{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T22:44:44Z","timestamp":1769553884944,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2012,10,1]],"date-time":"2012-10-01T00:00:00Z","timestamp":1349049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sensors"],"abstract":"<jats:p>The performance of implantable electrochemical glucose sensors is highly dependent on the flux-limiting (glucose, H2O2, O2) properties of their outer membranes. A careful understanding of the diffusion profiles of the participating species throughout the sensor architecture (enzyme and membrane layer) plays a crucial role in designing a robust sensor for both in vitro and in vivo operation. This paper reports the results from the mathematical modeling of Clark\u2019s first generation amperometric glucose sensor coated with layer-by-layer assembled outer membranes in order to obtain and compare the diffusion profiles of various participating species and their effect on sensor performance. Devices coated with highly glucose permeable (HAs\/Fe3+) membranes were compared with devices coated with PSS\/PDDA membranes, which have an order of magnitude lower permeability. The simulation showed that the low glucose permeable membrane (PSS\/PDDA) sensors exhibited a 27% higher amperometric response than the high glucose permeable (HAs\/Fe3+) sensors. Upon closer inspection of H2O2 diffusion profiles, this non-typical higher response from PSS\/PDDA is not due to either a larger glucose flux or comparatively larger O2 concentrations within the sensor geometry, but rather is attributed to a 48% higher H2O2 concentration in the glucose oxidase enzyme layer of PSS\/PDDA coated sensors as compared to HAs\/Fe3+ coated ones. These simulated results corroborate our experimental findings reported previously. The high concentration of H2O2 in the PSS\/PDDA coated sensors is due to the low permeability of H2O2 through the PSS\/PDDA membrane, which also led to an undesired increase in sensor response time. Additionally, it was found that this phenomenon occurs for all enzyme thicknesses investigated (15, 20 and 25 nm), signifying the need for a holistic approach in designing outer membranes for amperometric biosensors.<\/jats:p>","DOI":"10.3390\/s121013402","type":"journal-article","created":{"date-parts":[[2012,10,2]],"date-time":"2012-10-02T02:39:08Z","timestamp":1349145548000},"page":"13402-13416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Theoretical Analysis of the Performance of Glucose Sensors with Layer-by-Layer Assembled Outer Membranes"],"prefix":"10.3390","volume":"12","author":[{"suffix":"Jr.","given":"Robert A.","family":"Croce","sequence":"first","affiliation":[{"name":"Electrical and Computer Engineering, University of Connecticut, 371 Fairfield Way, Storrs, CT 06269, USA"}]},{"given":"Santhisagar","family":"Vaddiraju","sequence":"additional","affiliation":[{"name":"Biorasis Inc., Technology Incubation Program, University of Connecticut, Storrs, CT 06269, USA"},{"name":"Nanomaterials Optoelectronics Laboratory, Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA"}]},{"given":"Fotios","family":"Papadimitrakopoulos","sequence":"additional","affiliation":[{"name":"Nanomaterials Optoelectronics Laboratory, Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA"},{"name":"Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA"}]},{"given":"Faquir C.","family":"Jain","sequence":"additional","affiliation":[{"name":"Electrical and Computer Engineering, University of Connecticut, 371 Fairfield Way, Storrs, CT 06269, USA"}]}],"member":"1968","published-online":{"date-parts":[[2012,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1109\/TITB.2004.834389","article-title":"An Implantable Telemetry Platform System for In Vivo Monitoring of Physiological Parameters","volume":"8","author":"Valdastri","year":"2004","journal-title":"IEEE Trans. Inform. Technol. Biomed."},{"key":"ref_2","unstructured":"Valdastri, P., Rossi, S., Menciassi, A., Lionetti, V., Bernini, F., Recchia, F.A., and Dario, P. (September, January 7\u2013). An Implantable ZigBee Ready Telemetric Platform for In Vivo Monitoring of Physiological Parameters. Dresden, Germany."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Valdastri, P., Susilo, E., F\u00f6rster, T., Strohh\u00f6fer, C., Menciassia, A., and Dario, P. (2009, January 6\u20139). Wireless Implantable Electronic Platform for Blood Glucose Level Monitoring. Lausanne, Switzerland.","DOI":"10.1016\/j.proche.2009.07.313"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1109\/TBCAS.2009.2016844","article-title":"A Wireless-Implantable Microsystem for Continuous Blood Glucose Monitoring","volume":"3","author":"Ahmadi","year":"2009","journal-title":"IEEE Trans. Biomed. Circ. Syst."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.snb.2006.05.013","article-title":"Design and Construction of a Low Cost Single-Supply Embedded Telemetry System for Amperometric Biosensor Applications","volume":"122","author":"Serra","year":"2007","journal-title":"Sens. Actuat. B Chem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bolomey, L., Meurville, E., and Ryser, P. (2009, January 6\u20139). Implantable Ultra-Low Power DSP-Based System for a Miniature Chemico-Rheological Biosensor. Lausanne, Switzerland.","DOI":"10.1016\/j.proche.2009.07.308"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1016\/j.bios.2004.12.003","article-title":"Biosensors for Real-Time In Vivo Measurements","volume":"20","author":"Wilson","year":"2005","journal-title":"Biosens. Bioelectr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1177\/193229681000400632","article-title":"Technologies for Continuous Glucose Monitoring: Current Problems and Future Promises","volume":"4","author":"Vaddiraju","year":"2010","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/j.bios.2009.12.001","article-title":"Emerging Synergy between Nanotechnology and Implantable Biosensors: A Review","volume":"25","author":"Vaddiraju","year":"2010","journal-title":"Biosens. Bioelectr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1016\/j.bios.2008.08.015","article-title":"The Role of H2O2 Outer Diffusion on the Performance of Implantable Glucose Sensors","volume":"24","author":"Vaddiraju","year":"2009","journal-title":"Biosens. Bioelectr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1177\/193229681100500504","article-title":"Design and Fabrication of a High-Performance Electrochemical Glucose Sensor","volume":"5","author":"Vaddiraju","year":"2011","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1177\/193229680700100209","article-title":"Layer-by-Layer Assembled Semipermeable Membrane for Amperometric Glucose Sensors","volume":"1","author":"Tipnis","year":"2007","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Vaddiraju, S.H., Burgess, D.J., Jain, F.C., and Papadimitrakopoulos, F. (2009). Enhanced Glucose Sensor Linearity Using Poly(vinyl Alcohol) Hydrogels. J. Diabetes Sci. Technol., 863\u2013874.","DOI":"10.1177\/193229680900300434"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1039\/b408051n","article-title":"The Selectivity of Electrosynthesised Polymer Membranes Depends on the Electrode Dimensions: Implications for Biosensor Applications","volume":"21","author":"McMahon","year":"2004","journal-title":"Chem. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1021\/ac00063a023","article-title":"Performance of Subcutaneously Implanted Needle-Type Glucose Sensors Employing a Novel Trilayer Coating","volume":"65","author":"Moussy","year":"1993","journal-title":"Anal. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"420","DOI":"10.3390\/s7040420","article-title":"Modifications of Poly(o-phenylenediamine) Permselective Layer on Pt-Ir for Biosensor Application in Neurochemical Monitoring","volume":"7","author":"Kirwan","year":"2007","journal-title":"Sensors"},{"key":"ref_17","unstructured":"Shuler, M.L., and Kargi, F. (2002). Bioprocess Engineering: Basic Concepts, Prentice Hall."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Baronas, R., Ivanauskas, F., and Kulys, J. (2009). Mathematical Modeling of Biosensors: An Introduction for Chemists and Mathematicians, Springer.","DOI":"10.1007\/978-90-481-3243-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1063\/1.2836111","article-title":"Computational Modelling of Amperometric Enzyme Electrodes with Selective and Perforated Membranes","volume":"963","author":"Baronas","year":"2007","journal-title":"AIP Conf. Proc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3390\/s30700248","article-title":"The Influence of the Enzyme Membrane Thickness on the Response of Amperometric Biosensors","volume":"3","author":"Baronas","year":"2003","journal-title":"Sensors"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s10910-006-9102-0","article-title":"Computational Modelling of the Behaviour of Potentiometric Membrane Biosensors","volume":"42","author":"Baronas","year":"2007","journal-title":"J. Math. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.jelechem.2004.09.015","article-title":"Improved Platinization Conditions Produce a 60-Fold Increase in Sensitivity of Amperometric Biosensors Using Glucose Oxidase Immobilized in Poly-o-phenylenediamine","volume":"575","author":"Cavalieri","year":"2005","journal-title":"J. Electroanal. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1021\/ac015628m","article-title":"Electrochemically Mediated Electrodeposition\/Electropolymerization to Yield a Glucose Microbiosensor with Improved Characteristics","volume":"74","author":"Chen","year":"2002","journal-title":"Anal. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.simpat.2008.05.004","article-title":"Numerical Simulation of a Plate-Gap Biosensor with an Outer Porous Membrane","volume":"16","author":"Ivanauskas","year":"2008","journal-title":"Simul. Modell. Pract. Theory"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jelechem.2010.03.027","article-title":"Mathematical Modeling of Amperometric and Potentiometric Biosensors and System of Non-Linear Equations\u2014Homotopy perturbation approach","volume":"644","author":"Meena","year":"2010","journal-title":"J. Electroanal. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.3390\/s6111513","article-title":"Modelling of Amperometric Biosensors in the Case of Substrate Inhibition","volume":"6","author":"Kulys","year":"2006","journal-title":"Sensors"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1080\/03091900600926898","article-title":"Mathematical Model of an Amperometric Biosensor for the Design of an Appropriate Instrumentation System","volume":"31","author":"Patre","year":"2007","journal-title":"J. Med. Eng. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0925-4005(96)80099-2","article-title":"Modelling and Simulation of a Diffusion Limited Glucose Biosensor","volume":"33","author":"Cambiaso","year":"1996","journal-title":"Sens. Actuat. B Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"359","DOI":"10.15388\/NA.2007.12.3.14697","article-title":"A Comparison of Finite Difference Schemes for Computational Modelling of Biosensors","volume":"12","author":"Gaidamauskait","year":"2007","journal-title":"Nonlin. Anal. Model. Control"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1021\/ac00106a004","article-title":"Transient Response of Multilayer Electroenzymic Biosensors","volume":"67","author":"Bacha","year":"1995","journal-title":"Anal. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.15388\/NA.2003.8.1.15174","article-title":"Computer Simulation of the Response of Amperometric Biosensors in Stirred and Non Stirred Solution","volume":"8","author":"Baronas","year":"2003","journal-title":"Nonlin. Anal. Model. Control"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.mcm.2011.02.003","article-title":"Finite Difference Schemes for Multilayer Diffusion","volume":"54","author":"Hickson","year":"2011","journal-title":"Math. Comput. Modell."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0022-0728(94)03804-C","article-title":"Improved Model of a Polypyrrole Glucose Oxidase Modified Electrode","volume":"386","author":"Gros","year":"1995","journal-title":"J. Electroanal. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lowry, J.P., McAteer, K., Atrash, S.S.E., and O'Neill, R.D. (1994). Efficient Glucose Detection in Anaerobic Solutions Using an Enzyme-Modified Electrode Designed to Detect H2O2: Implications for Biomedical Applications. J. Chem. Soc. Chem. Commun.","DOI":"10.1039\/c39940002483"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1021\/ac0518194","article-title":"Control of the Oxygen Dependence of an Implantable Polymer\/Enzyme Composite Biosensor for Glutamate","volume":"78","author":"McMahon","year":"2006","journal-title":"Anal. Chem."}],"container-title":["Sensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8220\/12\/10\/13402\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:52:40Z","timestamp":1760219560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8220\/12\/10\/13402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10,1]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2012,10]]}},"alternative-id":["s121013402"],"URL":"https:\/\/doi.org\/10.3390\/s121013402","relation":{},"ISSN":["1424-8220"],"issn-type":[{"value":"1424-8220","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,10,1]]}}}