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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 9  |  Issue : 1  |  Page : 60-66

Oral fluid-based biosensors: A novel method for rapid and noninvasive diagnosis


1 Department of Oral Pathology, GSL Dental College and Hospital, Rajahmundry, Andhra Pradesh, India
2 Department of Oral Pathology, Navodaya Dental College, Raichur, Karnataka, India

Date of Web Publication6-Mar-2017

Correspondence Address:
K Roja Lakshmi
Department of Oral Pathology, GSL Dental College and Hospital, Rajahmundry, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJDS.IJDS_6_17

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  Abstract 

In the recent times, chair-side/bed-side monitoring tests have gained importance over the routine laboratory tests as they are easier and faster to perform without requiring skilled personnel. Biosensors refer to such type of point-of-care devices that are developed to help in the early diagnosis, periodic monitoring, and treatment of disease. These devices utilize biological reactions for detecting and measuring a particular substance (analyte) of interest. Till date, blood has been the gold standard diagnostic fluid for various diseases. However, oral fluids such as saliva and gingival crevicular fluid offer advantages such as noninvasive collection of sample, smaller sample aliquots, easy storage and transportation, repeated sampling for monitoring over time, and greater sensitivity, making them an alternative clinical tool over serum and tissues for many biomedical diagnostic assays. This review highlights the use of oral fluid-based biosensors for diagnosis of caries, periodontitis, oral cancer, and various systemic diseases.

Keywords: Biosensors, gingival crevicular fluid, saliva


How to cite this article:
Lakshmi K R, Nelakurthi H, Kumar A S, Rudraraju A. Oral fluid-based biosensors: A novel method for rapid and noninvasive diagnosis. Indian J Dent Sci 2017;9:60-6

How to cite this URL:
Lakshmi K R, Nelakurthi H, Kumar A S, Rudraraju A. Oral fluid-based biosensors: A novel method for rapid and noninvasive diagnosis. Indian J Dent Sci [serial online] 2017 [cited 2019 Jan 18];9:60-6. Available from: http://www.ijds.in/text.asp?2017/9/1/60/201637


  Introduction Top


Emerging trends in the field of research led to the development of diagnostic tools which have improved sensitivity and turnaround time. These technologies undoubtedly aid the clinicians in early diagnosis and treatment of various conditions. One of such advances is the development of biosensors. Biosensors have several applications in medical field, such as monitoring of glucose levels in diabetic patients, detection of pathogens and toxic metabolites, as well as measurement of Folic acid, Biotin, Vitamin B12, and Pantothenic acid.[1],[2] However, this technology is still emerging in dentistry. With the availability of these devices, diagnostic tests can be rapidly performed chair-side within the clinics. This current review emphasizes on the use of oral fluid-based biosensors in oral and systemic diseases.

By definition, a biosensor is a self-contained analytical device that incorporates a biologically active material in intimate contact with an appropriate transduction element for the purpose of detecting (reversibly and selectively) the concentration or activity of chemical species in any type of sample.[3] The first biosensor was an enzyme-based glucose sensor, developed by Clark and Lyons.[4] These devices are more specific, have a short response time, and can measure nonpolar molecules. A biosensor is composed of six elements, which include bioreceptor, transduction element, electrochemically active interface, signal amplifier, signal processor, and display. The analyte binds to the immobilized biological material and forms a product. The product-linked changes are then converted by the transducer into electric signals which can be amplified, measured, and read out in detector. After processing, the values are displayed on monitor and controlling system.[5] Biosensors are classified into various groups according to their biorecognition element (antibody [Ab], enzymes, nucleic acids, and whole cells) or their transduction element (electrochemical, electric, optical, piezoelectric, and thermal).[5],[6] The most commonly used transduction methods and their principles are summarized in [Table 1].
Table 1: Transduction methods and their principles

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Oral fluids as biomedia

The common media used for routine laboratory techniques are blood and urine. They contain various biochemical substances that help in diagnosing the diseases. However, the drawbacks in using blood as biomedia lie in the invasive sample collection, fear and anxiety in patients, and risk of disease transmission. The other media is urine, where the collection of sample is cumbersome, particularly in ambulatory patients. These limitations resulted in greater demand for alternative biomedia. Oral fluids (gingival crevicular fluid [GCF] and Saliva) are the easily accessible biofluids which can give quick and noninvasive sample that does not need any trained medical skill. As the technique is noninvasive, collection of samples for any number of times can be done for the patients who need periodic monitoring. Most of its constituents resemble serum and it can detect drugs immediately when compared to urine drug testing. All these advantages made oral fluids as an emerging diagnostic media.[7]


  Oral Fluid-Based Biosensors Top


Oral fluid-based biosensors are the biosensors which use GCF and saliva as the biomedia.

Gingival crevicular fluid-based biosensors

GCF is a serum transudate or inflammatory exudate collected at the gingival margin or within the gingival crevice. It contains several diagnostic and prognostic markers for periodontal diseases and certain systemic disorders. Hence, the detection of these markers with the biosensors can help the clinicians for risk assessment and decision-making for treatment planning.[8]

Saliva-based biosensors

Saliva is a thin, watery liquid secreted into the mouth by the salivary glands. Salivary components may originate from salivary glands or their vasculature by active transport or passive diffusion. These components have been recognized as proteomic, microbiome, immunologic, genomic (transcriptomic and epigenome), and metabolomic biomarkers, whose presence and values correlate with various diseases. With funding support from the NIDCR, three groups of investigators in the United States have successfully identified 1166 proteins in human saliva. They reported markers such as matrix metalloproteinases (i.e., MMP1, MMP3, and MMP9), cytokines i.e., interleukin-6 [IL-6], IL-8, vascular endothelial growth factor A tumor necrosis factor-alpha (TNF-α), transferrins, and fibroblast growth factors which are associated with various malignancies such as oral, breast lung, and pancreatic cancers. Recent evidence has shown that saliva is a powerful diagnostic tool for diseases such as human immunodeficiency virus (HIV) and hepatitis A, B, and C where immunologic markers such as IgG and microbics play a key role. A variety of metabolics in saliva have been implicated in periodontitis and Sjogren's syndrome. By analyzing micro-RNA (mi-RNA) markers, the genomic differences in patients can be identified. Thus, these biomarkers make saliva a promising diagnostic fluid.[9],[10]

However, there are several limitations to use saliva as a diagnostic fluid, the main drawbacks being low specificity and sensitivity. However, with advent of new and sensitive techniques such as microfluidics and nanotechnologies which have improved sensitivity and assay speed, the lower level of analytes in saliva is no longer a limitation. NIDCR funded UO1 awards to develop microfluidics and microelectromechanical systems for DNA, gene transcripts (mRNA), proteins, electrolytes, and small molecules in saliva as well as overall profile correlates of a particular disease state. These technologies use a combination of multiple biomarkers instead of a single biomarker in disease detection, thus overcoming lack of sensitivity and specificity in single-marker tests.[11]


  Role of Oral Fluid-Based Biosensors in Dentistry Top


Dental caries

Dental caries is an irreversible multifactorial disease affecting the tooth, which often leads to cavitation. It is a major health problem affecting all age groups. Clinical and radiographic examination of carious lesions cannot predict caries activity or susceptibility. Hence, caries activity tests are performed to measure the caries activity which helps in motivating patients in caries prevention.[12] However, caries activity tests consume a lot of time, and so to save time of clinicians, a fiberoptic biosensor was developed to monitor Streptococcus mutans in human saliva. In this biosensor, the bacterium reacts with sucrose and forms lactic acid and extracellular polysaccharide. Formation of acid results in lowering of the pH of the medium which is detected by a photosensitive pH indicator immobilized in the glass. The extracellular polysaccharide formed decreases the evanescent absorbance, and the entire effect is spectroscopically observed. A negative correlation was observed between transmitted intensity at 597 nm and pH. This finding confirmed that there is a decrease in absorbance of saliva with increased bacterial activity. Hence, this test can be used to monitor S. mutans activity in saliva as its levels correlate with dental caries.[13]

Salivary α-amylase (sAA), one of the components in human saliva, binds with high affinity to a selected group of oral streptococci. Further, this enzyme is also found in acquired enamel pellicle, suggesting its role in the adhesion of α-amylase-binding bacteria.[14] Shetty et al.[15] developed an sAA biosensor on a colorimetric assay platform wherein the color intensity of the reaction product is measured photometrically to determine the concentration of sAA.

Periodontitis

Periodontitis is a chronic inflammation of the periodontium caused by persistent bacterial infection that results in tooth loss. Recent research studies have shown that periodontal disease can act as a risk factor for cardiovascular and cerebrovascular diseases. Clinical parameters such as probing pocket depth, bleeding on probing and clinical attachment level, and radiographic assessment of bone loss provide information on severity of periodontitis but not on disease activity. This need resulted in the development of biomarkers which can measure periodontal disease at the molecular, cellular, tissue, and clinical levels. Several biomarkers associated with inflammation, soft tissue, and bone destruction have been identified in saliva and GCF. However, no single marker is sufficient for reliable diagnosis.[16]

IL-1 β, MMP-8, TNF-α, IL-6, and C-reactive protein (CRP) are the biomarkers associated with periodontitis, for which saliva-based biosensors have been developed by a group at the University of Texas at Austin. It is a Lab-on-a-chip (LOC) system that combines microfluidics and fluorescence-based optical system. In this sensor, sandwich immunoassays are performed on chemically sensitized beads.[17] Another biosensor called the Integrated Microfluidic Platform for Oral Diagnostics was developed by Herr et al.[18] which can detect biomarkers such as MMP-8, TNF-α, CRP, and IL-6. This device incorporates photopolymerized gels for immunoassays, microfluid chip, optical elements, and data acquisition software.

Oral cancer

Oral cancer is the eighth most common cancer in men and fourteenth most common cancer in women worldwide. It is the most common cause of mortality and morbidity among the developing countries.[19] Hence, for early detection and assessment of risk, various biological markers have been developed. Estimation of these can be used for the diagnosis and monitoring the prognosis of malignancies. Various salivary proteomes such as IL-8, TNF-α, epidermal growth factor receptor (EGFR), and salivary transferrin and genomes such as mi-RNA can be used as potential biomarkers for oral cancer detection as the oral cancer lesions are in direct contact with saliva.[20]

IL-8 is a pro-inflammatory chemokine which plays vital role in tumor angiogenesis and metastasis. A surface-immobilized optical protein sensor has been used to detect IL-8 protein cancer marker. In this sensor, the analyte immobilized on the surface with the capture probe reacts with biotinylated monoclonal Ab. The emission light from fluorophore conjugated with the reporter probe is then used as the detection signal, and the optical noise is reduced using confocal optics.[21]

The use of saliva-based biosensors for exfoliated cells in the oral cavity allows screening and identification of potential biomarkers for oral cancer. In addition, it can reduce anxiety and discomfort in the patient compared to routine biopsy techniques. Weigum et al.[22] developed a new nano-bio-chip cellular (NBC) analysis technique for characterizing oral malignant and premalignant lesions to evaluate EGFR and cytomorphometry in exfoliative cytology specimen. The morphological alterations in the nucleus and EGFR expression were detected successfully and quantitated in the NBC sensor assay, suggesting that it can reflect cellular alterations in tumor tissue.

mi-RNA are short noncoding RNAs encoded throughout the genome. Some of these genomic regions are prone to alterations; as a result, mi-RNA deregulation can be seen in oral cancer, the early detection of which helps in diagnosis and better treatment. An electrochemical biosensor method for the detection of oral cancer-related mi-RNAs at attomolar levels was developed which detects mi-RNA using a magnetic-controllable gold electrode. The advantage of this biosensor is magnetic beads-based enzymatic catalysis amplification which improves the sensitivity of biosensor.[23]

The University of California, Los Angeles Collaborative Oral Fluid Diagnostic Research Laboratory, developed point of care device used to detect oral cancer in saliva. Oral fluid nanosensor test (OFNASET) enables simultaneous and rapid detection of multiple salivary proteins and nucleic acid targets. The OFNASET technology platform combines leading technologies such as self-assembled monolayers, microfluidics, and cyclic enzymatic amplification. In addition to oral cancer detection, it can assess for breast, pancreatic, and lung cancers, Type II diabetes, Alzheimer's disease, and Sjogren's syndrome. OFNASET can measure up to eight different biomarkers in a single test.[24]


  Role of Oral Fluid-Based Biosensors in Systemic Diseases Top


Diabetes

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, in which the patient should be regularly monitored to prevent further complications such as neuropathy, vascular diseases, and predisposition to infection. For continuous monitoring of glucose levels, researchers have investigated the possibility of using GCF and saliva. Yamaguchi et al.[25] developed a GCF-collecting device which was small enough to be inserted in the gingival crevice for collection of a submicroliter sample of GCF and incorporated testing tape in the device. Both GCF glucose levels (GCFLs) and blood glucose levels in conjunction with meal loads were evaluated by measuring the color density of the testing tape using red laser light. No significant difference between these two glucose levels was observed, suggesting evaluation of GCFLs as a screening method among diabetics.

Glucose levels in saliva can be measured by a salivary nanobiosensor which is an on-chip electrochemical sensing device. It has a working electrode, reference electrode, and counter electrode. The working electrode is functionalized with single-walled carbon nanotubes and multilayers of chitosan, gold nanoparticles and glucose oxidase, using a layer-by-layer assembly technique. The charge transfer complex formed on the working electrode allows the direct oxidation of the glucose oxidase enzyme and thus determines salivary glucose levels. When the glucose levels in saliva and that of blood, before and 2 h after glucose intake was observed and compared, a good correlation was observed. Thus, this disposable biosensor can be used as an alternative method for glucose testing.[26]

Human immunodeficiency virus

Saliva is used for the detection of Abs that are produced against specific bacteria, viral, fungal, parasitic agents, and allergy reactions. It can also be used widely as a diagnostic tool for HIV and hepatitis C virus infection as it forgoes blood testing for Ab screening, particularly home testing. Electrochemical peptide-based sensors are fabricated for anti-HIV Ab detection which uses X-ray photoelectron spectroscopy to analyze salivary DNA on the sensor surface.[27]

Psychiatric disorders

Increased stress levels are observed due to changes in lifestyle. This can lead to physical disorders such as cardiovascular disease, diabetes, obesity, cancer, and psychiatric disorders such as depression, schizophrenia, attention deficit, and bipolar disorders. Early recognition of stress subsequently improves the quality of life and protects us from all stress-associated diseases.[28] In saliva, cortisol and sAA are recognized as biomarkers for stress. A flow filtered ported, surface plasmon resonance (SPR) biosensor was developed to detect cortisol levels in saliva.[29],[30] In SPR biosensors, receptor molecules are immobilized on gold sensor for detecting cortisol. The biochemical reaction between target analyte and receptor is then measured by the changes in refractive index. For determining sAA levels, sAA biosensor is used which can act as a biomarker of autonomic dysregulation.[15] Salivary testosterone levels can also be used as stress biomarker, which shows lower value in female patients with a depressive disorder and generalized anxiety disorder. A SPR biosensor surface was designed to measure the testosterone levels. In this biosensor, testosterone is conjugated with oligoethylene which is covalently immobilized on sensor surface.[31],[32]

An individual's circadian rhythm governs cycles of fatigue and alertness. The classic phase marker for measuring the timing of a mammal's circadian rhythm is melatonin.[33] Melatonin can be detected directly on a disposable ceramic screen-printed electrode (SPE) surface that has been chemically modified with a highly specific anti-melatonin Ab.[34]

Sexual hormone disorders

Salivary testosterone is a reliable marker of testosterone bioavailability. The detection of this hormone levels using a nanoparticle-enhanced SPR biosensor helps in the diagnosis of this male androgen deficiency.[32],[35] Salivary androgen levels are also useful in diagnosing polycystic ovarian syndrome.[36] Assessment of salivary phosphate and estradiol concentrations are useful for monitoring pregnancy and menstrual cycle changes.[37],[38] A point of care device was proposed utilizing immunoassay through a photoelectrochemical process to measure estradiol levels.[39]

Cardiovascular diseases

Cardiovascular disease is one of the leading causes of death worldwide. Inflammation is an important contributing factor for coronary heart diseases and atherosclerosis. CRP appears to be as a strong independent risk factor for the development of cardiovascular disease.[40] Hence, an LOC system is developed for detection of CRP in human saliva based on antigen and Ab interactions.[41] Lactate, a metabolite of anaerobic glycolysis, is marker for acute myocardial infarction.[42] A disposable electrochemiluminescent biosensor was developed for the analysis of lactate which uses lactate oxidase-based enzymatic recognition system and luminol-based transduction system.[43]

In patients undergoing dialysis, increased levels of phosphates form cardiovascular calcifications. These are responsible for the high morbidity and mortality in patients with chronic renal failure.[44] Kwan et al.[45] constructed an amperometric biosensor for analysis of human salivary phosphate using immobilized pyruvate oxidase enzyme. Enzymatically generated hydrogen peroxide (H2O2) by pyruvate oxidase in salivary phosphate solution was in proportion to the concentration of human salivary phosphate and is monitored by a potentiostat.

Obesity

People who are obese are at increased risk of coronary heart diseases, stroke, and cardiovascular death when compared to those with a normal/healthy weight. It is the second leading cause of preventable death in the United States.[46] Human salivary phosphate and uric acid levels can be predictive markers for obesity in children.[47],[48] Hence, the early detection of these markers may aid in the treatment and further prevention of related systemic diseases. Salivary phosphate levels are measured by an amperometric biosensor and for monitoring salivary uric acid levels, a wearable wireless mouth guard biosensor is developed.[45] This biosensor contains a wireless amperometric circuit board and enzyme (uricase)-modified SPE assembled into the mouthguard using medical adhesive (Loctite).[49]

Drug abuse

Drug abuse is a serious problem with long-term consequences. Illicit drugs can be detected in oral fluids, and in contrast to urine, they contain parent drugs rather than metabolites. Hence, they can be used as screening and confirmatory tests for illicit drug abuse.[50] Marijuana refers to the commonly used illicit drug which may lead to breathing and mental problems. Lee et al.[51] developed giant magnetoresistive biosensors integrated with a portable reading system using competitive assays to trace tetrahydrocannabinol levels in saliva.

Cancer

Several salivary biomarkers were identified in breast, pancreatic, and lung cancer.[9] In breast cancer, mammography fails to detect malignancy when the tumor is small at an early stage. To enhance the survival rate of patient, early detection of breast cancer is a crucial factor. To overcome this problem, biomarkers are developed. However, serum-based detection of biomarkers involves risk of disease transfer and hence salivary biosensors are designed using salivary autoantibodies. Few examples of such biosensors include quartz crystal biosensor for ATPase H + transporting, lysosomal accessory protein (ATP6AP1), and surface plasma resonance biosensor for cancer antigen 15-3 (CA 15-3), a breast cancer biomarker in human saliva.[52],[53] To detect cancer early, a group of biomarkers needs to be multiplexed. A microfluidic biosensor was constructed with the integration of semiconductor nanoparticle quantum dots into a module for the multiplexed quantitation of three important cancer markers: carcinoembryonic antigen, CA125, and Her-2/Neu (C-erbB-2).[54] OFNASET can be used to detect breast, pancreatic, and lung cancers.

Few proposals have been put forward to develop biosensors for the various other salivary biomarkers. They include design of the simple analyzer to measure biomarkers for chronic pulmonary obstructive disorder exacerbations; installation of the biosensor incorporating cardiac markers (cardiac troponin I, creatine kinase MB, myoglobin, CRP, soluble intracellular adhesion molecular protein-1, IL-1 beta, fatty acid binding protein) in the dental implant, denture.[55],[56] An US-patented salivary monitoring electrical toothbrush biosensor has also been designed for performing the routine saliva tests. However, their emergence into use must be awaited.[57] [Table 2] summarizes various salivary biosensors which are used for various systemic diseases.
Table 2: Salivary biosensors for various diseases

Click here to view



  Conclusion Top


Oral fluid biosensors have the advantages of easy accessibility and noninvasive sample collection, making them a novel method in disease diagnostics. However, its limitations such as less sensitivity and specificity are overcome by the advent of new technologies such as microfluidics and nanofluidics. In spite of these advantages, unfortunately, the lack of market readiness and awareness of these biosensors have restricted their wide usage for disease diagnostics. It is almost certain, that in the forthcoming years, home testing kits incorporating oral fluid biosensors will begin to appear, outperforming the routine laboratory tests in the diagnosis of diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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