 2467.3 nm/RIU.
Fig. 5. (a) SEM images of the surface of the sensing region modified with 20 nm gold nanoparticles; (b) SEM images of the surface of the sensing region modified with 20 nm gold nanoparticles and MOF-74.
MOF-74 dispersion (XFF17, XFNANO) with a concentration of 0.5 mg/mL was passed into the sensing area and kept for 1 h, washed with deionized water and blown dry with nitrogen gas. The surface of the sensing area has been successfully modified with gold nanoparticles and MOF-74, as shown in Fig. 5(b). The SPR transmission spectrum was shown in Fig. 6(c), and working range of the SPR resonance valley was red-shifted to 644.6-790.2 nm, and the sensitivity was increased to 2800 nm/RIU. The refractive index of sensing resonance wavelengths before and after microfluidic modification was shown in Fig. 6(d). The result showed that with the superposition of sensitizing materials, working range of the SPR resonance valley shifted to the long wavelength direction and the sensitivity gradually increased. The refractive index sensing test experiments for each modification step were performed three times and error bars were made. The deviation of the single experiment results from the arithmetic mean of three experiments was within 12 nm, indicating that the sensing area sensitization modification has a strong repeatability for the performance improvement.
Fig. 6. Refractive index sensing test results of microfluidic chips before and after sensitization modification. (a) before modification (b) after modification of 20 nm gold nanoparticles (c) After modification of 20 nm gold nanoparticles and MOF-74 (d) SPR resonance wavelength fitting diagram
3.2 Specific modifications
To achieve specific detection of GDF11, the sensing area of the microfluidic chip was specifically modified. After the sensitization, 200 ug/mL of Staphylococcal protein A(P6860, Solarbio) solution was passed into the sensing zone and kept for 1 h. The sensing area was washed with PBS buffer and blown dry with nitrogen. The GDF11 antibody solution of 100 ng/mL was passed into the sensing area and kept for 30 min. The sensing area was washed and dried with PBS buffer to modify the GDF11 antibody (ab239515, Abcam) on the surface of the sensing area. Finally, 10 mg/mL of BSA solution was passed into the sensing area and kept for 30 min to block the unbound sites on the surface of the sensing area. The sensing area was washed with PBS buffer and blown dry. The SPR specific detection can be performed by transmitting different concentrations of GDF11 solution into the sensing area.
4. Results
After the surface modification of the sensing area of the microfluidic chip was completed, different concentrations of GDF-11 (ab239515, Abcam) were passed to the sensing area for SPR detection experiments. Firstly, 1 µL GDF-11 solution with a concentration of 1 pg/mL was injected into the sensing area, and the SPR spectrum was collected at this time. The SPR resonance valley wavelength value was recorded as the initial wavelength, then the SPR spectra were collected every 3 min. The SPR resonance valley wavelength value was subtracted from the initial wavelength to obtain the SPR resonance wavelength shift, and the SPR spectra continued to be collected every 3 min to calculate the wavelength shift. The SPR wavelength shift was calculated every 3 min until the SPR wavelength shift was 0 (usually about 20 min), and the SPR detection experiment at this concentration was completed. The sensing area was washed with PBS buffer and dried with nitrogen and we repeated the above steps. 1 pg/mL, 10 pg/mL, 100 pg/mL, 1 ng/mL, 10 ng/mL and 100 ng/mL GDF-11 solution with the volume of 1µL were injected into the sensing area and detected. The experimental results showed that the antigen and antibody started to bind when the antigen solution was first added. The SPR resonance valley wavelength continued to move toward the long wavelength with the increase of time, and the antigen and antibody were fully bound at about 20 min, and the SPR resonance valley wavelength no longer moved. The relationship between the amount of SPR resonance valley wavelength movement with time at different GDF11 concentrations was shown in Fig. 7(a). At each concentration, the SPR spectrum after the stabilization of the SPR wavelength shift (27 min) was shown in Fig. 7 (b). It can be seen that as the GDF11 concentration increased from 1 pg/mL to 100 ng/mL, the resonance valley wavelength gradually moves to the long wavelength when the SPR spectrum was stabilized. The working range of SPR resonance valley was 647-653.9 nm, with the sensitivity as 1.38 nm/lg(g/mL), and the detection limit as 0.52 pg/mL. This experiment was repeated three times, and the relationship between SPR resonance valley shift and GDF11 concentration was plotted in Fig. 7(c). The deviation of the data of three experiments from its arithmetic mean was within 0.5 nm with a good repeatability.
Fig. 7. The results of microfluidic GDF-11 concentration detection. (a) SPR resonance valley wavelength shift versus time for different concentrations of GDF11; (b) SPR resonance spectra after the resonance valley shifts smoothly at different concentrations of GDF11; (c) shift amount versus GDF11 concentration after the resonance valley shifts smoothly.
5. Discussion
This paper presented an all-fiber SPR microfluidic detection chip that can be used for trace cytokine detection such as GDF-11. The D-shaped multimode fiber was designed and fabricated with the overall fiber and core in D-shape. The flat side of the D-shaped core was exposed to the air with a straight edge length of 24 µm. Since the core was directly exposed to the outside, and the size of 24 µm can ensure the existence of high-order modes in the core and the number of modes is small, the flat surface of the D-shaped fiber was easy to construct the SPR sensing area, and the sensitivity was high. The D-shaped optical fiber was semi-cylindrical in shape, which was nested in the quartz tube optical fiber. The lower half of the quartz tube was filled with D-shaped optical fiber, and the upper half was surrounded with D-shaped optical fiber to form a semi-cylindrical microfluidic channel, which realized the all-fiber structure of microfluidic chips.
Compared with other microfluidic chips for biomarker detection, the SPR sensing unit and microfluidic channel of this microfluidic chip were both formed by D-shaped optical fiber with higher detection throughput. The minimum volume for a single detection was only 0.4 µL. For the chip, it further reduced the size of the microfluidic chip and simplifying the integration process, with the outer diameter as only 200 µm. The microfluidic channel of the chip was sealed by quartz tube fiber, which can avoid the interference of external environment to a certain extent. To further improve the detection sensitivity of the microfluidic chip, 20 nm gold nanoparticles and MOF-74 were modified on the surface of the sensing area. SPA and GDF11 antibody were modified in the sensing area to achieve specific recognition of GDF11. The final detection sensitivity was 1.38 nm/lg(g/mL) and the detection limit was 0.52 pg/mL.
We compared different microfluidic chips for biological detection in these aspects: microfluidic channel processing, fabrication cycle, channel sealing situation, and sample consumption volume. The results were shown in Table 1. It showed that the all-fiber SPR microfluidic detection chip proposed in this paper had been simplified compared with other microfluidic chips. The consumption of sample volume was reduced by one order of magnitude, and the detection limit was reduced by two orders of magnitude compared with other microfluidic chips.
Table 1. Comparison of the performance of different bioassay microfluidic chips
The all-fiber detection microfluidic chip proposed in this paper can be further developed and enhanced in the future. The ambient temperature has a large impact on the sensing results of the SPR mechanism. In the future, this all-fiber microfluidic chip can be designed with multiple detection channels. One channel is used for biochemical detection and the other is used for detecting temperature changes. It realizes the function of temperature compensation and eliminates the influence of ambient temperature changes on the detection results. In addition, we used single-mode optical fiber as the lead-in fiber for this microfluidic detection chip, which can meet the detection requirements under the testing conditions of this paper. If this chip is used for dual-channel detection or temperature compensation in the future, light is injected in the single-mode fiber, and the energy coupled from the light source may not be sufficient. We can choose a few-mode fiber with a core diameter smaller than the core diameter of a D-shaped fiber as an lead-in fiber. Or, the light source can be replaced with a more powerful supercontinuum source.
6. Conclusion
This paper presented an all-fiber optic SPR microfluidic chip that can be used for micro detection of cytokines such as GDF11. It realized all-fiber optic integration of microfluidic channel and SPR sensing detection module. The design was flexible and can be fabricated rapidly. The sensitivity of this chip for GDF11 specific detection was 1.38 nm/lg (g/mL), and the LOD was 0.52 pg/mL. The outer diameter of the microfluidic chip was only 200 µm and the sample consumption for a single detection was only 0.4 µL. The structure of the microfluidic chip was compact and the sample consumption was small. If SPR all-fiber detection microfluidic chip and the blood vessel form a detection circuit, a small amount of blood in the blood vessel will be detected by the microfluidic chip and then flow back to the blood vessel to make a wearable biosensing monitoring device, which is expected to realize real-time online monitoring of trace cytokines in human body.
Funding
National Natural Science Foundation of China (No. 61705025); Chongqing Natural Science Foundation (cstc2019jcyj-msxmX0607,cstc2019jcyj-msxmX0431); the Science and Technology Project Affiliated to the Education Department of Chongqing Municipality (No. KJZD-M202201201); Chongqing Postgraduate Research and Innovation Project; Chongqing Key Laboratory of Geological Environment Monitoring and Disaster Early-Warning in Three Gorges Reservoir Area (ZD2020A0102, ZD2020A0103); Fundamental Research Funds for Chongqing Three Gorges University of China (No. 19ZDPY08); Open Project Program of Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area (No.KFKT2022005).
Disclosures
The authors declare that there are no conflicts of interest related to this manuscript.
Data availability
Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request.
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