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Ultrasonic standing wave preparation of a liquid cell for glucose measurements in urine by midinfrared spectroscopy and potential application to smart toilets

Ultrasonic standing wave preparation of a liquid cell for glucose measurements in urine by... Ultrasonic standing wave preparation of a liquid cell for glucose measurements in urine by midinfrared spectroscopy and potential application to smart toilets Naoyuki Yamamoto Natsumi Kawashima Tomoya Kitazaki Keita Mori Hanyue Kang Akira Nishiyama Kenji Wada Ichiro Ishimaru Naoyuki Yamamoto, Natsumi Kawashima, Tomoya Kitazaki, Keita Mori, Hanyue Kang, Akira Nishiyama, Kenji Wada, Ichiro Ishimaru, “Ultrasonic standing wave preparation of a liquid cell for glucose measurements in urine by midinfrared spectroscopy and potential application to smart toilets,” J. Biomed. Opt. 23(5), 050503 (2018), doi: 10.1117/1.JBO.23.5.050503. JBO Letters 1 Introduction Ultrasonic standing Early treatment is important in the prevention of lifestyle-related diseases, such as diabetes and gout. Smart toilets that could wave preparation of measure glucose and protein in urine in daily life are of interest in this area. To date, smart toilets can only control cleaning and a liquid cell for glucose measure the volume of urine using flow rate sensors, motion detectors, and other technology. Currently, there is no sensor measurements in urine that can be installed in a toilet and measure different components by midinfrared of interest in urine. If glucose or protein is present in urine, it is possible that the person has diabetes or chronic kidney 3,4 spectroscopy and disease. Early detection of these diseases by smart toilets in daily life could prompt an individual to seek treatment at 5,6 potential application an early stage of the disease. Many approaches have been investigated for smart toilets and noninvasive blood glucose sen- to smart toilets 7,8 sors, with most using near-infrared spectroscopy and wave- lengths from 800 to 1500 nm. Near-infrared light can pass through a sample more easily than midinfrared light because a a Naoyuki Yamamoto, Natsumi Kawashima, it is absorbed less by water. Therefore, near-infrared spectros- a a a Tomoya Kitazaki, Keita Mori, Hanyue Kang, copy can be used for noninvasive analysis of biological samples. b b Akira Nishiyama, Kenji Wada, and a, However, the near-infrared absorption of glucose is weak Ichiro Ishimaru * because the absorption peak in the near-infrared region appears Kagawa University, Faculty of Engineering, Takamatsu-City, Kagawa, Japan as an overtone and combination band. Furthermore, it is dif- Kagawa University, Faculty of Medicine, Miki-Cho, Kita-gun, ficult to identify the absorption peak of glucose because there Kagawa, Japan are also absorption peaks for water, proteins, and hemoglobin in 11,12 the near-infrared region. Abstract. Smart toilets could be used to monitor different Smart toilets using midinfrared spectroscopy could be used components of urine in daily life for early detection of life- to detect the fundamental vibration of glucose. We have already style-related diseases and prompt provision of treatment. proposed a small (bean-sized) midinfrared Fourier spectroscopic For analysis of biological samples such as urine by mid- imager. However, because midinfrared light is absorbed infrared spectroscopy, thin-film samples like liquid cells are strongly by water, this imager requires thin-film samples with needed because of the strong absorption of midinfrared thicknesses of <100 μm for midinfrared spectroscopy detection light by water. Conventional liquid cells or fixed cells are of transmitted or reflected light. Conventional liquid cells and prepared based on the liquid membrane method and sol- fixed cells prepared based on the liquid membrane method ution technique, but these are not quantitative and are and solution techniques are used for optical transmission difficult to set up and clean. We generated an ultrasonic measurements. Unfortunately, these cells are not quantitative standing wave reflection plane in a sample and produced and are difficult to set up and clean. Another option is the an ultrasonic liquid cell. In this cell, the thickness of the 16–18 attenuated total reflectance method, which uses an evanes- optical path length was adjustable, as in the conventional cent wave that can travel several micrometers into a sample. method. The reflection plane could be generated at However, the light must be reflected many times in the attenu- an arbitrary depth and internal reflected light could be ated total reflectance prism to meet the required optical path detected by changing the frequency of the ultrasonic length, and light intensity is an issue because increased reflec- wave. We could generate refractive index boundaries tion leads to increased absorption by the prism and samples. using the density difference created by the ultrasonic In this paper, we describe development of an ultrasonic liquid standing wave. Creation of the reflection plane in the cell, with a reflection plane generated inside the sample by an sample was confirmed by optical coherence tomography. ultrasonic standing wave, for midinfrared spectroscopy and Using the proposed method and midinfrared spectroscopy, application to smart toilets [Fig. 1(a)]. We used optical coher- we discriminated between normal urine samples spiked ence tomography (OCT) to investigate the reflection plane of the with glucose at different concentrations and obtained ultrasonic standing wave in the sample and applied our method a high correlation coefficient. © The Authors. Published by SPIE to normal urine samples spiked with different concentrations of under a Creative Commons Attribution 3.0 Unported License. Distribution or glucose. The urine used in the study was collected from a 24- reproduction of this work in whole or in part requires full attribution of the original year-old adult male. Additionally, we determined the correlation publication, including its DOI. [DOI: 10.1117/1.JBO.23.5.050503] coefficient for measurement of the glucose concentration to evaluate the feasibility of this method for quantitative measure- ment of glucose concentrations and the realization of smart Keywords: optic; Fourier spectroscopy; smart toilet; ultrasonic stand- ing wave; glucose; midinfrared light. toilets. Glucose is typically excreted from blood into urine when the blood glucose level reaches around 180 mg∕dL. Paper 170800LR received Dec. 11, 2017; accepted for publication May 1, 2018; published online May 22, 2018. However, because this level can vary, we instead used the level (50 mg∕dL) for a positive result with a urine test strip. For the realization of smart toilets, we believe that a glucose target concentration of 50 mg∕dL and measurement accuracy *Address all correspondence to: Ichiro Ishimaru, E-mail: ishimaru@eng. of 30 mg∕dL will be relevant. kagawa-u.ac.jp Journal of Biomedical Optics 050503-1 May 2018 Vol. 23(5) JBO Letters Mounted Incident light Surface reflection light Internal Illumination Refractive reflection light Diameter of index lens is 5mm. Toilets H H Reflection plane H H One-shot Standing Urine Fourier wave H H spectroscopy H H = Node Transducer L = Anti node (a) (b) Fig. 1 (a) Schematic diagram of a smart toilet and (b) the liquid cell with variable optical path length. at a frequency of 10 MHz and a voltage of 10 V to generate an 2 Principles of the Ultrasonic Liquid Cell and ultrasonic standing wave inside the target. The OCT image con- Verification Experiments firmed that the particles in the water aggregated at the node of If a sample is homogeneous, some incident light will be detected the ultrasonic standing wave and formed lines [Fig. 2(c)]. The as surface reflected light. However, light absorbed within the particles near the boundaries with the optical windows were not sample cannot be detected. Therefore, in this method, an ultra- trapped by the standing wave and did not aggregate. Because sonic standing wave was used to generate refractive index incident light is reflected by a node with a large refractive boundaries inside the sample, and internal reflected light was index difference, the incident light is considered to be reflected detected at an arbitrary depth [Fig. 1(b)] Because the ultrasonic 0.05 mm from the wall surface. In this case, the optical path wave is a compressional wave, it propagates while generating a length is the sum of that of the incident light and the reflected density difference within the sample. The refractive index dis- light from the reflection plane. We selected a reflectance depth tribution is also stabilized by the ultrasonic standing wave. The of 0.05 mm, because it provided an optical path length of about incident light is reflected at the node of the ultrasonic standing 100 μm, which is suitable for midinfrared spectroscopy. To gen- wave where the refractive index differences are maximized, and erate a reflection plane at this position, a frequency of 10 MHz is it is detected as internal reflected light. The position of the node required. Even though the sample is homogeneous and internal of the ultrasonic standing wave depends on the frequency of reflected light cannot usually be detected, it could be detected the ultrasonic wave. By manipulating the frequency of the ultra- from node positions by generating a refractive index difference sonic standing wave, we could obtain an arbitrary optical path with an ultrasonic standing wave. length in the depth direction. In this study, the ultrasonic standing wave was generated 3 Measurement of Glucose in Normal Urine inside a container fabricated of BaF optical windows with by Midinfrared Spectroscopy high transmittance of midinfrared light, and the internal reflec- We constructed an optical system for detecting internal reflected tion plane was confirmed using OCT (IVS-2000, Santec, light in pure water [Fig. 3(a)]. We used a small graphite light Komaki, Japan). Figure 2(a) shows the optical system. To visu- source (EK8620, Helioworks, Santa Rosa, California) with an alize the generated reflective surface, pure water containing attached setup for Kohler illumination. To shorten the optical red fluorescent polymer microspheres (36-3, Thermo Fisher path length, the incident light from the optical system entered Scientific, Waltham, Massachusetts) was used as a sample. through the wall of the target at an angle of about 45 deg. An ultrasonic transducer (PN-10C10N, Japan Probe Co. Ltd., The ultrasonic vibrator was placed on the bottom of the target. Yokohama, Japan) was attached behind the target, and vibrated We detected internal reflected light using the two-dimensional Measurement area Before vibration OCT Plane wave Node generation Window (Image) area Detective head In water Window BaF After vibration Container Aggregated at node Transducer Voltage: 10V 0.05mm Reflection plane Frequency: 10MHz (a) (b) (c) Fig. 2 A reflection plane generated by an ultrasonic standing wave is detected by OCT. (a) Experimental setup, (b) a detailed image of the container, and (c) the results of an experiment. Journal of Biomedical Optics 050503-2 May 2018 Vol. 23(5) JBO Letters Internal Light source Spectroscopic characteristics for comparing reflected light with the relative intensities before and after vibration Ultrasonic standing wave After vibration Imaging Expand the container lens Objective The relative intensity lens (the internal reflected light) increased about 25%. Before vibration Imaging type 810 12 14 2-dimensional Fourier Wavelength [µm] spectroscopy (a) (b) Fig. 3 (a) The optical system for the experiment and (b) comparison of the intensities before and after ultrasonic vibration. Fourier spectroscopic imager. This light was reflected from the for urine tested with a glucose test strip (100 mg∕dL). The rel- reflection plane, which was generated 0.05 mm from the surface ative intensity of the urine after ultrasonic vibration was used as by the ultrasonic standing wave using the wall surface as the a reference for calculating the absorbance of glucose in urine. reflective material. Next, we compared the relative intensities We repeated the measurement 30 times and calculated the aver- before and after generation of the ultrasonic wave to confirm age. Absorption peaks for glucose were observed at 9.25 and detection of internal reflected light by our proposed liquid 9.65 μm, respectively [Fig. 4(a)]. The peak at 9.25 μm was cell. The relative intensities were evaluated for areas of five not obstructed by other components in the urine [Fig. 4(b)], and we obtained a high correlation coefficient (0.91) for meas- pixels by five pixels [Fig. 3(b)]. The relative intensity from urement of the glucose concentration in urine using this peak. 8to 14 μm after ultrasonic vibration was about 25% more than Therefore, this method is feasible for quantitative measurements that before ultrasonic vibration. These results confirmed that of glucose concentrations in urine without a complex setup. internal reflected light was detected by our method. The refrac- However, the 3σ value calculated from the standard deviation tive index of the optical window material (BaF ) is 1.414 at for the 30 measurements at 9.25 μm was about 0.015, and the 9 μm. Thus, the reflectance after vibration was calculated reproducibility of this method cannot be guaranteed. This could as 8% using Fresnel equations. Additionally, using the be caused by absorption of midinfrared light by water in the 25% increase in the relative intensity, the reflectance before atmosphere, or by fluctuation of the output from the light source. vibration was calculated as 2% (25% of 8%). Consequently, Our proposed method of one-shot Fourier spectroscopy could the refractive index of water was calculated as 1.1 using the overcome this problem, because it has high time resolution. reflectance formula, and the refractive index difference was around 0.3. This value is equivalent to the refractive index when light is reflected on the reflection plane. In future work, 4 Conclusions we will verify this and determine the theoretical relationship between the reflected light intensity and the ultrasonic standing Our liquid cell, generated by an ultrasonic standing wave in wave. a sample, could be used for realization of smart toilets using Next, a solution of glucose in urine was poured into the con- midinfrared spectroscopy. In future work, we will study the opti- tainer and we measured the glucose absorbance with the optical mum shape of this liquid cell for installation into smart toilets. system using the internal reflected light [Fig. 3(a)]. We spiked Additionally, the stability and repeatability of the liquid cell for the urine with glucose at three concentrations (50, 100, and urine glucose and protein measurements will be verified by 200 mg∕dL). These concentrations were selected because developing a one-shot Fourier spectroscopic imager for use in they are around the level that is considered a positive result the midinfrared region. 0.04 0.06 Correlation coefficient: 0.91 200 mg/dL 9.25 µ m 9.65 µ m 100 mg/dL 0.02 0.04 50 mg/dL 0 0.02 8 8.5 9 9.5 10 -0.02 0 0 50 100 150 200 250 -0.04 -0.02 Wavelength [µ m] The concentration of glucose [mg/dL] (a) (b) Fig. 4 (a) Absorbance of glucose in urine (n ¼ 30) and (b) verification of the measurement accuracy at 9.25 μm. Journal of Biomedical Optics 050503-3 May 2018 Vol. 23(5) Absorbance Relative intensity Absorbance JBO Letters 11. M. Pleitez et al., “Infrared spectroscopic analysis of human interstitial Disclosures fluid in vitro and in vivo using FT-IR spectroscopy and pulsed quantum We declare no conflict of interest. cascade lasers (QCL): establishing a new approach to non invasive glucose measurement,” Spectrochim. Acta 85(1), 61–65 (2012). 12. A. Schwaighofer et al., “Quantum cascade lasers (QCLs) in biomedical Acknowledgments spectroscopy,” Chem. Soc. Rev. 46(19), 5903–5924 (2017). We thank the Japan Agency for Medical Research and 13. S. Sato et al., “Ultra-miniature one-shot Fourier-spectroscopic tomog- Development. We thank Gabrielle David, PhD, from Edanz raphy,” Opt. Eng. 55(2), 025106 (2016). 14. S. Liakat et al., “In vitro measurements of physiological glucose con- Group (www.edanzediting.com/ac) for editing a draft of this centrations in biological fluids using mid-infrared light,” Biomed. Opt. letter. Express 4(7), 1083–1090 (2013). 15. Shimadzu Corporation, “Measurement methods for liquid samples,” 2017, https://www.shimadzu.com/an/ftir/support/ftirtalk/talk9/intro.html References (1 December 2017). 1. J. A. M. Bispo et al., “Correlating the amount of urea, creatinine, and 16. H. M. Heise et al., “Multivariate calibration for the determination of glucose in urine from patients with diabetes mellitus and hypertension analytes in urine using mid-infrared attenuated total reflection spectros- with the risk of developing renal lesions by means of Raman spectros- copy,” Appl. Spectrosc. 55(4), 434–443 (2001). copy and principal component analysis,” J. Biomed. Opt. 18(8), 087004 17. G. Budinova, J. Salva, and K. Volka, “Application of molecular spec- (2013). troscopy in the mid-infrared region to the determination of glucose and 2. D. R. Hall et al., “Smart flush toilet system,” U.S. Patent No. 0254060 cholesterol in whole blood and in blood serum,” Appl. Spectrosc. 51(5), A1 (2017). 631–635 (1997). 3. C. Wald et al., “Diagnostics: a flow of information,” DHR Int. J. 18. S. Kino et al., “Hollow optical-fiber based infrared spectroscopy for Biomed. Life Sci. 551, S48–S50 (2017). measurement of blood glucose level by using multi-reflection prism,” 4. D. J. F. Rowe et al., “Microalbuminuria in diabetes mellitus: review and Biomed. Opt. Express 7(2), 701–708 (2016). recommendations for the measurement of albumin in urine,” Ann. Clin. 19. R. Guptal et al., “Diabetes mellitus: the pandemic of 21st century!” Biochem. Int. J. Lab. Med. 27(4), 297–312 (1990). Asian J. Exp. Biol. Sci. 23(1), 261–268 (2009). 5. S. Saito et al., “Method and apparatus for detecting urinary constitu- 20. Y. Inoue et al., “Variable phase-contrast fluorescence spectrometry for ents,” U.S. Patent No. 5073500 (1991). fluorescently stained cells,” Appl. Phys. Lett. 89, 121103 (2006). 6. W. R. Premasiri, R. H. Clarke, and M. E. Womble, “Urine analysis by 21. “Refractive index of barium fluoride (BaF ), aerosol refractive index laser Raman spectroscopy,” Lasers Surg. Med. 28(4), 330–334 (2001). archive,” Earth Observation Data Group, 2018, http://eodg.atm.ox.ac. 7. U. A. Müller et al., “Non-invasive blood glucose monitoring by means uk/ARIA/data?Salts/Barium_Fluoride_(Querry_1987)/BaF2_Querry_ of near infrared spectroscopy: methods for improving the reliability of 1987.ri (20 March 2018). the calibration models,” Int. J. Artif. Organs 20(5), 285–290 (1997). 22. B. E. A. Saleh et al., Fundamentals of Photonics, Wiley-Interscience, 8. H. M. Heise et al., “Noninvasive blood glucose sensors based on near- New York (1991). infrared spectroscopy,” Artif. Organs 18(6), 439–447 (1994). 23. V. Ivanovski et al., “Polarized IR reflectance spectra of the monoclinic 9. H. Büning-Pfaue et al., “Analysis of water in food by near infrared single crystal K NiðSO Þ · 6H O: dispersion analysis, dielectric and 2 4 2 2 spectroscopy,” Food Chem. 82(1), 107–115 (2003). optical properties,” Spectrochim. Acta Part A 69(2), 629–641 (2008). 10. V. A. Corro-Herrera et al., “In-situ monitoring of Saccharomyces 24. A. Ishida et al., “Quantitative measurement of biological substances in cerevisiae ITV01 bioethanol process using near-infrared spectroscopy daily-life environment with the little-finger-size one-shot spectroscopic NIRS and chemometrics,” Biotechnol. Prog. 32(2), 510–517 (2016). tomography,” Proc. SPIE 8951, 89510Y (2014). Journal of Biomedical Optics 050503-4 May 2018 Vol. 23(5) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Biomedical Optics SPIE

Ultrasonic standing wave preparation of a liquid cell for glucose measurements in urine by midinfrared spectroscopy and potential application to smart toilets

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SPIE
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DOI
10.1117/1.JBO.23.5.050503
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Abstract

Ultrasonic standing wave preparation of a liquid cell for glucose measurements in urine by midinfrared spectroscopy and potential application to smart toilets Naoyuki Yamamoto Natsumi Kawashima Tomoya Kitazaki Keita Mori Hanyue Kang Akira Nishiyama Kenji Wada Ichiro Ishimaru Naoyuki Yamamoto, Natsumi Kawashima, Tomoya Kitazaki, Keita Mori, Hanyue Kang, Akira Nishiyama, Kenji Wada, Ichiro Ishimaru, “Ultrasonic standing wave preparation of a liquid cell for glucose measurements in urine by midinfrared spectroscopy and potential application to smart toilets,” J. Biomed. Opt. 23(5), 050503 (2018), doi: 10.1117/1.JBO.23.5.050503. JBO Letters 1 Introduction Ultrasonic standing Early treatment is important in the prevention of lifestyle-related diseases, such as diabetes and gout. Smart toilets that could wave preparation of measure glucose and protein in urine in daily life are of interest in this area. To date, smart toilets can only control cleaning and a liquid cell for glucose measure the volume of urine using flow rate sensors, motion detectors, and other technology. Currently, there is no sensor measurements in urine that can be installed in a toilet and measure different components by midinfrared of interest in urine. If glucose or protein is present in urine, it is possible that the person has diabetes or chronic kidney 3,4 spectroscopy and disease. Early detection of these diseases by smart toilets in daily life could prompt an individual to seek treatment at 5,6 potential application an early stage of the disease. Many approaches have been investigated for smart toilets and noninvasive blood glucose sen- to smart toilets 7,8 sors, with most using near-infrared spectroscopy and wave- lengths from 800 to 1500 nm. Near-infrared light can pass through a sample more easily than midinfrared light because a a Naoyuki Yamamoto, Natsumi Kawashima, it is absorbed less by water. Therefore, near-infrared spectros- a a a Tomoya Kitazaki, Keita Mori, Hanyue Kang, copy can be used for noninvasive analysis of biological samples. b b Akira Nishiyama, Kenji Wada, and a, However, the near-infrared absorption of glucose is weak Ichiro Ishimaru * because the absorption peak in the near-infrared region appears Kagawa University, Faculty of Engineering, Takamatsu-City, Kagawa, Japan as an overtone and combination band. Furthermore, it is dif- Kagawa University, Faculty of Medicine, Miki-Cho, Kita-gun, ficult to identify the absorption peak of glucose because there Kagawa, Japan are also absorption peaks for water, proteins, and hemoglobin in 11,12 the near-infrared region. Abstract. Smart toilets could be used to monitor different Smart toilets using midinfrared spectroscopy could be used components of urine in daily life for early detection of life- to detect the fundamental vibration of glucose. We have already style-related diseases and prompt provision of treatment. proposed a small (bean-sized) midinfrared Fourier spectroscopic For analysis of biological samples such as urine by mid- imager. However, because midinfrared light is absorbed infrared spectroscopy, thin-film samples like liquid cells are strongly by water, this imager requires thin-film samples with needed because of the strong absorption of midinfrared thicknesses of <100 μm for midinfrared spectroscopy detection light by water. Conventional liquid cells or fixed cells are of transmitted or reflected light. Conventional liquid cells and prepared based on the liquid membrane method and sol- fixed cells prepared based on the liquid membrane method ution technique, but these are not quantitative and are and solution techniques are used for optical transmission difficult to set up and clean. We generated an ultrasonic measurements. Unfortunately, these cells are not quantitative standing wave reflection plane in a sample and produced and are difficult to set up and clean. Another option is the an ultrasonic liquid cell. In this cell, the thickness of the 16–18 attenuated total reflectance method, which uses an evanes- optical path length was adjustable, as in the conventional cent wave that can travel several micrometers into a sample. method. The reflection plane could be generated at However, the light must be reflected many times in the attenu- an arbitrary depth and internal reflected light could be ated total reflectance prism to meet the required optical path detected by changing the frequency of the ultrasonic length, and light intensity is an issue because increased reflec- wave. We could generate refractive index boundaries tion leads to increased absorption by the prism and samples. using the density difference created by the ultrasonic In this paper, we describe development of an ultrasonic liquid standing wave. Creation of the reflection plane in the cell, with a reflection plane generated inside the sample by an sample was confirmed by optical coherence tomography. ultrasonic standing wave, for midinfrared spectroscopy and Using the proposed method and midinfrared spectroscopy, application to smart toilets [Fig. 1(a)]. We used optical coher- we discriminated between normal urine samples spiked ence tomography (OCT) to investigate the reflection plane of the with glucose at different concentrations and obtained ultrasonic standing wave in the sample and applied our method a high correlation coefficient. © The Authors. Published by SPIE to normal urine samples spiked with different concentrations of under a Creative Commons Attribution 3.0 Unported License. Distribution or glucose. The urine used in the study was collected from a 24- reproduction of this work in whole or in part requires full attribution of the original year-old adult male. Additionally, we determined the correlation publication, including its DOI. [DOI: 10.1117/1.JBO.23.5.050503] coefficient for measurement of the glucose concentration to evaluate the feasibility of this method for quantitative measure- ment of glucose concentrations and the realization of smart Keywords: optic; Fourier spectroscopy; smart toilet; ultrasonic stand- ing wave; glucose; midinfrared light. toilets. Glucose is typically excreted from blood into urine when the blood glucose level reaches around 180 mg∕dL. Paper 170800LR received Dec. 11, 2017; accepted for publication May 1, 2018; published online May 22, 2018. However, because this level can vary, we instead used the level (50 mg∕dL) for a positive result with a urine test strip. For the realization of smart toilets, we believe that a glucose target concentration of 50 mg∕dL and measurement accuracy *Address all correspondence to: Ichiro Ishimaru, E-mail: ishimaru@eng. of 30 mg∕dL will be relevant. kagawa-u.ac.jp Journal of Biomedical Optics 050503-1 May 2018 Vol. 23(5) JBO Letters Mounted Incident light Surface reflection light Internal Illumination Refractive reflection light Diameter of index lens is 5mm. Toilets H H Reflection plane H H One-shot Standing Urine Fourier wave H H spectroscopy H H = Node Transducer L = Anti node (a) (b) Fig. 1 (a) Schematic diagram of a smart toilet and (b) the liquid cell with variable optical path length. at a frequency of 10 MHz and a voltage of 10 V to generate an 2 Principles of the Ultrasonic Liquid Cell and ultrasonic standing wave inside the target. The OCT image con- Verification Experiments firmed that the particles in the water aggregated at the node of If a sample is homogeneous, some incident light will be detected the ultrasonic standing wave and formed lines [Fig. 2(c)]. The as surface reflected light. However, light absorbed within the particles near the boundaries with the optical windows were not sample cannot be detected. Therefore, in this method, an ultra- trapped by the standing wave and did not aggregate. Because sonic standing wave was used to generate refractive index incident light is reflected by a node with a large refractive boundaries inside the sample, and internal reflected light was index difference, the incident light is considered to be reflected detected at an arbitrary depth [Fig. 1(b)] Because the ultrasonic 0.05 mm from the wall surface. In this case, the optical path wave is a compressional wave, it propagates while generating a length is the sum of that of the incident light and the reflected density difference within the sample. The refractive index dis- light from the reflection plane. We selected a reflectance depth tribution is also stabilized by the ultrasonic standing wave. The of 0.05 mm, because it provided an optical path length of about incident light is reflected at the node of the ultrasonic standing 100 μm, which is suitable for midinfrared spectroscopy. To gen- wave where the refractive index differences are maximized, and erate a reflection plane at this position, a frequency of 10 MHz is it is detected as internal reflected light. The position of the node required. Even though the sample is homogeneous and internal of the ultrasonic standing wave depends on the frequency of reflected light cannot usually be detected, it could be detected the ultrasonic wave. By manipulating the frequency of the ultra- from node positions by generating a refractive index difference sonic standing wave, we could obtain an arbitrary optical path with an ultrasonic standing wave. length in the depth direction. In this study, the ultrasonic standing wave was generated 3 Measurement of Glucose in Normal Urine inside a container fabricated of BaF optical windows with by Midinfrared Spectroscopy high transmittance of midinfrared light, and the internal reflec- We constructed an optical system for detecting internal reflected tion plane was confirmed using OCT (IVS-2000, Santec, light in pure water [Fig. 3(a)]. We used a small graphite light Komaki, Japan). Figure 2(a) shows the optical system. To visu- source (EK8620, Helioworks, Santa Rosa, California) with an alize the generated reflective surface, pure water containing attached setup for Kohler illumination. To shorten the optical red fluorescent polymer microspheres (36-3, Thermo Fisher path length, the incident light from the optical system entered Scientific, Waltham, Massachusetts) was used as a sample. through the wall of the target at an angle of about 45 deg. An ultrasonic transducer (PN-10C10N, Japan Probe Co. Ltd., The ultrasonic vibrator was placed on the bottom of the target. Yokohama, Japan) was attached behind the target, and vibrated We detected internal reflected light using the two-dimensional Measurement area Before vibration OCT Plane wave Node generation Window (Image) area Detective head In water Window BaF After vibration Container Aggregated at node Transducer Voltage: 10V 0.05mm Reflection plane Frequency: 10MHz (a) (b) (c) Fig. 2 A reflection plane generated by an ultrasonic standing wave is detected by OCT. (a) Experimental setup, (b) a detailed image of the container, and (c) the results of an experiment. Journal of Biomedical Optics 050503-2 May 2018 Vol. 23(5) JBO Letters Internal Light source Spectroscopic characteristics for comparing reflected light with the relative intensities before and after vibration Ultrasonic standing wave After vibration Imaging Expand the container lens Objective The relative intensity lens (the internal reflected light) increased about 25%. Before vibration Imaging type 810 12 14 2-dimensional Fourier Wavelength [µm] spectroscopy (a) (b) Fig. 3 (a) The optical system for the experiment and (b) comparison of the intensities before and after ultrasonic vibration. Fourier spectroscopic imager. This light was reflected from the for urine tested with a glucose test strip (100 mg∕dL). The rel- reflection plane, which was generated 0.05 mm from the surface ative intensity of the urine after ultrasonic vibration was used as by the ultrasonic standing wave using the wall surface as the a reference for calculating the absorbance of glucose in urine. reflective material. Next, we compared the relative intensities We repeated the measurement 30 times and calculated the aver- before and after generation of the ultrasonic wave to confirm age. Absorption peaks for glucose were observed at 9.25 and detection of internal reflected light by our proposed liquid 9.65 μm, respectively [Fig. 4(a)]. The peak at 9.25 μm was cell. The relative intensities were evaluated for areas of five not obstructed by other components in the urine [Fig. 4(b)], and we obtained a high correlation coefficient (0.91) for meas- pixels by five pixels [Fig. 3(b)]. The relative intensity from urement of the glucose concentration in urine using this peak. 8to 14 μm after ultrasonic vibration was about 25% more than Therefore, this method is feasible for quantitative measurements that before ultrasonic vibration. These results confirmed that of glucose concentrations in urine without a complex setup. internal reflected light was detected by our method. The refrac- However, the 3σ value calculated from the standard deviation tive index of the optical window material (BaF ) is 1.414 at for the 30 measurements at 9.25 μm was about 0.015, and the 9 μm. Thus, the reflectance after vibration was calculated reproducibility of this method cannot be guaranteed. This could as 8% using Fresnel equations. Additionally, using the be caused by absorption of midinfrared light by water in the 25% increase in the relative intensity, the reflectance before atmosphere, or by fluctuation of the output from the light source. vibration was calculated as 2% (25% of 8%). Consequently, Our proposed method of one-shot Fourier spectroscopy could the refractive index of water was calculated as 1.1 using the overcome this problem, because it has high time resolution. reflectance formula, and the refractive index difference was around 0.3. This value is equivalent to the refractive index when light is reflected on the reflection plane. In future work, 4 Conclusions we will verify this and determine the theoretical relationship between the reflected light intensity and the ultrasonic standing Our liquid cell, generated by an ultrasonic standing wave in wave. a sample, could be used for realization of smart toilets using Next, a solution of glucose in urine was poured into the con- midinfrared spectroscopy. In future work, we will study the opti- tainer and we measured the glucose absorbance with the optical mum shape of this liquid cell for installation into smart toilets. system using the internal reflected light [Fig. 3(a)]. We spiked Additionally, the stability and repeatability of the liquid cell for the urine with glucose at three concentrations (50, 100, and urine glucose and protein measurements will be verified by 200 mg∕dL). These concentrations were selected because developing a one-shot Fourier spectroscopic imager for use in they are around the level that is considered a positive result the midinfrared region. 0.04 0.06 Correlation coefficient: 0.91 200 mg/dL 9.25 µ m 9.65 µ m 100 mg/dL 0.02 0.04 50 mg/dL 0 0.02 8 8.5 9 9.5 10 -0.02 0 0 50 100 150 200 250 -0.04 -0.02 Wavelength [µ m] The concentration of glucose [mg/dL] (a) (b) Fig. 4 (a) Absorbance of glucose in urine (n ¼ 30) and (b) verification of the measurement accuracy at 9.25 μm. Journal of Biomedical Optics 050503-3 May 2018 Vol. 23(5) Absorbance Relative intensity Absorbance JBO Letters 11. M. Pleitez et al., “Infrared spectroscopic analysis of human interstitial Disclosures fluid in vitro and in vivo using FT-IR spectroscopy and pulsed quantum We declare no conflict of interest. cascade lasers (QCL): establishing a new approach to non invasive glucose measurement,” Spectrochim. Acta 85(1), 61–65 (2012). 12. A. Schwaighofer et al., “Quantum cascade lasers (QCLs) in biomedical Acknowledgments spectroscopy,” Chem. Soc. Rev. 46(19), 5903–5924 (2017). We thank the Japan Agency for Medical Research and 13. S. Sato et al., “Ultra-miniature one-shot Fourier-spectroscopic tomog- Development. We thank Gabrielle David, PhD, from Edanz raphy,” Opt. Eng. 55(2), 025106 (2016). 14. S. Liakat et al., “In vitro measurements of physiological glucose con- Group (www.edanzediting.com/ac) for editing a draft of this centrations in biological fluids using mid-infrared light,” Biomed. Opt. letter. Express 4(7), 1083–1090 (2013). 15. 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Published: May 1, 2018

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