This review introduces biosensing research and development activities at the University of Tartu. The biosensor studies were initiated by Jaak Järv and Toomas Tenno at the beginning of the 1980s when a biosensor combining the enzyme glucose oxidase and a cylindrical Clarktype oxygen sensor was constructed in Tartu. Since then, a lot of theoretical research has been carried out in this field, and several original ideas for constructing biosensing devices have been proposed. Different biosensor systems, from singleuse immunosensors to reusable enzyme sensors, have been developed and tested for environmental analysis, food analysis, and clinical and veterinary diagnostics. These solutions have a high potential for practical, everyday applications and automated monitoring. Until now, biosensor research at the University of Tartu has resulted in five patents and more than one hundred scientific papers. Although some biosensor developments have been prototyped, none have been commercialized to date.
1. Bhalla, N., Jolly, P., Formisano, N. and Estrela. P. Introduction to biosensors. Essays Biochem., 2016, 60(1), 1–8.
https://doi.org/10.1042/EBC20150001
2. Clark, L. C., Jr. and Lyons, C. Electrode systems for continuous monitoring in cardiovascular surgery. Ann. N. Y. Acad. Sci., 1962, 102(1), 29–45.
https://doi.org/10.1111/j.1749-6632.1962.tb13623.x
3. Past, V. Keemikute koolitamisest Tartu Ülikoolis (Training chemists at the University of Tartu). In TRÜ Keemiaosakond 1977–1987 (Tartu State University, Faculty of Chemistry 1977–1987) (Pullerits, R., ed.). University of Tartu Press, Tartu, 1989, 32–42.
4. Palm, U. Elektrokeemia arengust Tartu Ülikoolis läbi aegade (The development of electrochemistry at the University of Tartu through the ages). In TRÜ Keemiaosakond 1977–1987 (Tartu State University, Faculty of Chemistry 1977–1987 (Pullerits, R., ed.). University of Tartu Press, Tartu, 1989, 10–22.
5. Tenno, T. Электрохимические средства анализа и охрана окружающей среды (Electrochemical analysis and environmental protection). In Тезисы докладов респ. конференции (Abstracts of the republic’s conference presentations), Тartu, Estonia, 10–11 June 1986, 65–71.
6. Kosk, M. Ensüümelektroodi konstrueerimine hapnikuanduri baasil glükoosi määramiseks lahuses (Construction of an enzyme electrode on the basis of an oxygen sensor for the determination of glucose in solution). Diploma thesis. University of Tartu, Estonia, 1983.
7. Lihu, T. Glükoosi oksüdaasi immobiliseerimine (Glucose oxidase immobilization). Diploma thesis. University of Tartu, Estonia, 1985.
8. Rinken, T., Järv, J. and Rinken, A. Production of biosensors with exchangeable enzyme-containing threads. Anal. Chem., 2007, 79(15), 6042–6044.
https://doi.org/10.1021/ac070327j
9. Kivirand, K. and Rinken, T. Preparation and characterization of cadaverine sensitive nylon threads. Sens. Lett., 2009, 7(4), 580–585.
https://doi.org/10.1166/sl.2009.1113
10. Kivirand, K., Rebane, R. and Rinken, T. A simple biosensor for biogenic diamines, comprising amine oxidase – containing threads and oxygen sensor. Sens. Lett., 2011, 9(5), 1794–1800.
https://doi.org/10.1166/sl.2011.1713
11. Kagan, M., Printsmann, G., Kivirand, K. and Rinken, T. Determination of penicillins in milk by a dual-optrode biosensor. Anal. Lett., 2017, 50(5), 819–828.
https://doi.org/10.1080/00032719.2016.1202957
12. Ben-Othman, S. and Rinken, T. Immobilization of pectinolytic enzymes on nylon 6/6 Carriers. Appl. Sci., 2021, 11(10), 4591.
https://doi.org/10.3390/app11104591
13. Rinken, T., Järv, J., Rinken, A. and Tenno, T. Biosensor and method of its construction. Patent EE04250B1, 2004-02-16.
14. Rinken, T. The construction and modelling of glucose biosensor. MSc thesis. University of Tartu, Estonia, 1995.
15. Rinken, T. The modelling of amperometric biosensors based on oxidoreductases. PhD thesis. University of Tartu, Estonia, 2000.
16. Rinken, T. and Tenno T. Dynamic model of amperometric biosensors. Characterisation of glucose biosensor output. Biosens. Bioelectr., 2001, 16(1–2), 53–59.
https://doi.org/10.1016/S0956-5663(00)00133-0
17. Rinken, T. Determination of kinetic constants and enzyme activity from biosensor transient signal. Anal. Lett., 2003, 36(8), 1535–1545.
https://doi.org/10.1081/AL-120021535
18. Kivirand, K., Floren, A., Kagan, M., Avarmaa, T., Rinken, T. and Jaaniso, R. Analyzing the biosensor signal in flows: studies with glucose optrodes. Talanta, 2015, 131, 74–80.
https://doi.org/10.1016/j.talanta.2014.07.061
19. Rinken, T., Rinken, P. and Kivirand, K. Signal analysis and calibration of biosensors for biogenic amines in the mixtures of several substrates. In Biosensors – Emerging Materials and Applications (Serra, P. A., ed.). InTech, 2011, 1–16.
https://doi.org/10.5772/16308
20. Orupõld, K. Treatment and analysis of phenolic wastewater with microorganisms. PhD thesis. University of Tartu, Estonia, 2000.
21. Velling, S. Amperomeetrilises biosensoris kulgevate mittestatsionaarsete protsesside modelleerimine (Modeling of non-stationary processes in an amperometric biosensor). MSc thesis. University of Tartu, Estonia, 2001.
22. Tungel, R., Rinken, T., Rinken, A. and Tenno, T. Immobilisation and kinetic study of tyrosinase for biosensor construction. Anal. Lett., 1999, 32(2), 235–249.
https://doi.org/10.1080/00032719908542818
23. Kuusk, E. and Rinken, T. Transient phase calibration of tyrosinase-based carbaryl biosensor. Enzyme Microb. Technol., 2004, 34(7), 657–661.
https://doi.org/10.1016/j.enzmictec.2004.03.004
24. Viirlaid, E., Ilisson, M., Kopanchuk, S., Mäeorg, U., Rinken, A. and Rinken, T. Immunoassay for rapid on-site detection of glyphosate herbicide. Environ. Monit. Assess., 2019, 191(8), 507.
https://doi.org/10.1007/s10661-019-7657-z
25. Viirlaid, E., Riiberg, R., Mäeorg, U. and Rinken, T. Glyphosate attachment on aminoactivated carriers for sample stabilization and concentration. Agron. Res., 2015, 13(4), 1152– 1159.
26. Viirlaid, E. Biosensing pesticides in water samples. PhD thesis. University of Tartu, Estonia, 2020.
27. Rohtla, R. Aptasensor tsüanobakterite toksiini mikrotsüstiin-LR määramiseks (Aptasensor for the detection of cyanobacterial toxin microcystine-LR). BSc thesis. University of Tartu, Estonia, 2021.
28. Rohtla, R., Kivirand, K., Jõgi, E. and Rinken, T. Biosensor for the detection of cyanobacterial toxin microcystin-LR. In Biotechnology. Biosensors, Biomaterials and Tissue Engineering Annual Volume 2023. (Villarreal-Gomez, L. J. and Koprowski, R., eds). InTech, 2022. https://doi.org/10.5772/intechopen.107366
29. Jõgi, E., Väling, I. and Rinken, T. Assessment of bathing water quality with an E. coli immunosensor. Int. J. Environ. Anal. Chem., 2020, 102(16), 4652–4663.
https://doi.org/10.1080/03067319.2020.1786549
30. Jõgi, E. Development and applications of E. coli immunosensor. PhD thesis. University of Tartu, Estonia, 2022.
31. Jõgi, E., Väling, I. and Rinken, T. The assessment of coli index with E.coli immunosensor in natural water. Int. J. Environ. Sci. Technol., 2023, 20, 4893–4904.
https://doi.org/10.1007/s13762-022-04280-y
32. Kikas, T. Biokeemilise hapnikutarbe bakteranduri väljatöötamine ja uurimine (Development and study of bacterial BOD sensor). MSc thesis. University of Tartu, Estonia, 1996.
33. Velling, S. Microbial BOD biosensor for wastewater analysis. PhD thesis. University of Tartu, Estonia, 2011.
34. Raud. M. Study of semi-specific BOD biosensors for biosensor array. PhD thesis. University of Tartu, Estonia, 2013.
35. Orupõld, K., Tenno, T., Henrysson, T. and Mattiasson, B. The application of genetically engineered Pseudomonas putida strains and activated sludge in biosensors for determination of phenol(s). Resour. Environ. Biotechnol., 1997, 1(3), 179–191.
36. Kivirand, K. Diamine oxidase-based biosensors: construction and working principles. PhD thesis. University of Tartu, Estonia, 2011.
37. Vaarik, A. and Rinken, T. Purification of amine oxidase from Pisum sativum for the construction of amine biosensor. Proc. Estonian Acad. Sci. Chem., 2004, 53(4), 165–173.
https://doi.org/10.3176/chem.2004.4.02
38. Kivirand, K. and Rinken, T. Purification and properties of amine oxidase from pea seedlings. Proc. Estonian Acad. Sci. Chem., 2007, 56(4), 164–171.
https://doi.org/10.3176/chem.2007.4.01
39. Kivirand, K., Sõmerik, H., Oldekop, M.-L., Rebane, R. and Rinken, T. Effect of spermidine and its metabolites on the activity of pea seedlings diamine oxidase and the problems of biosensing of biogenic amines with this enzyme. Enzyme Microb. Technol., 2016, 82(1), 133–137.
https://doi.org/10.1016/j.enzmictec.2015.09.007
40. Riik, H. Saasteainete määramine piimas laktaadi biosensoriga (Detection of contaminants in milk by lactate biosensor). MSc thesis. University of Tartu, Estonia, 2004.
41. Rinken, T. and Riik, H. Determination of antibiotic residues and their interaction in milk with lactate biosensor. J. Biochem. Biophys. Methods, 2006, 66(1–3), 13–21.
https://doi.org/10.1016/j.jbbm.2005.04.009
42. Kagan, M., Kivirand, K. and Rinken, T. Modulation of enzyme catalytic properties and biosensor calibration parameters with chlorides: studies with glucose oxidase. Enzyme Microb. Technol., 2013, 53(4), 278–282.
https://doi.org/10.1016/j.enzmictec.2013.02.011
https://doi.org/10.5772/54127
43. Kivirand, K., Kagan, M. and Rinken, T. Calibrating biosensors in flow-through set-ups: studies with glucose optrodes. In State of the Art in Biosensors – General Aspects (Rinken, T., ed.). InTech, 2013, 331–351. https://doi.org/ 10.5772/45832
44. Peedel, D. and Rinken, T. Effect of temperature on the sensitivity of cascaded lactose biosensors. Proc. Estonian Acad. Sci., 2012, 61(4), 306–313.
https://doi.org/10.3176/proc.2012.4.05
45. Kagan, M. Biosensing penicillins’ residues in milk flows. PhD thesis. University of Tartu, Estonia, 2016.
46. Rinken, T. and Jaaniso, R. On-line süsteem, meetod selle kalibreerimiseks ning erinevate antibiootikumide jääkide samaaegseks tuvastamiseks ja kontsentratsioonide mõõtmiseks piimas (On-line system, method for its calibration and simultaneous detection of antibiotic residues and their concentration in milk). Patent EE05550, 2012-06-15.
47. Rinken, T. and Jaaniso, R. On-line system, method of its calibration and simultaneous detection of antibiotic residues and their concentration in milk. Patent EP2529217B1, 2013-10-23.
48. Rinken, T. and Jaaniso, R. On-line system, method of its calibration and simultaneous detection of antibiotic residues and their concentration in milk. Patent RU2524624, 2014-07-27.
49. Peedel, D., Rinken, T. Rapid Biosensing of Staphylococcus aureus bacteria in milk. Anal. Methods, 2014, 6(8), 2642–2647.
https://doi.org/10.1039/c3ay42036a
50. Juronen, D. Biosensing system for the rapid multiplex detection of mastitis-causing pathogens in milk. PhD thesis. University of Tartu, Estonia, 2018.
https://doi.org/10.1016/j.talanta.2017.10.043
51. Juronen, D., Kuusk, A., Kivirand, K., Rinken, A. and Rinken, T. Immunosensing system for rapid multiplex detection of mastitis-causing pathogens in milk. Talanta, 2018, 178, 949–954.
https://doi.org/10.1016/j.talanta.2017.10.043
52. Cai, Y., Ma, L. and Liu, G. Design and experiment of rapid detection system of cow subclinical mastitis based on portable computer vision technology. Trans. CSAE, 2017, 33(1), 63–69.
53. Estonian Veterinary and Food Laboratory. Report on infectious and parasitic animal diseases 2022.
https://labris.agri.ee/sites/default/files/2023-04/Aastaaruanne_2022_loomahaigused.pdf (accessed 2023-10-26).
54. Mihklepp, K., Kivirand, K., Nikopensius, M., Peedel, D., Utt, M. and Rinken, T. Design and production of antibodies for the detection of Streptococcus uberis. Enzyme Microb. Technol., 2017, 96(1), 135−142.
https://doi.org/10.1016/j.enzmictec.2016.10.009
55. Mihklepp, K., Kivirand, K., Juronen, D., Lõokene, A. and Rinken, T. Immunodetection of Streptococcus uberis pathogen in raw milk. Enzyme Microb. Technol., 2019, 130, 109360.
https://doi.org/10.1016/j.enzmictec.2019.109360
56. Vesi, K. Immunobiosensorsüsteemis kasutatavate mikrokolonnide optimeerimine erinevate mastiiti põhjustavate bakterite üheaegseks määramiseks (Optimization of microcolumns used in the immunobiosensor system for the simultaneous detection of different mastitis-causing bacteria). BSc thesis. University of Tartu, Estonia, 2021.
57. Kasak, K. Hapniku kontsentratsiooni määramine toorpiimas (Determination of oxygen concentration in raw milk). MSc thesis. University of Tartu, Estonia, 2010.
58. Rinken, T. and Jaaniso, R. Meetod mastiidi tuvastamiseks ja piima kvaliteedi määramiseks ning mastiidisensor (Method for detecting mastitis and determining the quality of milk, and mastitis sensor). Patent EE05552, 2012-08-21.
59. Nikopensius, M. Immunobiosensorsüsteem Escherichia coli määramiseks uriinis (Immunobiosensor system for the determination of Escherichia coli in urine). MSc thesis. University of Tartu, Estonia, 2018.
60. Nikopensius, M., Jõgi, E. and Rinken, T. Determination of uropathogenic Escherichia coli in urine by an immunobiosensor based upon antigen-antibody biorecognition with fluorescence detection and bead-injection analysis. Anal. Lett., 2022, 55(7), 1040–1051.
https://doi.org/10.1080/00032719.2021.1982958
61. Kuusk, A. Mahtuvusliku immunosensorsüsteemi konstrueerimine biomarkerite määramiseks (Construction of a capacitive immunosensor system for the determination of biomarkers). MSc thesis. University of Tartu, Estonia, 2015.
62. Jeppesen, D. K., Zhang, Q., Franklin, J. L. and Coffey, R. J. Extracellular vesicles and nanoparticles: emerging complexities. Trends Cell Biol., 2023, 33(8), 667–681.
https://doi.org/10.1016/j.tcb.2023.01.002
63. Laasfeld, T., Ehrminger, R., Tahk, M.-J., Veiksina, S., Kõlvart, K. R., Min, M. et al. Budded baculoviruses as a receptor display system to quantify ligand binding with TIRF microscopy. Nanoscale, 2021, 13, 2436–2447.
https://doi.org/10.1039/d0nr06737g
64. Rinken, A., Lavogina, D. and Kopanchuk, S. Assays with detection of fluorescence anisotropy: challenges and possibilities for characterizing ligand binding to GPCRs. Trends Pharmacol. Sci., 2018, 39(2), 187–199.
https://doi.org/10.1016/j.tips.2017.10.004
65. Link, R., Veiksina, S., Tahk, M.-J., Laasfeld, T., Paiste, P., Kopanchuk, S. et al. The constitutive activity of melanocortin-4 receptors in cAMP pathway is allosterically modulated by zinc and copper ions. J. Neurochem., 2020, 153(3), 346–361.
https://doi.org/10.1111/jnc.14933
66. Allikalt, A., Kopanchuk, S. and Rinken, A. Implementation of fluorescence anisotropy-based assay for the characterization of ligand binding to dopamine D1receptors. Eur. J. Pharmacol., 2018, 839, 40–46.
https://doi.org/10.1016/j.ejphar.2018.09.008
67. Mazina, O., Allikalt, A., Heinloo, A., Reinart-Okugbeni, R., Kopanchuk, S. and Rinken, A. cAMP assay for GPCR ligand characterization: application of BacMam expression system. Methods Mol. Biol., 2015, 1272, 65–77.
https://doi.org/10.1007/978-1-4939-2336-6_5
68. Mazina, O., Allikalt, A., Tapanainen, J. S., Salumets, A. and Rinken, A. Determination of biological activity of gonadotropins hCG and FSH by Förster resonance energy transfer based biosensors. Sci. Rep., 2017, 7, 42219.
https://doi.org/10.1038/srep42219
69. Koistinen, H., Koel, M., Peters, M., Rinken, A., Lundin, K., Tuuri, T. et al. Hyperglycosylated hCG activates LH/hCG-receptor with lower activity than hCG. Mol. Cell. Endocrinol., 2019, 479, 103–109.
https://doi.org/10.1016/j.mce.2018.09.006
