Electroanalysis and Biosensors - Analytical Chemistry (ACS

(E31) reported on the clinical evaluation of a new electrochemical meter for self-monitoring of blood glucose. Efforts continued toward the developmen...
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Anal. Chem. 1999, 71, 328R-332R

Electroanalysis and Biosensors Joseph Wang

Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003 This review covers primarily the development of biosensors and electrochemical schemes of clinical significance during the years 1997 and 1998. The review is not a comprehensive coverage of these topics. I have attempted to select those references that offer significant clinical relevance. Much of the general activity in the areas of electroanalysis and sensors has been documented in recent fundamental reviews in this journal (E1, E2). The interest in developing small sensing devices for biomedical use is growing rapidly. The potential clinical applications of such devices are enormous, particularly when point-of-care and criticalcare testing are concerned. Recent innovations are expected to provide the necessary improvements in convenience, patient care, cost, and turnout time and to have a major impact on health care early in the 21st century. Over the past two years we have witnessed new trends, including the integration of sensors with miniaturized (micromachined) analyzers, genetic design of recognition elements, rapid growth of genosensors, ultrafast monitoring of dynamic events in microscopic environments (including single-cell systems), molecular-sized electrodes, and introduction of advanced sensing materials. These emerging fields, along with continued investigations of novel biocatalytic and affinity biosensors, based on electrochemical, optical, or piezoelectric transducers, will no doubt enhance the power of biosensors and electroanalysis in the clinical arena. BOOKS AND REVIEWS Biosensors continue to be a popular topic for review. Hahn (E3) reviewed the development of electrochemical sensors for blood gases, Lauks (E4) discussed the microfabrication of biosensors for blood analysis, while Burritt (E5) assessed noninvasive and invasive sensors for patient monitoring. Other useful reviews covered the fields of molecular imprinting-based biomimetic sensors (E6), use of recombinant DNA technology for tailoring the recognition event (E7), piezoelectric quartz crystal biosensors (E8), self-assembled monolayers for biosensors (E9), and solgel sensing films (E10). Several books dealing with biosensors were also published since the 1997 review (E11-E13). Enzyme Electrodes. Enzyme electrodes represent the oldest group of biosensors and are being increasingly used for clinical testing of metabolites such as glucose, lactate, urea, creatinine, and bilirubin. The establishment of efficient electron transfer between redox proteins and electrode transducers is crucial for the design of novel amperometric enzyme electrodes. Various strategies for electrically connecting redox proteins and metal electrodes were reviewed (E14, E15). Other useful reviews were devoted to NAD-dependent dehydrogenase electrodes (E16), to enzyme-based potentiometric biosensors (E17), or to the use of electropolymerization for desigining amperometric biosensors (E18). 328R Analytical Chemistry, Vol. 71, No. 12, June 15, 1999

The challenge of providing a tight diabetes control remained a dominating force behind numerous efforts during the past two years. Electrochemical biosensors for glucose, based on the specificity of glucose oxidase, continued to play a key role in this direction. Kirk and Rheney (E19) reviewed the features of commercial meters for home monitoring of blood glucose, while Henry (E20) summarized the activity in the area of implantable sensors for continuous monitoring of glucose. Several groups have continued their efforts toward the development of needle-type electrodes for subcutaneous glucose measurements. Reach, Wilson, and their co-workers (E21) reported on a user-friendly method for calibrating a subcutaneous glucose sensor-based hypoglycemic alarm. Heller’s group used a subcutaneous electrode for monitoring glucose in diabetic chimpanzee (E22) and evaluated the transient difference between blood and subcutaneous glucose concentrations (E23); a new algorithm was developed for correcting this difference. Wilkins’s group (E24) reported on a needle-type sensor for intravascular monitoring of glucose, while Dempsey et al. (E25) described an integrated biosensor/microdialysis microsystem for continuous monitoring of glucose. Wang and Lu (E26) addressed the oxygen limitation of glucose biosensors by designing an oxygen-rich carbon-paste enzyme electrode. Bartlett’s group reported on the elegant modification of glucose oxidase via a covalent attachment of a tetrathiafulvalene mediator (E27). The same group also developed a microelectrochemical enzyme transistor for measuring low concentrations of glucose (E28). Nakata et al. (E29) exploited the multidimensional information contained in the dynamic nonlinear response for discriminating between glucose and its major interferences. Yao and Takashima (E30) eliminated potential interferences by coverage with a sol-gel/poly(diaminobenzene) composite membrane. Albertson et al. (E31) reported on the clinical evaluation of a new electrochemical meter for self-monitoring of blood glucose. Efforts continued toward the development of enzyme electrodes for other clinically relevant metabolites. Blood lactate levels are indicative of various pathological states. Palmisano et al. (E32) described an amperometric lactate biosensor based on lactate oxidase covalently attached to an electropolymerized anti-interference film. Vadgama’s group reported on the use of PVC membranes for improving the blood compatibility and extending the linearity of lactate enzyme electrodes (E33). Khan and Wernet (E34) developed a highly sensitive three-enzyme amperometric creatinine biosensor. A dual-analyte device was developed for the simultaneous determination of creatinine and urea in dialysis fluids (E35). Scheller and co-workers extended their bienzyme amplification approach for developing ultrasensitive enzyme electrodes for adrenaline (E36) and tyrosine-containing peptides (E37). Gooding and Hall (E38) described a new fill-and-flow biosensor design, with the reagents located upstream from the transducer. 10.1021/a1999905e CCC: $18.00

© 1999 American Chemical Society Published on Web 05/20/1999

Buck and co-workers (E39) developed a small-volume cell for amperometric enzyme-activity measurements. Immunosensors. The specificity of antigen-antibody interactions motivated further development of novel immunosensors with great potential for diagnostic use. Recent advances in electrochemical immunosensors were reviewed (E40). Most electrochemical devices continue to rely on the use of enzyme labels that generate a detectable (electroactive) species. Such use of an alkaline phosphatase label has been documented in connection to new sol-gel (E41) or carbon-composite (E42) immobilization strategies and for the selective detection of progesterone (E43) and Salmonella (E44). Wang et al. (E45) described a single-use immunosensor based on a highly sensitive stripping potentiometric detection of a metal (Bi) label. The simplified on-chip operation required 30-µL samples and offered a detection limit of 90 fmol. Degrand’s group (E46) continued its effort of enhancing the sensitivity through the accumulation of cationic redox labels onto cation-exchanger polymer-modified electrodes; applicability to the antiepileptic drugs phenytoin and phenobarbital was demonstrated (E47). Efforts continued also toward the direct label-free electrochemical detection of immonoreactions. Johansson’s group (E48, E49) demonstrated that changes of the capacitance of a thiolated antibody-modified electrode, provoked by the immunoreaction, can be used for the rapid and sensitive detection of the antigen. Femtomolar detection limits were reported for the chorionic gonadotropin hormone and interleukine 6. Cornell’s team (E50) described a novel biosensor platform based on the switching of synthetic ion channels assembled within a lipid bilayer membrane tethered to a gold surface. Wallace’s group (E51) exploited changes in the electronic properties of a conducting polyprrole film, doped with the antibody, for amperometric flow injection detection of the corresponding antigen. New optical and piezoelectric immunosensors were also reported. Helmerson et al. (E52) described the use of optical tweezer-based immunosensors for detecting femtomolar concentrations of antigens. A fiber-optic fluorescence immunosensor for detecting myoglobin, utilizing a dye-labeled antibody, was also described (E53). Willner’s group (E54) developed a piezoelectric immunosensor for urine specimens of Chlamydia trachomatis. DNA Biosensors. The emerging area of DNA hybridization biosensors has been a very popular topic during the past two years. Such devices hold an enormous promise for the clinical diagnosis of inherited diseases and for the rapid detection of infectious microorganisms. A full range of optical, electrochemical, and piezoelectric transduction modes, aimed at detecting the base pair hybridization between the immobilized probe and the target DNA has been developed. Increased attention has been given to new schemes that do not require an external label, as well as to improvements in the selectivity and sensitivity. Efforts for enhancing the specificity of these devices in connection to the use of peptide nucleic acids (PNA) probes were reviewed (E55). The high sensitivity of electrochemical devices coupled with their compatibility with modern microfabrication/miniaturization technologies make them very attractive for the shrinking of DNA diagnostics. Thorp’s group (E56) demonstrated the use of mediated electron-transfer reactions of DNA for detecting PCRamplified genomic DNA. Ihara et al. (E57) employed ferrocenemediated oligonucleotides for a sandwich-based electrochemical

detection of DNA hybridization. Takenaka’s team (E58) reported on a naphthalene-ferrocene redox indicator with a remarkable discrimination between the probe and duplex. Wang’s group (E59) employed PNA probes for the detection of point mutations in the p53 gene. The same group developed an electrochemical biosensor for detecting the Mycobacterium tuberculosis DNA in connection to a Co(phen)3 indicator (E60). New label-free strategies for detecting the hybridization event based on changes in the electronic properties of oligonucleotide-substituted polypyrrole film (E61) and the impedance of a field-effect device (E62) and of the microstructure of bilayer lipid membranes (E63) were also described. Optical transduction of DNA hybridization continued to attract considerable attention. Chen et al. (E64) reported on the combination of a sandwich hybridization with chemiluminscence transduction for the detection of hepatitis B virus DNA. Kleinjung et al. (E65) described a highly sensitive fiber-optic genosensor based on the use of PicoGreen indicator. The same group also reported on the use of high-affinity RNA as the molecular recognition element of a fluorescent biosensor (E66). Surface plasmon resonance spectroscopy with thiol-tethered DNA films was employed by Geogiadis’s group (E67) for the direct detection of DNA hybridization. Livache et al. (E68) reported on an oligonucleotide fluorescence array for genotyping of hepatitis C virus. These and similar high-density arrays are expected to be integrated with new microfabricated PCR devices (E69, E70) to perform all the steps of the clinical assay on a chip platform. Quartz crystal microbalance (QCM) DNA biosensors rely on the use of mass changes for the in situ detection of hybridization. Several new strategies were explored for increasing the hybridization capacity and hence the sensitivity of the QCM DNA biosensor. These included the use of highly branched DNA dendrimer probes (E71) and the design of multilayer DNA films (E72). Improved specificity was documentated by using PNA-modified crystals (E73). Willner’s group (E74) reported on a QCM DNA hybridization biosensor for the detection of the Tay-Sach disorder. Optical Sensors. Fiber optics possess an enormous potential for clinical analysis. Accordingly, the optical mode of transduction has received considerable attention since the 1997 review. Clinical applications of optical biosensors were reviewed (E75). Kopelman’s group (E76) reported on remarkable small and novel optical probes for intracelluar measurements of pH, potassium, and calcium. The same group also described a high-performance optical pH sensor using a dual-emission ratio (E77). Wolfbeis’s group reported on luminescene decay time optical pH (E78) and potassium (E79) sensors. The specific determination of nitric oxide is of tremendous interest for elucidating its physiological role. Barker and Kopelman (E80) reported on the cellular applications of a fiber-optic nitric oxide sensor based on a goldadsorbed fluorophore. Russell’s group described an optical biosensor for nitric oxide, based on sol-gel coatings with an encapsulated cytochrome c (E81). Fiber optics based on entrapped tris(4,7-diphenyl-1,10-phenanthroline)ruthenium complex were developed for the monitoring of free cholesterol (E82) and bilirubin (E83) in serum samples. Protein engineering was used for designing a novel fluorescent glucose sensor (E84). A multianalyte imaging optical fiber was developed for the simultaneous monitoring of pH, CO2, and O2 (E85). A solid-state Analytical Chemistry, Vol. 71, No. 12, June 15, 1999

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fluorescence sensor array was introduced for the determination of critical gases and electrolytes in blood (E86). A broad-base optical sensor system based on interferometric measurements was described for label-free affinity assays (E87). Near-IR spectroscopy holds great promise for clinical chemistry owing to its potential for noninvasive, reagentless measurements. The groups of Arnold and Small have made further progress in that direction by demonstrating the measurement of glucose in undiluted human serum (E88) and by developing new multivariate calibration methods (E89). Ion-Selective Electrodes. Ion-selective electrodes (ISEs) are currently the devices of choice for clinical monitoring of electrolytes, performing over 1 billion clinical assays every year. Several reviews have been devoted to the characteristics (E90) and selectivity (E91) of liquid membrane ISEs. Over the past two years, we witnessed the continued use of molecular recognition for developing even more selective ionophores for both cationic and anionic analytes. Particular attention was given to the important and challenging tasks of detecting blood magnesium and lithium. These efforts included a new highly selective ionophore for magnesium (E92), a flow injection protocol for addressing the calcium interference in blood magnesium assays (E93), a new photocured polymeric membrane for lithium (E94), and the development of lithium-selective ceramics (E95). Huijgen et al. (E96) reported on the critical comparison of three commercial magnesium-selective electrodes. Efforts continued for using a biomimetic approach for developing anion-selective electrodes. Bachas and co-workers (E97) described a salicylateselective electrode based on a biomimetic guanidinium ionophore. Umezawa’s group (E98) employed hydrogen bond-based recognition for potentiometric measurements of nucleotides. Polymermembrane ISEs were employed by Meyerhoff’s group for determining heparin in whole blood (E99) and for detecting phosphaterich biological polyanions (E100). Katsu and Mori (E101) described a new ISE for monitoring antiarrhythmic drugs in blood serum. Meyerhoff’s group (E102) demonstrated the improved biocompatability of potentiometric measurements in connection with nitric oxide-releasing films. Kimura et al. (E103) reported on the use of sol-gel membrane supports for neutral carrier potentiometric sensors. Malinowska and Meyerhoff (E104) investigated the effect of nonionic surfactants on the response of neutral carrier ISEs designed for blood electrolyte measurements. Pretsch’s group (E105) examined the influence of lipophilic salts upon the selectivity of polymer membrane electrodes. The same group demonstrated that a substantial lowering of the detection limits of carrier-based liquid membrane electrodes could be achieved by minimizing the release of the primary ion from the inner solution (via the use of an internal electrolyte with a low primaryion activity (E106)). Advances in microfabrication and miniaturization can further facilitate the widespread clinical use of ISEs. D’Ozario et al. (E107) described the microfabrication of a thick-film sensor for monitoring several blood electrolytes and metabolites. Uhlig et al. (E108) described miniaturized potentiometric devices based on thin-film silicon technology. Diamond’s group (E109) reported on the thickfilm microfabrication of solid-state sodium strips. Buck and coworkers (E110) described the fabrication and physiological 330R

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applications of a solid-state pH microsensor based on electrodeposited iridium oxide. Meruva and Meyerhoff (E111) reported on a catheter-type electrode for potentiometric monitoring of oxygen, pH, and carbon dioxide. Smith et al. (E112) described the utility of the i-STAT portable analyzer for monitoring electrolytes during space flight. Several studies were devoted to the development of improved potentiometric pCO2 electrodes. These included a new Severinghaus-type pCO2 electrode with reduced drift and lower detection limit (E113) and the use of an internal polyaniline-based pH electrode (E114). Potentiometry has also been shown very useful for detecting alkali and alkaline earth metal cations following their capillary electrophoretic separations (E115). Voltammetry and Amperometry. The inherent sensitivity of controlled-potential techniques, coupled with the portable nature of the instrumentation, holds great promise for various biomedical applications. The ability to fabricate ultramicroelectrodes allows convenient measurements in very small spaces. Ewing’s group (E116) reported on the voltammetric detection of dopamine release from single exocytotic events, while Xin and Wightman (E117) developed a dual microsensor for the simultaneous detection of catecholamine exocytosis and calcium ion release. The same group also developed a powerful three-dimensional color representation of ultrafast in vivo voltammetric data (E118). Kennedy’s group (E119) reported on the in vivo monitoring of oligopeptides. Modified carbon fiber electrodes were employed for the in vivo detection of nitric oxide (E120, E121), while a modified glassy carbon electrode was developed for the determination of serotonin in human blood (E122). New designs of microliter (E123) and picoliter (E124, E125) voltammetric cells should further facilitate assays of ultrasmall environments (including single-cell systems). The remarkable sensitivity associated with the “built-in” preconcentration step of electrochemical stripping analysis has continued to attract attention for the determination of trace elements in biological fluids. Efforts have continued toward the development of easy-to-use, portable stripping devices for blood lead analysis. Jaenicke et al. (E126) described the use of a flow injection system with a coated wall-jet detector for rapid stripping measurements of lead in blood. Osterloh’s group (E127) reported on a square-wave anodic stripping voltammetric protocol for blood lead using arrays of microelectrodes and an indium internal standard. Ciszewski et al. (E128) described a stripping voltammetric protocol, coupled to a microwave digestion, for measuring trace thallium in human hair. Adsorptive stripping voltammetry has been used for detecting trace aluminum in dialysis fluids (E129). Analogous measurements of nucleic acids were also described (E130). A preconcentrating modified electrode for voltammetric monitoring of radiopharmaceuticals was developed by Heineman’s group (E131). Electrochemical detection represents a very attractive detection approach for CE separations and has thus attracted considerable interest in the past two years. Recent advances in this field have been reviewed (E132). Efforts included the development of fastscanning voltammetric detection for CE systems (E133, E134), the integration of amperometric detection with CE systems (E135, E136) or with CE chips (E137), and new CE protocols with endcolumn amperometric detection of glutathione (E138) or purine

nucleobases (E139) or on-capillary detection of aminoglycoside antibiotics (E140). An amperometric detection scheme was also developed for detecting lithium in artificial serum, in connection with a flow injection system and a liquid-liquid type electrode (E141). Flow detectors for nucleic acids were also described (E142-E144). ACKNOWLEDGMENT

Financial support from the National Institutes of Health (Grant R01 RR14173-01) is gratefully acknowledged. Joseph Wang is Professor of Chemistry at New Mexico State University. He received his D.Sc. in 1978 from the Israel Institute of Technology. After serving as a postdoctoral fellow at the University of Wisconsins Madison, he joined New Mexico State University in 1980. His research interests include nucleic acid recognition for DNA diagnostics, enzyme electrodes, sensor coatings and materials, microfabrication and micromachining, and modified and miniaturized electrodes. He has authored over 450 papers, five books, and six patents. He is currently the chief editor of Electroanalysis, and a member of the editorial board of the Analyst, Analytical Chimica Acta, Analytical Communications, Talanta, Analylitical Letters, Analytical Instrumentation, Electrochemistry Communications, and Quimica Analitica.

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