Electrochemical non-enzymatic glucose sensors

Analytica Chimica Acta 556 (2006) 46–57

Review

Electrochemical non-enzymatic glucose sensors

Sejin Parka,b, Hankil Booa,b, Taek Dong Chunga,∗a Center for Nano-Bio Applied Technology and Department of Chemistry, Sungshin Women’s University, Seoul 136-742, Korea

b Department of Biomedical Engineering, College of Medicine and Institute of Medical and Biological Engineering,Medical Research Center, Seoul National University, Seoul 110-744, Korea

Received 21 March 2005; received in revised form 25 May 2005; accepted 26 May 2005Available online 11 July 2005

Abstract

The electrochemical determination of glucose concentration without using enzyme is one of the dreams that many researchers have beentrying to make come true. As new materials have been reported and more knowledge on detailed mechanism of glucose oxidation has beenunveiled, the non-enzymatic glucose sensor keeps coming closer to practical applications. Recent reports strongly imply that this progresswill be accelerated in ‘nanoera’. This article reviews the history of unraveling the mechanism of direct electrochemical oxidation of glucose

s involvese reactions

will leadn examplensitivitymistry of

47

48

949949

9505115252

and making attempts to develop successful electrochemical glucose sensors. The electrochemical oxidation of glucose moleculecomplex processes of adsorption, electron transfer, and subsequent chemical rearrangement, which are combined with the surfacon the metal surfaces. The information about the direct oxidation of glucose on solid-state surfaces as well as new electrode materialsus to possible breakthroughs in designing the enzymeless glucose sensing devices that realize innovative and powerful detection. Aof those is to introduce nanoporous platinum as an electrode, on which glucose is oxidized electrochemically with remarkable seand selectivity. Better model of such glucose sensors is sought by summarizing and revisiting the previous reports on the electrocheglucose itself and new electrode materials.© 2005 Elsevier B.V. All rights reserved.

Keywords: Non-enzymatic; Glucose sensor; Nanoporous; Glucose oxidation; Electrochemical sensor

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1. Brief history of electrochemical glucose sensors based on enzyme electrodes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471.2. Why enzymeless glucose sensor?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.2.1. Advantages of detecting glucose without using enzyme. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481.2.2. Key issues to non-enzymatic glucose sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. Electrochemical oxidation of glucose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1. Redox mechanism of glucose on metal surfaces. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.2. Platinum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2.1. In neutral condition (phosphate buffer). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.2.2. In basic condition[35] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.2.3. In acidic condition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3. Flat platinum as a non-enzymatic blood glucose sensor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.4. Ad-atoms on platinum or gold. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.5. Ni andCu. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author.E-mail addresses: [email protected] (S. Park), [email protected] (H. Boo), [email protected] (T.D. Chung).

0003-2670/$ – see front matter © 2005 Elsevier B.V. All rights reserved.doi:10.1016/j.aca.2005.05.080

S. Park et al. / Analytica Chimica Acta 556 (2006) 46–57 47

2.6. Alloy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532.7. Pt/WO3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532.8. Others. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

3. Electrochemical determination of glucose without enzyme. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533.1. Potentiometric glucose sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533.2. Voltammetric glucose sensor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533.3. Amperometric glucose sensor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

3.3.1. Nanotube. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543.3.2. Alloy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543.3.3. Nanoporous platinum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

4. Outlook on electrochemical non-enzymatic glucose sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

1. Introduction

1.1. Brief history of electrochemical glucose sensorsbased on enzyme electrodes

The efforts to develop and improve glucose sensors, par-ticularly based on amperometry, have been made over fourdecades since Clark and Lyons reported the first enzyme elec-trode in 1962[1]. Updike and Hicks immobilized glucoseoxidase (GOx) in a gel on an oxygen electrode for the firsttime and measured glucose concentration in biological fluids

tors to overcome oxygen limitation under low pressureof oxygen. The electron mediators facilitate the elec-tron transfer by shuttling electrons between the enzymeand electrode rapidly[4,5]. For high efficiencies or highturn-over-number, it is one of the key issues how todesign the redox system including the mediator, enzyme,and electrode. The electron mediators commonly usedare ferro/ferricyanide, hydroquinone, ferrocene, and vari-ous redox organic dyes[5]. The presence of other redox-active species, for instance oxygen, would compete with themediators.

irectpe,thethe

ns-oseen-tors.ess-lerden-

[2]. The urea sensor, which Guilbault and Montalvo madeby entrapping urease on an ammonia electrode, suggestedpotentiometric enzyme electrode as another kind of glucosesensors. The first example of potentiometric glucose sensorwas reported by Nilsson et al. who coupled GOx with a pHmeter[3].

The historical advances in the amperometric glucose sen-sors can be summarized into three generations. The glucosesensors of the first generation as illustrated inFig. 1exploitoxygen as an electron mediator between glucose oxidase andelectrode surface. GOx reduces O2 into H2O2 in the pres-ence of glucose. The rate of O2 reduction is proportional to

The glucose sensors based on the strategy of the delectron transfer belong to the third generation. In this tyelectrons are directly transferred from the enzyme toelectrode. If the electrode and the active redox sites ofenzyme were electrically wired, the direct electron trafer transforms the enzymatic recognition events of glucto amperometric signal effectively regardless of the conctration of co-substrates such as oxygen or redox mediaThe most valuable advantage in this design is the succful elimination of possible interferences. Degani and Helrealized direct electron transfer from GOx to the electroby covalently tethering a number of electron-relaying ce

the glucose concentration that can be determined by mea-suring increment of the H2O2 concentration or decrement of

suf-tive

d-ia-

o the

ters to the enzyme[6,7]. An interesting approach by themwas the use of osmium-based redox polymer as an electronrelay, which successfully works. Willner and co-workers,a ide( lays( andt -i elec-

F e sec-o

s illustrated inFig. 3, attached flavin adenine dinucleotFAD) to the self-assembled monolayer of electron rei.e., pyrroloquinoline quinone, PQQ) on the electrode,hen reconstituted the GOx[8,9]. By this strategy employng apo-GOx, they electrically connected enzyme and

ig. 2. Schematic diagram of enzyme glucose sensors belonging to thnd generation.

O2 concentration. The first generation of glucose sensorsfers from oxygen dependence or interference by redox-acspecies.

Fig. 2 depicts the general structure of the secongeneration glucose sensors that employ artificial med

Fig. 1. Schematic diagram of the enzyme glucose sensors belonging tfirst generation.

48 S. Park et al. / Analytica Chimica Acta 556 (2006) 46–57

Fig. 3. An example of the third generation glucose sensors. The assembly of the reconstituted GOx-electrode and the bioelectrocatalytic oxidation of glucosewith the enzyme-electrode (from Ref.[9]).

trode. Gooding and co-workers exploited carbon nanotubesto connect the active site of GOx to the electrode surface[10].

1.2. Why enzymeless glucose sensor?

1.2.1. Advantages of detecting glucose without usingenzyme1.2.1.1. Stability. Over the last decades, a number of studieshave been conducted to alleviate the drawbacks of enzy-matic glucose sensors. The most common and serious prob-lem is insufficient stability originated from the nature of theenzymes, which is hardly overcome. Although GOx is quitestable compared with other enzymes, the glucose sensorsbased on GOx are always exposed to the possible thermaland chemical deformation during fabrication, storage or use.According to the review of Wilson and Turner[11] and ref-erences therein, GOx quickly loses its activity below pH 2and above pH 8, and temperature above 40◦C can causefatal damages. Ionic detergents deactivate GOx as well. Theactivity of GOx is very sensitive to the presence of sodium-n-dodecyl sulfate at low pH and hexadecyltrimethylammoniumbromide at high pH. Thermal and chemical instability of GOxprohibits enzymatic glucose sensors from being used for con-tinuous monitoring in fermentation processes or in humanb pH,a glu-c lowh usea glu-c at thg m asi withn ity tog

1.2.1.2. Simplicity and Reproducibility. For an enzyme elec-trode, one or more enzyme layers should be placed on thebare electrode through carefully optimized process. Therehave been reported a number of methods for enzyme immobi-lization, which include direct adsorption, sol–gel entrapment,cross-linking, and so on[13,14]. With the aim of mass produc-tion and commercialization, simpler and more reproducibleway of GOx immobilization has been sought very intensively.Now most of the disposable glucose sensors, which are cur-rently commercialized, are fabricated by spotting thoroughlyoptimized cocktails of their own. Because the sensitivity ofthese glucose sensors essentially depends on the activity ofthe enzymes immobilized, the reproducibility is still a crit-ical issue in quality control. Another well-known methodis to entrap enzymes during electro-polymerization in thesolution containing enzymes, monomers, and cross-linkerswhen needed[15,16]. This method is attractive due to twoadvantages, which are the one-pot-immobilization of enzymeand the electrical control of enzyme layer thickness. It isbelieved that this method is especially suitable for miniatur-ized or micro-patterned glucose sensors and for the purposeof continuous glucose monitoring. However, it still requiresenzyme immobilization procedure on solid electrodes. Con-sequently all kinds of enzyme electrodes basically are notfree from the intrinsic uncertainly of biological componentsbound in artificial environments regardless of the immobi-l zed.I ctivea

1 -t odes.R sys-t tively[ rom

odies requiring sterilization. In addition to temperature,nd toxic chemicals for sterilization, the responses ofose sensors are a function of humidity. Both high andumidity may be significantly harmful to the sensors ins well as storage. All those are why the enzymelessose sensor receives keen interest. It does not seem thlucose sensors without using enzyme are just a drea

mplied by recent advances. For example, pure platinumanoporous surface shows high sensitivity and selectivlucose even after exposure to 1 M NaOH or H2SO4 [12].

e

ization method and the sorts of the enzymes immobilin this respect, the non-enzymatic sensor is an attralternative.

.2.1.3. Free from oxygen limitation. Low oxygen concenration regulates the responses of most enzyme electreportedly some sophisticated designs of electron relay

em can suppress the oxygen dependence very effec17–19]. But even the best one is not completely free f


oxygen effect because the electron-mediating sites shouldcompete with oxygen dissolved in the solution. Any glucosesensor generating electrical current by directly oxidizing glu-cose itself on the electrode surface would eliminate the worryabout oxygen limitation. It is noteworthy that the reductivecurrent of oxygen possibly interferes because the thermody-namic reduction potential of oxygen is more positive thanwhere glucose is oxidized. Fortunately, such interference canbe easily minimized by finding appropriate potential wherethe reduction kinetics of oxygen molecules is as sluggish aspossible.

1.2.2. Key issues to non-enzymatic glucose sensors1.2.2.1. Amperometric sensor. The enzymeless detection ofglucose by conventional amperometry is not just recent inter-est. Continued efforts to realize the idea have been madesince the early study on the electrochemistry of glucose itself[20–39]. Researchers kept focusing on two issues. One is themechanism of the glucose oxidation on bare platinum sur-face and the other is the electrocatalytic oxidation of glucose.The mechanism studies, which still need lots of further work,showed the overall kinetics of glucose oxidation is too slow toproduce significant faradaic current. Most of the pure metalsincluding platinum, which is currently the best, exhibit unsat-isfied sensitivity to glucose. For example, the sensitivity of aflat platinum with roughness factor of 2.6 in phosphate bufferi sl poi-s .T is sos uponc others

nsorh eak-t ancet ortsw witho sur-f , Bi,o i-d onlyi ofa thism thats ctives hichh nitionu romo ll aso ciesa ctivem

e lu-c t

remarkably negative potentials. That is why Pt2Pb is rela-tively insensitive to interfering species likel-ascorbic acid(AA), UA (UA) and 4-acetamidophenol (AP). In addition,Pt2Pb produces more stable and larger responses than pureplatinum. However, in spite of such valuable advantages,the surface poisoning of Pt2Pb by chloride ion remainsa critical problem. The amperometric signal diminishesrapidly in the presence of 0.01 N NaCl and eventually almostdisappears.

1.2.2.2. Potentiometric sensor. The potentiometric sensorsare usually suitable for determining the concentration higherthan 10−5 M, which is the range required to measure in mostcases. For instance the blood glucose level of a normal humanbody is between 4 and 7 mM. Potentiometry is compatible tomultichannel array type sensory instruments and needs verysimple operating circuit. Therefore, potentiometric glucosesensors without involving enzyme are attractive in terms ofintegrating with conventional ion-selective electrodes like pHmeter.

Selectivity is also the key issue for non-enzymatic andpotentiometric sensors. Only a few attempts were reportedwith respect to the potentiometric glucose sensor withoutusing enzyme by Shoji and Freund[40,41]. They employedpolymeric membranes with boronic acid units, which haveaffinity for diol unit of saccharide. This sensor did respond tog thang

2

2

ec is viaa� di-t y ass mt mi-a H( n of� di itht i-c tly.R sa ducto

2

2ical

o ffer

s hard to exceed 0.14�A cm−2 for 6 mM glucose. Besideow sensitivity, platinum electrode has other problems ofoning by adsorbed intermediates[31] and poor selectivityhe poisoning by chloride ion and adsorptive specieserious that the amperometric signals almost disappearontinued operation. This issue is discussed again in anection.

The interest in practical non-enzymatic glucose seas been centered on the efforts to find out the br

hrough in electrocatalysis. The first goal was to enhhe sensitivity to glucose. In order to do so, a lot of effere concentrated on the modification of noble metalsther metals. As a result, it was reported that platinum

aces modified by some heavy metals such as Tl, Pbr WO3 [20–23] showed catalytic activity for glucose oxation. However, the catalytic oxidation was observed

n acidic or basic condition. Moreover, the dissolutionnd the toxicity of the heavy metal elements preventethod from being put to practical use. Another point

hould be considered is the interference by electroapecies. Most of the non-enzymatic glucose sensors, wave been suggested to date, do not have any recognit for glucose. Thus it is hard to distinguish glucose fther electroactive interferents. Glucose is not as smaxygen or hydrogen peroxide so that the interfering spere hardly excluded by using conventional size-seleembranes.Such troubles can be partly cured by Pt–Pb alloy (Pt2Pb)

lectrodes[24]. Compared with pure platinum surfaces, gose is electrochemically oxidized on Pt2Pb surfaces a

lucose but showed even higher sensitivity to fructoselucose.

. Electrochemical oxidation of glucose

.1. Redox mechanism of glucose on metal surfaces

Two hemiacetal-types of glucose (�- and�-glucose) aronverted to each other through acid-catalyzed hydrolysldehyde-type glucose (�-glucose). Equilibrium ratio of�-,-, and�-glucose is 37:53:0.003 in the physiological con

ion. Ernst et al. illustrated the general reaction pathwahown inFig. 4 [25]. For�- and�-glucose, the hydrogen atoethered to C1 carbon is activated because the acidity of hecetalic OH group (pKa = 12.3) is stronger than alcoholic OpKa = 16). Thus the product of electrochemical oxidatio- and�-glucose is glucono-�-lactone, which is hydrolyze

nto gluconic acid with the half-life of ca. 10 min and whe rate constant of 10−3 s−1 at pH 7.5. The electrochemal oxidation of�-glucose produces gluconic acid direcegardless of whether the glucono-�-lactone is involved an intermediate or not, gluconic acid is the final stable prof two-electron oxidation of glucose.

.2. Platinum

.2.1. In neutral condition (phosphate buffer)As a result of early investigations on the electrochem

xidation of glucose on platinum in neutral phosphate bu


Fig. 4. The equilibria of glucose in an aqueous solution and schematicpathways of electrochemical electron transfer and the coupled reactions(summarized and redrawn from the figures in Ref.[25]).

[26–30], there was an agreement that the electrochemical oxi-dation of glucose involves the dehydrogenation at C1 carbon[20,25,31–33]. �-glucose is the most reactive species amongthe possible anomeric forms. The poor reactivity of�-glucoseis supposedly attributed to the geometric orientation of thehydrogen atom bound to the anomeric carbon[34]. Generallythe electrochemical oxidation of glucose has been discussedin three potential ranges.

In Fig. 5, the region between 0.15 and 0.35 V versus RHE(reversible hydrogen electrode) is called as ‘hydrogen region’[31]. Glucose produces the unique behavior of electrochem-ical oxidation in the hydrogen region when platinum is usedas a working electrode. We cannot observe voltammetricbehavior like this with electrode materials other than plat-inum. For instance other organic substances such as alcohols,acids, and aldehydes do not show the oxidative current in thehydrogen region like that shown inFig. 5. The glucose oxi-dation in hydrogen region is associated with the adsorbedhydrogen atoms. The reactive center for the reaction is thehemiacetal group of glucose. Adsorbed glucose and/or prod-ucts dominate the reaction. The proposed mechanism is asfollows:

‘Double layer region’ means the region between 0.40 and0.80 V versus RHE[25]. In the double layer region, thecyclic voltammogram measured in phosphate buffer at pH 7.5shows two separate oxidation peak observed only at low scanr d7 ases

Fig. 5. Cyclic voltammograms in the absence (dotted line) and presence(solid line) of 0.1 M glucose in phosphate buffer at pH 7.5 displaying threepotential regions where glucose is electrochemically oxidized at a platinumelectrode (redrawn from figures in Ref.[31]).

as anions or organic species, particularly glucono-�-lactone,are adsorbed. Neither pH between 5.5 and 9 nor potentialapplied between 0.2 and 0.5 V versus RHE affects the sur-face coverage by organic adsorbed. However, the adsorptionis a function of applied potential and glucose concentration.And the surface becomes less adsorptive when potential morepositive than 0.5 V is applied. The proposed mechanism isbelow (Figs. 6 and 7).

No result from systematic study has been reported yet onthe voltammetric behavior in the oxide region of more pos-itive than 1.1 V versus RHE. In this region, glucose reactswith the produced platinum oxide layer. The poisoning prod-uct of lactone-type are decomposed by further oxidation[20,25].

2.2.2. In basic condition [35]The oxidation of glucose at platinum in alkaline solu-

tions has been understood as illustrated inFig. 8. Instead ofhydrogen adsorption, the chemisorption of glucose on bareplatinum takes place initially. This step is a kind of ‘dehydra-tion step’.

When the potential in the hydrogen region under 0.3 V ver-sus RHE is applied, the adsorbed dehydrated intermediate isfurther oxidized to form weakly adsorbed gluconate. In dou-ble layer region between 0.3 and 0.6 V, further oxidation oft eakly-a eakena sitivet dro-gwd resulto

ates. For example, the peaks at 5 mV s−1 appear at 670 an50 mV versus RHE. The oxidation peak current decre

he adsorbed dehydrated intermediate produces more wdsorbed gluconate. The adsorption strength tends to ws the potential applied increases. At potentials more po

han 0.6 V and up to the anodic limit, the adsorbed dehyenated intermediate is oxidized to form a glucono-�-lactoneithout cleavage of the CO C bond. The glucono-�-lactoneesorbs slowly and eventually becomes gluconate as af hydrolysis in the basic media.


Fig. 6. Reaction mechanism of the electrochemical oxidation of glucose on platinum surface in neutral media in the potential range where hydrogen adsorptionor desorption takes place (hydrogen region) (summarized and redrawn from the figures in Ref.[31]).

2.2.3. In acidic conditionAccording to the related studies on the electrochemical

oxidation of glucose in acidic media[21,34,42,43], clearmechanism has not been proposed yet. Glucose is not veryreactive in acidic solution. The oxidative peaks in cyclicvoltammogram are rather small compared with those appear-ing in neutral or basic solutions[34]. Popovic et al. [42]conducted a mechanism study on the glucose oxidation in0.1 M HClO4. It showed that the glucose oxidation was sensi-tively dependent on the surface planes of platinum (i.e. (1 1 1)or (1 0 0)). The first reaction step involves the oxidation of thehydrogen atom bound to C1 carbon at two planes. The binding

strength of the intermediates to the surface are quite different.Glucono-�-lactone is adsorbed on Pt(1 1 1) whereas CO isbound to Pt(1 0 0). The single anodic peak in the linear sweepvoltammogram of Pt(1 1 1) is remarkably large (ca. 1 order)compared with the double peaks of Pt(1 1 0) or Pt(1 0 0) plane.

2.3. Flat platinum as a non-enzymatic blood glucosesensor

Platinum has several disadvantages for practical non-enzymatic detection of blood glucose. First, the catalyticactivity of platinum electrode for the electrochemical oxida-

F ose on chargind ion) (su

ig. 7. Reaction mechanism of the electrochemical oxidation of glucischarging due to double layer capacitance occurs (double layer reg

platinum surface in neutral media in the potential range where onlyg ormmarized and redrawn from the figures in Ref.[25]).


Fig. 8. Reaction mechanism of the electrochemical oxidation of glucose on platinum surfaces in basic media (summarized and redrawn from the figures inRef.[35]).

tion of glucose drops seriously by chloride ion that is presentin physiological fluids[26,27]. Second, the platinum elec-trode was seriously poisoned by various organic constituentssuch as amino acids[44,45]and biochemicals like AA, crea-tinine, ephinephrine, urea and UA[45] in blood. For example,the blood proteins occupy the catalytic sites on the platinumsurface, resulting in many malfunctions of platinum as a glu-cose sensing material. Most biochemicals and amino acids inblood mentioned above inhibits the oxidation of glucose[43]so that the platinum loses its sensitivity to glucose. Further-more, the linear range of glucose detection becomes narroweddown [45]. Third, platinum electrode features the lack ofselective catalytic activity[43].

2.4. Ad-atoms on platinum or gold

In acidic solutions, the sub-monolayers of metals suchas Bi, Pb, and Tl on platinum, which are formed by under-potential-deposition (UPD), give anodic currents of glucosemarkedly enhanced by about one order of magnitude[21,38].The adsorbed metals repel the adsorbed hydrogen atoms onthe bare platinum, which inhibit the formation of the poi-sonous species of lactone-type[20].

Au electrodes with the sub-monolayers of Ag[36,46]andHg [37] were also studied for glucose oxidation in alkalinesolutions. Aoun et al. investigated the glucose oxidation in0.1 M NaOH solution at Au(1 1 1) surface covered with var-ious Ad-atoms such as Cu, Ag, Ru, Pt, Pd, and Cd[36,46].Among them, the Au electrode with 1/3 monolayer of Agallows the largest potential shift in the negative direction andthe highest catalytic activity for glucose oxidation[36,46].The Au electrode modified by Hg Ad-atom gives large oxi-dation peak currents in comparison with bare Au in alkalinesolution[37]. Such enhancements in current are supposedlyascribed to the increase in the amount of the adsorbed OH−on the Hg Ad-atom modified Au electrode.

2.5. Ni andCu

Glucose at a Ni electrode shows anodic response in basicsolution according to Luo et al.[47]. It was suggested thatthe mechanism for this response involves Ni2+/3+ couple onthe oxidized Ni surface. You et al.[48] reported the responseof Ni nanoparticles dispersed in disordered graphite-like car-bon (Ni–NDC) to sugars. According to their report, Ni–NDCenhances the sensitivity to sugars of at least 1 order and sta-


bility of relative standard deviation of 1.75% for 40 repeateddetection compared with those of bulk Ni. On the other hand,Prabhu and Baldwin carried out constant potential ampero-metric detection of glucose with CuO coated on glassy car-bon, in basic solution[49]. The electrocatalysis for glucoseoxidation was mediated by Cu2+/3+ redox couple in similarway of the Ni-electrode.

2.6. Alloy

Mallouk and co-workers investigated the catalytic activ-ity of alloy electrode array containing Pt, Pb, Au, Pd, and Rhby combinatory methods converting anodic current to visiblefluorescence[24]. The alloy electrode with the best composi-tion (i.e., Pt2Pb) catalyzed glucose oxidation near its formalpotential in an enzyme-free and pH-neutral solution. More-over, it is insensitive to interfering agents such as AA, UA,and AP, which are oxidized at slightly more positive poten-tials.

On the other hand, Yeo and Johnson studied on the anodicresponses to glucose at the copper based alloys of Ni, Fe, andMn. Mn5Cu95 alloy out of the alloy electrodes tested showedthe largest enhancement in sensitivity for anodic detection ofglucose in 0.10 M NaOH. It was explained that such largeresponses to glucose at the Mn5Cu95 result from the pre-adsorption of glucose molecules at Mn sites[39].

2

-d stratess tialsb eg sr id.F iala

2

a ro-c ntly,Bp andc nateb rss

3e

3

sen-s ding

Fig. 9. A response curve of a poly(aniline boronic acid) electrode as afunction of time upon addition of 6.8 mM: (a)�-methyl-d-glucoside; (b)d-glucose; and (c) fructose in PBS at pH 7.4 (collected and rearranged fromRef. [40]).

boronic acid derivatives shown inFig. 9(A) [40,41]. Fig. 9(B)illustrates what happens in the presence of organic diols. Thedifference in the electrochemical potential, which is devel-oped across the polymer membrane, is sensitive to the changein the pKa of the conducting polymer as a result of boronicacid-diol complexation. As demonstrated in their reports, thissystem actually works as expected and offered new oppor-tunity of potentiometric glucose sensor without involvingenzyme. Despite its meaning as a new sort of glucose sen-sor, unfortunately, lack in selectivity for glucose prevents thismethod from its practical applications in real samples thatmight contain organic diols other than glucose. This sensorshows larger potential difference for fructose thand-glucoseas displayedFig. 9(C).

3.2. Voltammetric glucose sensor

Choi et al. tried electrochemical determination of�-d(+)-glucose using self-assembled monolayer (SAM) formed onthe gold surface from a solution of thiolated�-cyclodextrin(�-CD) [54]. Ferrocene is captured in the cage of�-CD andproduces amperometric current for its electrochemical oxi-dation. When the electrode covered by ferrocene-sequestered�-CD SAM was dipped in a solution containing glucose,

.7. Pt/WO3

In acidic solution of 0.5 M H2SO4, Pt and WO3 can be coeposited and the composite electrode as made demonteady activity for glucose oxidation at moderate potenelow 0.25 V versus SCE[50]. The major intermediate for thlucose oxidation on Pt/WO3 is glucono-�-lactone, which ieadily hydrolyzed in the bulk solution to form gluconic acurther oxidation of glucono-�-lactone occurs at potentbove 0.2 V versus SCE[23].

.8. Others

Chemically modified electrodes with phthalocyanine[51],nd copper oxide[52] on their surfaces bring about electatalytic oxidation of glucose in basic solutions. Receamba et al.[53] immobilized RuCl2(azpy)2 (azpy = 2-henylazopyridine) as an electron mediator on carbononducted long-term electrolysis of glucose in carbouffer. The �-RuCl2(azpy)2 among the possible isomehowed the best catalytic activity.

. Electrochemical determination of glucose withoutnzyme

.1. Potentiometric glucose sensors

Shoji and Freund reported a non-enzymatic glucoseor based on potentiometry using polymer coatings inclu


�-d(+)-glucose replaced ferrocene in equilibrium and the cur-rent for ferrocene decreased correspondingly. The decreasein current is directly proportional to the amount of glucose.However, the linear dynamic range of quantitative detectionof glucose lies below 0.8 mM, which is only one tenth oftypical physiological concentration in blood serum.

Arimori et al. reported a modular electrochemical sac-charide sensor. They introduced two boronic acid units tocombine selectively with saccharides and linked them with ahexamethylene linker unit that is appropriate for recognizingd-glucose in length. The molecular backbone like this canbe utilized for an electrochemical glucose sensor by attach-ing a ferrocene unit to itself for voltammetric read-out-unit(Fig. 10(B)) [55]. Replacing the ferrocene unit with pyreneas fluorophore (Fig. 10(A)) can lead to an optical sensorwith the same backbone. The interaction between the boronicaid and the neighbouring amine makes the electron densityreduced on the neighboring amine. Binding event of a saccha-ride molecule strengthens the bond between the boronic acidand the amine[56,57]. As a consequence, the ferroceniumion becomes destabilized and the extent of destabilization islarger at higher concentration of the saccharide, resulting inferrocene oxidation at more positive potential as depicted inFig. 10(C). Fig. 10(D) shows that the oxidation potential ofthe ferrocene in differential pulse voltammograms shifts inthe positive direction upon boronic acid binding with glucose.

3

tiono ro-g flatc ) ofg flowi tedP relydF ivitya werera lu-c ithN

nor-m ytice rfacee ubse-q

3ose

w withm nes tiona n att how

Fig. 10. Molecular backbone with two boronic acid units (saccharide selec-tivity) and hexamethylene linker unit (d-glucose selectivity) into which (A)fluorophore and (B) electron mediator were introduced to produce signal.(C) Schematic diagram for the interaction among saccharide, boronic acidand neighboring amine. (D) Differential pulse voltammograms obtained inthe solution of (B) (50�mol in 52.1 wt.% methanol, pH 8.21) in the absenceand presence of glucose (0, 0.111, 0.389, 0. 666, 1.04, 10.3, 102 mM in thearrow direction) (collected and rearranged from Ref.[55]).

poisoning by chloride ion, the glucose determination couldbe carried out at a less positive potential where commoninterfering agents such as AA and AP were not oxidized.Unfortunately the electrocatalytic effect of MWNT wasobserved only in basic condition at pH higher than 9.

3.3.2. AlloyMallouk and co-workers investigated the catalytic activity

of alloys of Pt, Pb, Au, Pd, and Rh. As a result they found the

.3. Amperometric glucose sensor

There are two classifications in amperometric detecf glucose, which are to extract information applying prammed potential pulses or to monitor the current at aonstant potential. Pulsed amperometric detection (PADlucose was developed for liquid chromatography or

njection system[58,59]. Johnson and co-workers reporAD of carbohydrates at Pt electrode in alkaline media raetected by constant potential amperometric method[60,61],or PAD of glucose, Au electrodes provided higher sensitnd lower detection limit rather than Pt electrodes andecommended as working electrodes for PAD[62]. Bindrand Wilson improved the selectivity of PAD method for gose by modifying the surface of Au working electrode wafion and collagen[58].On the other hand, constant potential amperometry is

ally poor in terms of sensitivity. However, some catallectrodes such as nanotube, alloy, or nanoporous intenhance the sensitivity for glucose as described in the suent sections.

.3.1. NanotubeYe et al. reported that electrocatalytic oxidation of gluc

as observed on the glassy carbon electrode modifiedulti-walled carbon nanotube (MWNT–GC) in alkali

olution[63]. Glucose underwent electrochemical oxidat the MWNT–GC electrode at less positive potential tha

he bare glassy carbon. Since the MWNT–GC did not s


composition of the best material, Pt2Pb[24]. The Pt–Pb alloy(Pt2Pb) catalyzed glucose oxidation in pH-neutral solutionsand was insensitive to interfering agents such as AA, UA, andAP whose oxidation occurred at slightly more positive poten-tials. Pt2Pb generated more stable and larger responses thanpure platinum. However, in spite of these valuable advan-tages, surface poisoning by chloride ion remains a seriousproblem. The amperometric signal diminished rapidly in thepresence of 0.01 N NaCl and eventually almost disappeared.

3.3.3. Nanoporous platinumRecently, new approach was conducted for another kind of

non-enzymatic glucose sensors by introducing nanoporousplatinum[12,64]. The key idea behind this is based on thefact that the diameter of the nanopores in this study is evensmaller than the scale of the chronoamperometric diffusionfield. Since the diffusion layers reach several micrometersaway from the electrode surface in milliseconds, reactantsinside the nanopores of 2–50 nm in diameter are depleted veryquickly in diffusion-controlled electrochemical systems[65].As a result, for rapidly oxidizable and/or reducible reactants,the faradaic current should be proportional to the apparentgeometric area of the electrode regardless of the nanoporousroughness[66]. On the other hand, faradaic current associ-ated with kinetic-controlled electrochemical events is sen-sitive to the nanoscopic area of the electrode rather than itsm orousp e thef thisi ipleb andc

to8 P,c lat-i thato rans-f Thed howt orousp

rousp se,A con-ts ereasfl st nos o AAas rouss lyd A andA rgedg andA valuee rents

Fig. 11. Current density vs. time curves showing the responses of (a) H1-ePt (roughness factor, 72) and (b) Pt-s (roughness factor, 2.6) to glucose,AA, and AP at +0.4 V vs. Ag/AgCl in aerated PBS (pH 7.4, 37.2± 0.2◦C).Glucose, AA, and AP were added at the points indicated by arrows to theconcentrations mentioned. Current spikes on addition were due to stirringfor a few seconds (from Ref.[12]).

and the roughness factors, which is established with H1-ePt.This implies that the sensitivity enhancement is not origi-nated merely from increased roughness factor. It is unclearwhat causes the signal enhancement in addition to surfaceroughness. Unlike glucose, nothing but the roughness factorsaffects the responses to AA and AP although their slopes arevery slow. As a glucose sensor, the performance that H1-ePtexhibited is good enough to make further efforts for practi-cal applications. For example, H1-ePt with roughness factorof 72 showed linear responses in the glucose concentrationranges of 0–10 mM and sensitivity of 9.6�A cm−2 mM−1.

The nanoporous surface of H1-ePt offers a number ofattractive features that was not realized previously. First, itshould be noted that just morphological modification pro-vides the platinum electrode with non-enzymatic selectivityto glucose over representative interfering species. AlthoughSun et al.[24] reported that the Pt2Pb alloy electrode wasinsensitive to interfering materials, this was achieved by sim-ply by lowering the potential whereby the interfering materi-

F ont mMA s aftera

acroscopic area (seemingly flat). Therefore, the nanoplatinum electrode should be able to selectively enhanc

aradaic current from a sluggish reaction. Addressingssue, the recent report showed the feasibility of this princy using the nanoporous structure made of pure platinumonfirmed the amperometric detection of glucose[12,64].

The normal physiological level of glucose is from 3mM, which is much higher than those of AA and Aa. 0.1 mM. However, the two interfering species at a pnum electrode generate oxidation currents larger thanf highly concentrated glucose because their electron t

er rates are considerably higher than that of glucose.irect oxidation of glucose is a suitable example that can s

he selective enhancement of faradaic current by nanoplatinum structures.

Fig. 11shows the amperometric responses of a nanopolatinum (H1-ePt) film with roughness factor of 72 to glucoA, and AP in phosphate-buffered saline (PBS) solution

aining 0.15 M NaCl at pH 7.4 and 37.2± 0.2◦C. The H1-ePturface was found to sensitively respond to glucose what Pt (Pt-s) with roughness factor of 2.6 produces almoignal. On the other hand, Pt-s was much more sensitive tnd AP while it gave negligible response to glucose.Fig. 12howed the selective signal amplification by the nanopourfaces. The responses of H1-ePt to glucose are linearependent on the roughness factors whereas those to AP are little affected. Consequently, the specifically enlalucose current leads to improved selectivity over AAP. The response of Pt-s to glucose deviates from thextrapolated from the linear relationship between the cur

ig. 12. Effect of the roughness factors of H1-ePt (solid) and Pt-s (open)he signals for 6 mM glucose (circles), 0.1 mM AA (triangles), and 0.1P (squares). The signals were determined in quiescent solutions 100dding glucose, AA, and AP and stirring (from Ref.[12]).


als were not oxidized. However, selectivity of the nanoporousplatinum is not a function of potential applied but of thedynamics of mass transport near the novel morphology of theelectrode surface. Considering the physiological level of glu-cose (4–7 mM) and that of the interfering agents (typicallynear 0.1 mM), H1-ePt shows sufficient selectivity for clin-ical application without involving enzyme or an additionalouter membrane. Second, the nanoporous surface retains highsensitivity in the presence of chloride ion, even at the PBSlevel (0.15 M). Most of the electrochemical sensors basedon novel metals for non-enzymatic glucose detection almostentirely lose their activities because of poisoning by chlorideion, which is abundant in nature, particularly, in physiolog-ical fluids. The excellent performance of this simple systemencourages us to find new applications for enzyme-free chem-ical sensors. Third, H1-ePt is mechanically and chemicallystable, and its surface can be easily regenerated by electro-chemical cleaning. If the glucose sensor based on H1-ePtis successfully commercialized, we can take many valuableadvantages. Humidity- and temperature-resistant propertieswill prolong the shelf life and allow thermal and chemicalsterilization processes for glucose sensors to be used forimplantable system as well as bioreactors of fermentation andcell culture. In addition this is supposedly favorable for massproduction because quality control of nanoporous platinumelectrodes should be easier than that of enzyme electrodes.

4s

ni-t mer-o theirn tionsN pect,s Thec ork-i Thef ll bee rmin-i tionw leadt thec icali tibleg t bea realt

A

ni-v

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Nanotechnology is certainly providing new opportuies to innovative non-enzymatic glucose sensors. Nuus nanostructured materials keep being reported andovel characteristics suggest new chances and inspiraanoporous platinum is a good example. In this resignificant advances are expected in a few years.ommercialization of non-enzymatic glucose sensor wng in human blood may be one of the key issues.uture research on non-enzymatic glucose sensor wixtended beyond just better disposable strips for dete

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ime.

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This work was supported by the Sungshin Women’s Uersity Research Grant of 2003.

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Electrochemical non-enzymatic glucose sensors