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Label-Free Biosensors: Exploring the Field

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A special issue of Biosensors (ISSN 2079-6374).

Deadline for manuscript submissions: closed (31 December 2014) | Viewed by 98197

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Special Issue Editor

Dr. Andrew M. Shaw

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Guest Editor

Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter EX4 4QD, UK
Interests: protein array screening with applications; biomarkers of recovery and biomarkers of disease; antibody array screening with applications in vaccine validation; mechanisms of allergy and auto-immune diseases

Special Issue Information

Dear Colleagues,

The “label-free biosensor” has been claimed by many researchers as a name for a wide variety of technologies that range from mass spectrometers to whole-cell sensors. This Special Issue of Biosensors should attempt to define the field: “a Label-free biosensor must detect a whole biologically active molecule in real time”. Also, the specificity and sensitivity common to all assays must apply.

This definition allows for techniques to use naturally occurring chromophores or fluorophores, such as enzyme cofactors, to confer specificity. In contrast, Raman, SERS or CARS signatures need to have a specific transduction technology (other than localization or imaging). A specific transduction event, such as antibody capture of the target analyte, confers specificity to a number of technologies, including electrochemistry and surface plasmon resonance. While mass spectrometry is exquisitely sensitive and will detect molecules at exceptionally low concentrations, these molecules are not intact and, without some pre-selection, biological activity is difficult to establish.

Sensitivity is also a key requirement for a label-free biosensor. A whole-cell sensor contains the biological specificity required for a biologically active sensor, but interrogation is rarely in real time. Sensitivity must be defined against the normal range for the biological species that causes the biological effect or that defines a profile. For example, in the case of a biomarker, the sensitivity should be at least as good as the lower limit of the normal range, and also have a reasonably dynamic range to accommodate the upper limit. However, biologically or medically important discoveries often occur when the detection limit is significantly lower than the normal range.

Dr. Andrew M. Shaw
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biosensors is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

sensitivity
specificity
biological activity
transduction
detection
electrochemistry
surface plasmon resonance
localized particle plasmon resonance
CARS
SERS
mass spectrometry
whole-cell sensors

Published Papers (11 papers)

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Research

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980 KiB

Open AccessArticle

Experimental Validation of the Sensitivity of Waveguide Grating Based Refractometric (Bio)sensors

by Thomas E. Gartmann and Florian Kehl

Biosensors 2015, 5(2), 187-198; https://doi.org/10.3390/bios5020187 - 13 Apr 2015

Cited by 9 | Viewed by 7608

Abstract

Despite the fact that the theoretical foundations of the sensitivity of waveguide grating based (bio)sensors are well-known, understood and their implications anticipated by the scientific community since several decades, to our knowledge, no prior publication has experimentally confirmed waveguide sensitivity for multiple film thicknesses, wavelengths and polarization of the propagating light. In this paper, the bulk refractive index sensitivity versus waveguide thickness of said refractometric sensors is experimentally determined and compared with predictions based on established theory. The effective refractive indices and the corresponding sensitivity were determined via the sensors’ coupling angles at different cover refractive indices for transverse electric as well as transverse magnetic polarized illumination at various wavelengths in the visible and near-infrared. The theoretical sensitivity was calculated by solving the mode equation for a three layer waveguide. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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894 KiB

Open AccessArticle

Biconically Tapered Fiber Optic Probes for Rapid Label-Free Immunoassays

by John Miller, Angelica Castaneda, Kun Ho Lee, Martin Sanchez, Adrian Ortiz, Ekrem Almaz, Zuleyha Turkoglu Almaz, Shelton Murinda, Wei-Jen Lin and Ertan Salik

Biosensors 2015, 5(2), 158-171; https://doi.org/10.3390/bios5020158 - 01 Apr 2015

Cited by 9 | Viewed by 8396

Abstract

We report use of U-shaped biconically tapered optical fibers (BTOF) as probes for label-free immunoassays. The tapered regions of the sensors were functionalized by immobilization of immunoglobulin-G (Ig-G) and tested for detection of anti-IgG at concentrations of 50 ng/mL to 50 µg/mL. Antibody-antigen reaction creates a biological nanolayer modifying the waveguide structure leading to a change in the sensor signal, which allows real-time monitoring. The kinetics of the antibody (mouse Ig-G)-antigen (rabbit anti-mouse IgG) reactions was studied. Hydrofluoric acid treatment makes the sensitive region thinner to enhance sensitivity, which we confirmed by experiments and simulations. The limit of detection for the sensor was estimated to be less than 50 ng/mL. Utilization of the rate of the sensor peak shift within the first few minutes of the antibody-antigen reaction is proposed as a rapid protein detection method. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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1217 KiB

Open AccessArticle

Label-Free Imaging and Biochemical Characterization of Bovine Sperm Cells

by Maria Antonietta Ferrara, Giuseppe Di Caprio, Stefano Managò, Annalisa De Angelis, Luigi Sirleto, Giuseppe Coppola and Anna Chiara De Luca

Biosensors 2015, 5(2), 141-157; https://doi.org/10.3390/bios5020141 - 01 Apr 2015

Cited by 41 | Viewed by 8696

Abstract

A full label-free morphological and biochemical characterization is desirable to select spermatozoa during preparation for artificial insemination. In order to study these fundamental parameters, we take advantage of two attractive techniques: digital holography (DH) and Raman spectroscopy (RS). DH presents new opportunities for studying morphological aspect of cells and tissues non-invasively, quantitatively and without the need for staining or tagging, while RS is a very specific technique allowing the biochemical analysis of cellular components with a spatial resolution in the sub-micrometer range. In this paper, morphological and biochemical bovine sperm cell alterations were studied using these techniques. In addition, a complementary DH and RS study was performed to identify X- and Y-chromosome-bearing sperm cells. We demonstrate that the two techniques together are a powerful and highly efficient tool elucidating some important criterions for sperm morphological selection and sex-identification, overcoming many of the limitations associated with existing protocols. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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494 KiB

Open AccessArticle

Whispering Gallery Mode Resonators for Rapid Label-Free Biosensing in Small Volume Droplets

by Sarah M. Wildgen and Robert C. Dunn

Biosensors 2015, 5(1), 118-130; https://doi.org/10.3390/bios5010118 - 23 Mar 2015

Cited by 21 | Viewed by 6536

Abstract

Rapid biosensing requires fast mass transport of the analyte to the surface of the sensing element. To optimize analysis times, both mass transport in solution and the geometry and size of the sensing element need to be considered. Small dielectric spheres, tens of microns in diameter, can act as label-free biosensors using whispering gallery mode (WGM) resonances. WGM resonances are sensitive to the effective refractive index, which changes upon analyte binding to recognition sites on functionalized resonators. The spherical geometry and tens of microns diameter of these resonators provides an efficient target for sensing while their compact size enables detection in limited volumes. Here, we explore conditions leading to rapid analyte detection using WGM resonators as label-free sensors in 10 μL sample droplets. Droplet evaporation leads to potentially useful convective mixing, but also limits the time over which analysis can be completed. We show that active droplet mixing combined with initial binding rate measurements is required for accurate nanomolar protein quantification within the first minute following injection. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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1096 KiB

Open AccessArticle

Label-Free Detection of Rare Cell in Human Blood Using Gold Nano Slit Surface Plasmon Resonance

by Mansoureh Z. Mousavi, Huai-Yi Chen, Hsien-San Hou, Chou-Yuan-Yuan Chang, Steve Roffler, Pei-Kuen Wei and Ji-Yen Cheng

Biosensors 2015, 5(1), 98-117; https://doi.org/10.3390/bios5010098 - 23 Mar 2015

Cited by 32 | Viewed by 7455

Abstract

Label-free detection of rare cells in biological samples is an important and highly demanded task for clinical applications and various fields of research, such as detection of circulating tumor cells for cancer therapy and stem cells studies. Surface Plasmon Resonance (SPR) as a label-free method is a promising technology for detection of rare cells for diagnosis or research applications. Short detection depth of SPR (400 nm) provides a sensitive method with minimum interference of non-targets in the biological samples. In this work, we developed a novel microfluidic chip integrated with gold nanoslit SPR platform for highly efficient immunomagnetic capturing and detection of rare cells in human blood. Our method offers simple yet efficient detection of target cells with high purity. The approach for detection consists of two steps. Target cells are firs captured on functionalized magnetic nanoparticles (MNPs) with specific antibody I. The suspension containing the captured cells (MNPs-cells) is then introduced into a microfluidic chip integrated with a gold nanoslit film. MNPs-cells bind with the second specific antibody immobilized on the surface of the gold nanoslit and are therefore captured on the sensor active area. The cell binding on the gold nanoslit was monitored by the wavelength shift of the SPR spectrum generated by the gold nanoslits. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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579 KiB

Open AccessArticle

Label-Free Sensing of Adenosine Based on Force Variations Induced by Molecular Recognition

by Jingfeng Li, Qing Li, Lucio Colombi Ciacchi and Gang Wei

Biosensors 2015, 5(1), 85-97; https://doi.org/10.3390/bios5010085 - 19 Mar 2015

Cited by 11 | Viewed by 6762

Abstract

We demonstrate a simple force-based label-free strategy for the highly sensitive sensing of adenosine. An adenosine ssDNA aptamer was bound onto an atomic force microscopy (AFM) probe by covalent modification, and the molecular-interface adsorption force between the aptamer and a flat graphite surface was measured by single-molecule force spectroscopy (SMFS). In the presence of adenosine, the molecular recognition between adenosine and the aptamer resulted in the formation of a folded, hairpin-like DNA structure and hence caused a variation of the adsorption force at the graphite/water interface. The sensitive force response to molecular recognition provided an adenosine detection limit in the range of 0.1 to 1 nM. The addition of guanosine, cytidine, and uridine had no significant interference with the sensing of adenosine, indicating a strong selectivity of this sensor architecture. In addition, operational parameters that may affect the sensor, such as loading rate and solution ionic strength, were investigated. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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639 KiB

Open AccessArticle

Direct Determination of a Small-Molecule Drug, Valproic Acid, by an Electrically-Detected Microcantilever Biosensor for Personalized Diagnostics

by Long-Sun Huang, Christian Gunawan, Yi-Kuang Yen and Kai-Fung Chang

Biosensors 2015, 5(1), 37-50; https://doi.org/10.3390/bios5010037 - 27 Jan 2015

Cited by 11 | Viewed by 6748

Abstract

Direct, small-molecule determination of the antiepileptic drug, valproic acid, was investigated by a label-free, nanomechanical biosensor. Valproic acid has long been used as an antiepileptic medication, which is administered through therapeutic drug monitoring and has a narrow therapeutic dosage range of 50–100 μg·mL⁻¹ in blood or serum. Unlike labeled and clinically-used measurement techniques, the label-free, electrical detection microcantilever biosensor can be miniaturized and simplified for use in portable or hand-held point-of-care platforms or personal diagnostic tools. A micromachined microcantilever sensor was packaged into the micro-channel of a fluidic system. The measurement of the antiepileptic drug, valproic acid, in phosphate-buffered saline and serum used a single free-standing, piezoresistive microcantilever biosensor in a thermally-controlled system. The measured surface stresses showed a profile over a concentration range of 50–500 μg·mL⁻¹, which covered the clinically therapeutic range of 50–100 μg·mL⁻¹. The estimated limit of detection (LOD) was calculated to be 45 μg·mL⁻¹, and the binding affinity between the drug and the antibody was measured at around 90 ± 21 μg·mL⁻¹. Lastly, the results of the proposed device showed a similar profile in valproic acid drug detection with those of the clinically-used fluorescence polarization immunoassay. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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597 KiB

Open AccessArticle

Tracking Traction Force Changes of Single Cells on the Liquid Crystal Surface

by Chin Fhong Soon, Kian Sek Tee, Mansour Youseffi and Morgan C. T. Denyer

Biosensors 2015, 5(1), 13-24; https://doi.org/10.3390/bios5010013 - 05 Jan 2015

Cited by 4 | Viewed by 6538

Abstract

Cell migration is a key contributor to wound repair. This study presents findings indicating that the liquid crystal based cell traction force transducer (LCTFT) system can be used in conjunction with a bespoke cell traction force mapping (CTFM) software to monitor cell/surface traction forces from quiescent state in real time. In this study, time-lapse photo microscopy allowed cell induced deformations in liquid crystal coated substrates to be monitored and analyzed. The results indicated that the system could be used to monitor the generation of cell/surface forces in an initially quiescent cell, as it migrated over the culture substrate, via multiple points of contact between the cell and the surface. Future application of this system is the real-time assaying of the pharmacological effects of cytokines on the mechanics of cell migration. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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885 KiB

Open AccessArticle

Evaluating the Equilibrium Association Constant between ArtinM Lectin and Myeloid Leukemia Cells by Impedimetric and Piezoelectric Label Free Approaches

by Fernanda C. Carvalho, Denise C. Martins, Adriano Santos, Maria-Cristina Roque-Barreira and Paulo R. Bueno

Biosensors 2014, 4(4), 358-369; https://doi.org/10.3390/bios4040358 - 03 Oct 2014

Cited by 13 | Viewed by 7789

Abstract

Label-free methods for evaluating lectin–cell binding have been developed to determine the lectin–carbohydrate interactions in the context of cell-surface oligosaccharides. In the present study, mass loading and electrochemical transducer signals were compared to characterize the interaction between lectin and cellular membranes by measuring the equilibrium association constant, , between ArtinM lectin and the carbohydrate sites of NB4 leukemia cells. By functionalizing sensor interfaces with ArtinM, it was possible to determine over a range of leukemia cell concentrations to construct analytical curves from impedimetric and/or mass-associated frequency shifts with analytical signals following a Langmuir pattern. Using the Langmuir isotherm-binding model, the obtained were (8.9 ± 1.0) × 10⁻⁵ mL/cell and (1.05 ± 0.09) × 10⁻⁶ mL/cell with the electrochemical impedance spectroscopy (EIS) and quartz crystal microbalance (QCM) methods, respectively. The observed differences were attributed to the intrinsic characteristic sensitivity of each method in following Langmuir isotherm premises. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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1487 KiB

Open AccessArticle

Study of Paclitaxel-Treated HeLa Cells by Differential Electrical Impedance Flow Cytometry

by Julie Kirkegaard, Casper Hyttel Clausen, Romen Rodriguez-Trujillo and Winnie Edith Svendsen

Biosensors 2014, 4(3), 257-272; https://doi.org/10.3390/bios4030257 - 13 Aug 2014

Cited by 24 | Viewed by 8897

Abstract

This work describes the electrical investigation of paclitaxel-treated HeLa cells using a custom-made microfluidic biosensor for whole cell analysis in continuous flow. We apply the method of differential electrical impedance spectroscopy to treated HeLa cells in order to elucidate the changes in electrical properties compared with non-treated cells. We found that our microfluidic system was able to distinguish between treated and non-treated cells. Furthermore, we utilize a model for electrical impedance spectroscopy in order to perform a theoretical study to clarify our results. This study focuses on investigating the changes in the electrical properties of the cell membrane caused by the effect of paclitaxel. We observe good agreement between the model and the obtained results. This establishes the proof-of-concept for the application in cell drug therapy. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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Review

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2199 KiB

Open AccessReview

Modified Electrodes Used for Electrochemical Detection of Metal Ions in Environmental Analysis

by Gregory March, Tuan Dung Nguyen and Benoit Piro

Biosensors 2015, 5(2), 241-275; https://doi.org/10.3390/bios5020241 - 29 Apr 2015

Cited by 264 | Viewed by 20959

Abstract

Heavy metal pollution is one of the most serious environmental problems, and regulations are becoming stricter. Many efforts have been made to develop sensors for monitoring heavy metals in the environment. This review aims at presenting the different label-free strategies used to develop electrochemical sensors for the detection of heavy metals such as lead, cadmium, mercury, arsenic etc. The first part of this review will be dedicated to stripping voltammetry techniques, on unmodified electrodes (mercury, bismuth or noble metals in the bulk form), or electrodes modified at their surface by nanoparticles, nanostructures (CNT, graphene) or other innovative materials such as boron-doped diamond. The second part will be dedicated to chemically modified electrodes especially those with conducting polymers. The last part of this review will focus on bio-modified electrodes. Special attention will be paid to strategies using biomolecules (DNA, peptide or proteins), enzymes or whole cells. Full article

(This article belongs to the Special Issue Label-Free Biosensors: Exploring the Field)

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