Elsevier

Biosensors and Bioelectronics

Volume 76, 15 February 2016, Pages 164-179
Biosensors and Bioelectronics

Progress in chemical luminescence-based biosensors: A critical review

https://doi.org/10.1016/j.bios.2015.06.017Get rights and content

Highlights

  • Biosensors are a very active research field.

  • Several biosensors based on chemical luminescence have been described.

  • We present advances in the field and discuss approaches, challenges, and open issues.

Abstract

Biosensors are a very active research field. They have the potential to lead to low-cost, rapid, sensitive, reproducible, and miniaturized bioanalytical devices, which exploit the high binding avidity and selectivity of biospecific binding molecules together with highly sensitive detection principles. Of the optical biosensors, those based on chemical luminescence detection (including chemiluminescence, bioluminescence, electrogenerated chemiluminescence, and thermochemiluminescence) are particularly attractive, due to their high-to-signal ratio and the simplicity of the required measurement equipment.

Several biosensors based on chemical luminescence have been described for quantitative, and in some cases multiplex, analysis of organic molecules (such as hormones, drugs, pollutants), proteins, and nucleic acids. These exploit a variety of miniaturized analytical formats, such as microfluidics, microarrays, paper-based analytical devices, and whole-cell biosensors. Nevertheless, despite the high analytical performances described in the literature, the field of chemical luminescence biosensors has yet to demonstrate commercial success.

This review presents the main recent advances in the field and discusses the approaches, challenges, and open issues, with the aim of stimulating a broader interest in developing chemical luminescence biosensors and improving their commercial exploitation.

Introduction

Chemical luminescence-based biosensors can exploit the measurement or imaging of the light emitted by a bio-chemiluminescence (BL, CL), thermochemiluminescence (TCL), or electrogenerated chemiluminescence (ECL) reaction. They offer an interesting and powerful alternative or complementary approach with respect to other optical biosensors, based on light absorption or photoluminescence, and different transduction principles (Roda and Guardigli, 2012).

The main advantage is their potentially high detectability. The photons are produced in the dark by a chemical reaction and are therefore easily and efficiently measurable without any nonspecific signal, such as that derived from the photoexcitation source in photoluminescence.

The light emitted by chemical luminescence derives from an exergonic chemical reaction yielding an intermediate in its singlet excited state, which undergoes radiative decay. Much effort has been dedicated to increasing light output yield, which is directly related to the quantum yield of the reaction. Despite rather low quantum yield values (about 0.01 for CL reactions), detectabilities down to attomoles can be reached when these labels are used in immunoassays or gene probe assays. Indeed, in the clinical chemistry field, chemical luminescence labels are most widely used in commercial ultrasensitive immunoassays.

Nevertheless, chemical luminescence biosensors have not significantly evolved from research laboratory prototypes to the marketplace. This is despite the very promising features of chemical luminescence detection techniques and continuous advances in the fields of chemistry, micro/nanotechnologies, nano-biotechnology, molecular biology, and microelectronics. Very few chemical luminescence biosensors are commercially available. The outlook becomes more positive if we consider those biosensors where analyte detection is not achieved in real-time and where all-in-one self-standing devices are not used (Park and Kricka, 2014).

The attraction of biosensor research is the possibility of producing miniaturized, multiplexing biosensors, suitable for use in any environment, and which can give semi-quantitative information in a few minutes at a relatively low cost. Point-of-need or point-of-care devices are the most challenging, since they require the minimum use of analytical steps, addition of reagents, and fluid manipulation. The ever growing use of nanotechnology and microfluidics technology could expand the potential of such devices (Marquette and Blum, 2011).

In this review we will critically evaluate the current outlook for chemical luminescence biosensors in terms of analytical performance, format, and light detection systems. In particular the review will be divided into three sections. The first will be about the light detection technologies for measuring luminescent signal, than we will discuss the different chemical-luminescence-based probes and labels focusing on the latest progress in this field. Finally we will report different biosensor format pointing out the pros and cons of the different analytical platforms. We will seek to clarify why, despite their enormous potential, these principles have not been translated into the commercial realm, with the exception of ECL-based biosensors and BL cell-based biosensors. To date, the chemical luminescence methods developed have not been defined as biosensors. But they could merge into this category if the definition of biosensors is extended, as has been observed in many recent publications in the field.

Section snippets

Light detection technologies for biosensing

The main requisite of chemical luminescence measurements is the ability to collect as much light as possible to achieve the highest detectability. In contrast to photoluminescence, where the optics geometry is crucial to minimizing the excited light interference, a much-simplified optics can be used. Several technological solutions have been proposed for ultrasensitive chemical luminescence detection in biosensors and bioassays (Fig. 1).

Chemiluminescence

In CL, the chemical reaction responsible for photon emission is simply triggered by mixing the reagents. This phenomenon has been exploited in a variety of bioanalytical formats including microtiter plate (96- and 384-well), microarrays, microfluidics, paper-based devices, and in vitro microscopy imaging (Marquette et al., 2012, Seidel and Niessner, 2014, Mirasoli et al., 2014b). Chemiluminescence labels can categorized as direct chemical or enzyme-based.

Biosensor format

The first CL–BL based biosensors used an analyte-specific enzyme coupled with one or more “indicating” enzymes, terminating with a CL or BL emission (Blum et al., 1989).

The most popular CL systems used the luminol/HRP system to measure hydrogen peroxide produced by any oxidase enzyme (e.g. glucose oxidase, ethanol oxidase, cholesterol oxidase). They also exploited the possibility of using oxidases as intermediate reactions in longer cascades (e.g. acetylcholinesterase/choline oxidase/peroxidase

On-line sample treatment and cleanup

Despite the fast development of new biosensors with different analytical formats, on-line preanalytical steps, which include sample clean up, analyte enrichment, and matrix treatment, remain an open issue. To improve selectivity, separation and purification procedures have been integrated into microfluidic devices, which use structural materials that can on-line extract the target analyte (Browne et al., 2011, Thongchai et al., 2010, Lin et al., 2011). Currently, microchip-based analytical

Conclusions

A critical review of the data and literature suggests the potential of chemical luminescence to compete with other more commonly used transduction principles based on electrochemistry or fluorescence. Miniaturized systems, using immobilized reagents on new materials and with nanoscale technology, have helped improve the analytical performance of these biosensors.

The main focus of chemical luminescence biosensors is the ultrasensitive detection and the portable point-of-need format using

Acknowledgments

The authors thank Grace Fox for editing and proofreading the manuscript. The authors acknowledge support from the University of Bologna (Programma FARB - Finanziamenti dell'Alma Mater Studiorum - Università di Bologna alla Ricerca di Base) and Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB- Biosystems National Institute).

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