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18830 R Sindhu 7

1Bachelor of Dental Surgery, Department of Public Health Dentistry, SRM Dental College and Hospital, SRM Institute of Science and Technology, Ramapuram, Chennai, India

2Senior lecturer Department of Public Health Dentistry, SRM Dental College and Hospital, SRM Institute of Science and Technology, Ramapuram, Chennai, India

3Professor and HOD, Department of Public Health Dentistry, SRM Dental College and Hospital, SRM Institute of Science and Technology, Ramapuram, Chennai, India

4Reader, Department of Public Health Dentistry, SRM Dental College and Hospital, SRM Institute of Science and Technology, Ramapuram, Chennai, India

5Reader, Department of Public Health Dentistry, SRM Dental College and Hospital, SRM Institute of Science and Technology, Ramapuram, Chennai, India

6Senior lecturer, Department of Public Health Dentistry, SRM Dental College and Hospital, SRM Institute of Science and Technology, Ramapuram, Chennai, India

7Senior lecturer ,Department of Public Health Dentistry, SRM Dental College and Hospital, SRM Institute of Science and Technology, Ramapuram, Chennai, India

ABSTRACT

Background: Oral cancer is the most common cancers occurring in the entire world. India has 1/3rd of oral cancer cases in the world, which accounts for around 30% of all the cancers in India, according to the National Cancer Registry Programme 2012–2014. Therefore, oral fluid-based biosensors for early detection and diagnosis can be very useful to humanity.

Aim: To assess the efficacy of biosensors in early detection and early treatment management of oral cancer.

Materials and Methods: A literature review was performed using various electronic databases like Pub Med, science direct, Wiley online library, lilacs and google scholar, using certain keywords. Of the 174 articles from various sources collected, four final articles were related to research topics. The review is described according to the PRISMA guidelines.

Keywords: biosensors, diagnosis, oral cancer, cancer screening, prevention and prompt diagnosis.

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18831

Biosensors are receptor–transducer devices, which provides quantitative or semi-quantitative information using a biological recognition element, utilizes biological material to interact with an analyte [1]

specifically.

In the field of medicine, biosensors are emerging spontaneously. Though very limited, they are used as diagnostic tools, detecting pathogens, monitoring and detecting toxic metabolites, glucose monitoring, cholesterol testing, and measuring vitamin and other nutrients. Biosensors are also be used in dentistry, such as oral fluid-based biosensors for diagnosis of caries, periodontitis, oral cancer by detecting samples of saliva and GCF [2].

Cancer involves a group of diseases involving abnormal cell growth to invade or spread to other parts of the body. Lung cancer is the most common in males, followed by oral cancer, and breast cancer is the most common in females.

Oral cancer involves the growth of cancerous tissue in the oral cavity, which most commonly involves the tongue, floor of the mouth, cheek, gingiva, lips or palate. India has 1/3rd of oral cancer cases globally, accounting for around 30% of all cancers in India [3].

The commonest signs of oral cancer can range from non-healing sore in the mouth to pain that is not relieved easily. Other signs include a lump or thickening in the cheek, white or red patches on the gums, the tongue and involving other areas of the oral cavity and occasionally sore throat that doesn't get relieved, along with trouble chewing or swallowing. Oral cancer can also be prevented by minimizing the risk factors like tobacco consumption in smokeless and chewable form and intake of alcohol and awareness regarding the same.

Biosensors can be used in the effective and early detection of oral cancer. Studies have shown that DNA biosensor, RNA biosensor, and protein biosensor can effectively detect oral cancer and provide beneficial information in developing non-invasive oral cancer diagnosis [4]. In addition, highly sensitive electrochemical biosensor techniques are emerging in the field of dentistry [5].

Though a lot of literature on the application of biosensors in medical and dental fields are available, the role in oral cancer detection did not provide adequate databases. Hence this study was carried out.

MATERIALS AND METHODS:

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18832 Inclusion criteria-

-Original articles -Full-text articles

-Articles showing the efficacy of biosensors in oral cancer detection.

-Articles in English.

Exclusion criteria- -Articles without full text -Systematic reviews

-Articles showing the use of biosensors in other fields.

-Articles in different languages.

-Articles showing the use of biosensors in the diagnosis of other cancers.

-Non-related and irrelevant articles.

-Review papers.

SEARCH STRATEGY: A thorough literature review was performed using the search engines like Pub Med, science direct, Wiley online library and Google scholar. The keywords used for the search were

"diagnosis", "oral cancer", "cancer screening", "prevention", and "prompt diagnosis".

SEARCH ENGINES: The search engines were used- -PubMed

-Wiley online library -Google Scholar -Scopus

-Elsevier science direct -Ovid medicine

-Cochrane library -Prospero

-Lilacs

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18833 SEARCH WORDS:

Specific keywords used for each electronic database can be found in Table 1.

Table 1: SEARCH DATABASE

S no Database Search terms Articles

found

1 PubMed

central (Advanced search)

Biosensors AND diagnosis AND oral cancer 59

2 Google Scholar

“cancer screening” AND “early detection” AND

“oral cancer” AND “biosensors” AND “prevention”

AND “prompt diagnosis”

7

3 Science Direct Biosensors AND diagnosis AND oral cancer 38 4 Wiley Online

library

Biosensors AND diagnosis AND oral cancer 74

RESULTS:

A Literature review was performed using the following search engines. The keywords used for searching were "diagnosis", "oral cancer", "cancer screening", "prevention", and "prompt diagnosis". A total of 174 articles from various search engines were collected, and out of which, four final articles related to research topics were finalized. Two duplicates were removed. Amongst the rest, the articles without full text were also removed, which led to 55 articles. Out of those 55 articles, four were selected for the final study purpose.

Figure 1 shows the PRISMA flowchart that depicts the articles identified, screened, duplicates removed, and the final articles included for qualitative analysis.

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18834

Figure 1: PRSIMA flowchart.

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18835

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18836

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18837

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18838

TABLE 2: CHARACTERISTICS OF THE INCLUDED STUDIES IN THE SYSTEMATIC REVIEW

S.NO AUTHOR S

NAME

JOURNAL NAME YEAR, VOLUME (ISSUE);

PAGE NO.

STUDY DESIGN

PURPO SE OF STUDY

MATERIA L USED

METHODOLOGY FOLLOWED

1. Fang Wei, Prabhudas Patel, Wei Liao, Kishore Chaudhry, Lei Zhang, Martha Arellano- Garcia, Shen Hu, David Elashoff, Hui Zhou,

Clinical Cancer

Research

July 1

2009 (15) (13) 4446- 4452

Experime ntal study

Use of biomarke rs for molecula r

diagnosti cs

Patient’s saliva specimens were

collected.

Oral cancer and control subject saliva were

obtained from the Gujarat Cancer &

Research Institute

Saliva crystals were loaded onto the probe- coated electrode. Briefly, Saliva samples were centrifuged at 2,600

× g for 15 min at 4°C. The crystals were removed from the pellet and processed for RNA and protein stabilization.

Electrodes coated with probes for IL-8 mRNA and IL-8 protein, the same saliva crystals were

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18839 Shah, Chih

- Ming Ho, and David T. Wong

Review Board from the respective institutions.

Electrochemi cal sensors were used for this study.

The

electrochemi cal sensor is a 16 array of gold

electrodes chip. For each unit of the array, there are working electrode, counter electrode, and reference electrode.

and standard IL-8 protein were spiked into the saliva crystals first, and then loaded onto the electrodes. For the specificity control, S100A8 RNA and IL-1β protein, which are both biomarkers in saliva, were loaded onto the electrodes.

2. Mohsen

Jafari, Mohamma d

Hasanzade h[7]

Biomedicine

&

Pharmacothe rapy,

Volume 131, 2020

Experime ntal study

Successf ul

detection and determin ation of the Cyfra21.

1

biomarke

r in

unproces sed human

Saliva sample collection was

performed All chemicals used in this research are in analytical grade.

Human Cytokeratin Fragment Antigen 21-1

The Au electrode was altered by Cys and GA respectively via self- assembly as a substrate to stabilize the biological

agents. The

immunosensor exhibits the excellent ability to detect and determine of Cyfra21.1 biomarker in low concentrations of the desired biomarker in unprocessed human saliva sample.

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18840

purchased.

Sodium hydrogen phosphate, Sodium dihydrogen phosphate monohydrate , Potassium ferrocyanide, Potassium ferricyanide, Potassium chloride were used.

Cysteamine, Glutaraldehy de, Bovine serum

albumin were used along with Ethanol and Sulfuric acid.

Electrochemi cal

experiments for

voltammetric measurement

s were

accomplishe d in three- electrode cell.

3. Winny Tana, Leyla Sabet, Yang Li, Tianwei

Biosensors and

Bioelectronic s 24 (2008) 266–271

Experime ntal study

Optical protein sensor for detecting cancer

The same monoclonal (MAb) and polyclonal

Three advances in optical protein biosensor are presented: (1) without enzymatic signal amplification,

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18841 ,

David T.Wong,Ch ih-Ming Ho[8]

the sandwich assay pair in the human IL-8 ELISA kits

were used in the detection scheme for the optical protein sensor.

ELISA kits forhumanIL- 8 protein were

purchased.

The mouse anti-human IL-8 MAb, biotin-

labelled (M802B), recombinant humanIL-8 (RIL810), and rabbit anti-human IL-8 PAb (P801) were used.

Molecular Probes, Invitrogen and Bovine Serum

Albumin (BSA) were used.

sensor by comparing with traditional ELISA measurements.

4. Ruchika Malhotra,V yomesh Patel,

Analytical.

Chemistry.

2010, 82, 3118–3123

Experime ntal study

Ultrasens itive electroch emical

Monoclonal antihuman interleukin-

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18842 Gutkind,

and

James F.

Rusling[9]

human IL-6 and proof-of- concept studies of IL-6 detection in

HNSCC cells.

6708), biotinylated antihuman IL-6 antibody, recombinant human IL-6 (carrier-free) in calf serum, and

streptavidin- horseradish peroxidase (HRP) were used.

TABLE 2[CONTINUED]: CHARACTERISTICS OF THE INCLUDED STUDIES IN THE SYSTEMATIC REVIEW

S.NO AUTHORS NAME

TOOLS OF

ASSESSMENT RESULTS OUTCOME OF

STUDY

1. Fang Wei,

Prabhudas Patel, Wei Liao, Kishore Chaudhry, Lei Zhang,

Martha Arellano- Garcia, Shen Hu, David Elashoff,

Amperometric detection was carried out by applying −200 mV potential to each electrode unit, followed by parallel amperometric signal

The EC sensor shows high sensitivity and specificity. The limit of detection is 3.9 fM for IL-8 mRNA and 7.4 pg/mL for IL-8 protein measured in saliva.

With the multiplexing EC sensor, 56 clinical

EC sensor is not only an alternative detection method to PCR/ELISA.

It provides fast, effective, and accurate multiplexing

measurements for real clinical diagnostics.

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18843 - Ming Ho, and

David T. Wong[6]

mRNA and IL-8 protein levels measured by the EC sensors show significant differences between the cancer sample and control sample.

Among the 2 subject groups, there were no significant differences in terms of mean age: oral squamous cell carcinoma (OSCC) patients, 46 ± 12.8 years; normal subjects, 44.9 ± 11.9 years (Wilcoxon rank sum test, P > 0.8); gender (P = 1); chewing history (P > 0.08); smoking history (P > 0.27); or alcohol drinking history (P > 0.06).

saliva oral cancer biomarkers initially discovered based on a U.S. population can also discriminate oral cancer in an Indian population.

2. Mohsen Jafari, Mohammad

Hasanzadeh[7]

The electrochemical behaviour of bare Au electrode before

and after

modification with mentioned materials and biological elements were investigated by some voltammetric techniques

including cyclic voltammetry (CV) and square wave voltammetry

(SWV).

The reproducibility of the immunosensor was evaluated assessed by fabricating five modified electrodes independently at under the same experimental condition, and using them for detection of 5–50 ng/L of Cyfra21.1. The relative standard deviations were 1.42 % and 1.79 % for detection of 5–50 ng/L of Cyfra21.1, respectively.

These results suggested

the acceptable

satisfactory fabrication reproducibility and

The engineered immunosensor exhibit the excellent ability to detect and determine of Cyfra21.1 biomarker in low concentrations of the desired biomarker in unprocessed human saliva sample. Under the optimized operating conditions, the results demonstrate that the desired platform has a good sensitivity detection of Cyfra21.

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18844 3. Winny Tana, Leyla

Sabet, Yang Li, Tianwei Yu, Perry R. Klokkevold, David

T.Wong,Chih- Ming Ho[8]

The original optical protein sensor has an LOD which is able to detect the IL-8 baseline concentrations (589.25 pg/ml (70 pM)) in the control group and the raised IL-8 levels in the cancer patients for salivary IL-8 detection.

However, this sensor can be applied to a variety of biomarkers, especially those that are clinically significant, but are present in very low concentrations.

A platform technology that can significantly increase the sensitivity and simplify the assay preparation for protein detection. The target protein is immobilized on the surface with capture probe. An advantage of the presented sensor is that it can be developed with attainable materials and instrumentation.

4. Ruchika

Malhotra,Vyomesh Patel,

Jose Pedro Vaque´, J. Silvio Gutkind, and

James F. Rusling[9]

Two strategies for multilevel detection in the amperometric

immunosensor: (A) immunosensor after treating with Ab2- biotinstreptavidin- HRP, providing 14-16 HRPs on one Ab2; (B) immunosensor after treating with HRP- MWNT-Ab2

bioconjugate having 106 active HRPs (enzyme labels) per 100 nm of carboxylated carbon nanotubes. The final detection step involves

immersing the

immunosensor in an electrochemical cell containing PBS buffer and mediator, applying voltage, and injecting a

Ultrasensitive,

selective, and accurate electrochemical

detection of IL-6 representative of normal patient to high cancer patient levels from a variety of head and neck cancer cells. The detection limit of 0.5 pg mL-1 for IL-6 is 16-fold lower than that of conventional ELISA and 60-fold lower than for our previously

reported IL-6

immunosensors.

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18845 TABLE 3: REASON FOR EXCLUSION OF ARTICLES:

REASONS FOR EXCLUSION

NO. OF ARTICLES EXCLUDED

1. Articles without full text 70

2. Systematic reviews 8

3. Articles showing the use of biosensors in other fields.

9 4. Articles in different languages. 6 5. Articles showing the use of

biosensors in the diagnosis of other cancers.

4

6. Non related and irrelevant articles. 22

7. Review papers 6

8. Duplicates 2

DISCUSSION:

The research yielded 174 researches which were assessed, and four final articles were selected for the study purpose. Though biosensors are used in various fields of medicine and dentistry, the use of the same in the detection of oral cancer was very limited. Hence this study was carried out.

The various papers selected for this study emphasized the use and efficacy of biosensors of different kinds in assessing oral cancer early. The papers used for this study purpose use biosensors for molecular-level detection of oral cancer, use of Cyfra21.1 biomarker in unprocessed human saliva samples, use of immunosenosrs and use of optical proteins.

The primary objective of this study was to know if the use of biosensors in the detection of oral cancer is available or not. All the studies included in this article support the statement that Biosensors can detect oral cancer and help in immediate treatment and management.

Though biosensors can be used as potential diagnostic criteria, their use in these fields is very limited.

However, biosensors as diagnostic criteria hold a great future in the field of medicine as well as dentistry.

Concluding, the use of biomarkers can provide excellent results in early and prompt detection of oral cancer, thereby helping in improving the quality and time of management and treatment provided to an individual. All the articles included in this study showed a positive use of biomarkers in detecting oral cancers.

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18846

1. Haoran Liu, Jun Ge, Eugene Ma, Lei Yang, Biomaterials in Translational Medicine,2019, Pages 213-255

2. Lakshmi, KRoja & Nelakurthi, Hasini & Kumar, ASudarshan & Rudraraju, Amrutha. (2017). Oral fluid-based biosensors: A novel method for rapid and noninvasive diagnosis. Indian Journal of Dental Sciences.

3. Borse V, Konwar AN, Buragohain P. Oral cancer diagnosis and perspectives in India. Sensors International. 2020;1:100046.

4. Lin, Y. T., Darvishi, S., Preet, A., Huang, T. Y., Lin, S. H., Girault, H. H., ... & Lin, T. E. (2020). A review: electrochemical biosensors for oral cancer. Chemosensors, 8(3), 54.

5. Mehrotra P. Biosensors and their applications - A review. J Oral Biol Craniofac Res. 2016;6(2):153- 159.

6. Wei, F., Patel, P., Liao, W., Chaudhry, K., Zhang, L., Arellano-Garcia, M., ... & Wong, D. T. (2009).

Electrochemical sensor for multiplex biomarkers detection. Clinical Cancer Research, 15(13), 4446- 4452.

7. Mohsen Jafari, Mohammad Hasanzadeh, Biomedicine & Pharmacotherapy, Volume 131, 2020, 110671,ISSN 0753-3322,

8. Tan, Winny, Leyla Sabet, Yang Li, Tianwei Yu, Perry R. Klokkevold, David T. Wong, and Chih-Ming Ho. "Optical protein sensor for detecting cancer markers in saliva." Biosensors and Bioelectronics 24, no.

2 (2008): 266-271.

9. Malhotra, Ruchika, Vyomesh Patel, Jose Pedro Vaqué, J. Silvio Gutkind, and James F. Rusling.

"Ultrasensitive electrochemical immunosensor for oral cancer biomarker IL-6 using carbon nanotube forest electrodes and multilabel amplification." Analytical chemistry 82, no. 8 (2010): 3118-3123.

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