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== State of the Art ==
=== Matrix ===
The fluid matrix for biosensor measurements in SensUs 2024 is Interstitial skin fluid (ISF). ISF is the most prevalent fluid in the body, making up 75% of extracellular fluid and 15-25% of body weight. <ref name = "Ref24">Samant, P. P., Niedzwiecki, M. M., Raviele, N., Tran, V., Mena-Lapaix, J., Walker, D. I., Felner, E. I., Jones, D. P., Miller, G. W., & Prausnitz, M. R. (2020). Sampling interstitial fluid from human skin using a microneedle patch. Science Translational Medicine, 12(571). https://doi.org/10.1126/scitranslmed.aaw0285</ref> ISF surrounds cells and tissues, serving as an interface between blood and cells. It may be a source of biomarkers in addition to blood biomarkers, as research shows that 83% of proteins found in blood serum are also present in ISF, but 50% of proteins in ISF are not found in serum. <ref name = "Ref25">Samant, Pradnya P, and Mark R Prausnitz. “Mechanisms of Sampling Interstitial Fluid from Skin Using a Microneedle Patch.” Proceedings of the National Academy of Sciences of the United States of America, 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939066/
</ref> Due to its accessibility and similarity in composition to serum, ISF is a suitable candidate for continuous monitoring <ref name = "Ref23">Friedel, M., Thompson, I. a. P., Kasting, G. B., Polsky, R., Cunningham, D., Soh, H. T., & Heikenfeld, J. (2023b). Opportunities and challenges in the diagnostic utility of dermal interstitial fluid. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-022-00998-9</ref> and is currently used in clinical settings for continuous glucose monitoring (CGM).
Worldwide research is ongoing on the development of continuous ISF biosensors for analytes such as glucose, urea, and cortisol, with urea being the most relevant to kidney failure. <ref name = "Ref26">Chen, Q., Zhao, Y., & Liu, Y. (2021b). Current development in wearable glucose meters. Chinese Chemical Letters, 32(12), 3705–3717. https://doi.org/10.1016/j.cclet.2021.05.043</ref> <ref name = "Ref27">Venugopal, M., Arya, S. K., Chornokur, G., & Bhansali, S. (2011b). A realtime and continuous assessment of cortisol in ISF using electrochemical impedance spectroscopy. Sensors and Actuators A: Physical, 172(1), 154–160. https://doi.org/10.1016/j.sna.2011.04.028
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=== Continuous glucose monitoring ===
Glucose sensors are commercially available for continuous monitoring, primarily used in diabetes management. <ref name = "Ref28">Johnston, L. et al. (2021) ‘Advances in biosensors for continuous glucose monitoring towards wearables’, Frontiers in Bioengineering and Biotechnology, 9. doi:10.3389/fbioe.2021.733810. </ref> Most of the CGM biosensors with ISF as a matrix are catalytic biosensors, using glucose oxidase (GOD) as the recognition molecule to bind with glucose. <ref name = "Ref28"/> Microneedle array electrodes have been used for CGM, e.g. by functionalizing them through entrapment of GOD in an electropolymerized film <ref name = "Ref30">Sharma, S. et al. (2016) ‘Evaluation of a minimally invasive glucose biosensor for continuous tissue monitoring’, Analytical and Bioanalytical Chemistry, 408(29), pp. 8427–8435. doi:10.1007/s00216-016-9961-6. </ref>, or by non-enzymatic amperometric readout. <ref name = "Ref31">Lee, S.J. et al. (2016) ‘A patch type non-enzymatic biosensor based on 3D sus micro-needle electrode array for minimally invasive continuous glucose monitoring’, Sensors and Actuators B: Chemical, 222, pp. 1144–1151. doi:10.1016/j.snb.2015.08.013.
</ref> Other examples of CGM biosensors in ISF include an enzymatic open circuit potential biosensor using GOD <ref name = "Ref32">Song, Y. et al. (2016) ‘Design and preparation of open circuit potential biosensor for in vitro and in vivo glucose monitoring’, Analytical and Bioanalytical Chemistry, 409(1), pp. 161–168. doi:10.1007/s00216-016-9982-1.
</ref> and an electrochemical glucose sensor composed of electroplated nanoporous platinum. <ref name = "Ref33">Yoon, H. et al. (2018) ‘Wearable, robust, non-enzymatic continuous glucose monitoring system and its in vivo investigation’, Biosensors and Bioelectronics, 117, pp. 267–275. doi:10.1016/j.bios.2018.06.008.
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=== Continuous sensing of cortisol ===
Continuous measurement of cortisol in ISF has been done using the electrochemical impedance (EIS) technique. <ref name = "Ref27"/> This technique involves gold microelectrode arrays functionalized with a self-assembled monolayer (SAM) to fabricate a disposable, electrochemical cortisol immunosensor. <ref name = "Ref27"/>
=== Continuous sensing of urea ===
Urea is an analyte that is relevant for AKI. Gold microneedle arrays have been studied for electrochemical sensing of urea. <ref name = "Ref35">Şenel, M., Dervisevic, M., & Voelcker, N. H. (2019). Gold microneedles fabricated by casting of gold ink used for urea sensing. Materials Letters, 243, 50–53. https://doi.org/10.1016/j.matlet.2019.02.014</ref> Furthermore, wearable potentiometric biosensors have been studied for on-body and on-site monitoring of urea in sweat. <ref name = "Ref36">Ibáñez-Redín, G., Cagnani, G. R., Gomes, N. O., Raymundo‐Pereira, P. A., Machado, S. a. S., Gutierrez, M. A., Krieger, J. E., & Oliveira, O. N. (2023). Wearable potentiometric biosensor for analysis of urea in sweat. Biosensors and Bioelectronics, 223, 114994. https://doi.org/10.1016/j.bios.2022.114994
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== Creatinine Biosensors ==
Creatinine is a key indicator of renal function and is measured using various methods. The Jaffe reaction involves creatinine reacting with alkaline picrate to form a measurable orange-red complex, but its drawback lies in low specificity, due to interference from substances like glucose and bilirubin. <ref name = "Ref38">Creatinine - SensUS Wiki. (n.d.). https://wiki.sensus.org/index.php?title=Creatinine</ref> Also enzymatic techniques are used for creatinine detection, e.g. creatininase amidohydrolase or creatinine deaminase in conjunction with other enzymes to convert creatinine to creatine and subsequently produce measurable hydrogen peroxide. <ref name = "Ref38"/> While enzymatic sensors are specific and sensitive, they have their drawbacks in terms of lack of stability and sensitivity to changes in pH, temperature and humidity. <ref name = "Ref38"/>
Commercially available analytical systems, such as Abbott's i-STAT system and Nova Biomedical's StatSensor CREAT, leverage enzymes and electrochemistry to provide creatinine measurements, offering a linear correlation between current and creatinine concentration. <ref name = "Ref38"/>
Potentiometric creatinine biosensors have been developed using different immobilization techniques and enzyme combinations. Potentiometric biosensors for creatinine detection rely on creatinine iminohydrolase (CIH) and subsequent ammonia detection. The sensors exhibit a linear range of 0.02 – 20.0 mM and a minimum detection limit of 10 µM, with 30 – 60 s response time. <ref name = "Ref37">Pundir, C., Kumar, P., & Jaiwal, R. (2019b). Biosensing methods for determination of creatinine: A review. Biosensors and Bioelectronics, 126, 707–724. https://doi.org/10.1016/j.bios.2018.11.031
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Nanomaterials are also being studied for creatinine detection. <ref name = "Ref40">Narimani, R., Esmaeili, M., Rasta, S. H., Khosroshahi, H. T., & Mobed, A. (2020). Trend in creatinine determining methods: Conventional methods to molecular‐based methods. Analytical Science Advances, 2(5–6), 308–325. https://doi.org/10.1002/ansa.202000074
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Sensors have been demonstrated with sensitivity in the range of 0.2 – 1.4 µM. <ref name = "Ref40"/>
Lastly, a biosensor based on particle motion (BPM) has been studied for continuous creatinine sensing. <ref name = "Ref42">Yan, J. et al. (2020) ‘Continuous small-molecule monitoring with a digital single-particle switch’, ACS Sensors, 5(4), pp. 1168–1176. doi:10.1021/acssensors.0c00220.</ref> The sensor has a competitive format, with anti-creatinine antibodies and creatinine-analogues. The measurement range was 10–1000 μM. <ref name = "Ref42"/>