interference elimination of an amperometric glucose biosensor using poly(hydroxyethyl methacrylate)...

Research Article

Interference elimination of an amperometricglucose biosensor using poly(hydroxyethylmethacrylate) membrane

A permselective membrane fabricated from photo-cross-linked poly(hydroxyethylmethacrylate) (pHEMA) was studied as a potential selective membrane that caneliminate electrochemical interferences commonly faced by a hydrogen peroxide-based biosensor. The quantitative selection of the permselective membrane wasbased on the permeabilities of hydrogen peroxide and acetaminophen (AC). ACwas used as a model of the interfering substance due to its neutral nature. pHEMAmembrane with the cross-linking ratio of 0.043 was found to achieve a selectivityof hydrogen peroxide over AC of 10, while maintaining an acceptable degree ofhydrogen peroxide response. A two-layer glucose biosensor model consisting ofglucose oxidase entrapped within a freeze-thawed poly(vinyl alcohol) matrix andthe cross-linked pHEMA membrane was challenged with AC, ascorbic acid anduric acid. 0.2 mM AC and 0.2 mM ascorbic acid were completely eliminated.However, 0.2 mM uric acid could not be completely eliminated and still gave abias of approximately 6.6% relative to 5 mM glucose. The results showed thatcross-linked pHEMA was quite promising as an interference eliminating innermembrane.

Keywords: Electrochemical interference / Hydrogen peroxide-based biosensor /Poly(hydroxyethyl methacrylate)

Received: March 10, 2010; revised: August 13, 2010; accepted: August 25, 2010

DOI: 10.1002/elsc.201000039

1 Introduction

A common approach in minimizing the interference signal in aperoxide-based electrochemical biosensor is by placing apermselective layer between the sensing layer and the electrodesurface [1–3]. The interference molecules are prevented fromreaching the electrode surface based on size and/or chargeeffects while allowing diffusion of the desired substances [2].Different kinds of materials have been used for this purpose.Nafion, an anionic membrane, has been widely used to mini-mize the interfering effect of negatively charged interferencespecies such as ascorbic acid (AA) and uric acid (UA) [4, 5].Other examples are cellulose acetate [6, 7] and silane film [8].

Composite membrane of cellulose acetate and nafion has alsobeen used to eliminate acetaminophen (AC) [1]. Electro-polymerized membranes have attracted the attention of manyresearchers due to its permselective property and controlleddeposition even on complex electrode shapes [2, 3, 8–13].Adsorption of anionic and cationic polyelectrolyte films onelectrodes has also been investigated [14, 15].

Photopolymerized poly (2-hydroxyethyl methacrylate)(pHEMA) has unique properties such as small pore size andlow swelling ratio [16]. Its good biocompatibility and hydro-philicity have also contributed to its wide application in thebiomedical field especially for drug delivery systems, contactlenses and biosensors [17]. The attractive property of pHEMAis that the hardness and porosity of the ensuing photo-polymerized membranes can be modified by varying theamount of water and cross-linking agent during the hydrogelpreparation. Detailed studies of these effects on the porosity ofpHEMA have been performed by different researchers [18, 19].

Azila Abdul-Aziz

Fui-Ling Wong�

Department of Bioprocess

Engineering, Universiti

Teknologi Malaysia, Skudai,

Johor, Malaysia

Abbreviations: AA, ascorbic acid; AC, acetaminophen; CR, cross-

linking ratio; EGDMA, ethylene glycol dimethacrylate; GOD, glucose

oxidase; LSV, linear sweep voltammetryD; pHEMA, poly(hydroxyethyl

methacrylate); PVA, poly(vinyl alcohol); RDE, rotating disk electrode;

UA, uric acid; WE, working electrode

�Current address: Fui-Ling Wong, Inno Biologics Sdn. Bhd, Lot 1,

Persiaran Negeri BBN, Putra Nilai, 71800 Nilai, Negeri Sembilan,

Malaysia

Correspondence: Dr. Azila Abdul-Aziz ([email protected]), Department

of Bioprocess Engineering, Universiti Teknologi Malaysia, 81300

Skudai, Johor, Malaysia

& 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim http://www.els-journal.com

20 Eng. Life Sci. 2011, 11, No. 1, 20–25

Many authors have demonstrated that by increasing thecross-linking agent when preparing cross-linked pHEMA, themesh size of the matrix can be reduced [18–20]. pHEMA atdifferent cross-linking ratios (CR) had been systematicallyinvestigated by Kermis et al. [20] as the outer membrane of anoptical glucose affinity sensor. They found that pHEMAmembrane hindered the diffusion of creatinine.

The objective of this work was to design a peroxide-basedglucose biosensor containing a permselective inner layer thatwould be able to eliminate electrochemical interferences basedon size exclusion. An effective permselective inner layerrequires a membrane with an appropriate permeability. Themembrane must be able to exclude the larger solutes, whilemaintaining adequate diffusion of the desired molecules. Inthis work, pHEMA was studied as a potential permselectivemembrane for a peroxide-based glucose biosensor as theporosity of the membrane can be modified through cross-linking and Kermis et al. [20] have shown that cross-linkedpHEMA can hinder the diffusion of creatinine, a substancethat is of comparable size to AC. AC was selected as therepresentative interfering substance because it was a neutralmolecule and it can cause a large bias to an amperometricglucose biosensor response [1].

2 Materials and methods

2.1 Materials

Glucose oxidase (GOD) (EC 1.1.3.4, type X-S, 190 000 units/gsolid), poly(vinyl alcohol) (PVA) with an average molecularweight of 70 000 – 100 000, D-(1)-glucose and UA 991% wereobtained from Sigma (Singapore). 2-Hydroxyethyl methacry-late (HEMA) 991%, 98% ethylene glycol dimethacrylate(EGDMA) solution, 99% 2,2-dimethoxy-2-phenylacetophe-none (DMPP) and AC 98% were purchased from Aldrich(Singapore). All chemicals were used as received.

2.2 Apparatus

Electrochemical measurements were carried out using aconventional rotating disk electrode system (RDE) (Autolab30, Methrohm, The Netherlands). The setup consisted of anAg/AgCl reference electrode and a platinum sheet counterelectrode. Gold and platinum disk electrodes with a surfacearea of 0.0707 cm2 were employed as the working electrode(WE) for permeability tests and two-layer biosensor evalua-tion, respectively. A spin coater (G-3P-8, Specialty CoatingSystems, IN, USA) was used for the membrane casting.

2.3 Casting of pHEMA membrane

HEMA monomer with 70 vol% water was mixed withEGDMA at different CRs. The photoinitiator, 2,2-dimethoxy-2-phenylacetophenone, was added to the mixture to achieve afinal concentration of 1.6 wt% [21]. An aliquot of the mixturewas transferred onto a clean glass slide or directly onto the

electrode surface and spin coated at 150 rpm for 1 min. Then,the disc was placed under a UV light and irradiated for 5 minunder continuous purging with nitrogen gas. The pHEMAlayer was then soaked in 0.1 M PBS pH 6.7 for 48 h to hydratethe layer.

2.4 Determination of water content

After the membrane was peeled off from the glass slides, theweight of the swollen membrane (Ww) was recorded untilequilibrium hydration was achieved. Subsequently, themembrane was left to dry at approximately 551C in the oven.The weight of the dehydrated membrane (Wd) was recordeduntil a constant weight was obtained. The water content, H,was determined according to

Hð%Þ ¼ ðWw �WdÞ=Ww � 100 ð1aÞ

2.5 Membrane thickness measurement

The thicknesses of the membranes were measured using adigimatic micrometer (Mitutoyo, Japan), based on analogousmembranes prepared on glass slides by an identical procedure.

2.6 Permeability analysis

Determination of permeability was performed using an RDEsystem and employing linear sweep voltammetry (LSV). ThepHEMA-covered WE was immersed into 10 mL of 0.1 mMphosphate buffer pH 6.7. At a scan rate of 1 mV/s and rotationspeeds from 100 to 400 rpm, voltammograms of the back-ground current were recorded by scanning from 200 to1150 mV (versus Ag/AgCl). After background recording,10 mM nitrogen-saturated AC stock solution was added to thebuffer solution to achieve a final concentration of 0.5 mM. LSVwas performed from 0.2 to 0.9 V (versus Ag/AgCl) for AC.Hydrogen peroxide experiments were performed using thesame procedures. LSV was performed from 0.2 to 1.15 V(versus Ag/AgCl) for hydrogen peroxide.

2.7 Two-layer evaluation

The glucose-sensing layer was prepared based on the freeze-thaw method using 10% PVA [22]. A mixture of PVA andGOD was pipetted onto glass slides and maintained at �201Cfor 6 h to induce crystallization. Following the freezing process,it was allowed to thaw at 251C for 6 h. The freezing andthawing cycles, n, were repeated five times. The membraneswere then immersed in the phosphate buffer at 41C.

pHEMA membrane with the CR of 0.043 was directlyattached onto the WE surface. Then, the sensing layer wasplaced on top of the pHEMA membrane and secured tightlywith gauze and rubber ring. The WE with two layers ofmembranes was immersed into 15 mL of 0.1 M phosphate

Eng. Life Sci. 2011, 11, No. 1, 20–25 pHEMA for glucose biosensor interference elimination 21


buffer pH 6.7 and rotated at 100 rpm. Following the stabili-zation of the background current at 1700 mV, 100 mM glucosesolution was added into the cell, giving a final glucoseconcentration of 5 mM. After the current response had reacheda plateau, AC, AA and UAacid solutions were injectedsuccessively. The final concentration of each substance was0.2 mM.

3 Results and discussion

3.1 Characterization of PHEMA membrane

Photopolymerized pHEMA membranes were prepared fromHEMA monomer containing 30 vol% of water at differentCRs. The pHEMA membranes obtained were very hard andtransparent. When immersed in buffer for a period of time,these membranes absorbed water and swelled to become softand rubbery. The higher the CR, the longer the time requiredto swell the membrane. The thickness of the swollenmembranes ranged from 150 to 230 mm.

As the water content of a membrane reveals the cross-linking density as well as the mesh size of the membrane, watercontents of the pHEMA membranes were measured. Figure 1shows the relationship of membrane water content with its CR.As predicted, equilibrium water content of the membranesdecreased as CR increased. This indicates that tighter mesh anddenser networks were obtained with higher amount of cross-linker. Increasing CR from 0.015 to 0.043 decreased watercontent by 23%. Further increase in CR from 0.043 to 0.060only decreased the water content by 8%. This indicated thatafter CR of 0.043, further cross-linking would not have asignificant effect on the mesh size.

3.2 Permselectivity analysis

An RDE system was used to measure the effective diffusioncoefficient of the electro-active species of interest. Thismethod has been widely used to measure diffusion coefficientsof electro-active compounds through a membrane

[23–26](http://eprints.utm.my/9648/). The permeability ofeach species could be calculated based on the followingequation [24, 27]:

1=ilim ¼ dm=nFAaDmCb1ð1=0:62nFACbD2=3dl n�1=6Þð1=o1=2Þ

ð1bÞ

where a is the partition coefficient, i the current, n the numberof electrons involved in the electrode reaction, F the Faradayconstant, A the electrode surface area, u the viscosity of bulksolution, o the rotating rate of RDE, Ddl the diffusion coeffi-cient of the electro-active species in bulk fluid, Dm the diffu-sion coefficient of the electro-active species in the membrane,dm the membrane thickness and Cb the concentration in bulksolution.

In this work, phosphate buffer pH 6.7 with the kinematicviscosity, n, of 9� 10�3 cm2 s�1 was used [28]. The number ofelectrons involved in the electrode reaction, n, was taken as 2 [29,30] and 2.1 [31] for hydrogen peroxide and AC, respectively.

For transport analysis purposes, a gold WE was used. Thiswas because slow electron transfer that resulted in a non-negligible intercept of the Koutecky–Levich plot (1/ilim versus1/o1/2) had been observed for the oxidation of AC on bareplatinum electrode [25]. Non-negligible intercept willcomplicate the calculation of the permeabilities of the electro-active species.

Figure 2(A) shows a typical Koutecky–Levich plot for theoxidation of hydrogen peroxide and AC on a bare gold elec-trode. The diffusion coefficients of hydrogen peroxide and ACin buffer were calculated from the slope of their respectiveKoutecky–Levich plots to be 1.14� 10�5 and 0.68� 10�5

cm2/s, respectively. These values are in agreement with thatobtained by Abdul-Aziz [25].

Using the same method, the Koutecky–Levich plots for theoxidation of hydrogen peroxide and AC on pHEMA-goldelectrode were constructed as shown in Fig. 2(B). Thepermeability (aDm) of each diffusing species through pHEMAwas then calculated from the intercept of the Koutecky–Levichplot.

The relationship of the permeability of AC and hydrogenperoxide with the degree of cross-linking is shown in Fig. 3.Similar to the trend of the water content, increase in CRresulted in the decrease in the AC permeability. Increasing theCR from 0.015 to 0.043 resulted in the decrease in the ACpermeability of approximately 58%. Further increase in CRfrom 0.043 to 0.060 decreased the AC permeability by 44%.

Although the objective of decreasing mesh size was toobstruct interfering molecules, however it was also importantto maintain the permeability of hydrogen peroxide. As shownin Fig. 3, an almost linear trend was obtained. Increasing theCR from 0.015 to 0.043 resulted in the decrease in thehydrogen peroxide permeability of approximately 31%.Further increase in CR from 0.043 to 0.060 decreased thehydrogen peroxide permeability by 33%.

To achieve the objective of rejecting AC while allowing thepassage of hydrogen peroxide, selection of an optimum CR wasbased on the permselectivity of hydrogen peroxide over AC.The selectivity of the membrane was expressed as the ratio ofhydrogen peroxide permeability to AC permeability (Eq. 1c).

Figure 1. The relationship between membrane water content (H)with CR.

22 A. Abdul-Aziz and F.-L.Wong Eng. Life Sci. 2011, 11, No. 1, 20–25


s ¼ aperoxideDperoxide=aacetaminophenDacetaminophen ð1cÞ

Figure 4 shows the relationship between selectivity and CR. Byincreasing the CR from 0.015 to 0.043, the selectivity was

almost doubled. Further increment of cross-linker concentra-tion resulted in only a slight improvement in selectivity. Figure4 suggested that cross-linking the membrane with a CR of0.043 was sufficient to obtain the optimum permselectivitywithout compromising excessively on the permeability ofhydrogen peroxide.

3.3 Performance of a two-layer biosensor

The performance of a freeze-thawed PVA-GOD enzymaticlayer combined with a pHEMA membrane with the CR of0.043 was studied. The sensitivity of the glucose biosensor was2.55 nA/mM mm2 and the Kapp

m was 3.31 mM. The linearequation for the sensor (r2 5 0.999) is shown in Fig. 5.

The current responses of the two-layer membrane to 5 mMglucose, 0.2 mM of AC (MW 151.17), AA (MW 176.13) andUA (168.11) were measured. Sample current responses withoutand with inner membrane are shown in Fig. 6.

The cross-linked pHEMA membrane effectively eliminatedthe interfering effects of AC and AA. However, UA was notcompletely blocked. An interfering current of approximately6.670.8% relative to glucose response was recorded. This falsesignal might be attributed to the interaction between thepHEMA network and that particular interference molecule.Ratner and Miller [32] studied the transport of urea and otherbiologically interesting solutes such as glucose, sodium chlo-ride and glycine through pHEMA at various cross-linkingdensities. They observed high permeability of urea acrosspHEMA relative to the other solutes and had attributed it tothe strong interaction between the polymer and urea and thatthe transport occurred through water regions little affected bythe surrounding polymer matrix. They, however, did notstudied the transport of UA through cross-linked pHEMA,although they suggested that it would be interesting to see ifthe same affinity could be demonstrated. Newer works showedbetter permeability of UA through pHEMA and HEMA-poly(tetramethylene glycol) block co-polymer compared topoly(ether-urethane) and other co-polymers [33] and throughPP-g-(HEMA) membrane compared to polypropylene [34]

Figure 2. Typical Koutecky–Levich plots of AC and hydrogenperoxide oxidations on (A) a bare electrode surface (B) pHEMA-goldelectrode with CR of 0.043. –~– Hydrogen Peroxide –&– AC.

Figure 3. The relationship of permeability with CR. –~– Hydro-gen Peroxide –&– AC.

Figure 4. The relationship of pHEMA membrane selectivity (s)with its CR.



suggesting that pHEMA might also have similar affinity to UAas urea.

This work showed that cross-linked pHEMA was quitepromising as an interference eliminating inner membrane. Itsanti-interfering property was comparable to other innermembranes described earlier [1–15]. In addition, since theporosity of pHEMA can be controlled by simple cross-linking,systematic quantitative permselectivity analysis of the anti-

interfering property of the membrane using the RDE systemcan be performed. This can pave the way for the systematicdesign of an effective glucose biosensor.

4 Concluding remarks

In this work, the focus was on the restriction of the passageof interfering substances through an amperometric peroxide-based glucose biosensor. The permselectivity of pHEMAmembrane cross-linked using EGDMA was evaluated. Thepermeabilities of AC and hydrogen peroxide weredetermined using an RDE system. Permeabilities of bothAC and hydrogen peroxide decreased with the increasein the CR of the pHEMA membranes. The optimum CRwas 0.043, where the selectivity of peroxide over AC was10. An overall evaluation of a freeze-thawed PVA-GODmembrane (sensing layer) combined with the selected pHEMAmembrane (inner layer) was performed. 0.2 mM AC and0.2 mM AA were completely blocked out by the membranes,while 0.2 mM UA showed an error of 6.670.8% relative to5 mM glucose.

This work was supported financially by the Intensification ofResearch in Priority Areas (IRPA) grant, project no: 03-02-06-0092 EA001 awarded by the government of Malaysia.

The authors have declared no conflict of interest.

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