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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 3  |  Page : 118-124

Intraoral biosensors: A promising diagnostic tool


1 Department of Prosthodontics and Crown and Bridge, Manav Rachna Dental College, Faridabad, Haryana, India
2 Manav Rachna Centre of Excellance, MRIIRS, Faridabad, Haryana, India
3 Intern, A B Shetty Memorial Institute of Dental Sciences, Mangaluru, Karnataka, India

Date of Submission04-Mar-2022
Date of Decision04-May-2022
Date of Acceptance11-May-2022
Date of Web Publication30-Jun-2022

Correspondence Address:
Dr. Shefali Dogra
Department of Prosthodontics and Crown and Bridge, Manav Rachna Dental College, Faridabad - 121 004, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_25_22

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  Abstract 


The article encompasses a research on intraoral biosensors, which was conducted using keywords such as “Intraoral biosensors,” “health care monitoring devices,” “biomarkers”, “cloud servers,” “Internet of dental things (IoDT)” and “wireless sensors” in the databases of PubMed/Medline and Google Scholar between 1990 and 2020. Biomedical devices such as intraoral biosensors that are involved in continuous healthcare monitoring have garnered the attention of several researchers across the world. These devices function as an interconnecting link between the human systems and the outer environment. Recently, chair-side monitoring and early diagnostic tests are highly valuable for periodic monitoring and treatment planning for patients. These devices use biological reactions to detect and measure a particular chemical compound substance and then send an electronic signal. The chief advantages of these ubiquitous devices are high sensitivity and fast response. Intraoral biosensors integrate various materials and devices on one unique chip, hence functioning as the latest analytical and diagnostic tool of dentistry. This review highlights the basic concepts, principles and role of intraoral biosensors in the diagnosis of caries, periodontitis, oral cancer and dental fluorosis.

Keywords: Biosensors, diagnostic, gingival crevicular fluid, saliva


How to cite this article:
Dogra S, Dhawan P, Tomar SS, Kakar A, Kakar E. Intraoral biosensors: A promising diagnostic tool. Curr Med Res Pract 2022;12:118-24

How to cite this URL:
Dogra S, Dhawan P, Tomar SS, Kakar A, Kakar E. Intraoral biosensors: A promising diagnostic tool. Curr Med Res Pract [serial online] 2022 [cited 2022 Aug 12];12:118-24. Available from: http://www.cmrpjournal.org/text.asp?2022/12/3/118/349291




  Introduction Top


The rise of emerging trends in dental research and advancements in technology has led to the evolution of diagnostic tools, improving their sensitivity and accuracy over time.[1] These advancements guaranteed help and assisted dentists in the diagnosis and treatment planning of the patients. An example of one such recent advancement is the development of “Biosensors.”[1] In the 1960s, Dr. Leland C Clark,[2] the Father of Biosensors, created biosensors using an enzyme electrode to measure the concentration of glucose using the enzyme, glucose oxidase. These devices were highly useful and have multiple applications in the field of medicine, such as monitoring levels of glucose in diabetics, pathogenic and toxic metabolites detection and measurement of folic acid, Vitamin B12, biotin and pantothenic acid.[1],[3] However, the role of biosensors in the field of dentistry as biomedical devices is still emerging and evolving.[1] The biosensors accumulate multimodal and physiological information digitally, thus providing an integral and extensive overview of the patient's health thereby enhancing the accuracy of diagnosis and treatment output.[4],[5] Due to their accessibility, clinicians can perform chair-side diagnostic tests.[1]

The oral cavity plays an important role because it is the connection between the human systems and the outer environment. Being the initial point of the respiratory and digestive system, it helps in the exchange of matter and protects against bacterial invasion.[6],[7] Due to its connection with the nervous and circulatory systems, it acts as an indicator of several systemic diseases. A biosensor, a self-contained analytical device, incorporates material that is biologically active material and present in the oral cavity in the form of saliva, gingival crevicular fluid (GCF) etc.[1]

The foundation of the intraoral biosensors lies in detecting biomarkers or any other substance working as an analyte (chemical compound).[2] The development of the intraoral biosensor into a distinguishing character in healthcare with the integration of the existing biosensing techniques and diagnostic databases that are already established and are used successfully.[8] These devices have the advantages of being non-invasive access, wear, comfortable and a large area for implementation. However, the lack of market readiness and the knowledge of biosensors have confined their usage significantly.[1]


  Biosensors Top


The term “Biosensors'” can be defined as an analytical device that converts a biological response into an electrical signal (Biosensors, Elsevier Applied Science). It is a device that detects chemical compounds by thermal, electrical or optical signals using biochemical reactions which are specifically mediated by isolated enzymes, immunological systems, organelles, tissues or whole cells.[5],[9] The elements of biosensors consist of a sensor element, may be an electric current and a bio-element may be an antibody, an enzyme, living cells or tissue.[2]


  Components of A Biosensor Top


The basic components of a biosensor are:[10],[11],[12]

  1. Biological component


    1. Sensitive bio-elements created by biological engineering – Enzyme antibody, nucleic acid, cells, tissue, etc
    2. Analyte – Serum, saliva, urine, stools, etc.


  2. Physical component


    1. Transducer/Detector – Helps in the transformation of the signal due to an interaction between the analyte and biological element into another signal which can be easily measured and then quantified
    2. Amplifier/Display Unit – The electric component/signal processor responsible for displaying the outcomes in a serviceable way.



  Principles of Detection Top


Biosensors comprise six elements including bioreceptor, electrochemically active interface, signal amplifier, transduction element, signal processor and display. After the analyte binds to the immobilised biological material, the product formed is then converted by a transducer into electric signals that are amplified, measured and read using a detector and displayed on the monitor.[13],[14],[15] These devices are classified into various groups according to their transduction element or biorecognition system. Based on the transduction system and its principles [Table 1], biosensors work as:[1]
Table 1: Transduction methods and principles[13]

Click here to view


The biosensors based on their location are divided into the skin, intraoral and implantable devices. One of the latest trends is the intraoral biosensor, an authentic, non-invasive medical device for healthcare monitoring.[8]


  Oral Cavity: The Indicator of Chemical and Physical Conditions Top


The oral cavity contains oral fluids that have biochemical substances that aid in detecting and diagnosing general as well as oral health, thereby helping in better treatment planning.[16] The relationship of the human oral cavity with the circulatory system is a transition of biomolecules by active transport, diffusion and ultrafiltration mechanisms from capillaries to the oral fluid.[11] The pharmacokinetic performance of various drugs is assessed systematically using Salivary Excretion Classification System.[16] Through this classification, the permeability (high/low) and plasma protein fraction unbound could be assessed. The free fraction of the drug which is pharmacologically active can enter through salivary tissues and eventually into saliva.[17],[18] Along with the concentration of the drugs, pH and flow rate of the saliva also play an important role in the pharmacokinetics investigation. Several disease-related biomarkers present in the blood tend to enter oral biofluids, hence making saliva a credible diagnostic tool.[19],[20] The level of hormones in the blood can also be monitored using oral biofluid. Due to its non-invasive sampling technique and direct association with blood, and ability to reflect the mental state of an individual, it is viewed as an optimistic alternative in healthcare monitoring.[21] Salivary amylase is known to be an indicator of the activity of the sympathetic nervous system. Hence, by monitoring the oral biofluid, mental and psychological health can be monitored and reflected making the saliva-based diagnosis, an advantageous diagnosis when compared to clinical.[1]


  Intraoral Biosensors – Advances in The Field of Dentistry Top


The intraoral biosensors contain biochemical and biophysical signals that aid in the designing of healthcare monitoring devices [Figure 1]. The oral cavity possesses well-assembled hard (teeth, hard palate, etc.) and soft (tongue and mucosal tissues) structures and has well-defined movements.[3]
Figure 1: Data collecting and processing. The data after screening and integration is stored into a comprehensive database after compilation from different sources. It is then used for the diagnosis of disease

Click here to view



  Biophysical Information Top


Several oral structures can be utilised as an attachment for intraoral devices, having minimal interference to the normal function.[22] There are a variety of valuable biomarkers present in humans that reflect health status that can be transferred from inner organs via high impedance tissues. The oral cavity has various distinctive biomarkers which are different from those present in skins and inner organs. For example, utilisation of tongue movements in the construction of tongue-computer interfaces, which, in turn, helps people with spinal cord injury to control computers and the patient's wheelchair.[23] Furthermore, the incorporation of force detectors in orthodontic brackets and mouthguards which could detect salivary uric acid proved to be effective diagnostics.[24]


  Biochemical Information Top


The biochemical information plays an important role in the performance of biosensors. The oral cavity interconnects the environment and human systems, thereby helping in the processes of exchanging matters.[25] As a consequence, stresses from both the human system (enzymes, electrolytes and other mechanisms) and the environment (food, air, bacteria, etc.) can be encountered by the intraoral biosensor.[26] The oral cavity has copious amounts of intraoral, environmental, systemic and pharmacokinetic biomarkers, providing complementary information to skin electronics and implantable devices which establishes a healthcare monitoring system, a more comprehensive diagnostic method.[26],[27]


  Oral Fluid-Based Biosensors Top


The oral fluid-based biosensors use saliva and GCF as their biomedia. These fluids are accessible, quick and non-invasive and the sample collection can be done repeatedly, hence making these oral fluids advantageous as an emerging diagnostic method.[17]


  Gingival Crevicular Fluid-Based Biosensors Top


The serum collected present within the gingival crevice or at the gingival margin, inflammatory or transudate exudate in nature is known as the gingival cervical fluid.[1] This fluid has an abundant diagnostic and prognostic marker for several oral diseases and certain systemic disorders. Hence, the GCF fluid-based oral biosensors help clinicians in risk assessment and decision-making for treatment planning.[28]


  Saliva-Based Biosensors Top


Saliva, a biofluid is a thin, watery, and clear liquid secreted by salivary glands into the mouth. The components in saliva usually originate from the salivary glands or through passive diffusion or active transport.[29] These components are identified as microbiome, proteomic, genomic (epigenome and transcriptomic), immunologic and metabolomic biomarkers, the presence, and values of these correspond to several diseases. Salivary markers such as cytokines such as interleukin (IL)-6 and matrix metalloproteinases such as MMP1, MMP3, transferrin, vascular endothelial growth factor A, tumour necrosis factor-alpha (TNF-α) and fibroblast growth factors play an important role in the diagnosis of many malignancies like oral cancers.[30] Recently, it was found that saliva is an important diagnostic marker in diseases such as hepatitis, A, B and C and human immunodeficiency virus where immunologic markers like IgG are key factors in diagnosis.[1] Similarly, saliva is implicated in Sjogren's syndrome, dental fluorosis, dental plaque and periodontitis. The genomic differences can be identified in patients by analysis of micro-RNA (mi-RNA).[29],[30]

The drawbacks to using saliva for diagnostic purposes are its low specificity and sensitivity. However, with improvements in newer and sensitive techniques like microfluidics and nanotechnologies, sensitivity and assay speed, a low level of salivary analytes is not a concern anymore.[29] Using a combination of multiple biomarkers instead of one for diagnosis of the disease overcomes the lack of specificity and sensitivity witnessed in single biomarker tests.[30]


  Role of Intraoral Biosensors in Dentistry Top


The intraoral biosensors are being used in the diagnosis of dental caries, periodontitis, dental fluorosis and oral cancer. In the 1960s, the first wearable biosensor was developed. This sensor monitored the masticatory functions and concentrations of plaque and fluoride. The drawback of these biosensors was that several teeth were replaced by sensors and there was a high potential risk of internal sensor solution leakage.

Dental caries

It is an irreversible multifactorial disease that affects the tooth and often results in cavitation. It is common in all age groups. Since clinical and radiographic examinations of caries do not predict microbial activity and susceptibility, caries activity tests have to be performed. These tests help in the patient's motivation for caries prevention and promotion of good oral health.[31] However, caries activity tests are time-consuming. Hence, to counter this, a fiberoptic biosensor was developed for monitoring Streptococcus mutans in human saliva, hence saving clinicians' time.[32] The mechanism of action is that S. mutans react with sucrose, thereby forming lactic acid and extracellular polysaccharides. Due to the formation of lactic acid, the pH of the medium is decreased; a photosensitive pH indicator immobilised in the glass is used for its detection. The formation of extracellular polysaccharides leads to a decrease in the evanescent absorbance, and this effect is observed spectroscopically. Therefore, the activity of S. mutans in saliva can be correlated to dental caries.[32]

Salivary α-amylase (sAA) present in human saliva has a high affinity to a selected group of Streptococci in the oral cavity and binds to it.[33] This enzyme is also found in acquired enamel pellicle, hence confirming its role in the adhesion of α-amylase-binding bacteria.[34] An sAA biosensor on a colourimetric assay platform was developed by Shetty et al.,[34],[35] wherein the colour intensity of the reaction product was measured photometrically and sAA concentration is determined. It was found that patients having BP suffered from increased depression, anxiety, anger and fatigue as compared to healthy controls. Therefore, the results suggested that sAA can be regarded as a useful biomarker for patients having BP.

An article in June 2012 was published on “Smart tooth” which was a wireless “tooth-tattoo' manufactured using graphene [Figure 2], silk and a tiny antenna attached to the tooth. It helped in the detection of microbes associated with caries and several diseases. Hence, this biosensor proved to be useful for the identification and detection of bacteria in plaque, infection or dental caries. This biosensor, however, is removed on brushing or flossing.[36]
Figure 2: Graphene biosensors

Click here to view


Periodontitis

It is a chronic inflammation of the periodontium, which is caused due to persistent infection by bacteria resulting in tooth loss. The disease activity cannot be assessed by clinical parameters like bleeding on probing and clinical attachment level, probing depth and radiographic assessment of bone loss, which provides information on the severity of periodontitis.[37] Hence, biomarkers are required which can measure periodontal disease at cellular, tissue, molecular and clinical levels. Several markers associated with soft tissue, inflammation and bone destruction have been found in GCF and saliva. However, for a reliable diagnosis, we need multiple markers, and no single marker is adequate.[38]

The biomarkers associated with periodontitis are IL-1 β, IL-6, TNF-α, MMP-8 and C-reactive protein (CRP). The University of Texas in Austin has developed saliva-based biosensors.[38] This is a lab-on-a-chip system, combining microfluidics and a fluorescence-based optimal system. The sandwich immunoassays in these sensors are performed using chemically sensitised beads.[38] Herr et al.[39] developed another biosensor known as microfluidic platform for oral diagnostic which detected biomarkers such as MMP-8, CRP, TNF-α and IL-6. This device integrated photopolymerised gels for microfluid chip, optical elements, immunoassays and data acquisition software.[39] With the introduction of Internet of dental things, the evolution of electric brushes technology has led to the development of smart toothbrushes. They have built-in sensors which are connected to mobile phones via an app, wherein they transfer the data extracted from the oral cavity of the patient and then transfer it to the cloud server.[39]

Oral cancer

The eighth most common cancer in men and fourteenth in women is oral cancer.[1] One of the most common causes of morbidity and mortality in developing countries is oral cancer.[40] Therefore, the risk and early detection of several biomarkers should be assessed. These biomarkers can be estimated for diagnosing and monitoring malignancies.[1] The potential biomarkers for oral cancer detection are salivary proteomes such as TNF-α, IL-8, epidermal growth factor (EGFR) and salivary genomes like mi-RNA and transferrin since the lesions are directly in contact with saliva.[41]

IL-8 plays a vital role in tumour metastasis and angiogenesis.[1] A surface-immobilised optical protein sensor for the detection of IL-8 was developed, pro-inflammatory chemokine, protein cancer marker. The analyte present in this sensor is immobilised on the surface with a capture probe that reacts with a biotinylated monoclonal antibody. The detection signal is the light emitted from fluorophore which is conjugated with a reporter probe, and optical noise generated is reduced with the help of confocal optics.[42] These saliva-based biosensors help in the reduction of discomfort and anxiety in the patients as seen in routine biopsy techniques.

Weigum et al.[43] for characterising oral premalignant and malignant lesions have developed a new nano-biochip cellular (NBC) analysis technique that evaluated cytomorphometry and EGFR in exfoliative cytology specimens. This biosensor detects alterations in the morphology of the nucleus and EGFR expression and is then quantitated in the NBC sensor assay. This suggests that it reflects cellular alterations in the cancerous tissue. mi-RNA, short non-coding RNAs encoding genome throughout, is used for early detection of oral cancer using an electrochemical biosensor method. In this, the biosensor detects mi-RNA using a gold electrode that is magnetically controlled. The magnetic beads-based enzymatic catalysis amplification is advantageous since it leads to improved sensitivity.[44] With the development of the Oral Fluid Nanosensor Test (OFNASET), rapid and simultaneous detection of numerous salivary nucleic acids and proteins was enabled. This biosensor combines the latest technologies such as microfluidics, self-assembled monolayers and cyclic enzymatic amplification. It also assesses breast, lung and pancreatic cancers, Alzheimer's disease, Type II diabetes and Sjogren's syndrome. OFNASET in a single test can measure as many as eight different biomarkers.[45]

Dental fluorosis

The alterations caused in the tooth's enamel are known as dental fluorosis. These variations range from hardly perceptible white-coloured spots in mild fluorosis to pitting along with staining in severe fluorosis.[46] To detect increased fluoride concentrations in water, one of the most powerful analyses and detection tools having vast applications in the field of healthcare and research is the optical biosensors. The optical sensors have a biological entity that can be an antibody, enzyme or nucleic acid. These entities interact with analytes producing an electrical signal which is then measured.[47] A two-dimensional photonic crystal-based biosensor could detect different fluorides in water with a line defect. The sensor design constitutes a two-dimensional square lattice waveguide photonic crystal structure in rods in air configuration.[48] The analyte is water absorbed on the surface of the photonic crystal.

The interaction occurs when light passes through a photonic crystal, this propagation of light varies with different dielectric constants. This biosensor detects toxic fluorides such as cesium fluoride, potassium fluoride, calcium fluoride, lithium fluoride and strontium fluoride which are present in water causing dental fluorosis. The refractive index and wavelength shift are detected by the optical biosensor which is sensitive to even the smallest of the changes in the fluoride inputs.[49]

Complete dentures

The University of Florida has successfully designed a Multifunctional Smart denture [Figure 3] which can detect gaps between the oral tissue and denture due to the incorporation of microsensors in the device. It also detects strain, stress, movement, pressure and temperature. They act as a non-invasive health monitoring device that uses wireless signals sent via microsensors containing patients' health data, which is then collected by healthcare professionals, hence avoiding patients' visits to the dental office. They ensure patient comfort and safety when detecting oral diseases, cancers, HIV and diabetes using oral biofluid and saliva. This biosensor also saves patients money and time spent on diagnostic procedures and is highly patient specific.[50],[51]
Figure 3: Multifunctional smart denture[9]

Click here to view


Manufacturers of commercial biosensors

The commercialisation of intraoral biosensors in India is not extensive yet. However, over time, newer developments will occur. Blood–glucose biosensors account for around 85% of the world market making it a highly successful device.[52] Another very popular biosensor uses optical biosensing which is based on the fluorescent phenomenon, where the fluorescent properties of the analytes are detected. Some manufacturers of biosensors are Biacore, Bio-Rad, Graffinity Pharmaceuticals and Research International.[53]


  Conclusion Top


With the advancements in technology in the field of biosensors, the application range is also increasing and broadening. The biosensors are now being used in diagnosis and treatment planning since they are less time-consuming, have easy accessibility and are a non-invasive method. However, they have certain drawbacks like less sensitivity and specificity which over time have been overcome by newer technologies such as nanofluidics and microfluidics. Unfortunately, due to the lack of readiness and awareness of these biosensors, usage as a disease diagnostic is still restricted. However, the future of intraoral biosensors in the forthcoming years will be bright with the incorporation of them with home testing kits for disease diagnosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Biosensors
Components of A ...
Principles of De...
Oral Cavity: The...
Intraoral Biosen...
Biophysical Info...
Biochemical Info...
Oral Fluid-Based...
Gingival Crevicu...
Saliva-Based Bio...
Role of Intraora...
Conclusion
References
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