Paper-based biosensor

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Schematic illustrating various methods of measuring contamination in samples Sensors-19-04476-g001.png
Schematic illustrating various methods of measuring contamination in samples

Paper-based biosensors are a subset of paper-based microfluidics used to detect the presence of pathogens in water. Paper-based detection devices have been touted for their low cost, portability and ease of use. [1] [2] Its portability in particular makes it a good candidate for point-of-care testing. [1] However, there are also limitations to these assays, and scientists are continually working to improve accuracy, sensitivity, and ability to test for multiple contaminants at the same time. [1]

Contents

History

Paper has been used in analytical chemistry as far back as the 1800s, when litmus paper was first reported, and has since been used for techniques such as paper chromatography and lateral flow assays. [3] However, it was only identified as a material for microfluidic assays in 2007, when patterned paper was proposed as a low-cost platform for bioassays. [3] [4]

Varieties of paper-based biosensors

A number of paper-based biosensors have been developed, which use a variety of approaches. [5] In general, pathogens are detected via colorimetric, electrochemical, fluorescent, and chemiluminescent detection, though there are other types of sensors as well. [3] Several examples of paper-based biosensors are described below.

Schematic representation of an electrochemical, paper-based biosensor which is capable of detecting bacteria in water samples Sensors-19-04476-g003.png
Schematic representation of an electrochemical, paper-based biosensor which is capable of detecting bacteria in water samples

For general bacterial detection

One device that has been described as being capable of detecting bacterial presence in water samples uses the common property of oligosaccharides and monosaccharides present on the surface of bacterial cells. It is an electrochemical device which uses hydrophobic paper that has been imbedded with carbon electrodes. Instead of using antibodies as the detectors, which are expensive, this device uses Concanavalin A (Con A), which is highly specific to the oligosaccharides and monosaccharides. [1] The Con A is attached to the carbon electrodes, which are also equipped with carboxyl groups. [6] The presence of bacteria triggers a series of electrochemical reactions, which are measured using a device called a potentiostat. [7] This device is less sensitive than some others, with a detection limit of 1.9 × 103 CFU/mL. [8] By comparison, some ELISAs range from 20 CFU/mL to 1 x 104 CFU/mL. [9] [10]

For detecting E. coli

Detection via bacteriophage

Hand-held, paper-based biosensor which uses the T4 bacteriophage to detect E. coli in water. E. coli biosensor.png
Hand-held, paper-based biosensor which uses the T4 bacteriophage to detect E. coli in water.

Multiple paper devices have been reported for the detection of E. coli specifically in water samples. One such device utilizes a recombinant version of the T4 bacteriophage which carries the gene for β-galactosidase. Water samples are filtered using membrane filters, then the filter papers are placed into the paper-based device which contains nutrient medium. They are then incubated for 4 hours at 37 °C. Next, the bacteriophage and the β-galactosidase indicator substrate are added to the sample. This causes the cells to lyse and release the β-galactosidase enzyme, which triggers the conversion of the substrate into a fluorescent product, indicative of the presence of the pathogen. Fluorescence is detected using a luminescence imaging device. The device was found to be highly specific to E. coli, and was tested against the presence of Enterobacter cloacae , Aeromonas hydrophila , and Salmonella Typhimurium . [1] [11] It has a detection limit of less than 10 CFU/mL, which is considered quite sensitive. [12]

Detection via blotting paper

Another device, called DipTest, has also been developed to detect E. coli. It utilizes porous cellulose blotting paper. One end of the paper strip is coated in a hydrophobic material, while the other is coated with a chemoattractant - a substance which attracts cells based on their chemical properties. At the hydrophobic end, customized chemical reagents are imbedded in the paper in a reaction zone. The paper is dipped in the water sample, and if E. coli is present, it will be attracted to the chemoattractant at one end of the paper. The bacterial cells will then move up the paper via capillary action, and once it reaches the reaction zone, it reacts with the reagents to produce a pink to red color. [1]

For detecting Salmonella

One paper-based biosensor that can be used to detect Salmonella, as well as E. coli, uses the nanomaterial graphene. These strips are a form of lateral flow assay, where the test line is composed of fluorescence antibody-labeled CdSe/ZnS quantum dots (Ab-QDs) as probes. After the sample has been applied, graphene oxide is added and it functions as the revealing agent. An energy transfer takes place between a donor molecule and an acceptor molecule. When no Salmonella is present, the Ab-QDs function as the donor, with graphene being the acceptor, and the fluorescence of the test line is quenched by this energy transfer. The presence of Salmonella, on the other hand, allows for fluorescence because of the manner in which the bacterial cells bind to the Ab-QDs: the distance between the donor and acceptor is too large to allow for the energy transfer, and thus fluorescence is not quenched. The strips have a detection limit of 100 CFU/mL. [1]

Applications

Context

Annually, over 1.6 million people die as a result of pathogens from contaminated water. [1] In the developing world, 2,200 children die per day from waterborne diseases. [13] Per World Health Organization (WHO) standards, for water to be considered clean enough for drinking, bacteria should be undetectable in any 100 mL sample. The primary contaminants of water are pathogens, such as the bacteria Campylobacter, Clostridium, Salmonella, Staphylococcous, Anabaena, Microcystis, worms such as Schistosoma mansoni, and Taenia saginata, protozoans such as Entamoeba histolytica and Giardia duodenalis, and viruses and fungi such as enteroviruses and microsporidia. Outbreaks of waterborne diseases, such as cholera, have affected millions in the 19th and 20th centuries over the course of several pandemics, usually as a result of inadequate wastewater treatment systems and general sanitation. [1] This is not a problem of decades past, however. As recently as 2015, it was found that 1.3 billion people are at risk for cholera annually, with 2.86 million annual cases and an estimated 95,000 deaths. [14] Cholera is just one example of waterborne disease, however, and more broadly, 780 million people worldwide still lack access to clean drinking water. [13]

Benefits

Traditional methods for detecting contamination in water, though highly accurate and sensitive, pose a number of obstacles. They are often costly, require the operation of a trained technician, and are labor intensive. [15] They can also be time consuming, for example, microbiological assays necessitate growing and isolating the pathogen from the sample, which can take several days or even weeks, in addition to preparing media. [1] [16] Paper-based biosensors address many of these problems. Specifically, paper as a material has several benefits. No external power is required, as the sample travels through the device via capillary action. Its fiber network structure allows for the storage of the necessary reagents in an active form. It is also cost-effective, has a high surface area to volume ratio, absorbs the sample efficiently, and is easily disposable by incineration. [1] [3]

In general, settings with limited resources could benefit from low-cost, easy to use, on-site, and rapid testing of water samples. In addition, there is a need for home-care testing. Widespread distribution of adequate but low-cost diagnostic devices, such as paper-based biosensors, could potentially alleviate disease burden. Beyond that, it could also result in more accurate epidemiological case data which could improve disease models. [17]

Limitations

The most significant limitation of this technology is its sensitivity, in other words, its ability to detect very low levels of a contaminant in the sample. Some of the most sensitive ELISAs can detect contaminants at levels as low as 20 CFU/mL. [10] In addition to improving accuracy - the correct identification of a particular pathogen - another challenge is developing biosensors which can readily distinguish between types of pathogens. [1] Finally, the material of paper itself, while it offers many benefits, has some drawbacks, too. For example, there is a limit to how well paper devices can control the rate and direction of flow of the sample. This introduces limitations regarding the handling of complex chemical compounds or managing multistep assays, depending on the biosensor in question. [3]

Related Research Articles

Microfluidics refers to a system that manipulates a small amount of fluids using small channels with sizes ten to hundreds micrometres. It is a multidisciplinary field that involves molecular analysis, molecular biology, and microelectronics. It has practical applications in the design of systems that process low volumes of fluids to achieve multiplexing, automation, and high-throughput screening. Microfluidics emerged in the beginning of the 1980s and is used in the development of inkjet printheads, DNA chips, lab-on-a-chip technology, micro-propulsion, and micro-thermal technologies.

<i>Campylobacter</i> Genus of gram-negative bacteria

Campylobacter is a type of bacteria that can cause a diarrhea disease in people. Its name means "curved bacteria", as the germ typically appears in a comma or "s" shape. According to its scientific classification, it is a genus of gram-negative bacteria that is motile.

<span class="mw-page-title-main">Digital microfluidics</span>

Digital microfluidics (DMF) is a platform for lab-on-a-chip systems that is based upon the manipulation of microdroplets. Droplets are dispensed, moved, stored, mixed, reacted, or analyzed on a platform with a set of insulated electrodes. Digital microfluidics can be used together with analytical analysis procedures such as mass spectrometry, colorimetry, electrochemical, and electrochemiluminescense.

A biosensor is an analytical device, used for the detection of a chemical substance, that combines a biological component with a physicochemical detector. The sensitive biological element, e.g. tissue, microorganisms, organelles, cell receptors, enzymes, antibodies, nucleic acids, etc., is a biologically derived material or biomimetic component that interacts with, binds with, or recognizes the analyte under study. The biologically sensitive elements can also be created by biological engineering. The transducer or the detector element, which transforms one signal into another one, works in a physicochemical way: optical, piezoelectric, electrochemical, electrochemiluminescence etc., resulting from the interaction of the analyte with the biological element, to easily measure and quantify. The biosensor reader device connects with the associated electronics or signal processors that are primarily responsible for the display of the results in a user-friendly way. This sometimes accounts for the most expensive part of the sensor device, however it is possible to generate a user friendly display that includes transducer and sensitive element. The readers are usually custom-designed and manufactured to suit the different working principles of biosensors.

Plate readers, also known as microplate readers or microplate photometers, are instruments which are used to detect biological, chemical or physical events of samples in microtiter plates. They are widely used in research, drug discovery, bioassay validation, quality control and manufacturing processes in the pharmaceutical and biotechnological industry and academic organizations. Sample reactions can be assayed in 1-1536 well format microtiter plates. The most common microplate format used in academic research laboratories or clinical diagnostic laboratories is 96-well with a typical reaction volume between 100 and 200 µL per well. Higher density microplates are typically used for screening applications, when throughput and assay cost per sample become critical parameters, with a typical assay volume between 5 and 50 µL per well. Common detection modes for microplate assays are absorbance, fluorescence intensity, luminescence, time-resolved fluorescence, and fluorescence polarization.

<span class="mw-page-title-main">Immunoassay</span> Biochemical test for a protein or other molecule using an antibody

An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay is often referred to as an "analyte" and is in many cases a protein, although it may be other kinds of molecules, of different sizes and types, as long as the proper antibodies that have the required properties for the assay are developed. Analytes in biological liquids such as serum or urine are frequently measured using immunoassays for medical and research purposes.

Fluorescence <i>in situ</i> hybridization Genetic testing technique

Fluorescence in situ hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed by biomedical researchers in the early 1980s to detect and localize the presence or absence of specific DNA sequences on chromosomes. Fluorescence microscopy can be used to find out where the fluorescent probe is bound to the chromosomes. FISH is often used for finding specific features in DNA for use in genetic counseling, medicine, and species identification. FISH can also be used to detect and localize specific RNA targets in cells, circulating tumor cells, and tissue samples. In this context, it can help define the spatial-temporal patterns of gene expression within cells and tissues.

A fecal coliform is a facultatively anaerobic, rod-shaped, gram-negative, non-sporulating bacterium. Coliform bacteria generally originate in the intestines of warm-blooded animals. Fecal coliforms are capable of growth in the presence of bile salts or similar surface agents, are oxidase negative, and produce acid and gas from lactose within 48 hours at 44 ± 0.5°C. The term thermotolerant coliform is more correct and is gaining acceptance over "fecal coliform".

Indicator bacteria are types of bacteria used to detect and estimate the level of fecal contamination of water. They are not dangerous to human health but are used to indicate the presence of a health risk.

<span class="mw-page-title-main">Lateral flow test</span> Immunochromatographic testing devices

A lateral flow test (LFT), is an assay also known as a lateral flow device (LFD), lateral flow immunochromatographic assay, or rapid test. It is a simple device intended to detect the presence of a target substance in a liquid sample without the need for specialized and costly equipment. LFTs are widely used in medical diagnostics in the home, at the point of care, and in the laboratory. For instance, the home pregnancy test is an LFT that detects a specific hormone. These tests are simple and economical and generally show results in around five to thirty minutes. Many lab-based applications increase the sensitivity of simple LFTs by employing additional dedicated equipment. Because the target substance is often a biological antigen, many lateral flow tests are rapid antigen tests.

<span class="mw-page-title-main">Bio-MEMS</span>

Bio-MEMS is an abbreviation for biomedical microelectromechanical systems. Bio-MEMS have considerable overlap, and is sometimes considered synonymous, with lab-on-a-chip (LOC) and micro total analysis systems (μTAS). Bio-MEMS is typically more focused on mechanical parts and microfabrication technologies made suitable for biological applications. On the other hand, lab-on-a-chip is concerned with miniaturization and integration of laboratory processes and experiments into single chips. In this definition, lab-on-a-chip devices do not strictly have biological applications, although most do or are amenable to be adapted for biological purposes. Similarly, micro total analysis systems may not have biological applications in mind, and are usually dedicated to chemical analysis. A broad definition for bio-MEMS can be used to refer to the science and technology of operating at the microscale for biological and biomedical applications, which may or may not include any electronic or mechanical functions. The interdisciplinary nature of bio-MEMS combines material sciences, clinical sciences, medicine, surgery, electrical engineering, mechanical engineering, optical engineering, chemical engineering, and biomedical engineering. Some of its major applications include genomics, proteomics, molecular diagnostics, point-of-care diagnostics, tissue engineering, single cell analysis and implantable microdevices.

Bioactive paper is a paper-based sensor that can identify various contaminants in food and water. First developed in 2009, bioactive paper research has been ongoing and in 2011 was awarded a 5-year grant totalling $7.5 million CAD. It has been developed at the biosensor stage level, which means it can detect pesticides but is not yet able to repel and deactivate toxins. However, its ability to detect potential hazards has applications for human health and safety. The benefits of bioactive paper are that it is simple, portable, disposable, and inexpensive.

<span class="mw-page-title-main">Centrifugal micro-fluidic biochip</span>

The centrifugal micro-fluidic biochip or centrifugal micro-fluidic biodisk is a type of lab-on-a-chip technology, also known as lab-on-a-disc, that can be used to integrate processes such as separating, mixing, reaction and detecting molecules of nano-size in a single piece of platform, including a compact disk or DVD. This type of micro-fluidic biochip is based upon the principle of microfluidics; to take advantage of noninertial pumping for lab-on-a-chip devices using noninertial valves and switches under centrifugal force and Coriolis effect to distribute fluids about the disks in a highly parallel order.

There are many methods to investigate protein–protein interactions which are the physical contacts of high specificity established between two or more protein molecules involving electrostatic forces and hydrophobic effects. Each of the approaches has its own strengths and weaknesses, especially with regard to the sensitivity and specificity of the method. A high sensitivity means that many of the interactions that occur are detected by the screen. A high specificity indicates that most of the interactions detected by the screen are occurring in reality.

Impedance microbiology is a microbiological technique used to measure the microbial number density of a sample by monitoring the electrical parameters of the growth medium. The ability of microbial metabolism to change the electrical conductivity of the growth medium was discovered by Stewart and further studied by other scientists such as Oker-Blom, Parson and Allison in the first half of 20th century. However, it was only in the late 1970s that, thanks to computer-controlled systems used to monitor impedance, the technique showed its full potential, as discussed in the works of Fistenberg-Eden & Eden, Ur & Brown and Cady.

Droplet-based microfluidics manipulate discrete volumes of fluids in immiscible phases with low Reynolds number and laminar flow regimes. Interest in droplet-based microfluidics systems has been growing substantially in past decades. Microdroplets offer the feasibility of handling miniature volumes of fluids conveniently, provide better mixing, encapsulation, sorting, sensing and are suitable for high throughput experiments. Two immiscible phases used for the droplet based systems are referred to as the continuous phase and dispersed phase.

Paper-based microfluidics are microfluidic devices that consist of a series of hydrophilic cellulose or nitrocellulose fibers that transport fluid from an inlet through the porous medium to a desired outlet or region of the device, by means of capillary action. This technology builds on the conventional lateral flow test which is capable of detecting many infectious agents and chemical contaminants. The main advantage of this is that it is largely a passively controlled device unlike more complex microfluidic devices. Development of paper-based microfluidic devices began in the early 21st century to meet a need for inexpensive and portable medical diagnostic systems.

Microfluidics refers to the flow of fluid in channels or networks with at least one dimension on the micron scale. In open microfluidics, also referred to as open surface microfluidics or open-space microfluidics, at least one boundary confining the fluid flow of a system is removed, exposing the fluid to air or another interface such as a second fluid.

<span class="mw-page-title-main">Electrochemical aptamer-based biosensors</span>

Aptamers, single-stranded RNA and DNA sequences, bind to an analyte and change their conformation. They function as nucleic acids selectively binding molecules such as proteins, bacteria cells, metal ions, etc. Aptamers can be developed to have precise specificity to bind to a desired target. Aptamers change conformation upon binding, altering the electrochemical properties which can be measured. The Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process generates aptamers. Electrochemical aptamer-based (E-AB) biosensors is a device that takes advantage of the electrochemical and biological properties of aptamers to take real time, in vivo measurements.

Open microfluidics can be employed in the multidimensional culturing of cell types for various applications including organ-on-a-chip studies, oxygen-driven reactions, neurodegeneration, cell migration, and other cellular pathways.

References

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