Functional Nanomaterials and Nanostructures Enhancing

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Cite This: Chem. Rev. 2019, 119, 120−194

Functional Nanomaterials and Nanostructures Enhancing Electrochemical Biosensors and Lab-on-a-Chip Performances: Recent Progress, Applications, and Future Perspective Nongnoot Wongkaew, Marcel Simsek, Christian Griesche, and Antje J. Baeumner*

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Institute of Analytical Chemistry, Chemo- and Biosensors, University of Regensburg, 93053 Regensburg, Germany ABSTRACT: Electrochemical biosensors and associated lab-on-a-chip devices are the analytical system of choice when rapid and on-site results are needed in medical diagnostics and food safety, for environmental protection, process control, wastewater treatment, and life sciences discovery research among many others. A premier example is the glucose sensor used by diabetic patients. Current research focuses on developing sensors for specific analytes in these application fields and addresses challenges that need to be solved before viable commercial products can be designed. These challenges typically include the lowering of the limit of detection, the integration of sample preparation into the device and hence analysis directly within a sample matrix, finding strategies for long-term in vivo use, etc. Today, functional nanomaterials are synthesized, investigated, and applied in electrochemical biosensors and lab-on-a-chip devices to assist in this endeavor. This review answers many questions around the nanomaterials used, their inherent properties and the chemistries they offer that are of interest to the analytical systems, and their roles in analytical applications in the past 5 years (2013−2018), and it gives a quantitative assessment of their positive effects on the analyses. Furthermore, to facilitate an insightful understanding on how functional nanomaterials can be beneficial and effectively implemented into electrochemical biosensor-based lab-on-a-chip devices, seminal studies discussing important fundamental knowledge regarding device fabrication and nanomaterials are comprehensively included here. The review ultimately gives answers to the ultimate question: “Are they really needed or can bulk materials accomplish the same?” Finally, challenges and future directions are also discussed.

CONTENTS 1. Introduction 2. Electrochemical Biosensors 2.1. Definition 2.2. General Layout 2.3. Electrode Materials and Their Performances 2.4. Electrochemical Biosensor Detection Strategies 2.4.1. Potentiometry 2.4.2. Voltammetry 2.4.3. Impedance Spectroscopy 2.4.4. Conductometry 2.4.5. Stripping Techniques 2.5. Integration with the Biorecognition Element 2.6. Biosensor Assay Strategy: Labeled vs Labelfree 2.7. Current Most Prominent Application Fields of Electrochemical Biosensors 2.8. Dealing with Challenges of Real-World Samples: Avoiding Interferences 2.9. Biosensors Require High Stability for LongTerm Analyses 3. Electrochemical Lab-on-a-Chip Systems 3.1. Definition 3.2. Design of Lab-on-a-Chip Systems © 2018 American Chemical Society

3.2.1. Materials and Fabrication 3.2.2. Integration of Sample Preparation 3.2.3. On-Chip Electrochemistry 4. Which Chemistries Do Nanomaterials Offer for Electrochemical Sensing? 4.1. Nanomaterials Made of Metals and Metal Oxide 4.2. Nanomaterials Based on Carbon and Nitrogen-Doped Carbon 4.3. Nanomaterials Based on Conducting Polymers 5. Functional Nanomaterials 5.1. Overview of Nanomaterials and Nanostructures Relevant to Electrochemical Sensing 5.1.1. Zero-Dimensional (0-D) Nanomaterials 5.1.2. One-Dimensional (1-D) Nanomaterials 5.1.3. Two-Dimensional (2-D) Nanomaterials 5.1.4. Three-Dimensional (3-D) Nanomaterials 5.1.5. Nanostructured Arrays 5.1.6. Hybrid Nanostructures

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Special Issue: Chemical Sensors Received: March 19, 2018 Published: September 24, 2018 120

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Chemical Reviews 5.2. Roles of Nanomaterials and Nanostructures (from 2013 to 2018) 5.2.1. Application for Sample Preparation (Examples) 5.2.2. Application for Immobilization (Examples) 5.2.3. Applications for Signal Enhancement (Examples) 5.2.4. Other Potential Applications 5.3. Integration of Nanomaterials or Nanostructures into Microfluidic Systems 5.3.1. In Situ Integration Strategy 5.3.2. Ex Situ Based Strategy 6. Challenges and Future Potential Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

Review

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Figure 1. Electrochemical biosensors and lab-on-a-chip devices. The photograph of the microfluidic chip was reprinted with permission from A. Georgescu. Copyright 2015 Andrei Georgescu.

1. INTRODUCTION The first biosensor concept was published in 1962 by Clark and Lyons1 and demonstrated the use of the Clark oxygen electrode as selective transducer for the detection of an enzymatic reaction, i.e. the oxidation of glucose by glucose oxidase (GOx). Since then, glucose biosensors have become the most studied and commercially most viable on-site, overthe-counter, rapid diagnostic tests. Still today, more than 50 years after its initial conception and its many advances, research is going strong, pursuing sensors that reliably detect glucose in tear fluid or can be implanted together with an insulin pump. The same success story is needed for a myriad of other analytes that often are more difficult to detect as they are available in significantly lower concentrations, as no equally excellent and specific biorecognition element (BRE) is available, or as the matrix may be yet more demanding. Nowadays, biosensors have become a valuable tool in a number of applications beyond the well-known glucose sensor. These include monitoring of treatment and progression of diseases, environmental monitoring, food safety concern, drug development, forensics, and biomedical research. In some cases, analytes in samples can be directly detected by the sensor unit without the need of sample preparation, for example, the online monitoring of hazard chemicals in disposed wastewater and cell-based bioassays. On the other hand, some samples may require more complicated preparation processes in order to isolate and/or enrich the target analytes with minimal interfering species prior reaching the sensor unit that ultimately enhances analytical performance. Lab-on-a-chip (LOC) is a platform that allows these modules to be integrated (Figure 1), providing a robust automated system for desired applications. This review discusses the possibilities functional nanomaterials can offer to the development of improved electrochemical biosensors and their associated LOC systems. Nanomaterials were already used long before the term was coined and before it became trendy.2,3 For decades now, colloidal gold has been the standard ingredient of most commercial lateral-flow tests, liposomesalso termed nano-

vesicles these daysshowed their superior signal generation capabilities in electrochemical sensors already in the 1990s, and enhancement through silver deposition was used for analytical purposes already in the 1970s. Thus, what kind of nanomaterials are synthesized today that are presumably so special for electrochemical biosensors and LOC devices? Which inherent properties do they offer; which chemistries do they make available for required functionalizations? How are they applied in biosensors? The ultimate question to be asked is, are they truly useful or can bulk materials provide the same result in the end when all optimization has been done? To facilitate readers’ insightful understanding on how functional nanomaterials can be beneficial and effectively implemented into electrochemical biosensor-based LOC devices, seminal studies (often publications older than 5 years) are comprehensively included. These provide important fundamental basics regarding device fabrication and critically relevant information on nanomaterials. So that the reader can find answers to these questions, this review is structured as follows: In section 2, electrochemical biosensors are defined, described, and put into context with respect to their analytical use. Material choices, immobilization chemistries, and biorecognition molecules are briefly discussed. Further described are the various electrochemical transduction principles and possible assay formats. Typical application areas are presented. In section 3, the same information is provided for LOC systems with special emphasis on material choices, and the added analytical capabilities offered by the miniaturized systems such as sample preparation and on-chip detection. In section 4, chemistries offered by the nanomaterials that are of interest to the analytical systems are discussed in detail. The focus is on metals and metal oxides, the various carbon nanomaterials and conducting polymers (CPs). Section 5 is the heart of the review. First, in section 5.1, an overview is provided of nanomaterials and nanostructures relevant to electrochemical biosensors. Zero-dimensional (0D) to three-dimensional (3-D) materials and nanoarrays are included here. This subsection includes an important table 121

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Figure 2. Layout of an electrochemical biosensor. In the case of analytes and biorecognition elements (BREs), only examples are given; especially the list of analytes is much longer (please also refer to Figure 1).

2.3. Electrode Materials and Their Performances

(Table 5) in which the nanomaterials are further summarized with respect to electrochemical performance, function, improved property, and where applicable and available. In section 5.2, relevant example publications from 2013−2018 are discussed in detail, and an enhancement factor in comparison to non-nanomaterial based approaches is given. In section 6, the review finishes with a discussion of remaining challenges and future directions. Electrochemical biosensors and LOC devices have to provide a large variety of analytical capabilities so that analytes can be detected specifically within a complex matrix. There is no limit to the variety of sample matrixes and the nature of the analyte for current and future developed analytical systems (Figure 1).

A variety of electrode materials ranging from noble metals to carbon to conductive polymers is available to enable specific biosensing applications. Noble metals (platinum, gold, silver) are often used due to their excellent conductivity and superior electron transfer kinetics. Moreover, those metals also possess a high stability and (except for silver) inertness. Since gold lends itself well to microfabrication and immobilization strategies, it is a highly favored biosensor material that can be used reliably between −0.1 and 1.3 V.7 Mercury, the most common electrode material in polarography, has limited applications in biosensors due to its inherent toxicity.8 Semiconductors such as indium tin oxide (ITO) gained much attention as electrode materials as they are cheaper than noble metals, transparent, and easy to process. Their potential window is larger than that of gold (−0.4 to 1.9 V). However, ITO has a significantly lower conductivity (104 S cm−1 vs 107 S cm−1)9,10 and is unstable in acidic environments.7 Also the electron transfer kinetics of ITO are typically worse than those of noble metals or glassy carbon.11,12 Carbon based electrodes include a variety of materials divided by the respective hybridization of the carbon atoms. Graphite, from simple graphene sheets to highly oriented pyrolytic graphite (HOPG), contains sp2 hybridized carbon atoms, whereas diamond is made up by sp3 hybridized carbon atoms. For the latter one to gain higher conductivity, doped diamond structures are developed, e.g. boron-doped diamond.13,14 Glassy carbon is one of the most popular carbon materials for application as an electrode as it can be easily processed and has a large usable potential range (ca. −0.4 to 1.7 V).7,15 Carbon electrodes are known to work best with organic redox molecules, but a major drawback is their inherent reactivity, which may cause problems with nonspecific reactions in complex sample matrixes. Electrodes made of CPs such as poly(3,4-ethylenedioxythiophene) (PEDOT),16,17 polyaniline (PANI), or polypyrrole (PPy)18 are typically chosen for offering mechanical flexibility or optical transparency. Yet, their conductivity and electroactivity typically are worse than those of noble metals and carbon materials. Also, long-term water stability can be a problem.19 The properties of the discussed electrode materials are summarized in Table 1.

2. ELECTROCHEMICAL BIOSENSORS 2.1. Definition

A biosensor is a device which contains a BRE that interacts with an analyte from a sample leading to a chemical/physical property change, which a transducer converts into a measurable signal. Moreover, an electrochemical biosensor according to IUPAC is defined as “a self-contained integrated device, which is capable of providing specific quantitative or semi-quantitative analytical information”.4 It should be noted that most DNA or protein biosensor-based electrochemical detection reported in the literature typically refer to “sensing systems” or “(bio)analytical assays”, involving discontinuous operation steps prior to data acquisition (the top loop in Figure 1), rather than “true biosensors”, acquiring information continuously (the bottom loop in Figure 1).5 2.2. General Layout

The biochemical receptor, such as an antibody, nucleic acid, enzyme, cell or receptor molecule, is ideally retained in direct spatial contact with an electrochemical transduction element (Figure 2) and must meet strict requirements with respect to sensitivity and selectivity toward a target analyte especially when contained at low concentrations in complex sample matrixes such as blood, food samples, or wastewater.6 Electrochemical signal transduction can occur through the measurement of current, potential, conductance, or field effect and is realized in either a label-free or labeled approach. Catalytic BREs, such as enzymes and cells, can produce electrochemically active products and afford, therefore, direct electrochemical detection. In the case of affinity BREs, labeled and label-free approaches can be realized in which nanomaterials play a fundamental role not only as labels but also as electrode material.

2.4. Electrochemical Biosensor Detection Strategies

2.4.1. Potentiometry. In potentiometry a potential difference between two half-cells (reference electrodes, REs) is measured. No current is flowing. The most prominent potentiometric sensors are ion-selective electrodes in which a membrane provides for the ion-selective response. The concept can also be used for the detection of gases and 122

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sophisticated approaches vary the potential over time to obtain better signal-to-noise ratios (such as differential pulse voltammetry (DPV) and square-wave voltammetry (SWV)) or to obtain analytical information on the redox reaction (cyclic voltammetry, CV). It can be a reliable method to determine analyte concentrations, reaction kinetics, diffusion properties, the size of an electrode, etc.24 2.4.3. Impedance Spectroscopy. Electrochemical impedance spectroscopy (EIS) is performed by monitoring the impedance, a frequency dependent resistance, after an electrical stimulation (voltage or current) in the ac mode. Some mathematical calculations are necessary to evaluate experimental results in comparison to an equivalent electrical circuit. EIS can deliver on the electrochemical characteristics of a studied system, which can be conductivity, reaction rates, dielectric constants, or mass transport.25,26 2.4.4. Conductometry. Based on Ohm’s law, conductance is the inverse value of resistance measured in dc mode. The resulting sensors are often referred to as chemiresistors and typically serve to measure conductivity changes within the bulk of an electrochemical cell, for gas sensing or enzyme-based strategies.27−29 2.4.5. Stripping Techniques. Stripping techniques involve an analyte preconcentration step raising the following detection to high sensitivity levels which makes trace-level analysis possible. After preconcentration the molecules are stripped off the electrode by electrochemical oxidation or reduction. The stripping analysis includes a variety of techniques related to voltammetry or potentiometry broadening the range of applications.30−32

Table 1. Examples of Electrode Materials and Their Properties electrode material

potential window/V

conductivity/S cm−1

gold

−0.1 to 1.3

ITO

−0.4 to 1.97

1049

carbona

−0.4 to 1.77

10315

conducting polymersb

−1.0 to 1.016

up to 10317

7

10

710

advantages inert, reusability, preparation of SAMs, easy to clean electrochemical stable, cheap, transparent solvent resistance, reproducible, mechanical stability, biocompatible low cost, adjustable redox activity, transparent, flexible

a

The potential window and the conductivity are given for glassy carbon. bThe potential window and the conductivity are given for PEDOT:PSS (poly(3,4-ethylenedioxythiophene) polystyrene sulfonate).

biomolecules.20,21 In most cases potentiometric sensors are chemosensors; however, when combined with a bioselective separation process they can also be assembled to be full biosensors.22 In field-effect transistors (FETs) the same principle is being applied through the measurement of ions present in the gate electrode area of the FET.6 As discussed by Jiri Janata in 2012,23 there has been a renewed interest in electrolyte-gated field-effect transistors; however, serious controversy exists with regard to the validity of FET (bio)sensing. Janata points out that the nonpolarized nature of, e.g., graphene/electrolyte interfaces does not allow direct measurement of interfacial charges albeit claimed by numerous FET biosensor publications. He proposes a small number of control experiments required to demonstrate actual FET sensing of the analytes rather than reporting likely measurement artifacts. The inclusion of FET sensors in this review does not imply their endorsement, but they were chosen as these introduce interesting and relevant functional nanomaterials. The readers interested in FET sensing are referred to Janata’s publication from 2012 for an in-depth discussion of this controversy. 2.4.2. Voltammetry. Voltammetric techniques are typically based on the application of a potential between a working electrode (WE) and an RE. A current is flowing and measured between a counter electrode (CE) and the WE as a result of reduction/oxidation processes at the surface of the electrodes. In its most simple form, a constant potential is applied and current is either measured at a specific time (amperometry) or integrated over a period of time (coulometry). Various more

2.5. Integration with the Biorecognition Element

According to the stringent IUPAC definition of biosensors, the BREs must be in intimate contact with the transducer. However, oftentimes, BREs can also be immobilized within other areas of the biosensor, or are not immobilized at all. In most instances, though, an appropriate immobilization strategy must be found that results in a highly functional and stable BRE that can provide specific reactions with the analyte. Typical strategies include adsorption/physisorption, covalent binding, membrane entrapment, embedment in gels/hydrogels, physisorption of thiol groups to gold, and combinations thereof. The standard chemical methods with the most important advantageous and disadvantageous characteristics are listed in Table 2. Furthermore, immobilization via biological functions can be achieved through histidine tags, biotinylation, DNA tags, and antigen tags.33 New strategies also include specific peptide

Table 2. Comparison of Standard Immobilization Methods immobilization method

biorecognition element

adsorption

small molecules

covalent binding

principle

examples

advantages

disadvantages

proteins, antibodies/antigens

simple, quick

weak forces, leakage, low reproducibility

proteins

van der Waals force, hydrophobic force, hydrogen bonds, ionic interaction electron sharing (functional groups)

−NH2, −COOH, −SH, −OH, imidazole, phenol, phosphate

irreversible (strong), mild

cross-linking

proteins, enzymes

two functional groups of cross-linker connect BRE to transducer

carbonyldiimidazole, SAM glutaraldehyde, EDC, NHS

entrapment

cells, proteins

restrain due to steric hindrance in matrix or membranes

polyacrylamide, gelatin, polyvinyl alcohol, alginate

many cross-linker options, simple, quick, mild conditions simple, quick

conformation change of BRE, molecular architecture difficult inter/intramolecular linking, sizing restrictions

123

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Figure 3. Examples of label-free and labeled assays.

biomedical research, among others. The simplicity of the required hardware combined with an inherent sensitivity resulted in early commercialization of electrochemical biosensors such as the glucose sensor, e.g. the i-STAT (Abbott Diagnostics), and biological oxygen demand sensors.43,44 In contrast to optical sensors, electrochemical biosensors can be employed in sample matrixes with high optical density, can easily be implanted and remote controlled, and offer minimal material costs. Typical examples are analyses in blood, serum, saliva, and urine;45−47 sweat and tear fluid are more recent developments.48,49 Future objectives are the commercialization of implantable and wearable sensors, e.g. temporary tattoos, or wearables such as contact lenses, eyeglasses, and mouth guards.50−53 In food and beverage analyses, bacterial contamination and toxic ingredients are of greatest interest, but many biosensors are also available to determine food ingredients such as carbohydrates, alcohols, carboxylic acids, biogenic amines, or adulterations such as antibiotics, herbicides, or pesticides. One of the current trends points toward the rapid, in-package determination of food freshness.54 In the case of environmental monitoring, long-term stability, autonomous systems, and wireless communication strategies are of greatest interest. Early examples included pesticide monitoring systems using flow-injection approaches (without wireless transmission)55 and today include the detection of microorganisms, organic and inorganic pollutants such as pesticides, dioxins, hormones, aromatic compounds, antibiotics, toxins, and polychlorinated biphenyls, metals, nitrate, and inorganic phosphate.56 Trends point also toward the detection of safe drinking water and determination of communal parameters in wastewater.57−60

sequences to promote binding to various sequences including cellulose, polystyrene (PS), agarose, and many more. For example, cellulose binding domains can be used to create fusion proteins or to immobilize whole living cells. The application of cellulose as a substrate is beneficial for developing biocompatible systems as it is inert and biologically degradable.34 Examples of other successful bioaffinity tags are given in the review by Terpe.35 2.6. Biosensor Assay Strategy: Labeled vs Label-free

Label-free electrochemical biosensors can monitor the biological reaction that occurs upon BRE-analyte reaction/binding directly. Examples include impedance and potentiometric based sensing, which are mostly performed label-free. Typically, these methods use DNA hybridization,36,37 aptamers,38 and also immunoassays,39 depicted in Figure 3, but also molecular imprinted and enzymatic approaches are done. Voltammetry-based techniques can be employed for label-free assays where the electrochemical signals are generated from oxidation or reduction of intrinsic electroactive components of (bio)analytes, e.g. nitrogenous bases in nucleic acids,5 and amino acids in proteins.30 In addition, the alteration of a BRE’s conformation driven by the binding of analytes that subsequently influences the accessibility of redox probes can be used. Alternatively, the label-free approach may not be feasible, not sensitive enough, or not appropriate for a chosen transduction principle. In these instances, different strategies are employed in which ultimately a label provides the electrochemical signal. These can be typical sandwich assays,40 sensors utilizing molecular beacons,41 or electrochemically active DNA intercalators.42 The respective strategies are also depicted in Figure 3. 2.7. Current Most Prominent Application Fields of Electrochemical Biosensors

2.8. Dealing with Challenges of Real-World Samples: Avoiding Interferences

Electrochemical biosensors are employed especially in areas in which in-field, point-of-care, or on-site sensing is necessary as they are easy to miniaturize and the required hardware is inexpensive and reasonably simple in comparison to optical approaches. This includes health care, food analysis, food safety, environmental monitoring, bioprocess industry, and

Each analytical technique is only as good as it is in avoiding false-positive and false-negative results. The conditions that interfere with the BRE in electrochemical biosensors are the same as for any other biosensor system. Further concerns are those components that directly interfere with the electro124

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3.2. Design of Lab-on-a-Chip Systems

chemical transducer. This can be divided into two categories: (1) electrode fouling and (2) nonspecific signal-producing reactions with the transducer. Electrode fouling refers to unspecific adsorption of molecules from a sample solution that leads to a blocking of the electroactive surface, which results in a loss of sensitivity and selectivity and can ultimately lead to false-negative signals. Some electrode materials allow (electro)chemical cleaning or polishing of the electrode surface for reuse; however, typically it is advisible to prevent the electrode from fouling, e.g. by electropolymerizing a protective film on its surface, protecting it with a membrane, or preblocking it with defined molecules such as bovine serum albumin (BSA).61,62 Nonspecif ic signal generation is caused by molecules of the sample matrix that undergo electrochemical reactions with the electrode and hence produce false-positive signals or misrepresent the concentration of actual analyte in the sample by providing a higher signal. This makes the quantification of the target analyte difficult and is typically more problematic in label-free assays. General strategies to avoid any type of interference include sample pretreatment to remove most of the undesired matrix molecules before the actual measurement, avoid unspecific interaction by means of a blocking agent, such as BSA, or by membranes/coatings on the electrode, which repel interferants by electrostatic interaction or permeability.63 Much research is required (as for any other analytical method) to ensure specific signal generation, and much research has been published about avoiding interferences.64 In the case of voltammetric sensors, a general trend is to use low detection potentials, and in most electrochemical systems ionic strength and temperature must be paid attention to.

As LOC systems enable the complete analysis of a sample, the components of each system are chosen according to the analysis. Usually LOC systems contain microfluidic channels for the transportation of the sample. In addition to the microfluidic system, several functionalities are combined on an LOC system according to the analytical problem. The most important features integrated into analytical LOC systems are sample preparation, separation, and a detection system. 3.2.1. Materials and Fabrication. Fabrications of LOC systems from a variety of materials are reported (Figure 4 and

2.9. Biosensors Require High Stability for Long-Term Analyses

Electrochemical transducers provide typically an inherent longterm stability, and little specific care has to be taken to ensure functionality throughout storage. Instead, in most cases longterm stability is determined by the BRE associated with the transducer and not by the transducer itself. However, electrode fouling must be controlled or cleaning procedures evaluated for long-term use. Here, noble metal electrodes typically outperform other electrodes as simple chemical and electrochemical cleaning procedures are available. Glassy carbon electrodes (GCEs) are regenerated through polishing procedures, but electrodes made of screen-printed surfaces or organic polymers typically lend themselves better to single-use. Microfabricated electrodes can also suffer from detachment upon high current flows and extreme potential uses and have a significantly more limited lifetime than macroelectrodes.65

Figure 4. Schematic presentation of the relationship between fabrication costs of LOC devices using common materials and fields of application. (1) Reproduced from ref 73. Copyright 2017 American Chemical Society. (2) Reproduced from ref 74. Copyright 2017 American Chemical Society. (3) Reproduced from ref 75. Copyright 2011 American Chemical Society. (4) Reproduced from ref 76. Copyright 2012 American Chemical Society.

Table 3). The first microfluidic devices were fabricated with inorganic substrates such as silicon or glass. With ongoing research and increasing popularity in the field of microfluidics, polymers became the most common substrate for the fabrication of LOC systems. More recently, LOC systems based on paper have been described. Three main factors have to be taken into account when designing the microfluidic system: required function, degree of integration, and application.68 A brief overview of LOC materials with respect to their characteristics and fabrication techniques is given in Table 3. Each material for fabrications of LOC systems has its pros and cons (shown in Table 4) that have to be taken into consideration for proper applications. Excellent comprehensive reviews about the fabrication of microfluidic chips have been published recently.68−72 3.2.2. Integration of Sample Preparation. When handling real samples, a variety of the sample characteristics can disturb the detection. Typically, interfering species, complex matrix effects, or nonspecific binding affect the detection signal in a negative manner up to a disabled analysis. One strategy to reduce matrix effects and unspecific binding is

3. ELECTROCHEMICAL LAB-ON-A-CHIP SYSTEMS 3.1. Definition

LOC is a device which is capable to scale down laboratory functions to a chip format up to a range of only a few square centimeters.66 An LOC platform integrates and automates different laboratory functions. For analytical LOC systems, as here reviewed electrochemical LOC, the term “miniaturized” or “micro total analysis system” (μTAS) is often used as a synonym. Manz et al. defined μTAS as a total analysis system performing all sample handling steps extremely close to the place of measurement.67 125

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Table 4. Evaluation of Practicability of LOC Materials for Use in Biosensor-Related Applications71

82−84, 88, 89 90

applications

$20−25/kg