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MTC和锥形光纤耦合的显微图像如图 8所示。作者使用熔融拉锥法实验制备了外径约为89.1μm的MTC,并通过管内气压控制法将MTC的壁厚拉伸到约2.5μm。通过锥形光纤与柱状微腔耦合激发WGM,测得MTC的Q因子约为1.1×106。MTC和锥形光纤(锥区直径约为2μm~3μm)之间的耦合距离由精度为20nm的高精度电控位移平台控制。过耦合用于确保整个传感系统的稳定性。MTC可以将WGM特性与其微流控的固有能力相结合,并且Q因子相对较高,MTC的管壁薄而弯曲,具有大表面积,可以增强光与物质的互作用。所有这些都有助于在小范围内有效激发强的倏逝场,并有助于实现葡萄糖浓度测试的低检测极限和高灵敏度检测。
Figure 8. a—microscope photos of MTC-tapered fiber coupling system b—WGM spectrum test results with Q value of 1.1×106
基于MTC的葡萄糖浓度生物光学传感器实验装置如图 9所示。使用蠕动泵将葡萄糖溶液注入MTC(型号TJ-3A,蠕动泵的最小流速为7μL/min)。调谐光源中心波长为1550nm,线宽小于5kHz,调谐范围为35GHz。通过锥形光纤耦合MTC激发WGM共振谱,并由光电探测器(photoelectric detector, PD)接收,其带宽为125MHz, 由偏振控制器(polarization controller,PC)控制入射光的偏振状态。
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采用过耦合方式实现微腔与锥形光纤的耦合,确保MTC耦合系统的稳定性。首先,将去离子水泵入MTC,测试传感器的稳定性,实验结果如图 10所示。每10min记录一次MTC的WGM光谱, 并连续测量1h。WGM光谱的最大波长漂移约为0.89pm。MTC中的WGM共振不仅对目标分析物敏感,而且对环境干扰(例如机械振动和温度变化)敏感。对于可检测的目标分析物变化,WGM光谱的波长偏移应大于0.89pm。传感系统放置在隔振光学平台上,温度扰动是潜在的噪声源,应考虑进一步改进以抑制传感器的不稳定。
Figure 10. WGM spectra of cylindrical microcavities measured within 1h(inset: enlarged view of WGM spectrum)
将具有5种不同质量分数的NaCl溶液泵入柱状微管腔中。溶液折射率测试结果如表 1所示,每种溶液的折射率(refractive index, RI)用阿贝折射仪测量5次取平均值。
Table 1. The refractive index of five different concentrations of NaCl solution was measured five times each time
mass fraction 1st 2nd 3rd 4th 5th average RI 0.026 1.3375 1.3374 1.3374 1.3374 1.3373 1.3374 0.028 1.3375 1.3376 1.3376 1.3378 1.3376 1.3376 0.030 1.3380 1.3381 1.3382 1.3381 1.3382 1.3381 0.032 1.3384 1.3384 1.3385 1.3385 1.3384 1.3384 0.034 1.3390 1.3388 1.3389 1.3386 1.3388 1.3388 保持锥形光纤-MTC的耦合条件稳定且不变, 逐步将质量分数为0.026,0.028,0.030,0.032,0.034的NaCl溶液泵入MTC,WGM光谱的对比结果如图 11所示。可以看出,随着泵入的NaCl质量分数的增加,WGM光谱会发生红移,因为溶液折射率的增加导致WGM谐振波长向长波长方向漂移。图 11b为测得的WGM波长偏移与NaCl溶液的折射率变化的关系。经计算MTC的体折射率灵敏度为23.36nm/RIU。
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结合微流控方法将被测液态分析物进入MTC时,分析物与MTC内表面的交联可被视为光传播的1阶扰动,可计算出传播常数的变化:
$ \frac{{\delta {{(\Delta \beta )}_{\rm{b}}}}}{{\Delta \beta }} = \frac{{\tau {\alpha _{{\rm{ex}}}}{\sigma _{\rm{p}}}\smallint {{\left| {E(x, y)} \right|}^2}{\rm{d}}L}}{{2{\varepsilon _{\rm{s}}}\smallint \smallint {{\left| {E(x, y)} \right|}^2}{\rm{d}}x{\rm{d}}y}} $
(1) 式中,Δβ表示传播常数的变化, 下标b表示生物分子与微腔表面综合处, σp是生物分子的表面密度,εs是相对介电常数,αex表示由于单个生物分子引起的过量极化,τ表示MTC表面功能化后内壁表面附近的场强变化,其大小与折射率和薄壁的厚度有关, E(x, y)表示电场强度,L代表传感区域长度。分母的积分表示整个波导截面上的模能量,由于大多数能量都限制在MTC内壁中,因此两种模式(光纤模式和混合模式)的积分振幅几乎相同;分子的积分表示MTC的内壁表面的能量密度,对(1)式进行变式可以获得:
$ \Delta \lambda = \frac{{{\rm{d}}(\Delta \beta )}}{{\frac{{\delta (\Delta \beta )}}{{\delta \lambda }}}} $
(2) (2) 式说明了光场在微腔内传播常数的变化可引起WGM波长的漂移。在MTC内壁上捕获更多的葡萄糖分子会导致更大的折射率变化,从而WGM波长偏移量增加。因此,通过对MTC的表面功能化以增强对葡萄糖分子的捕获,可以提高灵敏度。
实验过程中,利用葡萄糖氧化酶(glucose oxidase, GOD)对MTC的内壁进行表面功能化以捕获更多的葡萄糖分子。表面功能化所需的生化试剂为:去离子水、醋酸钠试剂、无水乙醇、无水葡萄糖、GOD、硝酸、浓硫酸和过氧化氢。
表面功能化步骤如下:(1)将去离子水多次泵入MTC中,以确保MTC清洁,再注入质量分数为0.05的稀硝酸并密封在MTC中,静置2.5h;(2)用去离子水和酒精交替清洁MTC, 注入食人鱼溶液浓硫酸溶液并在MTC中密封1h,以确保MTC内壁表面上的羟基被完全活化; (3)将MTC保持中空并在室温下干燥,然后将3-氨基丙基三乙氧基硅烷溶液泵入MTC,并静置30min,再用去离子水和酒精冲洗以除去腔室的非共价键合的硅烷化合物; (4)将10mg/mL葡萄糖氧化酶(GOD)溶液(溶剂为乙酸钠缓冲溶液)注入MTC中, 将该MTC静置2h, 以确保在MTC的内表面盐化后,GOD-COOH基团与NH3+充分反应; (5)依次用乙酸钠缓冲溶液和去离子水冲洗MTC的内部,然后使其干燥。在表面功能化过程中重要的是,保持MTC和锥形光纤耦合的稳定性。
由于实验制备的MTC具有较小的管径,结合微流控技术,实际实验测试用到的样品量可低至90nL。实验结果如图 12所示,随着葡萄糖溶液的浓度增加,测得的WGM光谱红移更大。从图 12a中可以看出,可检测到由2.65mmol/L的低葡萄糖浓度变化引起大约为3.04pm的波长偏移。葡萄糖浓度由0mmol/L变化到13.76mmol/L时,WGM共振波长从1547.122nm移至1547.139nm, 光谱位移范围达到13.76pm。图 12b中给出了波长偏移与葡萄糖浓度的函数线性拟合结果,表面功能化的MTC测试葡萄糖浓度具有较高的线性度,且其灵敏度约为0.911pm/(mmol/L)。
基于液芯MTC的低浓度血液葡萄糖光学传感器研究
Optical sensor for low concentration blood glucose detection based on liquid-core MTC
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摘要: 为了实现超低样本体积、高灵敏度的血液葡萄糖浓度检测,采用时域有限差分法分析了液芯微管腔(MTC)的壁厚和直径对回音壁模式(WGM)共振特性的影响。利用熔融拉锥法制备了MTC,通过高精度电控位移平台实现MTC和锥形光纤的高精度耦合以及WGM共振谱的激发,并对MTC进行表面功能化和过耦合方法以提高灵敏和稳定性, 同时进行了理论分析和实验验证。结果表明, 表面功能化的液芯MTC传感器取得的灵敏度约为0.911pm/(mmol·L-1),线性度为0.988;该低浓度血液葡萄糖光学传感器的灵敏度和稳定性很高。这一结果对运动员训练中血糖的实时、快速监测,保障运动安全性和持久性等是有帮助的。Abstract: In order to achieve blood glucose concentration detection with ultra-low sample volume and high sensitivity, the influence of the wall thickness and diameter of liquid-core microtube cavity(MTC) on whispery gallery mode(WGM) resonance property was analyzed based on finite-difference time-domain(FDTD) method. The MTC was fabricated by melt-taping method. High-precision coupling of MTC and tapered fiber and the excitation of WGM resonance spectrum were realized by high-precision electronically controlled displacement platform. The surface functionalization and over-coupling methods of MTC were carried out to improve sensitivity and stability. Theoretical analysis and experimental verification have been carried out. The experimental results show that the linearity and sensitivity of the surface functionalized liquid-core MTC sensor are 0.988 and 0.911pm/(mmol· L-1), respectively. The low-concentration blood glucose optical sensor has high sensitivity and stability. This result is helpful for real-time and rapid monitoring of blood sugar during training of athletes, and for ensuring the safety and durability of sports.
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Table 1. The refractive index of five different concentrations of NaCl solution was measured five times each time
mass fraction 1st 2nd 3rd 4th 5th average RI 0.026 1.3375 1.3374 1.3374 1.3374 1.3373 1.3374 0.028 1.3375 1.3376 1.3376 1.3378 1.3376 1.3376 0.030 1.3380 1.3381 1.3382 1.3381 1.3382 1.3381 0.032 1.3384 1.3384 1.3385 1.3385 1.3384 1.3384 0.034 1.3390 1.3388 1.3389 1.3386 1.3388 1.3388 -
[1] CUI Y Q, DAI K X. Sugar supplement and exercise ability [J]. Sports World (Academic Edition), 2008(6): 116-118(in Chin-ese). [2] LI L. Research on sugar supplement and improvement of endurance sports ability [J]. Sports World (Academic Edition), 2014(6): 124-125(in Chinese). [3] REN J H. Research on the influence of sugar supplement before competition on middle school students' endurance sports-taking Wuji ju-nior middle school in Shijiazhuang as an example [J]. Sports World (Academic Edition), 2017(11): 63-65(in Chinese). [4] ZHANG H Sh, WANG J. Some thoughts on sports rehydration [J]. Chinese Sports Coaches, 2015, 23 (4): 61-61(in Chinese). [5] YI M Q, ZHOU L L, ZHENG Sh Q, et al. Study on the supplement of sugar for cyclists [J]. Chinese Journal of Sports Medicine, 1999, 18 (1): 76-78(in Chinese). [6] XIAOFENG SOCIETY. Grief! After several marathons in China, two athletes died suddenly before the finish line: Blindly following the trend is not advisable [EB/OL]. (2019-10-21)[2020-08-14]. https://baijiahao.baidu.com/s?id=1647990350787957669&wfr=spider&for=pc (in Chinese). [7] PENG R X, XU W J, ZHANG Sh, et al. Measurement of blood sugar and blood lactate before and after middle and long-distance running[J]. Journal of Dalian University, 2004, 25(4): 83-85(in Chin-ese). [8] WU P. Research on glucose concentration measuring method based on fiber optic surface plasmon resonace technique[D]. Tianjin: Tianjin University, 2008: 3-14 (in Chinese). [9] MENG Q L, ZHANG Y, SHANG J. Nondestructive detection of apple defect combining optical fiber spectra with pattern recognition[J]. Laser Technology, 2019, 43(5): 676-680 (in Chinese). [10] ZHONG Y Q, YUAN X H, PENG Q B, et al. Effect of fingertip blood sampling on accuracy of rapid blood glucose level in ophthalmic patients[J]. International Journal of Nursing, 2018(1): 1723-1726(in Chinese). [11] ZHANG H Y. Study on nir spectroscopy application in human blood glucose noninvasive measure[D]. Changchun: Changchun Institute of Optics, Fine Mechanics and Physics of Chinese academy of Sciences, 2005: 17-25(in Chinese). [12] WAN H D, LIU L Q, DING Z Q. et al. Single-longitudinal-mode, narrow bandwidth double-ring fiber laser stabilized by an efficiently taper-coupled high roundness microsphere resonator[J]. Optics & Laser Technology, 2018, 102: 160-165. [13] LIN N, JIANG L, WANG S M, et al. Simultaneous measurement of refractive index and temperature using a microring resonator[J]. Chinese Optics Letters, 2012, 10(5): 052802. doi: 10.3788/COL201210.052802 [14] ZHANG F, WU G Zh, WANG Ch Ch. Influence of surface curvature on mode and sensing characteristics of quartz capillary microbo-ttles[J]. Laser Technology, 2018, 42(6): 840-844(in Chinese). [15] FOREMAN M R, SWAIMJ D, VOLLMER F. Whispering gallery mode sensors[J]. Advances in Optics and Photonics, 2015, 7(2): 168-240. doi: 10.1364/AOP.7.000168 [16] REYNOLDS T, HENDERSON M R, FRANCOIS A, et al. Optimization of whispering gallery resonator design for biosensing applications[J]. Optics Express, 2015, 23(13): 17067-17076. doi: 10.1364/OE.23.017067 [17] ZHOU Q, CHEN Y, HAN F K, et al. Liquid-core, thin-wall microcapillary electric field sensor with high quality factor[J]. Acta Photonica Sinica, 2020, 49(2): 0223002(in Chinese). doi: 10.3788/gzxb20204902.0223002 [18] ZHANG H W, LIU B, SONG B B, et al. Acoustooptic-mode-coupling-based whispering gallery mode excitation in silica-capillary microresonator[J]. Journal of Lightwave Technology, 2017, 35(2): 220-224. doi: 10.1109/JLT.2016.2638467 [19] LANE S, WEST P, FRANCOIS A, et al. Protein biosensing with fluorescent microcapillaries[J]. Optics Express, 2015, 23(3): 2577-2590. doi: 10.1364/OE.23.002577 [20] NADGARAN H, POURMAND R. Ultra-sensitive optical biosensor based on whispering gallery modes: The effect of buffer solutions refractive index on their sensitivity and performance[J]. Journal of Biomedical Physics & Engineering, 2013, 3(2): 57-62. [21] ROBISON H M, BAILEY R C. A guide to quantitative biomarker assay development using whispering gallery mode biosensors[J]. Current Protocols in Chemical Biology, 2017, 9(3): 158-173. doi: 10.1002/cpch.23