Electroanalysis and Biosensors Joseph Wang Deparfment of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003 This review covers the development of biosensing devices and electroanalytical procedures for use in the clinical arena. These fields have experienced an impressive growth in view of changes in medical practice, particularly pressures to implement point-ofcare (near patient) testing and reduce clinical costs. Basic and applied research on new sensing concepts, recognition processes, or molecular phenomena, coupled with numerous technological innovations, have opened the door to a wider clinical use of electrochemical and nonelectrochemical sensing devices. This review includes enzyme electrodes and immunoelectrodes,optical and mass sensors, ion-selective electrodes, modfied electrodes and microelectrodes, and controlled-potentialvoltammetric and stripping techniques. It is not a comprehensive coverage of these topics, but rather highlights the most important advances relevant to clinical analysis. The general activity in these fields has been documented in recent fundamental reviews in this journal (PI, P2). Several useful books on these topics have appeared during this review period, including Tran Minh’s book on biosensors (P3), Tumer’s volume on in vivo monitoring (P4), a contribution from Cordoba on flow-throughsensors (Pa, ACS volumes on biosensor polymers (P6),materials for molecular recognition (P7),and biomembrane electrochemistry (PS),and books on analytical electrochemistry (P9,P10). Review articles are cited in the appropriate sections below. ENZYME AND AFFINITY=BASEDELECTRODES
Enzyme electrodes, based on coupling the high specificity of biocatalytic reactions with electrochemical (amperometric or potentiometric) transduction of the recognition event, have continued to receive considerable attention. Research in past years has focused on improved devices for metabolites such as glucose, lactate, cholesterol, creatinine or amino acids, novel electron-transfer relays, new coatings and other strategies for minimizing electroactive interferences, new needle electrodes for in vivo monitoring, microfabrication of disposable electrodes and miniaturized devices, and new methods for enzyme immobilization or stabilization. Relevant reviews covered the immobilization of enzymes in electropolymerizedfilms (P11), the mass production of amperometric electrodes (PI,?), bioprobes for in vivo monitoring (P13), and noninvasive electrodes for in and ex vivo analyses
(Pl4). The great practical importance of glucose electrodes has generated an enormous number of publications, the flow of which shows no sign of diminishing. Two new commercial devices for self-monitoringof blood glucose, based on disposable (single-use) enzyme electrodes, were introduced by Miles and Boehringer Mannheim. Another commercial probe, from AVL Inc., integrates continuous subcutaneous glucose monitoring with feedbackcontrolled insulin delivery. Ciba Coming expanded the menu of its whole-blood analyzer to include glucose and lactate biosensors. A range of in vivo glucose electrodes have been explored in response to the need for continuous monitoring of glucose. Heller’s group (P15) developed a flexible subcutaneously implanted device which allows one-point in vivo calibration. Harrison and co-workers (PI@ described the performance of a subcutane-
ously implanted needle-type sensor based on a trilayer membrane configuration. Zhang and Wilson (PI7) investigated the oxygen effect on implantable glucose electrodes. Other useful glucose sensors for in vivo use in diabetic patients were developed in the United Kingdom (PIS), United States (P19, P20), and Japan (P.1). Enzyme ultramicroelectrodes for in vivo measurements of brain glucose were described by Lowry and O’Neill (P22). Continuous monitoring of glucose, based on coupling microdialysis with an enzyme electrode detector, was reported by Moscone and Mascini (P23). The establishment of electrical communication between the redox center of glucose oxidase and the electrode transducer has continued to receive considerable attention. Research at the molecular level has led to important advances in this direction. Wilner et al. (P24) reported on electron-transfer communication with an electrode coated with a glucose oxidase network on a self-assembledmonolayer of functionalizedthiols. Oyama’s group (P25) described a novel enzyme-exchangeable glucose electrode employing thermoshrinking redox gel. Three-dimensional osmium-based redox hydrogels, connecting (wiring) the redox center of glucose oxidase and the electrode, offered selective glucose detection in the presence of interfering species (P26). Eremenko’s group (P27)reported on monomolecular films of ferrocenecarboxylicacid and their reaction with glucose oxidase. Kaku et al. (P28) employed polyquinones as efficient electrontransfer relays in glucose biosensing. Turner and co-workers (P29)described the use of polymeric ferrocenes as mediators for glucose sensing, while Kulys et al. (P30)reported on the low potential detection of glucose at a Meldola Blue-containing carbon paste enzyme electrode. A dual-mediator strategy was described by Amine et al. (P31).Metalized carbon biosurfaces represent a new strategy for lowering the operating potential and minimizing contributions from oxidizable constituents. In particular, ruthenium- (P32)and rhodium- (P33, P34)based surfaces preferentially catalyze the oxidation of the enzymatically liberated peroxide species and offer remarkable selectivity (without a discriminative membrane). Palladiumcontaining carbon inks were used for screen printing of highly sensitive glucose strips (P35).Enzyme microelectrode array strips, prepared by combination of thickfilm, laser micromachining, and metal-deposition technologies, were described by Wang and Chen (P3@. A micromachined biosensor flow cell for glucose was designed by Karube’s group (P37). Electropolymerization represents a controllable approach for entrapping glucose oxidase (and other enzymes) onto electrode transducers, while imparting a high degree of selectivity. Christie et al. (P38)described the attractive permselective properties of oxidized polypyrrole layer. Similarly, Palmisano et al. (P39) reported on an interference-free glucose biosensor based on overoxidized polypyrrole !ilms. Yon-hin and Lowe (P40)evaluated enzyme films based on functionalized pyrrole-modified glucose oxidase. Highly stable glucose sensors based on electrodeposited poly(Smethy1thiophene) were described by Genies and Marcheseillo (P41).Electropolymerized poly(pheny1enediamine) was used for localizing glucose oxidase on nanoscopic electrodes of 35 nm thickness (P42). Dramatic improvements in the selectivity of Analytical Chernistty, Vo/. 67,No. 12, June 15, 1995
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glucose probes were achieved by coupling the size-exclusion sieving of poly(pheny1enediamine) with the hydrophobicity of lipid coatings (P43). Composite layers of Nafion and cellulose acetate were used for eliminating the acetaminophen interference in implantable glucose devices (P44). Microporous gas-permeable membrane barriers displayed excellent selectivity over ionic constituents (P45). The strong demand for. clinical lactate measurements has prompted significant activity toward the development of sensors for decentralized lactate monitoring. Shimojo et al. (P46) described a single-use mediated amperometric strip for determining lactate in whole blood. Kyrolainen et al. (P47) developed an online biosensor system for monitoring blood lactate during open heart surgery. Miniaturized sensors based on lactate oxidase were developed for in vivo lactate monitoring (P48, P49). Catheterbased portable devices for continuous measurements of lactate in blood were also described (P50, P51). Improved membrane technology facilitated the application of lactate probes in undiluted media (P52). Lactate dehydrogenase-based sensors were also examined (P53, P54) but require further investigation prior to routine clinical work. New biosensors for cholesterol were also developed in response to continuous concerns about cholesterol measurements in body fluids. Mascini’s group (P55) employed electropolymerization of pyrrole for preparing cholesterol biosensors. Crumbliss et al. (P56) used a colloidal gold multienzyme biosensor for detecting cholesterol in serum and whole blood. Osmium-based redox mediators were shown useful for operating cholesterol microsensors (P57). Catalytic palladium particles were used by Dong et al. (P58) for facilitating the biosensing of cholesterol. Other clinically useful enzyme electrodes and related systems include flow injection systems for potentiometric (P59) or amperometric (P60) determinations of creatinine in urine, microfab ricated (P61)or carbon-paste (P62) biosensors for amino acids, a peptide sensor for protein determination (P63), a polypyrrolebased potentiometric biosensor for urea (P64), an amperometric enzyme electrode for the detection of bile acids (P65), a gas-phase biosensor for ethanol (P66),and an amperometric enzyme microelectrode for the quantitation of choline in the brain (P67). Electrochemical monitoring of immunological interactions holds great promise as a useful alternative to assays involving radioisotopic labels. Heineman’s group has continued its major contributions to this route and reported several useful strategies, including a multianalyte immunoassay using anodic stripping voltammetric detection of different metal labels (P68),a capillary (20 pL) electrochemical enzyme immunoassay of digoxin in connection with flow injection amperometric analysis (P69), the use of interdigitated array electrodes for small-volume voltammetric enzyme immunoassay ( P r o ) , and an electrochemical homogeneous enzyme immunoassay of theophylline (P71). Useful homogeneous amperometric immunoassays for theophylline were described by McNeil’s (P72) and Edmonds’ (P73) groups. Duan and Meyerhoff (P74) reported on a separation-free enzyme immunoassay using microporous gold electrodes and self-assembled monolayer/immobilized capture antibodies. Wilner and co-workers (P75) described a novel approach for reusable immunosensors. Such an important scheme relies on a modified electrode with a self-assembled antigen monolayer that can be regenerated by irradiation with light. Another promising approach for immobilizing antibodies onto working electrodes (while 488R
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maintaining their bioactivity) involves incorporation into a conductive polymer film (P76).Such sensors have been used with pulsed amperometric detection in a flow injection system. Nikolelis et al. (P77)reported on the use of bilayer lipid membranes for electrochemical transduction of immunological reactions. Cardosi et al. (P78) reviewed the principles of electrochemical immunoassay protocols, while Panfill et al. (P79) reviewed the concept of light-addressable potentiometric immunosensors. The coupling of receptor binding processes with electrochemical transduction forms the basis for another, relatively new, type of affinity biosensors. Leech and Rechnitz (P80) demonstrated the use of the crayfish nerve bundle for the detection of local anesthetics. Wang et al. (P81) developed a new preconcentration/ voltammetric affinity biosensing scheme, based on the detection of phenothiazine drugs at Langmuir-Blodgett films of their tyrosine hydroxylase receptors. Van den Heuvel (P82) explored the utility of synthetic peptides as self-assembled receptor layers. Selective interactions between analytes and membrane-embedded receptors were reviewed by Nikolelis and Krull (P83),while Leech (P84) reviewed the detection of ligand-receptor binding processes. DNA probes represent an important type of affinity biosensor that holds great promise for early screening of inherited human diseases. Mikkelsen’s group (P85, P86) developed sequenceselective biosensors for DNA based on electroactive hybridization indicators. The concept was applied to the selective detection of cystic fibrosis mutation. Hashimoto et al. (P87) used the intercalation of daunomycin for electrochemical detection of target genes. The same group also reported on a sequencespecific gene detection with a DNA-modified gold electrode (P88). Pandey and Weetall (P89) employed photochemical reactions in the electrochemical detection of DNA intercalation. OPTICAL AND MASS SENSORS Optical fiber sensors, which rely on spectroscopic monitoring of the interaction between the analyte and an indicator (fixed at fiber’s distal tip) offer several advantages over other sensing devices. The literature on optical sensors continues to grow at an increasing rate. Several groups reported on the coupling of biocatalytic layers with fiber-optic probes. Schubert (P90)described an optical multienzyme biosensor for the determination of adenosine diphosphate (ADP). High sensitivity was achieved by using internal analyte recycling. Optical sensors for urea, based on the immobilization of urease onto an ammonium ion optrode, were described by several groups ( H I , P92). Immobilized phenylalanine dehydrogenase was employed for the bioluminescent sensing of L-phenylalanine [including flow monitoring in serum (P93)l. Coimmobilization of xanthine oxidase and peroxidase led to a useful chemiluminescent probe for xanthine (P94). Several groups reported on the optical sensing of glucose in connection with immobilized glucose oxidase (P95) or glucose dehydrogenase (P96).Arnold’s group (P97) demonstrated the feasibility of using near-infrared spectroscopy for measuring glucose in a protein matrix. Such a strategy has a tremendous potential for noninvasive monitoring of blood glucose. An affinity optical sensor for glucose, based on a homogeneous fluorescence energy-transfer assays system, was developed by Meadows and Schultz (P98).Astles and Miller (P99) reported on a useful fiber-optic immunosensor for measuring micromolar concentrations of phenytoin in human blood. Other groups
described new optical immunosensors for monitoring IgG and other large molecules (P100,P101). Piunno et al. (P102) developed a fiber-optic probe for the fluorometric detection of DNA hybridization. Other useful optical sensors, developed over the last two years include a phosphorescence device for tetracyclines (P103),a fluorescence probe for serotonin (P104), and optical sensors for ions such as sodium or ammonium (P105),lithium (P106), and calcium or chloride (P107).Such ion sensors rely on modulation of the optical properties of chromogenic ionophores by the binding event. Kopelman's group (P108)developed a submicrometer fiber-optic pH probe, Bachas and co-workers (P109) used an electropolymerized cobalt porphyrin for optical pH sensing, Wong and co-workers (P110)described a useful luminescent sensor for oxygen, Kar and Arnold (PI 11)reported on an air-gap fiber-optic ammonia gas sensor, while Weigl and Wolfbeis (P112)introduced a fast responding reversible capillary device for carbon dioxide. Useful reviews covered the utility of optical sensors for in vivo monitoring of blood gases (PI 13),fiber-optic immunosensors based on continuous reagent delivery (P114,and optical sensors in flow injection analysis (P115). Efforts continued toward coupling the remarkable sensitivity of piezoelectric transducers with the inherent specificity of immunoreactions. Such devices rely on the immobilization of the antibody on the crystal surface and detection of mass increases associated with the binding of the complimentary antigen. Monitoring of mass changes arising from these selective interactions led to several clinically useful devices. Piezoelectric immunosensors were developed for the detection of human erythrocytes (P116), T typhocytes, (P117),and herpes viruses (P118).Muratsugu et al. (P119) described a similar device for the flow detection of human serum albumin, while Imai et al. (PlZ0) reported on a total urinary protein sensor based on a piezoelectric quartz crystal. Aberl et al. (P121) described a piezoelectric immunosensor for the detection of the human immunedeficiency virus. The coupling of piezoelectric immunosensors with a flowthrough system was reported by Koesslinger et al. (P122),while highly sensitive piezoelectric monitoring of solution-phaseimmunoreactions was reported by Geddes et al. (P123).Despite this significant progress, routine clinical applications of mass immunosensors are still hindered by problems such as reversibility or unspecific adsorption. POTENTIOMETRIC SENSORS
With potentiometric sensors (i.e., ion-selective electrodes, ISEs), the recognition process is a selective binding event which transduces analyte ionic activity into a potential readout. Such devices are used routinely in clinical laboratories in connection with high-speed electrolyte (e.g., K+, Na+, Ca2+,pH) profiling. Efforts during the past two years have focused primarily on the development of ISEs for additional clincially relevant analytes, the synthesis of new (more selective) ionophores, and the microfab rication and integration of miniaturized potentiometric probes. Several useful reviews described trends in blood gas analyzers (P124),progress and challenges in in vivo gas and electrolyte sensing (P125), the status of magnesium and calcium monitoring in blood (P126-P128),the development of new recognition membranes (P129, P130),and the status of chemically sensitive field effect transistors (P131).
The challenges and prospects of reliable lithium and magnesium determinations have led to highly selective lithium ionophores based on krown-4 derivatives (P132),to new neutral carrier-based magnesium electrodes (P133, P134,and to a critical evaluation of lithium determinations in eight analyzers (P135). Efforts continued also toward improved ISEs for sodium determinations based on calix[4larene- (P136, P137) or dibenzo-l& crown-5 (P138) ionophores. Other advances in host-guest chemistry led to useful ISEs for diabasic phosphate (P139) and organic ions such as primary amines (P140)or heparin (P141). An alternative to selective-ion recognition is the use of an array of ISEs, as was illustrated for ammonium detection (P142). Continuous efforts toward miniaturization,point-ofcaretesting, and automation have resulted in major technological innovations, including a user-friendly hand-held electrolyte analyzer for critical care environments (P143), a dual-lumen catheter for simultaneous monitoring of carbon dioxide and pH (P144,a new solid-state transcutaneous device for measurements of carbon dioxide (P145),disposable electrodes for sodium (P146)and pH (P147), calcium-specific microelectrodes (P148),flexible microsensor arrays for cardiovascular applications (P149), new automated multiion analyzers (P150, P151),integrated blood gas sensors for on-line monitoring of pCO2, pOz, and pH (P152, P153), a micromachmed flow injection system with ion-sensitivefield effect transistors (P154,and a miniaturized blood gas analyzer on a chip (P155).Many of these new systems and probes have been designed for use by nonlaboratory health care professionals. Some of these compact electrolyte and gas analyzers are currently being coupled with enzymebased metabolite sensors (for glucose, lactate, urea, or creatinine). Other new applications of ISEs include their utility as oncolumn detectors for capillary electrophoresis (P156, P157) or as probe tips in scanning electrochemical microscopic characterization of biological surfaces (P158). VOLTAMMETRY AND AMPEROMETRY The remarkable sensitivityof controlled-potentialvoltammetric and amperometric techniques is often hindered by their low selectivity in biological media. The deliberate modification of electrode surfaces holds great promise for enhancing the ability of these techniques to handle clinically relevant samples. The electrocatalyticaction of such surfaces led to useful applications, including the detection of insulin secretion at ruthenium-modified microelectrodes (P159), of nitric oxide at phorphyrinic microsensors (P160), or of NADH at Meldola Bluecontaining sensor strips (P161). Coverage of electrochemcial devices with permselective coatings can also be advantageous in biological media. For example, enhanced detection of neurotransmitters was reported at Nation/crown ether (P162), calixarine (P163), or Nafion/ polyester ionomer (P164)coated electrodes. Enhanced sensitivity can be achieved by tailoring the interface with an appropriate preconcentrating agent. Useful examples are the voltammetric determination of trimipramine at lipid-modified electrodes (P165), the use of Nationcoated electrodes for improving the measurement of radiopharmaceuticals (P166) or P-agonist drugs (P167), and the uptake of cadmium from dilute solutions by charged selfassembled monolayers (P168). Another useful approach for controlling the interface, electrochemical pretreatment, was used for reproducible voltammetric measurements of adenosine at carbon fiber electrodes (P169). Analytical Chemistry, Vol. 67, No. 12, June 15, 1995
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Several papers reported on the utility of the most sensitive electroanalytical technique, stripping analysis, for the determination of trace metals in biological fluids. Such interest has resulted from the growing needs for decentralized screening of toxic metals. Particular attention has been given to the development of portable blood lead measurement systems. Jagner et al. (PI70) described a rapid potentiometric stripping protocol, based on a matrix-modifymg solution, for the determination of lead in whole blood. Feldman et al. (PI 71) employed square-wave stripping voltammetry at carbon microelectrodes for blood lead analysis. Other useful clinical applications of stripping analysis included potentiometric stripping measurements of copper in blood (P172) and flow injection determination of metals in tears (PI 73). Single use microfabricated devices circumvent the passivation of stripping electrodes in complex biological media. Wang and Tian (PI 74) developed disposable stripping sensors for lead, based on mercuryfree gold strips. Kounaves et al. (PI 75) described the lithographic fabrication of iridium-based metal sensors. Nanoband electrodes for submicroliter stripping measurements down to the attomole range were also described (PI76). Adsorptive stripping procedures can extend the scope of stripping analysis toward clinically important analytes (that cannot be plated electrolytically). The adsorptive accumulation of theophylline, ceftriaxone, and trimipramine was thus exploited for measuring ultralow levels of these drugs (PI 77-Pl79). Adsorptive stripping voltammetry was also employed for measuring picomole levels of RNA in the presence of an excess of DNA (P180). Differential pulse polarography was employed for measuring the activity of lactate dehydrogenase in human serum (P181). The use of amperometric detection for separation techniques has continued to be an area of great interest. Such a detection scheme offers remarkably low detection limits, high selectivity (toward electroactive biomolecules) , and ultralow dead volumes. One of the most active areas has been the development of new detectors for capillary zone electrophoresis (CZE). Ewing et al. (P182) assessed various electrochemical detection strategies for CZE. O'Shea and Lunte (P183) reported on modified carbonpaste microelectrode detectors for thiols after CZE separations. Copper electrodes were used for detecting amino acids and peptides separated by CZE (P184). Liquid chromatographic separations of amino acids and peptides were also coupled with improved (Ru-based) electrochemical detectors (P185, P186). Photolytic derivitization was employed to improve the amperometric detection of peptides (P187). Modded electrodes were used for enhancing the detection of local anesthetics (P188) or hydrophobic drugs (P189), while microelectrode arrays offered subfemtomole detection of catecholamines (P190). Amperometric detectors have been coupled also to microdialysis probes, as was illustrated in the biosensing of brain glutamate (P191). Joseph Wang is Professor of Chemistry at NewMexico State Universg He recezved hzs D.Sc. in 1978 at the Israel Instztute of Technology. zs research interests include the develo ment of electrochemical sensing devicesfor clinical and environmenta monitoring, the development and characterization of new surfaces for electroanalysis, sensor/recognition coatings, microfabrication and miniaturization, the develofiment of techniques for ultratrace measurements, and the design of on-line flow detectors. He has authored over 300 research papers and four books. He is current1 the ChiefEditor of Electroanalysis and a member of the Advisory 8ditor Board of Analytica Chimica Acta, Analyst, Talanta, Analytical Letters, Analytical Instrumentation, Encyclopedza of Analytzcal Sciences, Analysis Europa, and Croatia Chimica Acta.
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