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Development of an Integrated Optical Sensor for Determination of β-Hydroxybutyrate Within the Microplatform

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Abstract

Ketone bodies (acetoacetate, beta-hydroxybutyrate (βHB), acetone) are generated as a result of fatty acid oxidation in the liver and exist at low concentrations in urine and blood. Elevated concentrations can indicate health problems such as diabetes, childhood hypoglycemia, alcohol, or salicylate poisoning. Development of portable and cost-effective bedside point-of-care (POC) tests to detect such compounds can help to reduce the risk of disease progression. In this study, βHB was chosen as a model molecule for developing an optical sensor–integrated microplatform. Prior to sensor optimization, βHB levels were measured at a concentration range of 0.02 and 0.1 mM spectrophotometrically, which is far below the reported elevated ranges of 1–2 mM and resulting absorbance changes were converted into an Arduino microcontroller code for the correlation. Measurements performed with the designed integrated microplatform were found significant. Integrated microplatform was verified with the benchtop spectrophotometer. Measurements between 0.02 and 0.1 mM substrate concentration were found highly sensitive with “y = 0.7347x + 0.00184” with R2 value of 0.9796, and the limit of detection was determined as 0.02 mM. Based on these results, the proposed system will allow on-site and early intervention.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

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References

  1. Laffel, L. (1999). Ketone bodies: A review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes/metabolism research and reviews, 15(6), 412–426.

    Article  CAS  Google Scholar 

  2. Dashti, H. M., & Mathew, T. C. (2009). Prevention of obesity using low carbohydrate ketogenic diet. Kuwait Medical Journal, 41(1), 3–12.

    Google Scholar 

  3. Newman, J. C., & Verdin, E. (2014). β-hydroxybutyrate: Much more than a metabolite. Diabetes Research and Clinical Practice, 106(2), 173–181. https://doi.org/10.1016/j.diabres.2014.08.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Robinson, A. M., & Williamson, D. H. (1980). Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiological Reviews, 60(1), 143–187. https://doi.org/10.1152/physrev.1980.60.1.143.

    Article  CAS  PubMed  Google Scholar 

  5. Laeger, T., Metges, C. C., & Kuhla, B. (2010). Role of β-hydroxybutyric acid in the central regulation of energy balance. Appetite, 54(3), 450–455. https://doi.org/10.1016/j.appet.2010.04.005.

    Article  CAS  PubMed  Google Scholar 

  6. Lopez-Barbosa, N., Gamarra, J. D., & Osma, J. F. (2016). The future point-of-care detection of disease and its data capture and handling Young Investigators in Analytical and Bioanalytical Science. Analytical and Bioanalytical Chemistry, 408(11), 2827–2837. https://doi.org/10.1007/s00216-015-9249-2.

    Article  CAS  PubMed  Google Scholar 

  7. Chin, C. D., Chin, S. Y., Laksanasopin, T., & Sia, S. K. (2013). Point-of-care diagnostics on a chip. Biological and Medical Physics, Biomedical Engineering, 3–22. https://doi.org/10.1007/978-3-642-29268-2.

  8. Warsinke, A. (2009). Point-of-care testing of proteins. Analytical and Bioanalytical Chemistry, 393(5), 1393–1405. https://doi.org/10.1007/s00216-008-2572-0.

    Article  CAS  PubMed  Google Scholar 

  9. Li, G., Ma, N. Z., & Wang, Y. (2005). A new handheld biosensor for monitoring blood ketones. Sensors and Actuators, B: Chemical, 109(2), 285–290. https://doi.org/10.1016/j.snb.2004.12.060.

    Article  CAS  Google Scholar 

  10. Rewers, A., Mcfann, K., & Chase, H. P. (2006). Bedside monitoring of blood β-hydroxybutyrate levels in the management of diabetic ketoacidosis in children. Diabetes Technology and Therapeutics, 8(6), 671–676. https://doi.org/10.1089/dia.2006.8.671.

    Article  CAS  PubMed  Google Scholar 

  11. Wang, C. C., Hennek, J. W., Ainla, A., Kumar, A. A., Lan, W. J., Im, J., Smith, B. S., Zhao, M., & Whitesides, G. M. (2016). A paper-based pop-up electrochemical device for analysis of beta-hydroxybutyrate. Analytical Chemistry, 88(12), 6326–6333. https://doi.org/10.1021/acs.analchem.6b00568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Klasner, S. A., Price, A. K., Hoeman, K. W., Wilson, R. S., Bell, K. J., & Culbertson, C. T. (2010). Paper-based microfluidic devices for analysis of clinically relevant analytes present in urine and saliva. Analytical and Bioanalytical Chemistry, 397(5), 1821–1829. https://doi.org/10.1007/s00216-010-3718-4.

    Article  CAS  PubMed  Google Scholar 

  13. Kuru, B., Sever, M., Aksay, E., Dogan, T., Yalcin, N., Seker Eren, E., & Ustuner, F. (2014). Comparing finger-stick β-hydroxybutyrate with dipstick urine tests in the detection of ketone bodies. Turkiye Acil Tip Dergisi, 14(2), 47–52. https://doi.org/10.5505/1304.7361.2014.14880.

    Article  Google Scholar 

  14. Guo, J. (2017). Smartphone-powered electrochemical dongle for point-of-care monitoring of blood β-ketone. Analytical Chemistry, 89(17), 8609–8613. https://doi.org/10.1021/acs.analchem.7b02531.

    Article  CAS  PubMed  Google Scholar 

  15. Saygili, E., Orakci, B., Koprulu, M., Demirhan, A., Ilhan-Ayisigi, E., Kilic, Y., & Yesil-Celiktas, O. (2020). Quantitative determination of H2O2 for detection of alanine aminotransferase using thin film electrodes. Analytical Biochemistry, 591(November 2019), 113538. https://doi.org/10.1016/j.ab.2019.113538.

    Article  CAS  PubMed  Google Scholar 

  16. Cheng, J., & Deming, T. J. (2011). Optical detection systems on microfluidic chips. Peptide-Based Materials, 310(September), 1–26. https://doi.org/10.1007/128.

    Article  Google Scholar 

  17. Thiruvengadam, M., Venkidasamy, B., & Subramanian, U. (2020). Up-converting phosphor technology-based lateral fl ow assay for quantitative detection of β -hydroxybutyrate in biological samples. Analytical Biochemistry, 591(December 2019), 113546. https://doi.org/10.1016/j.ab.2019.113546.

    Article  CAS  PubMed  Google Scholar 

  18. Steigert, J., Grumann, M., Brenner, T., Riegger, L., Harter, J., Zengerle, R., & Ducrée, J. (2006). Fully integrated whole blood testing by real-time absorption measurement on a centrifugal platform. Lab on a Chip, 6(8), 1040–1044. https://doi.org/10.1039/b607051p.

    Article  CAS  PubMed  Google Scholar 

  19. Khanfar, M. F., Al-Faqheri, W., & Al-Halhouli, A. (2017). Low cost lab on chip for the colorimetric detection of nitrate in mineral water products. Sensors (Switzerland), 17(10), 1–9. https://doi.org/10.3390/s17102345.

    Article  CAS  Google Scholar 

  20. Oscar, S. V., Fernando, O. C. L., & del Pilar, C. M. M. (2017). Total polyphenols content in white wines on a microfluidic flow injection analyzer with embedded optical fibers. Food Chemistry, 221, 1062–1068. https://doi.org/10.1016/j.foodchem.2016.11.055.

    Article  CAS  PubMed  Google Scholar 

  21. Schmidt, O., Bassler, M., Kiesel, P., Knollenberg, C., & Johnson, N. (2007). Fluorescence spectrometer-on-a-fluidic-chip. Lab on a Chip, 7(5), 626–629. https://doi.org/10.1039/b618879f.

    Article  CAS  PubMed  Google Scholar 

  22. Takayama, N., Ohara, T., & Yamamoto, N. (2012). Enzymatic fluorometric microplate assay for quantitative analysis of 3-hydroxybutyric acid in mouse plasma. Analytical Biochemistry, 425(2), 114–116. https://doi.org/10.1016/j.ab.2012.03.011.

    Article  CAS  PubMed  Google Scholar 

  23. Hofmann, O., Miller, P., Sullivan, P., Jones, T. S., Demello, J. C., Bradley, D. D. C., & Demello, A. J. (2005). Thin-film organic photodiodes as integrated detectors for microscale chemiluminescence assays. Sensors and Actuators, B: Chemical, 106(2), 878–884. https://doi.org/10.1016/j.snb.2004.10.005.

    Article  CAS  Google Scholar 

  24. Waswa, J., Irudayaraj, J., & DebRoy, C. (2007). Direct detection of E. Coli O157:H7 in selected food systems by a surface plasmon resonance biosensor. LWT - Food Science and Technology, 40(2), 187–192. https://doi.org/10.1016/j.lwt.2005.11.001.

    Article  CAS  Google Scholar 

  25. Pires, N. M. M., Dong, T., Hanke, U., & Hoivik, N. (2014). Recent developments in optical detection technologies in lab-on-a-chip devices for biosensing applications. Sensors (Switzerland), 14(8), 15458–15479. https://doi.org/10.3390/s140815458.

    Article  CAS  Google Scholar 

  26. Weng, X., Zhao, W., Neethirajan, S., & Duffield, T. (2015). Microfluidic biosensor for β-Hydroxybutyrate (βHBA) determination of subclinical ketosis diagnosis. Journal of Nanobiotechnology, 13(1), 1–8. https://doi.org/10.1186/s12951-015-0076-6.

    Article  CAS  Google Scholar 

  27. Sharifi, F., Htwe, S. S., Righi, M., Liu, H., Pietralunga, A., Yesil-Celiktas, O., Maharjan, S., Cha, B. H., Shin, S. R., Dokmeci, M. R., Vrana, N. E., Ghaemmaghami, A. M., Khademhosseini, A., & Zhang, Y. S. (2019). A foreign body response-on-a-chip platform. Advanced Healthcare Materials, 8(4), 1–10. https://doi.org/10.1002/adhm.201801425.

    Article  CAS  Google Scholar 

  28. Lam, L. H., Shimamura, T., Manabe, S., Ishiyama, M., & Ukeda, H. (2008). Assay of angiotensin I-converting enzyme-inhibiting activity based on the detection of 3-hydroxybutyrate with water-soluble tetrazolium salt. Analytical Sciences, 24(8), 1057–1060. https://doi.org/10.2116/analsci.24.1057.

    Article  CAS  Google Scholar 

  29. Cruces Blanco, C., García Campaña, A. M., & Alés Barrero, F. (1996). Derivative spectrophotometric resolution of mixtures of the food colourants Tartrazine, Amaranth and Curcumin in a micellar medium. Talanta, 43(7), 1019–1027. https://doi.org/10.1016/0039-9140(96)01847-4.

    Article  CAS  PubMed  Google Scholar 

  30. Children Hospitals and Clinics of Minnesota. 2016. https://www.childrensmn.org/references/lab/chemistry/beta-hydroxybutyrate.pdf, 2016 (accessed 29 June 2020).

  31. Iwersen, M., Falkenberg, U., Voigtsberger, R., Forderung, D., & Heuwieser, W. (2009). Evaluation of an electronic cowside test to detect subclinical ketosis in dairy cows. Journal of Dairy Science, 92(6), 2618–2624. https://doi.org/10.3168/jds.2008-1795.

    Article  CAS  PubMed  Google Scholar 

  32. Fang, L., Wang, S. H., & Liu, C. C. (2008). An electrochemical biosensor of the ketone 3-β-hydroxybutyrate for potential diabetic patient management. Sensors and Actuators, B: Chemical, 129(2), 818–825. https://doi.org/10.1016/j.snb.2007.09.066.

    Article  CAS  Google Scholar 

  33. Renumadhavi, C. H., Jamuna, N., Chandana, A. N., Balamurali, V., Gupta, P. K., Sheriff, R. S., et al. (2020). Microcontroller-based detection of diabetes and ketosis state using breath sensors. In Recent Trends in Image and Signal Processing in Computer Vision, 1124, 1–17. https://doi.org/10.1007/978-981-15-2740-1_1.

    Article  Google Scholar 

  34. Teshima, N., Li, J., Toda, K., & Dasgupta, P. K. (2005). Determination of acetone in breath. Analytica Chimica Acta, 535(1–2), 189–199. https://doi.org/10.1016/j.aca.2004.12.018.

    Article  CAS  Google Scholar 

  35. Weng, X., Chen, L., Neethirajan, S., & Duffield, T. (2015). Development of quantum dots-based biosensor towards on-farm detection of subclinical ketosis. Biosensors and Bioelectronics, 72, 140–147. https://doi.org/10.1016/j.bios.2015.05.008.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Armagan Ergun for his contributions to PMMA mold production. E.S gratefully acknowledges the TUBITAK 2211-A National Graduate Scholarship Program.

Funding

The study was financially supported by the Scientific and Technological Research Council of Turkey (TUBITAK) 2209/A University Students Research Project Support Program (1919B011800241).

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Authors and Affiliations

  1. Department of Bioengineering, Faculty of Engineering, Ege University, 35100, Bornova, Izmir, Turkey

    Utku Devamoglu, Irem Duman, Ecem Saygili & Ozlem Yesil-Celiktas

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  1. Utku Devamoglu
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  2. Irem Duman
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  3. Ecem Saygili
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Contributions

Utku Devamoglu (U.D.), Irem Duman (I.D.), and Ecem Saygili (E.S.) designed and performed the experiments; U.D., I.D, and E.S wrote the paper; Ozlem Yesil-Celiktas (O.Y.C.) supervised the research and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ozlem Yesil-Celiktas.

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The research does not involve human participants and/or animals.

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Devamoglu, U., Duman, I., Saygili, E. et al. Development of an Integrated Optical Sensor for Determination of β-Hydroxybutyrate Within the Microplatform. Appl Biochem Biotechnol 193, 2759–2768 (2021). https://doi.org/10.1007/s12010-021-03563-3

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  • DOI: https://doi.org/10.1007/s12010-021-03563-3

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