Electrochemical Biosensor PDF

Biosensors & Bioelectronics 16 (2001) 121– 131 www.elsevier.com/locate/bios Technical report Electrochem...

Biosensors & Electrochemical biosensors: recommended classification Daniel R. Thévenot a,*,1, Klara Toth a Centre d’Enseignement et de Recherche Uni6ersité Paris XII-Val b Institute of General and Analytical c Department of Food d Chemistry Abstract Two Divisions of the International Union of I.7 on Biophysical Chemistry formerly Steering on Electroanalytical Chemistry) have prepared electrochemical biosensors; these recommendations ical biosensor is a self-contained integrated analytical information using a biological recognition an electrochemical transduction element. Because should be clearly distinguished from a bioanalytical A device that is both disposable after one measurement, continuously or after rapid and reproducible classified according to the biological specificity-conferring transduction. The biological recognition element with macromolecules that have been isolated, equilibrium is generally reached and there is agent incorporated into the sensor. Biosensors direct monitoring of analyte concentration or monitoring of inhibitor or activator of the biological proliferation of biosensors and their diversity biosensor can only truly be evaluated for a particular performance criteria may be defined in accordance for authors, referees and educators and include detection and quantitative determination limits), reproducibility, stability and lifetime. © 2001 Keywords: Electrochemical biosensor; definition; Abbre6iations: Ab, antibody; Ag, antigen; ENFET, enzyme field-effect transistor; FET, field-effect IMFET, immunological field-effect transistor; time; LOD, limit of detection; LOQ, limit of alcohol); SAM, self assembled monolayer; SPR, Membership of the working party for the Cammann, R.A. Durst, K. Toth and G.S. Wilson * Corresponding author. Tel.: + 33-145-171625; E-mail address: [email protected] (D.R. Thévenot). Chemistry: Physical Chemistry Division, Commission I.7 (Biophysical Chemistry); Analytical Chemistry). Science B.V. All rights reserved. et al. / Biosensors & Bioelectronics 16 (2001) 121–131 While all biosensors are more or less selective (non-spe- cific) for a particular analyte, some are, by design and construction, only class-specific, since they use class enzymes, e.g. phenolic compound biosensors, or whole cells, e.g. used to measure biological oxygen demand. Because in sensing systems present in living organisms/ systems, such as olfaction, and taste, as well as neuro- transmission pathways, the actual recognition is performed by cell receptor, the word receptor or biore- ceptor is also often used for the recognition system of a chemical biosensor. Examples of single and multiple signal transfer are listed in Table 1. These examples are limited to the most common sensor principles, exclud- ing existing laboratory instrumentation systems. The transducer part of the sensor serves to transfer the signal from the output domain of the recognition system, mostly to the electrical domain. Because of the general significance of the word, a transducer provides bi-directional signal transfer (non-electrical to electrical and vice versa); the transducer part of a sensor is also electrochemical measurement techniques, linked to them that recognize specific speciesa. Receptor/Chemical recognition Measurement technique/ Transduction mode system mixed valence metal oxides potentiometric, voltammetric permselective, ion-conductive inorganic crystals trapped mobile synthetic or biological ionophores ion exchange glasses enzyme(s) bilayer lipid or hydrophobic in series with 1. membrane inert metal electrode amperometric enzyme(s) amperometric or potentiometric antibody, receptor amperometric, potentiometric or impedance, piezoelectric, optical enzyme(s) amperometric or potentiometric in series with 1. or 2. or metal or carbon electrode, conductometric, piezoelectric, optical, calorimetric whole cells as above membrane receptors as above plant or animal tissue as above antigen/antibody oligonucleotide amperometric, potentiometric or impedimetric, duplex, aptamer piezoelectric, optical, surface plasmon resonance enzyme labelled in series with 3. chemiluminescent or fluorescent optical labelled specific ligands as 4. protein receptors and channels enzyme labelled fluorescent labelled biosensors, are indicated in bold characters Bergveld and Thévenot, 1993. Besides biosensors are also used for detection and quantification of micro-organisms: receptors are to electrochemical, piezoelectric, optical or calorimetric transducers. et al. / Biosensors & Bioelectronics 16 (2001) 121–131 123 type of measurements, with corresponding analytes to be measured Bergveld and Thévenot, Transducer analyte K+, Cl−, Ca2+, F− H+, Na+... CO2, NH3 redox species O2, sugars, alcohols... sugars, alcohols, phenols, oligonucleotides... metal electrode urea, charged species, oligonucleotides... effect transistor (ISFET), enzyme FET (ENFET) H+, K+... used within biosensors: (a) piezoelectric (shear and surface acoustic wave); (b) calorimetric fibre optic, surface plasmon resonance...) Although biosensors with different transducer types, e.g. electrochemical, optical, piezoelectric or thermal types, show common features, this report is restricted to electrochemical biosensors (indicated in bold characters in Table 1). Optical, mass and thermal sensors will be described in future IUPAC reports. For example opti- cal biosensors will be described by IUPAC commission V.4 in Spectrochemical and other optical procedures for analysis (project number 540 / 19 / 95). being pack- 1.3. Limitations in the use of the term ‘biosensor’ Since a biosensor is a self contained integrated device, we recommend that it should be clearly distin- guished from an analytical system which incorporates additional separation steps such as high performance liquid chromatography (HPLC), or additional hard- ware and/or sample processing such as specific reagent introduction, as flow injection analysis (FIA). Thus, a biosensor should be a reagentless analytical device, although the presence of ambient co-substrates, such as water for hydrolases or oxygen for oxidoreductases, may be sufficient for the analyte determination. On the other hand, it may provide, as part of an integrated system, some separation or amplification steps achieved by inner or outer membranes or reacting layers. In conclusion, an HPLC or FIA system may incorporate a biosensor as a detecting device, and FIA is often conve- nient to evaluate the biosensor analytical performance (see Section 5.) On the contrary, an FIA system con- taining a reagent reservoir, an enzymatic or immuno- logical reactor and, downstream, an electrochemical sensor, is not a biosensor. Because of the importance of their ability to be repeatedly calibrated, we recommend that the term multiple-use biosensor be limited to devices suitable for monitoring both the increase and decrease of the ana- et al. / Biosensors & Bioelectronics 16 (2001) 121–131 viously or have been manufactured. Thus, a continuous consumption of substrate(s) is achieved by the immobi- lized biocatalyst incorporated into the sensor: transient or steady-state responses are monitored by the inte- grated detector. Three types of biocatalyst are com- monly used: 1. Enzyme (mono- or multi-enzyme), the most com- mon and well developed recognition system, 2. Whole cells (micro-organisms, such as bacteria, fungi, eukaryotic cells or yeast) or cell organelles or particles (mitochondria, cell walls), 3. Tissue (plant or animal tissue slice). The biocatalytic-based biosensors are the best known and studied and have been the most frequently applied to biological matrices since the pioneering work of Clark Clark et al., 1962. One or more analytes, usually named substrates S and S%, react in the presence of enzyme(s), whole cells or tissue culture and yield one or several products, P and P%, according to the general reaction scheme: biocatalyst S+ S% P+ P% con- There are four strategies that use adjacent transduc- ers for monitoring the analyte S consumption by this biocatalysed reaction: detection of the co-substrate S’ consumption, e.g., oxygen depleted by oxidase, bacteria or yeast react- ing layers, and the corresponding signal decrease from its initial value; recycling of P, one of the reaction products, e.g., hydrogen peroxide, H+, CO2, NH3, etc. production by oxidoreductase, hydrolase, lyase, etc., and corre- sponding signal increase; detection of the state of the biocatalyst redox active centre, cofactor, prosthetic group evolution in the presence of substrate S, using an immobilized media- tor which reacts sufficiently rapidly with the biocata- lyst and is easily detected by the transducer; various ferrocene derivatives as well as tetrathiafulvalene-te- tracyanoquinodimethane (TTF+ TCNQ − ) organic salt, quinones, quinoid dyes, Ru or Os complexes in a polymer matrix, have been used Bartlett et al., 1991; direct electron transfer between the active site of a redox enzyme and the electrochemical transducer. The third strategy attempts to eliminate sensor re- sponse dependence on the co-substrate, S%, concentra- tion and to decrease the influence of possible interfering species. The first goal is only reached when reaction rates are much higher for immobilized mediator with biocatalyst than those for co-substrate with biocatalyst. An alternative approach to the use of such mediators consists in restricting the analyte (substrate) concentra- tion within the reaction layer through an appropriate outer membrane, whose permeability strongly favours et al. / Biosensors & Bioelectronics 16 (2001) 121–131 125 sensitivity of immuno-sensors, enzyme labels are frequently coupled to Ab or Ag, thus requiring additional chemical synthesis steps. Even in the case of the enzyme-labelled Ab, these biosensors will essentially operate at equilibrium, the enzymatic activity being there only to quantify the amount of complex produced. As the binding or affinity con- stant is usually very large, such systems are either irreversible (single-use biosensors) or placed within an FIA environment where Ab may be regenerated by dissociation of complexes by chaotropic agents, such as glycine-HCl buffer at pH 2.5. 2. Receptor/antagonist/agonist. More recently, at- tempts have been made to use ion channels, mem- brane receptors or binding proteins as molecular recognition systems in conductometric, ISFET or optical sensors Sugawara et al., 1997a. For example, the transport, protein lactose permease (LP), may be incorporated into liposome bilayers thus allowing coupling of sugar proton transport with a stoichio- metric ratio of 1:1, as demonstrated with the fluores- cent pH-probe pyranine entrapped in these liposomes Kiefer et al., 1991. These LP-containing liposomes have been incorporated within planar lipid bilayer coatings of an ISFET gate sensitive to pH. Preliminary results have shown that these modified ISFETs enable rapid and reversible detec- tion of lactose in an FIA system. Protein receptor based biosensors have been recently developed Sug- awara et al., 1997b. The result of the binding of the analyte, here named agonist, to immobilized channel receptor proteins, is monitored by changes in ion fluxes through these channels. For example gluta- mate, as target agonist, may be determined in the presence of various interfering agonists, by detecting Na+ or Ca2 + fluxes, using conductivity or ion selective electrodes. Due to the dependence of ion channel switching on agonist binding, there is usu- ally no need for enzyme labelling of the receptor to achieve the desired sensitivity. A developing field in electrochemical biosensors is the use of chips and electrochemical methods to detect binding of oligonucleotides (gene probes) (Table 1). There are two approaches currently developed. The fist one intercalates into the oligonucleotide duplex, during the formation of a double stranded DNA on the probe surface, a molecule that is electroactive. The second approach directly detects guanine that is electroactive. In conclusion, biocomplex-based biosensors although showing promising behaviour, have not yet reached the advanced development stage of the biocatalyst-based systems. Being based on equilibrium reactions, they generally present a very narrow linear operating range of concentration and are often unable to monitor con- tinuously the analyte concentration. Furthermore, some of these biosensors may be difficult to operate in a et al. / Biosensors & Bioelectronics 16 (2001) 121–131 steady-state or transient, but it is never an equilibrium response. The situation is more complex for enzyme-la- belled immuno-sensors: although the Ab-Ag complex is expected to reach an equilibrium and reactions to be either reversible or irreversible, the labelled enzyme activity is measured under steady-state analyte con- sumption conditions. Another important feature of the ISE based biosen- sors, such as pH electrodes, is the large dependence of their response on the buffer capacity of the sample (see Section 4.2) and on its ionic strength. usually per- 2.2.3. Surface charge using field-effect transistors (FETs) An important variation of the systems used to deter- mine ion concentrations are the ion-sensitive field-effect transistors (ISFETs). An ISFET is composed of an ion-selective membrane applied directly to the insulated gate of the FET Covington, 1994. When such ISFETs are coupled with a biocatalytic or biocomplexing layer, they become biosensors, and are usually called either enzyme (ENFETs) or immunological (IMFETs) field- effect transistors. Operating properties of ENFET and IMFET-based devices are strongly related to those of the ISE based biosensors. 2.2.4. Conductometry indicator Many enzyme reactions, such as that of urease, and many biological membrane receptors may be monitored by ion conductometric or impedimetric devices, using The trans- interdigitated microelectrodes Cullen et al., 1990. Be- cause the sensitivity of the measurement is hindered by or selec- the parallel conductance of the sample solution, usually a differential measurement is performed between a sen- sor with enzyme and an identical one without enzyme. (F−, I−, (CO2, NH3) differ- 3. Analytes or Reactions monitored activity or Biosensors may be further classified according to the analytes or reactions that they monitor. One should clearly differentiate between the direct monitoring of analytes, or of biological activity, and the indirect monitoring of inhibitors. except at 3.1. Direct monitoring of analyte, or, alternati6ely, of biological acti6ity producing or consuming analytes Direct monitoring of analytes has clearly been the major application of biosensors. Nevertheless, one should be aware that the same biosensor can be a useful tool also for the direct monitoring of enzyme or living cell activities, by measuring, continuously or sequen- tially, the production or consumption of a given compound. et al. / Biosensors & Bioelectronics 16 (2001) 121–131 127 SAMs or multilayers, avidin-biotin silanization, some of such activated membranes being commer- cially available; 5. Bulk modification of entire electrode material, e.g. enzyme modified carbon paste or graphite epoxy resin Gorton, 1995. Receptors are immobilized either alone or they are mixed with other proteins, such as bovine serum albu- min (BSA), either directly on the transducer surface, or on a polymer membrane covering it. In the latter case, preactivated membranes can be used directly for the enzyme or antibody immobilization without further chemical modification of the membrane or macromolecule. Apart from the last example, reticulation and cova- lent attachment procedures are more complicated than entrapment ones, but are especially useful in cases where the sensor is so small that the appropriate mem- brane must be fabricated directly on the transducer. Under such conditions more stable and reproducible activities can be obtained with covalent attachment. 4.2. Inner and outer membranes Besides the reacting layer or membrane, many biosensors, especially those designed for biological or clinical applications, incorporate one or several inner or outer layers. These membranes serve three important functions: 1. Protecti6e barrier. The outer membrane prevents large molecules, such as proteins or cells of biologi- cal samples, from entering and interfering with the reaction layer. It also reduces leakage of the reacting layer components into the sample solution. This function of the outer membrane is important, for example, for implanted glucose sensors, since its glucose oxidase is of non-human origin and may cause immunological reactions. Furthermore, a properly chosen membrane exhibits permselective properties, which may be additionally beneficial to the biosensor function. It may decrease the influence of possible interfering species detected by the trans- ducer. For example, most in vivo or ex vivo glucose biosensors present a negatively charged inner cellu- lose acetate membrane in order to decrease the interfering effect of ascorbate or urate, electrochem- ically detected together with enzymatically gener- ated hydrogen peroxide. 2. Diffusional outer barrier for the substrate. As most enzymes follow some form of Michaelis-Menten kinetics, enzymatic reaction rates are largely non- linear with concentration. Nevertheless, linear dy- namic ranges may be large if the sensor response is controlled by the substrate diffusion through the membrane and not by the enzyme kinetics. This control is achieved by placing a thin outer mem- et al. / Biosensors & Bioelectronics 16 (2001) 121–131 methods, e.g. precision, accuracy, interlaboratory and interpersonal reproducibility, it is recommended that standard IUPAC definitions be followed Inczedy et al., 1998; Buck and Lindner, 1994. Most of the discussion below relates to enzyme-based biosensors. In the case of immunosensors, a key issue is the capture capacity of the surface, i.e. the number of molecules on the surface which are actually biologically active. One of the methods for assessing this parameter consists in measuring the specific activity, i.e. the ratio of the number of active molecules/the total number of immobilized molecules. This figure is very dependent on the mode of immobilization (molecular orientation, number of points of attachment) and can range from about 0.15 to 0.3, rarely reaching 1. This capture capacity becomes especially important when the surface is decreased, as in microfluidic applications. Another important issue for immunosensors is the question of whether the surface can be regenerated without signifi- cant loss of activity (see Section 2.1.2). The rapid proliferation of biosensors and their diver- sity has led to a lack of rigour in defining performance criteria. Although each sensor can only truly be evalu- ated for a particular application, it is still useful to establish standard protocols for evaluation of perfor- mance criteria, in accordance with standard IUPAC protocols or definitions Inczedy et al., 1998. These protocols are recommended for general use and include four sets of parameters, described below. 5.1. Calibration characteristics: sensiti6ity, working and linear concentration range, detection and quantitati6e determination limits Sensor calibration is performed, in general, by adding standard solutions of the analyte and by plotting steady-state responses Rss, possibly corrected for a blank (often called background) signal Rbl, versus the analyte concentration, c, or its logarithm, log c/c°, where c° refers to a reference concentration, usually 1 mol l − 1, although such high concentration value is never used, the highest values reaching usually 1–10 mmol l − 1. Transient responses are important for se- quential samples but are less significant for continuous monitoring: within several possibilities, they are gener- ally defined as the maximum rates of variation of the sensor response (dR/dt) max, after addition of analyte into the measurement cell. A convenient way to per- form such calibrations, under well-defined hydrody- namic conditions, is to place the biosensor in a FIA system for sequential sample analysis. The sensitivity and linear concentration range of steady-state calibration curves are determined by plot- ting the ratio (Rss − Rbl)/c or (Rss − Rbl)/log c/c° versus log c/c°. This method is much more concise than plotting the usual calibration curves (Rss − Rbl) versus c et al. / Biosensors & Bioelectronics 16 (2001) 121–131 129 Naught and Wilkinson, 1997; Umezawa et al., 1995. It depends both upon the choice of biological receptor and transducer. Many enzymes are specific. Neverthe- less, class (non-selective) enzymes, such as alcohol, group sugar or amino-acid oxidases, peroxidases, lac- case, tyrosinase, ceruloplasmin, alcohol or glucose NAD-dehydrogenase, etc, have been used for the devel- opment of class biosensors, such as those for determi- nation of phenols, used in environmental monitoring or food analysis. Bacteria, yeast or tissue cultures are naturally non-specific. Whereas oxygen electrodes, pH electrodes and ISFETs show appropriate selectivity, metal electrodes are often sensitive to numerous inter- fering substances. This direct selectivity can be modified when these transducers are associated with receptors. For example, when pH-sensitive ENFETs are used as transducers, their responses are influenced by the buffer capacity of the sample, since part of the released pro- tons react with the buffer components and only the remainder is sensed by the transducer. In this case, it is, in fact, the sensitivity of the biosensor, which is modified, and not its selectivity. When transducer interfering substances are well iden- tified, such as ascorbate or urate in glucose sensors based on hydrogen peroxide detection, their influence may be restricted by the application of appropriate inner or outer membranes (see Section 4.2.). Alterna- tively, a compensating sensor may be introduced in the set-up, without biological receptor on its surface Thév- enot et al., 1979. Such a differential design is frequently used for ISFET- or ENFET-based sensors. Within various methods for biosensor selectivity determination, two are recommended depending upon the aim of its measurement. The first one consists in measuring the biosensor response to interfering substance addition: a calibration curve for each interfering substance is plot- ted and compared to the analyte calibration curve, under identical operating conditions. Selectivity is ex- pressed as the ratio of the signal output with the analyte alone and with the interfering substance alone, at the same concentration as that of the analyte. In the second procedure interfering substances are added, at their expected concentration, into the measuring cell, already containing usual analyte concentration, at the mid-range of its expected value. Selectivity is then expressed as the percentage of variation of the biosen- sor response: although more easily quantified than the calibration curve comparison performed in the first procedure, the second method is characteristic of each application and presents a more restricted significance. Such selectivity may depend on the analyte concentra- tion range that is determined. The reliability of biosensors for given samples de- pends both on their selectivity and their reproducibility. It has to be determined under actual operating condi- tions, i.e. in the presence of possible interfering sub- et al. / Biosensors & Bioelectronics 16 (2001) 121–131 factors mentioned above on response time Eddowes, 1990. Modeling is somewhat limited by the necessary knowledge of a large number of sensor parameters (thickness, partition and diffusion coefficients of each membrane or layer for each species, distribution of biocatalytic or biocomplexing activity within the sensor layers, transducer operating properties, etc.). Often, such modelling is restricted to steady-state operation and is not sufficiently advanced for the evaluation of transient responses and response in general Albery et al., 1987. 5.4. Reproducibility, stability and lifetime Definition of reproducibility is the same for electro- chemical biosensors as for any other analytical device: reproducibility is a measure of the scatter or the drift in a series of observations or results performed over a period of time. It is generally determined for the ana- lyte concentrations within the usable range. The operational stability of a biosensor response may vary considerably depending on the sensor geometry, method of preparation, as well as on the applied recep- tor and transducer. Furthermore it is strongly depen- dent upon the response rate limiting factor, i.e. a substrate external or inner diffusion or biological recog- nition reaction. Finally, it may vary considerably de- the shorter pending on the operational conditions. For operational stability determination, we recommend consideration of the analyte concentration, the continuous or sequential contact of the biosensor with the analyte solution, temperature, pH, buffer composition, presence of or- ganic solvents, and sample matrix composition. Al- though some biosensors have been reported usable under laboratory conditions for more than one year, their practical lifetime is either unknown or limited to days or weeks when they are incorporated into indus- trial processes or to biological tissue, such as glucose biosensors implanted in vivo Pickup and Thévenot, 1993. For storage stability assessment, significant parameters are the state of storage, i.e. dry or wet, the atmosphere composition, i.e. air or nitrogen, pH, buffer composition and presence of additives. While it is relatively easy to determine the laboratory bench stability of biosensors, both during storage and operation in the presence of analyte, procedures for assessing their behaviour during several days of intro- duction into industrial reactors is much more complex and difficult to handle. 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