Optimization of Extraction Parameters of Reverse Iontophoretic Determination of Blood Glucose in an Artificial Skin Model

Author(s): Cigdem Yengin, Emrah Kilinc*, Fatma Gulay Der, Mehmet Can Sezgin, Ilayda Alcin

Journal Name: Current Analytical Chemistry

Volume 16 , Issue 6 , 2020

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Graphical Abstract:


Background: Reverse İontophoresis (RI) is one of the promising non-invasive technologies. It relies on the transition of low magnitude current through the skin and thus glucose measurement becomes possible as it is extracted from the surface during this porter current flow.

Objective: This paper deals with the development and optimization of an RI determination method for glucose. CE dialysis membrane based artificial skin model was developed and the dependence of RI extraction on various experimental parameters was investigated.

Methods: Dependence of RI extraction performance on noble electrodes (platinum, silver, palladium, ruthenium, rhodium) was checked with CA, CV and DPV, in a wide pH and ionic strength range. Optimizations on inter-electrode distance, potential type and magnitude, extraction time, gel type, membrane MWCO, usage frequency, pretreatment, artificial body fluids were performed.

Results: According to the optimized results, the inter-electrode distance was 7.0 mm and silver was the optimum noble metal. Optimum pH and ionic strength were achieved with 0.05M PBS at pH 7.4. Higher glucose yields were obtained with DPV, while CA and CV achieved almost the same levels. During CA, +0.5V achieved the highest glucose yield and higher potential even caused a decrease. Glucose levels could be monitored for 24 hours. CMC gel was the optimum collection media. Pretreated CE membrane with 12kD MWCO was the artificial skin model. Pretreatment affected the yields while its condition caused no significant difference. Except PBS solution (simulated as artificial plasma), among the various artificial simulated body fluids, intestinal juice formulation (AI) and urine formulation U2 were the optimum extraction media, respectively.

Conclusion: In this study, various experimental parameters (pretereatment procedure, type and MWCO values of membranes, inter-electrode distance, electrode material, extraction medium solvents, ionic strength and pH, collection medium gel type, extraction potential type and magnitude, extraction time and etc) were optimized for the non-invasive RI determination of glucose in a CE dialysis membrane-based artificial skin model and various simulated artificial body fluids.

Keywords: Artificial skin, glucose, method optimization, reverse iontophoresis, simulated body fluid, noble electrodes.

World Health, Statistics. 2018 Report. Monitoring Health for the SDGs, Sustainable Development Goals. Geneva World Health Organization; (WHO), 2018. http://apps.who.int/iris/bitstream/handle/10665/272596/9789241565585-eng.pdf
International Diabetes Federation. IDF Diabetes Atlas, 2017.http://www.diabetesatlas.org
Yoo, E.H.; Lee, S.Y. Glucose biosensors: An overview of use in clinical practice. Sensors (Basel), 2010, 10(5), 4558-4576.
[http://dx.doi.org/10.3390/s100504558] [PMID: 22399892]
Clark, L.C., Jr; Lyons, C. Electrode systems for continuous monitoring in cardiovascular surgery. Ann. N. Y. Acad. Sci.,, 1962,, 102,, 29-45..
[http://dx.doi.org/10.1111/j.1749-6632.1962.tb13623.x] [PMID: 14021529]
So, C.F.; Choi, K.S.; Wong, T.K.S.; Chung, J.W.Y. Recent advances in noninvasive glucose monitoring. Med. Devices (Auckl.), 2012, 5, 45-52.
[PMID: 23166457]
Tura, A.; Maran, A.; Pacini, G. Non-invasive glucose monitoring: Assessment of technologies and devices according to quantitative criteria. Diabetes Res. Clin. Pract., 2007, 77(1), 16-40.
[http://dx.doi.org/10.1016/j.diabres.2006.10.027] [PMID: 17141349]
Koschwanez, H.E.; Reichert, W.M. In vitro, in vivo and post explantation testing of glucose-detecting biosensors: Current methods and recommendations. Biomaterials,, 2007, 28(25), 3687-3703..
[http://dx.doi.org/10.1016/j.biomaterials.2007.03.034] [PMID: 17524479]
Ferrante do Amaral, C.E.; Wolf, B. Current development in non invasive glucose monitoring. Med. Eng. Phys.,, 2008, 30(5), 541-549.
[http://dx.doi.org/10.1016/j.medengphy.2007.06.003] [PMID: 17942360]
McCormick, C.; Heath, D.; Connolly, P. Minimally invasive sensing biosensors - emerging materials and applications. Prof. PierAndrea Serra (Ed.), , 2011; 978-953-307-328-6., .
Summary of Safety and Effectiveness Data. GlucoWatch G2 Biographer, 2002.https://www.accessdata.fda.gov/cdrh_docs/pdf/P99 0026S008b.pdf
Emma, Y. Non-invasive glucose monitoring for diabetes: five strategies under development. Pharm J.,, 2017., Available from:https://www.pharmaceutical-journal.com/news-and-analysis/features/non-invasiveglucose-monitoring-for-diabetes-five-strategies-underdevelopment/20203666.article
Santi, P.; Guy, R.H. Reverse iontophoresis- parameters determining electro-osmotic flow: I. pH and ionic strength. J. Control. Release, 1996, 38, 159-165.
Santi, P.; Guy, R.H. Reverse iontophoresis- parameters determining electro-osmotic flow. II. Electrode chamber formulation. J. Control. Release, 1996, 42, 29-36.
Sekkat, N.; Naik, A.; Kalia, Y.N.; Glikfeld, P.; Guy, R.H. Reverse iontophoretic monitoring in premature neonates: Feasibility and potential. J. Control. Release, 2002, 81(1-2), 83-89.
[http://dx.doi.org/10.1016/S0168-3659(02)00046-9 PMID: 11992681]
Sieg, A.; Guy, R.H.; Delgado-Charro, M.B. Noninvasive glucose monitoring by reverse iontophoresis in vivo: Application of the internal standard concept. Clin. Chem., 2004, 50(8), 1383-1390.
[http://dx.doi.org/10.1373/clinchem.2004.032862] [PMID: 15155544]
Kalia, Y.N.; Naik, A.; Garrison, J.; Guy, R.H. Iontophoretic drug delivery. Adv. Drug Deliv. Rev., 2004, 56(5), 619-658.
[http://dx.doi.org/10.1016/j.addr.2003.10.026] [PMID: 15019750]
Leboulanger, B.; Guy, R.H.; Delgado-Charro, M.B. Reverse iontophoresis for non-invasive transdermal monitoring. Physiol. Meas., 2004, 25(3), R35-R50.
[http://dx.doi.org/10.1088/0967-3334/25/3/R01] [PMID: 15253111]
Sieg, A.; Guy, R.H.; Delgado-Charro, M.B. Electroosmosis in transdermal iontophoresis: Implications for noninvasive and calibration-free glucose monitoring. Biophys. J., 2004, 87(5), 3344-3350.
[http://dx.doi.org/10.1529/biophysj.104.044792] [PMID: 15339817]
Connolly, P.; Cotton, C.; Morin, F. Opportunities at the skin interface for continuous patient monitoring: A reverse iontophoresis model tested on lactate and glucose. IEEE Trans. Nanobioscience, 2002, 1(1), 37-41.
[http://dx.doi.org/10.1109/TNB.2002.806939] [PMID: 16689220]
Ching, C.T.S.; Camilleri, I.; Connolly, P. IEEE/EMBS International Summer School on Medical Devices and Biosensors, China, July 8-10, 2004.
Ching, C.T.S.; Camilleri, I.; Connolly, P. A low-cost, programmable device for versatile current delivery in iontophoresis applications. Sens.and Act. B, 2005, 106, 534-540.
Ching, C.T.S.; Connolly, P. Reverse iontophoresis: A new approach to measure blood glucose level. Asian J. Health and Info. Sci., 2007, 1, 393-410.
Ching, C.T.S.; Connolly, P. A novel diffusion cell ideal for the study of membrane extraction/permeation processes and for device/sensor development. Sens. and Act. B, 2008, 129, 30-34.
Ching, T.S.; Connolly, P. Simultaneous transdermal extraction of glucose and lactate from human subjects by reverse iontophoresis. Int. J. Nanomedicine, 2008, 3(2), 211-223.
[PMID: 18686780]
McCormick, C.; Heath, D.; Connolly, P. Towards blood free measurement of glucose and potassium in humans using reverse iontophoresis. Sens. and Act. B, 2012, 166-167, 593-600.
Tokmakçi, M.; Ekmekçioglu, O.; Alçi, M. A programmable iontophoretic instrument and its application for local anesthesia before surgery in urology. J. Med. Syst., 2005, 29(2), 197-204.
[http://dx.doi.org/10.1007/s10916-005-3007-5] [PMID: 15931805]
Ching, C.T.S.; Chih, W.Y. Design and evaluation of an affordable and programmable mobile device, capable of delivering constant current and high voltage electric pulses of different waveforms for biomedical and clinical applications. Sens. and Act. B, 2014, 194, 361-370.
Determination of electrode area with chronocoulometry, (1998), Notes and applications from Bioanalytical Systems, Inc. Application Capsule, 1998..www.basinc.com/library/capsules/CAP133 mgdI.pdf
Sriveeraraghavan, S.; Krishnan, R.M.; Natarajan, S.R. Silver electro-deposition from thiosulfate solutions. J. Met Finish, 1989, 87(7), 115-117.
Rao, C.R.K.; Trivedi, D.C. Chemical and electrochemical depositions of platinum group metals and their applications. Coord. Chem. Rev., 2005, 249, 613-631.
Jayakumar, M.; Venkatesan, K.A.; Sudha, R.; Srinivasan, T.G.; Rao, P.R.V. Electrodeposition of ruthenium, rhodium and palladium from nitric acid and ionic liquid media: Recovery and surface morphology of the deposits. Mater. Chem. Phys., 2011, 128, 141-150.
King, R.L.; Botte, G.G. Investigation of multi-metal catalysts for stable hydrogen production via urea electrolysis. J. Power Sources, 2011, 196, 9579-9584.
Comisso, N.; Cattarin, S.; Fiameni, S.; Gerbasi, R. Electrodeposition of Cu–Rh alloys and their use as cathodes for nitrate reduction. Electrochem. Commun., 2012, 25, 91-93.
Cheng, S.; Kuehlert, E.; Panchap, L.; Young, K. Modelling reverse iontophoresis for noninvasive glycemic monitoring. Comp. Aided Eng. Appl. Biomed. Process., 2015, BEE4530, 1-28.
Windmiller, J.R.; Bandodkar, A.J.; Valdés-Ramírez, G.; Parkhomovsky, S.; Martinez, A.G.; Wang, J. Electrochemical sensing based on printable temporary transfer tattoos. Chem. Commun. (Camb.), 2012, 48(54), 6794-6796.
[http://dx.doi.org/10.1039/c2cc32839a] [PMID: 22669136]
Bandodkar, A.J.; Jia, W.; Yardımcı, C.; Wang, X.; Ramirez, J.; Wang, J. Tattoo-based noninvasive glucose monitoring: A proof-of-concept study. Anal. Chem., 2015, 87(1), 394-398.
[http://dx.doi.org/10.1021/ac504300n] [PMID: 25496376]
Puissant, C.; Abraham, P.; Durand, S.; Humeau-Heurtier, A.; Faure, S.; Leftheriotis, G.; Mahé, G. Assessment of endothelial function by acetylcholine iontophoresis: Impact of inter-electrode distance and electrical cutaneous resistance. Microvasc. Res., 2014, 93, 114-118.
[http://dx.doi.org/10.1016/j.mvr.2014.04.001] [PMID: 24735977]
Delgado-Charro, M.B.; Guy, R.H. Iontophoretic delivery of nafarelin across the skin. Int. J. Pharm., 1995, 117, 165-172.
Arunkumar, S.; Shivakumar, H.N.; Narasimha, M.S. Effect of terpenes on transdermal iontophoretic delivery of diclofenac potassium under constant voltage. Pharm. Dev. Technol., 2018, 23(8), 806-814.
[http://dx.doi.org/10.1080/10837450.2017.1369110 PMID: 28814142]
Nolan, L.M.A.; Corish, J.; Corrigan, O.I.; Fitzpatrick, D. Iontophoretic and chemical enhancement of drug delivery. Part I: Across artificial membranes. Int. J. Pharm., 2003, 257(1-2), 41-55.
[http://dx.doi.org/10.1016/S0378-5173(03)00108-X PMID: 12711160]
Spectrum Labs. Biotech Grade Dialysis Membranes: Cellulose Ester (CE), Regenerated Cellulose (RC), Product Information & Operating Instructions., 2019.http://spectrumlabs.com/lit/420x 10688x000.pdf
Degim, I.T.; Ilbasmis, S.; Dundaroz, R.; Oguz, Y. Reverse iontophoresis: A non-invasive technique for measuring blood urea level. Pediatr. Nephrol., 2003, 18(10), 1032-1037.
[http://dx.doi.org/10.1007/s00467-003-1217-y] [PMID: 12898373]
Monika, P.; Adam, V. Stability of simulated body fluids such as blood plasma, artificial urine and artificial saliva. Microchem. J., 2017, 134, 197-201.
Karavana, S.Y.; Güneri, P.; Ertan, G. Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: Preparation, rheological, textural, mucoadhesive and release properties. Pharm. Dev. Technol., 2009, 14(6), 623-631.
[http://dx.doi.org/10.3109/10837450902882351] [PMID: 19883251]
United States Pharmacopea USP36 NF31. U.S. Pharmacopoeia National Formulary by United States Pharmacopeial Convention., 2013, 13, 9781936424122
Pham, Q.D.; Björklund, S.; Engblom, J.; Topgaard, D.; Sparr, E. Chemical penetration enhancers in stratum corneum - Relation between molecular effects and barrier function. J. Control. Release, 2016, 232, 175-187.
[http://dx.doi.org/10.1016/j.jconrel.2016.04.030] [PMID: 27108613]

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Article Details

Year: 2020
Published on: 13 August, 2020
Page: [722 - 737]
Pages: 16
DOI: 10.2174/1573411015666190710232858
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