Biosensor Boot Camppart 2

David E Williams

Title: ELECTRODE SYSTEMS FOR CONTINUOUS MONITORING IN CARDIOVASCULAR SURGERYAuthor(s): CLARK, LC; LYONS, CSource: ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Volume: 102 Issue: 1 Pages: 29-& DOI: 10.1111/j.1749-6632.1962.tb13623.x Published: 1962Times Cited: 1,093 (from Web of Science

Glucose oxidase-containing membrane

glucose oxygen

Gox-containing membrane

Ag anode

Pt cathode

Signal decreases as glucose increases in this configuration

This model was the first whole-blood glucose analyzer. The instrument directly measures the whole-blood glucose level from a 25-microliter sample within a ±2% accuracy. The sensor created for the Model 23A was the first commercial biosensor and was used in the Miles Biostator, the first artificial pancreas. The U.S. Food and Drug Administration has identified the YSI Model 23A and subsequent designs as the reference standard for measuring glucose.

In 1970, Dr. Clark demonstrated the enzyme-activated polarographic measurement of glucose in water and pointed out that glucose could be measured in whole blood with the presence of the glucose oxidase enzyme. Within a couple of years, YSI was able to market its pioneering Model 23 Glucose Analyzer with a polarographic electrode.

http://www.ysi.com/history.php

http://www.chemheritage.org/discover/collections/collection-items/scientific-instruments/ysi-blood-glucose-analyzer-model-23a.aspx

Hydrogen peroxide readily depolarizes the polarographic anode and current flow, at a given applied voltage (usually about 0.9 volt), is proportional to the hydrogen peroxide concentration. If glucose were to be measured in blood by mixing the enzyme and the blood, no glucose would be detected because blood contains the enzyme, catalase, which destroys hydrogen peroxide at a very fast rate. This difficulty, and others, are circumvented through the use of a cellulose or other membrane which is permeable to small molecules, such as glucose, but is impermeable to proteins. The membrane serves to keep the glucose oxidase on the side of the membrane with the anode and at the same time to keep other enzymes, some of which, such as catalase, would ruin the reaction, on the other side of the membrane. Glucose has a molecular weight of 180 and can freely diffuse through the membrane. The product of the reaction, hydrogen peroxide, has a low molecular weight, only 34, but by virtue of the design of the present invention is formed directly on the platinum electrode surface where it is detected, and in the process of being detected is, in part at least converted to H20 and oxygen.

Pt anode: H2O2 oxidation

Ag/AgCl cathode

This model was the first whole-blood glucose analyzer. The instrument directly measures the whole-blood glucose level from a 25-microliter sample within a ±2% accuracy. The sensor created for the Model 23A was the first commercial biosensor and was used in the Miles Biostator, the first artificial pancreas. The U.S. Food and Drug Administration has identified the YSI Model 23A and subsequent designs as the reference standard for measuring glucose.

In 1970, Dr. Clark demonstrated the enzyme-activated polarographic measurement of glucose in water and pointed out that glucose could be measured in whole blood with the presence of the glucose oxidase enzyme. Within a couple of years, YSI was able to market its pioneering Model 23 Glucose Analyzer with a polarographic electrode.

http://www.ysi.com/history.php

http://www.chemheritage.org/discover/collections/collection-items/scientific-instruments/ysi-blood-glucose-analyzer-model-23a.aspx

Think a bit… the assumptions connecting the measurement to the desired quantity

conc

entr

ation

position

In the space: Glucose + O2 -> H2O2

Glucose conc

At the electrode: H2O2 -> O2

Oxygen conc

H2O2 conc

Small gap underneath membrane relative to membrane thickness

Gap is controlled – another membrane

Large excess of Gox – fast reaction

Current ~ gradient of H2O2 at electrode

Home use glucose

Development of the home-use glucose sensorFerrocene-Mediated Enzyme Electrode for Amperometric Determination of GlucoseAnthony E. G. Cass,’ Graham Davis, Graeme D. Francis, and H. Allen 0. Hill*Inorganic Chemistry Laboratory, University of Oxford, Oxford OX1 3QR, United KingdomWilliam J. Aston, I. John Higgins, Elliot V. Plotkin, Lesley D. L. Scott, and Anthony P. F. TurnerBiotechnology Centre, Cranfield Institute of Technology, Bedford MK43 OAL, United Kingdom

Anal. Chem., 1984, 56 (4), pp 667–671

Fcor Fc + glucoseor Fc + GOx

Fc + glucose + GOx

Removes oxygen dependence

Eliminates uric acid and ascorbate interference

Concept for a single use, batch calibrated device

the reaction : Fc+ + glucose + GOxregenerates Fc near the electrode so current doesn’t decrease

Fc → Fc+ + e-

anodic current decreases when Fc is depleted near the electrode

glucose + M(ox) gluconolactone + M(red)GOx

Fc+ Fc

for glucose measurement, hold potential constant at ~ 0.4 V and measure current

The reaction of Fc+ and GOx(red): a classic ErCi’ system

E = electrochemical stepC’ = homogeneous catalytic chemical reactionr = reversiblei = irreversible

Examples of some other classic mechanisms:ErCr

ErCiEr

CrEi

(C = homogeneous chemical reaction)

Fc/GOx system

R (Fc) O (Fc+) + e

O (Fc+) + Z (glucose) R + Y (gluconolactone) k’

bulk concentrations, i.e. what’s added at the start

A.J. Bard, L.R. Faulkner, Electrochemical Methods: Fundamentals and Applications, ed. John Wiley: New York, 2001; Chapter 12.

R (Fc) O (Fc+) + e

O (Fc+) + Z (glucose) R + Y (gluconolactone) k’

Reaction consumes ‘O’ and regenerates ‘R’ in the boundary layer near the electrode as ‘O’ is produced at the electrode

Technology and market drivers

• Lower blood volume• More precision• Avoiding other peoples’ patents

• -> coulometers• -> high concentration solutions of enzyme and

mediator• -> old (ferrocyanide) and new (osmium)

mediators

Chamber of precisely known volume, capillary fill

Dried reagents give high concentration solutions

Complete conversion of glucose in sample to gluconolactone with equivalent reduction of ferricyanide

Coulometric determination of amount of ferrocyanide produced

Precision determined by precision of manufacture of the defined sample volume

Electrodes in chamber

spacer

reagents

100um gap

Lifescan ‘one-touch’

~1uL sample volume; 5s measurement; made by web printing process : 106 / hr

Therasense : Adam Heller

http://ubimon.doc.ic.ac.uk/bsn/public/bsn-2005-Heller.pdf

Glucose gluconolactone

GoX

Os(III) Os(II)

http://ubimon.doc.ic.ac.uk/bsn/public/bsn-2005-Heller.pdf

http://www.boots.com/en/Pharmacy-Health/Health-shop/Diagnostics-electrical-health/Blood-glucose-monitors/

Random Thoughts list

• Strep – antigen extraction• Glucose – how devices changed and the

assumptions behind operation• Flow injection, protective membranes,

Bourtelle and Albery, one shot• Microfluidics• Surfaces and interactions• Immunoassay theory

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percentage of readings ±5 mg/dL0 20 40 60 80

Freckmann et al. “System Accuracy Evaluation of 27 Blood Glucose Monitoring Systems According to DIN EN ISO 15197”. Diabetes Technol. Ther. 2010, 12. 221-231, DOI: 10.1089/dia.2009.0128