Chemical sensors and biosensors for medical and biological applications ursula e spichiger keller (wiley VCH, 1998)

Ursula E Spichiger-Keller Chemical Sensors and Biosensors for Medical and Biological Applications @ WILEY-VCH Further titles of interest: W Gopel, J Hesse, J N Zemel (eds.) Sensors - A Comprehensive Survey Volumes 1-9 ISBN 3-527-26538-4 New! The on-going series that keeps you up-to-date: H Baltes, W Gopel, J Hesse (eds.) Sensors Update Volumes 1-3 ISSN 1432-2404 Ursula E Spichiger-Keller Chemical Sensors and Biosensors for Medical and Biological Applications 8WILEY-VCH Weinheim - New York Chichester Brisbane - Singapore Toronto Prof Dr Ursula Spichiger-Keller Zentrum fur Chemische Sensoren/Biosensoren und bioAnalytische Chemie Departement fur Pharmazie ETH-Technopark TechnoparkstraSe CH-8005 Zurich This book was carefully produced Nevertheless, author and publisher not warrant the information contained therein to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate Library of Congress Card No applied for A catalogue record for this book is available from the British Library Die Deutsche Bibliothek - CIP-Einheitsaufnahme Spichiger-Keller,Ursula E.: Chemical.sensors and biosensors for medical and biological applications / Ursula E Spichiger-Keller - Weinheim ; Wiley-VCH, 1998 ISBN 3-527-28855-4 WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 1998 Printed on acid-free and low chlorine paper All rights reserved (including those of translation in other languages) No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Printing: strauss offsetdruck GmbH, D-69509 Morlenbach Bookbinding: Wilh Osswald Co., D-67433 Neustadt Printed in the Federal Republic of Germany + Preface Chemical sensors are intended to solve analytical problems complementary to that provided by standard analytical instruments In order to become commercially viable, chemical sensors have to be combined with an appropriate sampling device and electronics in such a way that the overall dimensions of the final device, the price and ease in handling, are acceptable These parameters determine the profile of sensing devices in the vast range of applications in industrial and bio-process control, in environmental monitoring and in monitoring of toxic effluents (e.g cyanide), in food technology, in field measurements, in emergency-care analysis, and point-of care testing (POCT) in medicine An unexplored area is the use of chemical sensors in toxicology In order to cope with various fields of applications, the brand "the Lab in the Bag" was coined specifying the trend of further developments Several comprehensive volumes on chemical sensors had been published However most of them are more focused on the development of the physical part, the transducers This volume intends to provide an overview on the variety of chemical sensors focusing on analyticalchemical aspects generally, and on biological applications specifically The field of chemical sensors could be depicted as a space which is spread by coordinates: the biological or life sciences along one axis, physical-chemistry and chemistry along another, and mathematics and statistics along the third axis This %pace'' reflects the complexity of the field This volume tries to take sufficient account of each axis and gives an overview of the field with special focus on the developments in the goup of Prof W Simon, Laboratory for Organic Chemistry, involving the habilitation thesis of the author, and on developments in the Centre for Chemical Sensors/Biosensors and bioAnalytical Chemistry at ETH Ziirich-Technopark Each chapter is devoted to a separate theme So the references have been inserted after each thematic block or chapter, beginning with chapter Each thematic block or section is closed by conclusions In the first chapter, the question as to whether chemical sensors and biosensors have to be differenciated is discussed In the course of this chapter, chemical sensors are defined and related to particular areas in analytical chemistry A brief history of the field is given describing the development of chemical sensors This is followed by a discussion of market trends and comments on possible future developments of the general situation in analytical laboratories The second and third chapter sets out to give an overview on the chemical and physicochemical principles underlying the preparation of chemical and biochemical sensors These chapters cope with the modelling of interactions, the investigation of interactions, and the basic theories underlying a reversible response which enables continuous monitoring An understanding of these principles is assumed in chapter five and six, where some sensors developed and tested by the author's own research group are presented In many cases, only a brief description is given, but this is compensated for by the provision of extensive references A major subject of the author%research has been the investigation of the influence of the medium, the bulk of the sensing layer, incorporatingthe active compounds (chapter 4), and the development of the magnesium-selective electrode so that it can be routinely used in plasma and whole blood Major efforts were devoted to the synthesis of the magnesium-selectiveionophore VI Preface ETH 5506 in order to make this ligand accessible as ETHT 5506 to industrial production (appendix 10; ETHT means ETH-Technopark) The seventh chapter discusses the problems of reliability and interpretability of results In all fields of analytical chemistry, these are at least as important as the development of new methods and procedures Several sections focus on decision and discrimination problems analogous to analytical data treatment in medicine, in order to solve decision problems in general analytical chemistry The author's experience with quality control and discrimination analysis is referred to h the interests of completing this book, it has not been possible to go into great detail about the experimental conditions and fundamental explanations for all results presented However, many of these can be found in the references provided In selecting topics, I was governed by a desire to cover those which fill a gap in the existing comprehensivevolumes of other authors In addition, these topics provide insights into the actions of specific sensors, which illustrate their characteristics in detail, and which show the differences of basic concepts I would like to dedicate this book first to the memory of the late Prof Wilhelm Simon in recognition of his outstanding contribution to the field It was in his laboratory that I realised that productive research is, among other things, the reflection of personal and scientific discipline, the unguarded exchange of ideas and daily critical discussions In writing the Habilitation thesis, I missed his critical comments and suggestions, and his sometimes strange, but always stimulating ideas Secondly, I dedicate this book to those students and colleagues who are new to the field of chemical sensors and who will, I hope, find it a useful reference work The appendices, in particular, are intended to be helpful for those involved in the development and in practical applications of chemical sensors The appendices, specifically appendix 9, contain much information not easily available elsewhere I would especially like to thank my assistants and my doctoral students for their collaboration and support They contributed to the writing of this book in many ways, not least, through their knowledge and energy, and their humour and optimism These are Angela Schmid, Ursula Wiesli, Remo Wild and Bruno Rusterholz; Gudrun Rumpf, Aiping Xu, Ruedi Eugster, Ulrich Schaller, Erika Haase, Ulrich Korell, Daniel Freiner, Mathias Nagele, Daniel Citterio, Jurg Muller, Caspar Demuth, Alphons Fakler, Wei Zhang, Michael Linnhoff, Thomas Roth I am also grateful to my teachers, my colleagues and the postdoctoral fellows who had been working with me in the group, Dres Maria Csosz, Maria Bochenska, Nik Chaniotakis, Kemin Wang, Honbing Li, Peter Holy, Eva Vaillo, Luzi Jenny, Stefan Rasonyi and Gerhard Mohr for their contributions My special thanks go to Dr Silvia Dingwall who checked my English professionally, and Dr.Markus Rothmaier who formatted this manuskript This work was supported by the Swiss National Science Foundation, by the Swiss Commission for Technology and Innovation, the Swiss Priority Programmes "Optique" and "MIOS", by AVL LIST GmbH, 8020-Graz, Austria, and by Orion Research, Inc., Beverly, MA 02129, USA Ursula E Spichiger, August, 1997 Contents Preface v Introduction 1.1 Chemical Sensors as Alternative Analytical Tools 1.2 The Concept of Chemical and Biochemical Sensors 1.3 Recognition Processes and Sensor Technology: Milestones 1.4 Goals for Future Developments and Trends 1.4.1 Trends 1.4.2 Miniatuization Nanotechnology 1.4.3 In Vivo and In Situ Monitoring 1.4.4 The Analytical Laboratory in the 21SfCentury 10 13 13 16 21 25 27 Chemical and Biochemical Sensors 33 References 2.1 Classification Specification and Nomenclatureof Chemical Sensors 33 2 Molecular Recognition Processes for Ions and Neutral Species 2.2.1 Introduction 2.2.2 Molecular Interactions: Tools and Calculations 2.2.3 Molecular Recognition of Ions 2.2.4 Hydrogen Bonds 2.2.5 Molecular Recognition of Enantiomers 2.2.6 Molecular Interactions within the Aqueous Medium 2.2.7 Catalysis by Enzymes, Enzyme Mimics and Host-Reactands 2.2.8 Catalytic Antibodies 2.2.9 Multitopic Recognition of Immunological Systems 2.2.10 Conclusions and Considerations for Ligand Design References 38 38 41 48 56 58 59 63 70 71 74 76 VIII Contents Controlling Sensor Reactions 83 3.1 ThermodynamicallyControlled Sensor Reactions: Reversibility and ThermodynamicEquilibrium 83 3.1.1 The Chemical Potential and the Partition Equilibrium 83 3.1.2 The Recognition and Transduction Process 93 3.1.3 The ElectrochemicalPotential and the @otentiometric) Sensor Response 100 3.2 Thermodynamics of Nonequilibria: D f i s i o n and Steady-State 104 3.3 Rate Controlled Sensor Reactions: Mediated Enzyme Reactions 106 3.4 Nonthermodynamic Assumptions 114 3.4.1 Activity Versus Concentrations 114 3.4.2 Ionic Strength and Estimates of Activity Coefficients 118 3.4.3 Activity and Concentration of an Electrolyte: IFCC / TUPAC Definitions 121 124 3.4.4 The Osmotic Coefficient 3.4.5 Calibration, Standardization and Comparison with Definitive or Reference Procedures 127 3.4.6 The Liquid Junction Potential under Physiological Conditions 134 References The Artificial Analyte-Selective Membrane Limitations Technological Precautions and Developments 136 139 139 4.2 Types of Membranes and Membrane Models 4.2.1 The BiologicalMembrane 4.2.2 MicialMembranes 140 140 144 4.1 Introduction 4.3 The Selectivity Coefficient 155 Contents IX 4.4 The Membrane Composition and the Membrane Medium 161 4.4.1 The Influence of the Permittivity and of Plasticizers 162 4.4.2 The Effect of Electron Pair Donor (EPD) and Acceptor (EPA) Properties of Solvents SolubilizationProperties of the Membrane 169 4.4.3 The Influence of the Aqueous Sample Environment 170 4.4.4 The Influence of the Surface Tension 172 4.4.5 The Effect of Lipophilic Anionic Sites 173 4.4.6 The Effect of the Ligand Concentration 176 4.5 Response Behavior Sensitivity and Detection Limit 4.6 Lifetime Lipophilicity and Immobilization 179 182 4.7 Interactions by the Biological Matrix and Precautions 183 4.7.1 Biocompatibility 183 4.7.2 Possible Mechanism of Protein Adsorption 185 4.7.3 Influence of Thrombocytes on Solvent Polymeric Membranes 188 4.7.4 The Donnan Potential 188 4.7.5 The Influence of Anticoagulants 191 References 193 Potentiometric Chemical Sensors and Biological Applications 199 199 5.1 Principles of Ion-Selective Electrodes 5.2 The Symmetric Potentiometric Cell 203 5.2.1 The Asymmetry of ISE Membranes and Reference'Electrodes 205 5.2.2 Analysis During Hemodialysis 211 5.2.3 How About Human Whole Blood? 214 5.3 The Magnesium-Selective Electrode 215 217 5.3.1 Characteristics of the Magnesium Ion 5.3.2 Analytical Techniques 217 5.3.3 Natural Carriers 222 5.3.4 Synthetic Carriers 225 5.3.5 Applications 237 5.3.6 Stop-Flow Analysis, the Continuous Flow System 239 5.3.7 Significance of Magnesium-SelectiveAssays 240 5.4 Microelectrodes for IntracellularMeasurements 5.4.1 The Nitrite-SelectiveMicroelectrode 242 245 400 Appendices Ligand + o-NPOE n m R1 R2 R3 ETH 4361 log KPot(MgCa) log KPot(MgNa) -C7H15 -CH3 -H Ligand + o-NPOE R ETH 4377 log KPOt(MgCa) log KPOt(MgNa) Appendices Ligand + o-NPOE 401 R ETH 5381 log KPot(MgCa) log KPO'(MgNa) Appendix 12 IUPAC Units and Statistical Considerations Table In 1960, the International System of units (SI) was adopted by the 11th General Conference on Weights and Measures (CGPM).a It relies on seven base units, each linked with one of the seven dimensionally independent, base quantities The base quantities, units and the symbols used to denote them are: m n t T Z, I mass amount of substance ime thermodynamic temperature length luminous intensity electriccumnt with the unit kilogram mole second kelvin metre candela kg mol ampere A S K m cd All further quantities used in characterizinga dataset are derived from these base quantities 402 Appendices Table Units and quantities supported by the International Federation of Clinical Chemistry (IFCC) b Volume Substance concentration Molality, ionic strength Buffer capacity Mass concentration, mass density Catalytic activity Energy Electric charge Chemical potential Pressure, partial pressure, osmotic pressure Temperature 1;L mol 1-1 (mol L-l; M) rnol kg' mol = mole kg L-' mol s-l= kat N m =joule, J C (A s) = coulomb J mol-1 molar volume: molar mass: mol-1 kg mol-1 entropy: J K-1 electric potential: V (J (2-1) Pa (N m-2) = pascal O C = degree Celsius Statistical Overview The total analytical error [TE] includes the systematic error (inaccuracy) and the random error [RE] (reproducibility, repeatability) Systematic errors may contribute to the total analytical error as a proportional error [PE] or a constant bias [CE] or [SE], seen as an intercept in linear regressi0n.C Even preanalytical errors can contribute to the total error, as indicated by the following equation: TE =RE + SE + CE + PE (12-3) where RE [random error] SE [systematic error] CE [constant error] PE [proportional error] x, = * = I (a + bX - XI = bias I f t (sa /fi) = I R~C%- 100 I X t(n The coefficients of variation Cva and CVb,intra are convenient parameters for decisions at different concentration levels The preanalytical variance sm2 adds to the analytical variance sa2 In this case, cv, represents the total uncertainty q i n t m represents the coefficient of variation of the single source studied, whereas CVb.inter denotes the variation between a population of sources under investigation The root of the sum of the squared terms is equivalent to q,in Eq (12-5): ma 112 0b.intra (12-4) For group screening or screening of populations, cvinba must be replaced by the maximum variation of the regular mean setting point over all the sources investigated: (12-5) The total observed variation sTvis equal to the square root of the sum of the variance of the sources sb2, the analytical variance sa2, and the technical and biological preanalytical errors s2,, given by the following equation: (12-6) where the variation Srv is the variation observed within the regular range of measured values The reference value is consideres to be any value which is representative of a selected score of sources described by similar features cv, = (0.52 ~ "22), + C V2 ~ (12-7) and C V =~ (1.25 CVt,)" = 1.118 CVb (1 2-8) The minimum difference in concentration (Ac) to distinguish between two values on a significance level accordingto z-statistics: bi,tot 2 > [(ma + CVb.inm z2 I lR (12-9) where z is a multiple in z-statistic which depends solely on the probability selected for significance This value, derived from the Gaussian distribution, is 1.65 in the unidirectional case at a level of significanceof 95%, and 1.96 in the bidirectional case Any further optimization of the analytical reliability relative to the variability of the source is uneconomic for mass products of average quality 404 Appendices Harris Ratio The ratio between intraindividual and interindividual variation corresponds then to the so-called individuality index [I], or Harris ratio.h (12-10) For I > 1.4, comparison with the reference interval creates a large number of false-positive results; for I c 0.6, the comparison to the reference interval is of little value International Union of Pure and Applied Chemistry, Physical Chemistry Division (ed.), Quantities, Units and Symbols in Physical Chemistry Oxford: Blackwell Scientific Publ., 1988 International Federation of Clinical Chemistry (IFCC), International Union of Pure and Applied Chemistry, Approved Recommendations (1984)on Physico-Chemical Quantities and Units in Clinical Chemistry with Special Emphasis on Activities and Activity Coefficients, J Clin Chem Clin Biochem., 1987,25,369 Carey, R.N., Garber C.C., in: Kaplan, LA., Pesce, A.J., Clinical Chemistry, Theory, Analysis, and Correlation, St Louis: The C.V Mosby Company, 1984;pp 338-359 Young, D.S., Harris, E.K., Cotlove, E., Clin Chem., 1971,17,403 Harris, E.K., Am J Clin Pathol., 1979,72,374 College of American Pathologists (CAP) (ed.), Analytical Goals in Clinical Chemistry, Proceedings of the Aspen Conference on "Analytical Goals in Clinical Chemistry" 1976,Aspen, U.S.A g Fraser, C.G., JIFCC, 1990,2, 84 Harris, E.K., Clin Chem., 1975,21,1475 a Chemical Sensors and Biosensors for Medical and BiologicalApplications Ursula E Spichiger-Keller copyright WILEY-VCH Verlag GmbH, 1998 absorption - molar decadic coefficient 301 accufacy 345,401 - assessment 286,352 acridhes, ethenyl 10 activity 4,90,114 -molal 215 - IFCCAUPAC conventions 120 activity coefficient 90,117 - blood serum 206 - Debye-Hlickel convention 118 -human blood plasma 206,361 -patients 130 - Pitzer calculus 119 - Stokes-Robinson approximation 118 -volunteers 130 active molality 4,7,114,200,215 -abinitio 204 - IFCC/IUPAC conventions 120 - electrolytes in human plasma and serum 363 adsorption 184,298 - mechanism 186 affinity 71 alcohol dehydrogenase(ADH) 65 allowable analyticalemrs 365 amine 263 ammonia 10 amperometric sensors 19, 107, 199 -mediated 111 analyte , 3 analytical chemistry 1-4 analytical errors 160 analytical instruments analytical procedure 2-4 analyst 2-3 anion-selective optodes 275 antibodies - antigen interaction 71 -catalytic 70 anticoagulants 192 antithrombine III (see heparin) 192 application to - diluted plasma 285 Arrhenius equation 107 artefacts 211 artificial enzymes asymmetry - of membranes 205 - of the reference electrode 205,210 association - constant 95 AT-III Inhibitor 62 attenuated reflection (ATR) 300,152 - effective pathlength 300 - lanthanum fluoride crystal 302 - sapphire crystal 303 - set-up 302, 152 availability 345 avidity 71 azobenzene 272 Bates convention 118 Baysian theorem 330 Beer-Lambert law 299 benzo[a]phenoxazin 272 Berger diagram 329 bilayers 140 biocompatibility 183,189 biocompatiblematerials 212,249 - hydroxy-PVC, synthesis 376 biocopolymer 212 biological -adsorption 185 -activity 108 -matrix 183 - membranes 139,140 - setting points 363 biooptodes 280 biosensors 4,280, 199 - antigen-antibodies 71 -definition - generations 109 406 Index - graphical presentations 111 - immunological - mediated enzyme electrodes 106, 112 - Michaelis Menten constant 109 - apparent 111 - selectivity 7,67, 155 - turnover rate 109 - turnover number 109 biotechnology 10 blood plasma - potentiometry 206,227,238,248 Born cyclic process 94 Briggs-Haldane conditions 110 calcium - selective optode membrane 290, 152 - transmission spectrum 299 -ATR-spe~trum 303 - calculated dispersion spectrum 307 calibration - potentiometric electrodes 127 - scheme for real specimen 129 CAP postulates 346,350 carbon dioxide 10 carriers -chiralneutral 60 catalysis - electrophilic 64 -metalion 64 -nucleophilic 64 catalytic antibodies 9,70 catalytic rate constant 109 cation-selectiveoptodes 272 channel model 140 chemical analysis chemical effects 33 chemical information - (see information) 33 chemical potential 83,116 chemical sensors - analytical strategies - chemical potential 83,93 -control 83 -definition - reversibility 83 - recognition process 89 -thermodynamics 83 chemoreceptors chip technology 16-24 chiral neutral carriers 60 chloride - selective optode membrane 290 - selectiveelectrode 247 chromogenic ligands 41 chromoionophores 267,271 -neutral 271 clinical chemistry classifications 33 cluster analysis 342 Col-Cole Plot 150 compensation - enthalpy-mtropy 96 computationalchemistry 46 concentration 114 - mold 114,121 -1igand 176 - lipophilic counterions 173 - elecrrolytes - IFCCnUPAC conventions 120 -human blood plasma 363 continuous flow analysis - chloride-selective 251 - hydrodynamics 181 - magnesium-selective 239 -system 240 coronand 268 Coulomb potential 117 counter-ions, lipophilic 173 - optimum ratio 174 coupling efficiency 305 creatinine 1,267 cross-reactivity cryptahemispheraplexes 41 cyanme dyes 272,3 10 - streptocyanines 272,310 - neutrocyanines 10 - squarylium dye 272,310 data,hard 322 -data validation 321,331,361 Debye-Huckel - convention 118 -equation 118 - potential 117 -radius 116 -Theory 116 decision making 323, 361 dedicated system 2-4 depletion - analyte from sample 297 detection limit 179 - ion-selective microelectrodes 242 - magnesiumselective 243 diagnostic tests -planning 354 -parameters 361 - sensitivity 361 - selectivity 361 dicyanovinyl dyes 272,310 diffusion 104 -equilibrium 104 - limited response 151 - overall diffusion coefficient 151 -potential 134 dipole moments - plasticizers 165 discriminant analysis 340 discriminator 333 distribution, overall 89 Dixon-Hanes-Woolf 111 Donnan potential 103, 105, 187, 189 dry chemistry 270 dyes 272,310 dynamicrange 350 - ion-selective optodes 295 - ion selective electrodes 202 - microelectrodes 242 Eddie-Hofstree plot 111 effectiveness 325 - cost 345 efficacy 2-3,325,361 efficiency 3,325,361 electrochemical potential 99 electronic noses 20 electrode - combined catheter, pH- 248 - micro 16, 242 electrolytes 115 - conductivity 115, 134 - IFCCAUPAC conventions 120 - mobility 134 electromotoricforce (emf) 199 electron pair donor 169 electron pair acceptor 169 electrophoresis 116 electrostaticinteractions 186 enantiomers 58 environmentalchemistry enzymatic sensors 63 - generations 109 - graphical presentations 111 -mediated 112 - electron transfer 112 -enzymemimics 63 -optical 280 - Steady-shte 107 enzyme kinetics 106,108 enzyme linked optodes 280 equilibrium constants -optodes 282 equilibriumreaction 83 equitransferent solutions 135 errors - allowable analytical 349,402 - random 345,401 - systematic 345,401 -total analytical 345,401 erythrocytemembrane 216 ethanol 65,263 evanescent field 300 Eyring's rate theory 146 Faraday constant 99 Ficks diffusion 153 fish acute toxicity syndrome (FATS) 408 I&x flame atomic emission spectroscopy (FAES) 206 flow-through cell -optical 152 - potentiometric 240 fluorescein dye 272 fluorescence 263 fluoroionophores 268 flow-chart of electron transfer of mediated biosensors 112 forecasts 13-16 fouling 298 free analyte 4,7 frequency distribution 333 gas-selective optodes 278 gastricjuice, pH monitoring 246 Gibb's free energy 86 Gibbs-Duham equation 87 glucose 10,261,264 grating coupler 305 guest 11 guided wave 300,305 Hamaker constant 186 Hammett substituentconstant 67 Hanes plot 111 Harrisratio 350 Hawaiiancrabs hemodialysis 129,211 Hendersson equation 134 Henry's law 116 heparin 62,192 - influence, effect 192 - molecular recognition in aqueous media 62 high throughput analyzers history 10, 259,359 Hofmeister -behavior 91 -series 91 host 11, 39,41 -host reactand 41,63 humidity 10 hydrodynamics 181 hydrogen bonds 43,56 hydrogen sulfite 10 hydroxy-PVC 376 immobilization 297, 182 individualityindex 350 information 1-5,321 - acquisition 324 -base 323 -biological membranes 142 - entropy of 326 -gainin 327 -biological membranes 142 integrated chemical sensors 19 interaction, -s 41 - electrostatic 42, 186 -energies 42 -hydrophobic 44 - Lennard-Jones Potential 44,186 - van der Waals 43,186 interferometer,Mach-Zehnder 308 intracellular measurements 242 in vivotests ion channels 141 ionic strength 90, 117, 186 -bloodser~m 206 - calculation 117 -human blood plasma 206,227,363 - real specimen 130 ionophores - chloride-selective 247 - chromogenic 267 - magnesium-selective 225 - nitrite-selective 245 - pH-selective 246 ion-selective -electrodes 199,100 - materials and preparation 376 - synthesis of OH-PVC 376 - microelectrodes 242 I R - ~ p e ~ t r ~ s260 ~~py IUPAC quantities 321,401 ISES 9-10 ISFET 19 isoinformation curve 337 Kemp's triacid derivatives 62 Kohlrausch's law 115 Kramers-Kronig transformation 307 LASF 35 -crystal 302 leaching 297 Levich equation 108 lifetime 182 -optodes 296 Lifshits treatment 186 ligands 10,41, 176 -activity 90 - concentration profile 179 - inorganic ions 48 likelihood ratio 332,338 Linewaever-Burk plot 111 lipophilic sites, counterions 173 - anionic sites 173 - optimum ratio 174 lipophilicity 90, 173, 182,296 liquid junction -potential 202,134 long-term stability 296, 182 - chloride-selectiveelectrode 250 luminescence 26 Mach-Zehnder interferometer 308 magnesium concentration analysis -byAAS 217 - chelating agents 219 - fluorescence indicators 218 - intracellular measurements 18 - photometric assay 217 -31PMMR 219 - X-ray fluorescence 218 magnesium ion - active molality in blood plasma 227 - free molar concentration 227 - required selectivity coefficient 227 - selective electrode 215 - structure-breakingproperties 171 magnesium ion chelators 219,223,235 - antibiotics 226,228 - chlorophyll 222 - natural carriers 222 - noncyclic synthetic ligands 228 -peptides 226 - polyphosphates 224 - synthetic carriers 225 - teichoic acid 224 - tripodale ionophores 232,230 - ETH 3832 233,238 - modifications of ETHT 5506 235 - synthesis of ETHT 5506 387 - ETH 7025 230,392 - model calculations 229 magnesium-selective - continuous flow analysis 239 - electrodes - applications 237 - comparison 234 - interferences 239 - instruments and results 238 - pH correction 238 - pH buffering 238 - ionophores 387,392 - measurements - significance 241 -membranes 234 market 13 mass equilibria 92 measurand 31 mediator 112 -7"lT-TCNQ 112 medical analysis 10 medical assay -optodes 285 membrane - artificial (see solvent polymeric) 139, 144 -bilayer 140 -biological 139, 140 - composition 161 - Donnan potential 189 - electroneutrality 173,189 -environment 39,162,170 - hydrodynamics, surface 181 -medium 161 -optical 151 -permittivity 162 - solvent polymeric 144, 161 - specimen, aqueous 170 - surface tension 172 - thrombocytes 189 -transport 139 -active 139, 141 - facilitated 139 -passive 139 membrane models 145,179 -asymmetric 144 -optical 151 -bilayer 143 - concentration profiles 179 - electrical circuit 149 - mixed potential 148 - multilayer, segmented 145 - Nemst-Planck 134 -optical 151 - segmented 145,179 -symmetric 144 metabolites 267,280 metabolic pathway 68 method comparison - electrolyteconcentrations 127,287 micellar optode, reverse 280 Michaelis Menten kinetics 109 microelectrodes 17,242 - magnesium-selective 243 - nitrite-selective 245 milestones 359 miniaturization 16 - integrated optical sensors 304 -pHprobe 246 mixed potentials 115,148 mobility 115 models 8, 36 mold -activity 121 - real specimen - concentration 130 121 -water 119,128 - real specimen 130 -conductivity 115 molecular recognition process 38 - analytical tools 45 - antigen-antibody 61 - aqueous media 60 - enantiomers 58 -enzymes 63 - enzyme mimics 63 - inorganic ions 8,50 - multitopic - nucleic acids - nucleophiles 64 - organic ammonium ions 58,61 molecular modelling 46 - phosphate ligands 48 monactin 12 multiple internal reflection (MIRE) 300 -set-up 305 multivariateanalysis 339 NAD +-oxidoductase 65 nanoelectrdes 242 nanotechnology 16 Nemst equation 201 - diffusion layer 108 Nemst-Planck equation 134,146 neutral analytes 264,278,280 neutralcarriers 11 Nikolsky-Eisenman equation 200 NIR-absorbing dyes 309 nitrite-selective -electrode 245 -optode 275 nomenclature -electrolytes 120 - IFCC/IUPAC conventions 120 nonactin 12 nonideal behavior 117 nonthermodynamic assumptions 90, 114 Nyquist diagram 150 Index on-site analysis 1-4 optical - absorbance 299 - characteristics,inherent 261 - effects, intrinsic 260,261 - effects, extrinsic 260 - waveguide 299 optode, optrode 13,270 optodes 270 osmolality 124 - isotonic solutions 125 - human blood plasma 126 osmometry 125 osmotic pressure 87 osmotic coefficient 124 oxazine dyes 271,310 oximetry 13 oxygen 12-13,23,260 partition coefficient 84,89,282 partition equilibrium 83,89 permittivity 162,186 phases -aqueous 88 -hydrophobic 88 phosphorescence 261 photoacoustic spectroscopy 261 photolithographictechniques - miniaturized optical sensors 305 pH indicators 27 pH sensor 12-13,260 -miniaturized 246 - monitoring of gastricjuice 246 physical sensors 33 physical effects 33 piezoelectricresonator 20 Pitzer calculus 19 plasticizers 162,369,373 - electron pair donors 169 - electron pair acceptors 169 point of care testing - POCT 21,27,265,267 polymethines 310 411 polyurethane 212 potassium 11-12 - complexation 57 - selective optode membrane 290,303 potential -electric 99,199 - electrochemical 99 -chemical 83 potentiometric electrode 199 - chloride-selective 248,251 -cell 99 -notation 99 - combined pH-probe 248 - electromotoricforce 99, 199 - magnesium-selective 225 -micro- 242 potentiometry 199 - poteatiometriccell 200 - symmetric cell 203 principal component analysis 342 predictive value 339, 361 - positive 332,361 - negative 332,361 prevalence 332 protein - adsorption mechanism 186 - Lifshits treatment 186 - plasma composition - isoelectric point (IP) 190 - specific volume 190 proton motoric force 141 pulse oximetry 13 PVC - hydroxy 212 quality assessment - optode membranes 287,290 quartz crystal microbalance (QCM) 20 Raoult's law 116 rate-controlled reactions 106 reactand 41,63,263 real solutions 116 receiver operating characteristics 412 Index (ROC) 333,335 receptor -biotic 39 receptrodes 5-6 recognition process 33,38,89,93 reference -electrode 200,210 - half-cell 200 -material 287 -methods 288 - procedures 127 refractive index -effective 305 regression analysis - least squares 288 - Passing and Bablok 288 Reilly-Wood approximation 119 relevance 345 reliability 345 response function 179 - combined pH-probe 248 -optodes 282 - potentiometric electrodes 202,179 - miniaturizedpH-probe 248 results - false negative 333,361 - false positive 333,361 reverse micellar optode 280 reversibility 41, 83 - ion transfer catalysis 171 ruthenium(@ complexes 261 sample 1,88 - biological 206, 184 scanning electrochemical microscopy (SECM) 17 selectivity 7, 155,376 - anionic sites 173 - coefficient 201, 155,97 -required 160,383 -enzymes 7,67,155 - fixed interference method (FRM) 156 - ion-selectiveelectrodes 201,251 - ion-selective optodes 291 - lipophilic sites 173 - IUPAC recommendations 155 - mixed potential method 159 - separate solution method (SSM) 201, 376,383 - specific applied method ( S A M ) 158, 159,376 sensing layer 37,52 sensitivity - diagnostic 332,361 - optode membranes 295 sensor -array 19 -chip 17-24 - components 16 - development 10 - milestones 10 -model 8,36 - reaction, reversible 83 - recognition process 38 -transducers 34 Seralyzer 270 Simon optodes 270 sodium 11 - seIectiveoptode membrane 290 solvents 162, 369,373 - electron pair donors 169 - electron pair acceptors 169 solvent polymeric bulk membranes 161 - dielectric constant 162 -permittivity 162 specificity -diagnostic 332 specimen 1,88,184 - anticoagulants 192 -blood plasma 190,206,216,249,88 - compatibility 183 -erythrocytes 216 - thrombocytes 189 -urine 249 -whole blood 214 spec- calcium-selectiveoptode 299 specific partial volume Index - proteins, peptides 128 squaraine dye 272 stability constants 49,95 standard electrode potential 202 standardization - electrolytes 127 STAT-ION 215 steady-state 68,83, 104, 199 - current 108 Stokes-Robinson approximation 118 stop-flow analysis 376 - chloride-selective 250 - magnesium-selective 239 - hydrodynamics 181 structure elucidation 45 structure-selectivity relationship (QSSER) 68 substrates 63,264,278,280 sulfur dioxide 10 surface acoustic wave (SAW) 20 surface compatibility 183 - thrombocytes 188 - Donnan potential 189 surface tension 172 suitability test 353 symmetric potentiometric cell 203 - miniaturized 205 toxicity tests 4-6 toxic substances control act (TSCA) transport 139 -passive 139 -active 139, 141 -facilitated 139, 143, 144 transporter 140 ultramicroelectrode 17 uncertainty - a posteriori 327 -apriori 327 valinomycin 12,57 Van der Waals interactions 39 Van? Hoff plot 96 variation -biological 345,402 - analytical 345,401 volume replacement by proteins lipids 128 Warburg impedance 150 water concentration in biological specimen 128,130 waveguide 305,152 zinc-selective optode 269 teichoic acid 224 TekoflexB 212,249 thermodynamic equilibrium 83 -parameters 45 thermodynamics - irreversible 83, 105 - nonequilibria 105 -optodes 282 - reversible 83 - steady-state 105 - standard state 84 transducers 33,34 -optical 299 transmission mode 299 transduction 93 throughput 413 ... qualified researchers in Europe were expected to increase competiveness There are several reasons for the comparatively modest performance of Europe, which include: an unbalanced and fragmented distribution... (see 1.2 The Concept of Chemical and Biochemical Sensors Table 1-1 Features and benefits of chemical and biochemical sensors Features Benefits targeted specificity, selectivity versatility, dedicated.. .Ursula E Spichiger- Keller Chemical Sensors and Biosensors for Medical and Biological Applications @ WILEY-VCH Further titles of interest: W Gopel, J Hesse, J N Zemel (eds.) Sensors - A Comprehensive