Salivary Biosensors in Oral Cancer Detection: A Balanced Overview

International Journal of Dental Science and Innovative Research (IJDSIR) IJDSIR : Dental Publication Service Available Online at:www.ijdsir.com Volume – 8, Issue – 4, July – 2025, Page No. : 84 - 96 Corresponding Author: Dr. Rajalekshmi M P, ijdsir, Volume – 8 Issue - 4, Page No. : 84 - 96 Page84 ISSN: 2581-5989 PubMed - National Library of Medicine - ID: 101738774 Salivary Biosensors in Oral Cancer Detection: A Balanced Overview 1Dr. Rajalekshmi M P, Assistant Professor, Department of Oral and Maxillofacial Pathology, Sree Mookambika Institute of Dental Sciences, Kulasekharam, Tamil Nadu 2Dr. Angelin D, Associate Professor, Department of Oral and Maxillofacial Pathology, Sree Mookambika Institute of Dental Sciences, Kulasekharam, Tamil Nadu 3Dr. Franklin R, Assistant Professor, Department of Oral and Maxillofacial Pathology, Sree Mookambika Institute of Dental Sciences, Kulasekharam, Tamil Nadu 4Dr. Jeslin Mary S, Associate Professor, Department of Oral and Maxillofacial Pathology, Sree Mookambika Institute of Dental Sciences, Kulasekharam, Tamil Nadu 5Dr. Percy Ida A, Consultant Oral and Maxillofacial Pathologist, Joannas Dental Care, Thirunelveli, Tamil Nadu Corresponding Author: Dr. Rajalekshmi M P, Assistant Professor, Department of Oral and Maxillofacial Pathology, Sree Mookambika Institute of Dental Sciences, Kulasekharam, Tamil Nadu. Citation of this Article: Dr. Rajalekshmi M P, Dr. Angelin D, Dr. Franklin R, Dr. Jeslin Mary S, Dr. Percy Ida A, “Salivary Biosensors in Oral Cancer Detection: A Balanced Overview”, IJDSIRJuly – 2025, Volume – 8, Issue – 4, P. No. 84 – 96. Copyright: © 2025, Dr. Rajalekshmi M P, et al. This is an open access journal and article distributed under the terms of the creative common’s attribution non-commercial License. Which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given, and the new creations are licensed under the identical terms. Type of Publication: Review Article Conflicts of Interest: Nil Abstract A transformative phase in health care is under way with significant leap in clinical research, biosensing technologies, nanoparticles, embedded electronics, cloud-distributed software and services, and artificial intelligence. This current scenario describes the relevance of the term digital health and digital health technologies among the health professionals. Despite of these recent breakthroughs in early detection and diagnosis of oral cancer, it still possesses a major threat especially in developing countries like India with 60,000 new cases reported annually. Early detection and early treatment has become the motto for cancer diagnosis and the applications of biosensors in this aspect is limitless theoretically. Oral biosensors are basically receptor– transducer devices that uses biological material in the saliva to interact with an analyte embedded with the device and deliver quantitative or semi-quantitative information utilizing a biological recognition element, processed and transferred to any smart devices. They offer real time biomarker monitoring, minimal biomolecule concentration along with high sensitivity and specificity, thus reducing the possibility of false positive and false negative in testing process. This would Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 Page85 in turn enable the opportunity to share clinical data with clinicians could enable better predictions based on innovative algorithms based on big data ultimately better diagnosis, prognosis, and treatment for the patient. This narrative reviews the developments and advancements in different saliva based biosensors used in the early detection of oral cancer. We also explain the methods used by biosensors to target different types of biomarkers and focused on biosensors that function at the molecular level. Keywords: Oral biosensors, Oral cancer, Salivary biomarkers, Microfluidics Introduction A transformative phase in health care is under way with significant leap in clinical research, biosensing technologies, nanoparticles, embedded electronics, cloud-distributed software and services, and artificial intelligence. This current scenario describes the relevance of the term digital health and digital health technologies among the health professionals. According to the World Health Organization (WHO), digital health technologies can be defined as: “the field of knowledge and practice associated with the development and use of digital technologies to improve health. Digital health expands the concept of eHealth to include digital consumers, with a wider range of smart and connected devices. It also encompasses other uses of digital technologies for health such as the Internet of Things, advanced computing, big data analytics, artificial intelligence including machine learning, and robotics”1. In this context the purpose for a WHO global strategy on Digital Health 2020-2025 focuses to promote healthy lives and wellbeing for everyone, everywhere, at all ages2. Despite of these recent breakthroughs in early detection and diagnosis OC still possess a major threat especially in developing countries like India. OC accounts for approximately 5% of all cancers globally, while in India it is about 40% of all types of cancer. It is estimated that in India nearly 60,000 new cases of OC are reported annually and over 5 people die every hour everyday indicating the disease is highly fatal in nature(3). According to the date retrieved from most relevant organizations and institutions, in India cancers in lip and oral cavity is ranks first in top three leading cancer with respect to number of cases and number of deaths. In males, OC is the most common cancer with a reported incidence of 1,07,812 cases that constitutes about 15.6% of male population. In females, it is the fourth most common cancer with 35,947 new cases reported that constitutes 5% of the female population. Considering both sexes, OC still ranks second position with a reported new cases of 1,43,759 and 10.2% of the total population(4). Growth of malignant tissue in the oral cavity is recognized as OC, which usually affects the tongue, floor of the mouth, cheek, gingiva, lips, or palate. The most persistent signal of OC is non-healing sore in the mouth. In early stages more of anatomical symptoms like white or red spots or lesions in the oral mucosa occurs whereas in advanced stages functional symptom pain, persistent sore throat and difficulty eating or swallowing are reported (5.6). The oral symptoms usually begin with a burning sensation in the mouth along with mild restriction in mouth opening and possibly with a white or red lesion that histologically may show dysplastic characteristics. Such precancerous lesions and conditions are categorized under oral potentially malignant disorders (OPMDs). Early identification plays a critical role in disease progression, morbidity and mortality 5-11. Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Page86 Need For Early Detection of Oral Cancer Even though occurring in one of the most accessible anatomical sites of the body, OC can be easily and quickly detected and treated, it still represent a major problem to humankind due to the increasing frequency, as well as serious consequences. Studies reported an average time delay of 9 months from the onset of symptoms to diagnosis, out of which 7 months is attributed to delay in medical pathways. The key reason is need for biopsy to confirm the diagnosis. Most of the population lives in rural areas where access to advanced healthcare infrastructures are limited and these patients do not have access to pathological service and expertise. In such areas it is often referred to larger centers which may be hundreds of miles away. In addition to that it takes around 2 days for a biopsy report 13,14. All these gets added on to suspected patient’s physical and mental hardship to establish a diagnosis. Hence a need for early diagnosis and initiation of treatment is a prerequisite for all cancer suspects 15. As suggested by the WHO and the National Institute of Dental and Craniofacial Research(NIDCR), mucosal lesions which persist for two weeks or more after removing possible local irritants should be biopsied, which can be incisional, excisional and incisional biopsies are the most diffused among the two16,17. Coreneedle aspiration, punch forceps or fine-needle aspiration are recommended for visible lesions, while posteriorly located lesions may require general anesthesia. The drawbacks are biopsy procedure can be extremely stressful, uncomfortable and invasive for the patients; moreover, it involves high costs, time consuming, a high degree of complexity which require clinician training, and can cause infection or damage to nearby tissues. On the contrary, cytological examination of a smear is less invasive but also less sensitive and specific than biopsy. Modern cytological procedures, such as brush-biopsy and micro biopsy, offered a wealth of opportunities in OC screening. However, still, there is a need for a more accessible version of a test for immediate response18. This narrative reviews the developments and advancements in different saliva based biosensors used in the early detection of OSCC. We also explain the methods used by biosensors to target different types of biomarkers and focused on biosensors that function at the molecular level. Biosensors and Oral Cancer Personalized medicine and noninvasive diagnosing techniques are gaining wide popularity across the globe. The significant advancement in precision medicine is the integration of biosensors which are receptor–transducer devices that uses biological material to interact with an analyte and deliver quantitative or semi-quantitative information utilizing a biological recognition element. Biosensors are widely used as diagnostic instruments for identifying infections, monitoring and detecting hazardous metabolites, glucose monitoring, cholesterol testing, and vitamin and other nutrient measurements19,20. The vision of the future for biosensors even includes chip-scale devices placed on the human body for monitoring vital signs, correcting abnormalities, or even signaling a call for help in an emergency. Early detection and early treatment has become the motto for cancer diagnosis and the applications of biosensors in this aspect is limitless theoretically. The fact that early cancer detection can improve survival rate and prognosis, necessitates noninvasive, patient friendly diagnostic tools. Because of this researches are carried out worldwide to improvise the practicality of the biosensors in daily life. The term bio refers to the biological element that is been detected. Oral biosensors Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 Page87 are basically receptor–transducer devices that uses biological material in the saliva to interact with an analyte embedded with the device and deliver quantitative or semi-quantitative information utilizing a biological recognition element, processed and transferred to any smart devices21. Cornerstones in the Development The development of biosensors dates back to 1962 Dr. Leland C. Clark Jr introduced the first enzyme based electrode for glucose detection, marking the birth of modern biosensors22. Since then the biosensor technology has rapidly evolved, expanding into various fields including medical diagnostics. In 1970s-1980s exploration of saliva as a diagnostic fluid for biosensors started. Next decade witnessed the electrochemical biosensors that enabled detection of salivary biomarkers in oral health and also introduction of miniaturized sensor components. In early third millennium techniques to incorporate into wearable oral devices like mouth guards, orthodontic appliances have gained popularity. Further the researches are emphasized on the biosensor application to detect cancer biomarkers in saliva. In 2010 nanotechnology experienced a major breakthrough and nanomaterial like gold nanoparticles are grapheme enhanced sensor sensitivity and selectivity23-25. Further the emergence of optical and piezoelectric biosensors and progress in wireless data transmission in real time monitoring had a great impact in the field of oral biosensors26. Recent years with a substantial leap in personalized medicine and point of care devices, development of flexible and compatible biosensors for continuous saliva monitoring and early OC detection is widely accepted. However this technology in dentistry is still developing and with the availability of such devices tests can be rapidly performed within clinical setups. Microfluidics Saliva The concept of simple, sensitive and noninvasive techniques for early diagnosis to save more lives gained popularity in the recent COVID-19 pandemics. In addition the real time and portable LOC devices based on saliva as a medium also gained wide popularity. In modern health care systems, saliva is used an ideal specimen since it reflects the physiologic and pathologic state of the body. Studies documented suggests saliva can contain DNA, RNA, exosomes, hormones, mucins, enzymes, secretions from the nasal cavity, serum and blood. It also contains derivatives from the oral ulcers and lesions, microorganisms their products and finally food debris. In addition to being of more convenient, saliva samples does not require any additional action as in blood samples and lower risk of personal contamination urges to move from blood to saliva. Despite of all these the use of saliva based techniques in detection of OC is still needs further refinement and improvement. The usage of saliva as diagnostic and monitoring fluid for OC was extensively studied and pioneered by D.T. Wong and his research group since that moment the field has seen a marked increase in interest among the scientific community (27,28). Prior to any salivary analysis, understanding the human saliva profile is essential to determine if the salivary composition differs due to gender, stimulation, or smoking status. Takeda and co-workers established the composition and concentration of salivary metabolites in a normal human population and how health choices, such as smoking, may affect the metabolic profile29. However, there are a number of downsides to using saliva as a diagnostic fluid, the most significant of which is its low specificity and sensitivity. Due to the lack of a consistent quantity of saliva in people, the concentration of analytes might vary substantially depending on when Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 Page88 the sampling/collection method is performed30. With the innovations in microfluidics and nanotechnologies, even the lower level of analytes in saliva can be detected, which have enhanced controllability, throughput, reliability and assay speed. Microfluidic based biosensors utilize micro scale fluid flow and nanotechnology principle to detect and quantify biological molecules such as proteins, DNA and cells. They offer real time biomarker monitoring, minimal biomolecule concentration along with high sensitivity and specificity, thus reducing the possibility of false positive and false negative in testing process31. Components and Working Principle Oral biosensor is a completely equipped analytical device that detects and measures the concentration or activity of a chemical molecule in the salivary sample. The basic principle of biosensor is that it transforms a biological entity like DNA, RNA and proteins into an electrical signal, detected and processed to detect a specific biological analyte. It consists of following components: Analyte, Bio receptors, Transducers and Displays. The material of interest that need to be detected is referred as Analyte. The molecule that primarily recognizes the analyte is known as Bio receptors if it is of natural such as DNA, RNA, enzymes, proteins and peptides. Lab derived synthetic receptors like such as molecular imprinted polymers, C-allotropes, nanomaterial or a combination of both natural and synthetic receptors can also be used. This immobilized probes interact with the analyte and signals are generated. It can be heat, pH, light, charge or mass charge etc. Transducer is the component that converts the bio recognition event into a signal which can be measured easily. This process is referred to as signalization. The signal from transduced analyte-bio receptor interaction and prepares it for display on the device. Display unit constitutes an interface system that generates measurable values or curves easily comprehendible by the user32, 36. Types of Biosensors Biosensors used for identifying OC are all proven in studies for their efficiency in detection of early stages of cancer, thus forms a reliable noninvasive method in early detection. Based on the components biosensors can be divided as follows: 1. Based on the bio receptor molecule. Bioreceptor is the critical component in a biosensor. Early biosensors used naturally occurring recognition elements. Now a day with the advances in technology and synthetic chemistry, many biosensor recognition elements are synthesized in the laboratory to improve the stability and reproducibility of biosensor function. A. DNA In the development and progression of OC in normal oral epithelium mutations like tumor protein p53 (TP53), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) plays an important role. TP53 mutations can cause loss of normal p53 protein function which is required for cell cycle regulation and death. HER2 overexpression and mutation will lead to development of OC and also contribute to aggressive illness and bad prognosis. EGFR overexpression and mutation activate downstream signaling pathways promoting survival cell proliferation and migration. Oncogene Ras, promotes cell growth and survival and hence its activation plays an important role in the malignant transformation of cells. On the other hand, tumor suppressor genes which serves as a barrier to cancer formation, the loss of function is a hallmark for oral carcinogenesis. In general, cells with genetic mutation or damaged DNA thus evade normal regulatory processes contributing to carcinogenesis and cancer Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 Page89 progression (37,38). The identification DNA sequence and discreteness of sequence is usually identified is done by DNA based diagnostic methods like restriction fragment length polymorphism (RFLP), random amplified polymorphic DNA (RAPD), polymerase chain reaction (PCR) etc., these current procedures are difficult, time consuming and costly. DNA based biosensors is an innovative method that overcome these issues as they are reliable, affordable, sensitive, cost effective and reduces effort and time. The added benefits are ease of manufacturing and operation procedures and the cheap costs, make it an attractive option for the non-invasive early detection of OC in saliva in mass populations (39,40). B. RNA The cancer causing aberrations produces microRNAs (miRNA) following inactivation of the anti-tumor gene, chromosomal degradation, and gene hyper methylation are considered in RNA based biosensors which can detect cancer even when no physical signs are present. miRNAs as a biomarker for early detection and development of OC was discussed in detail by Osan et al. and reported many key role miRNAs including miRNA-21, miRNA-24, miRNA-31, miRNA-145, miRNA-196b etc. miRNA-21 plays a critical role in perineural invasion in turn associated with poor survival rate in OC patients. miRNA-24 is associated with cell proliferation in OC. Similarly, miRNA-31 is an oncogenic factor and is significantly up regulated in saliva in OC patients (41-44). The current methodologies for the detection of miRNAs include reverse transcription quantitative PCR (RTqPCR), droplet digital PCR (ddPCR), and next generation sequencing. Nucleic acid amplification test (NAAT) is an alternative that allows rapid detection without thermo cycling. However all these techniques are complex, expensive and time consuming. In contrast RNA based biosensors facilitate detection with greater precision and hence aligns with the demand of efficient and timely cancer diagnosis. C. Protein biosensors Protein biosensors for cancer detection measures components t that are thought to be indicators of aberrant biological processes, disease processes, or treatm enintermediation responses. They make use of electrochemical transducers that provide a sensitive, fast, and low-cost diagnostic framework for detection. In these biosensors the electrode surfaces are modified with synthetic receptors such as antibodies or aptamers. The interactions between an antibody and an antigen operate similar to a lock-and-key binding mechanism that makes the immunosensors are very selective. The presence of protein biomarkers and their expression level in saliva indicates the disease status21, 44. Wei et al. pioneered in the development of multiplexed electrochemical sensors for the measurement of salivary biomarkers interleukin-8 (IL-8) (both mRNA and protein) for precise diagnosis of OC (45). The enzyme-linked immunosorbent test (ELISA) is the gold standard approach for clinical biomarker detection for protein analytes with the limits of detection (LOD) 1–3 pg mL. When it comes to POC diagnostics ELISA is not a first option because of the expense of the test kits and equipment, the length of time it takes to measure, and the difficulty of multiplexing. When compared to standard biosensors, aptamer-based biosensors are label-free and high sensitivity for electrochemical detection. Lin etal created a capacitive aptasensor to track the overexpression of the HER2 in oral malignancies46. Anti-HER2 aptamers (ssDNA) are immobilized on a gold microelectrode surface and various doses of HER2 were spiked in diluted human serum. The link between capacitance and the HER2 concentration was finally determined47,48. Aptamers were Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 Page90 also used to identify the IL-6 protein in which electrochemical impedance spectroscopy (EIS) was used to develop a nano-aptamer sensor to detect IL-6 in bio fluids and 0.02 pg mL was considered to be the detection limit. Furthermore, after two weeks, the aptasensors had 90% of their original impedance response signal, indicating the sensor’s great stability49. Yet another type of immunoassays are protein sensors in which recognized element mostly a primary antibody is immobilized on an electrode surface in a sandwich immunoassay to capture the specific analyte. A secondary antibody coupled with an enzyme, such as horseradish peroxidase (HRP), is added to the solution which binds with the antigen. HRP can convert its substrate to electrochemically active species, allowing it to translate chemical signals into electrochemical signals50. Biosensors are further categorised into the following groups based on the signal transduction mechanism: electrochemical, thermal, optical, and nano biosensors. 1. Electrochemical transducers The signals from the transducer are amplified and displayed by an electrical systems and hence referred to as electrochemical biosensors. It shows a higher rate of implementation than other biosensor technologies and can detect practically any type of biomarker and are simple to combine with typical laboratory bench top equipment. Furthermore, because they are easily downsized, they are likely to be integrated into wearable and portable devices. The integration of electrochemical sensors into compact devices enhances the requirements for comfort, convenience, ease of operation, and flexibility, making the creation of dependable, wearable, and portable POC ultrasensitive devices difficult51-54. To functionalize the surface of the sensing electrodes, a variety of methods have been explored including antibodies, magnetic beads, and aptamers. Cyfra21.1 a fragment of cytokeratin-19 that has been extensively researched in saliva using electrochemical biosensors in detection of OC. Jafari et al. in 2020 fabricated an immunosensor wherein anti-Cyfra21.1 is immobilized on a cysteamine (CysA) and glutaraldehyde (GA) modified gold electrode. The device performance was investigated through square wave voltammetry (SWV) and further validation with ELISA test reported a LOD of 2.5 ng/mL and a linear range between 2.5 and 50 ng/Ml (55). This platform thus provides a low-cost, reliable, and robust method to perform non-invasive OC detection. Other biomarkers include interleukin-1, Hypoxia inducible factor-1 alpha (HIF-1), Oral Cancer Overexpressed 1 (ORAOV1), TNFand IL-8 were extensively studied and incorporated in electrochemical platform for biosensors26,56,57. An innovative research by Aydin et al. resulted in the use of 6-phosphonohexanoic acid (PHA) as a biomolecule immobilization matrix to attach anti-IL-1β for selective binding of the analyte and verified through electrochemical impedance spectroscopy it to be a suitable material for specific, reliable, reproducible, repeatable and stable operation. The impedimetric immunosensor reached a LOD of 7.5 fg/mL in a 0.025–3 pg/mL concentration range (58). Yet another potential biomarker for the prognosis of OSCC is HIF-1α, involved in tumoral hypoxia. Munoz-San Martìn et al. made use of magnetic beads coated with HIF-1α in a electrochemical assay designed with a sandwich configuration, exhibited a low LOD of 76 pg/mL59. 2. Optical transducers: Optical systems provide a new pathway to perform salivary analysis with high sensitivity, selectivity, and label-free operation. Transducers are optical sensors which includes microfluidic channels that ensures the Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 Page91 delivery of biofluid in the area of where the detector/reader is positioned. Some of the recently developed optical biosensors in detection of OC includes fluorescence-based biosensors, surface-enhanced Raman spectroscopy (SERS) biosensors, photonic crystal biosensors and surface plasmon resonance (SPR) biosensors. Among these SERS is versatile and most frequently used due to its ease of operation and multiplexed capability. Liu et al. developed plasmonic Ag nano-cubes (AgNCs) based platform nicking endonuclease assisted signal amplification (NESA) with heated electrodes to enhance SERS signals for the detection of a DNA sequence related to OC60. Song et al. developed a fluorescence based immunosensor in which to detect Cyfra21.1, OC biomarker. A three dimensional network of antibody-functionalized carbon nanotubes is created among these Si pillars and, through the use of a specific tag, fluorescence images are obtained61. Yet another breakthrough by Dong and Pires, absorbance based microfluidic biosensor for the multiplexed detection of three salivary biomarkers, IL-8, IL-1β and MMP-8 commonly associated with oral cancer. Organic photodetectors (OPDs), have photoactive area on a glass substrate, and vertically aligned with the microfluidic polymeric channel, featuring chambers with antibody-functionalized goldsilver immunoassays are also validated to prove its utility in clinical practice62. a fluorescent biosensor based on magnetic and fluorescent bio-probes (MFBPs) loaded with quantum dots (QDs) for an efficient signal amplification was developed by Wu et al. to detect salivary exosomes associated with OC. Specific aptamers were immobilized on the surface of magnetic microspheres (MMs) to selectively bind CD63 proteins on exosomes. This technique reached a lower LOD of 500 particles per microliter of solution63. 3. Nano biosensors Integration of nanotechnology aids in biosensing methods helps in overcoming the restraints like affordability, simplicity of handling, miniaturisation, and the lack of the need for an expert to analyse the data. In this context, gold nanoparticles (AuNPs), quantum dots (QDs), dendrimers, metal oxides, carbon-based nanocomposites, and other nanomaterials (NMs) have been employed to fabricate nanobiosensors. With these functionality has significantly increased as a result of the unique features like quicker detection, improved detection limits, and enchanced repeatability, require a smaller sample volume and offer high precision, specificity, cost-effectiveness and reduced time and ease of implementation for automatic analysis. Nano-based biosensing for the early identification of OC could lead to enhanced patient treatment outcomes and care. Nanotechnology-based miniaturised devices are a breakthrough in pre-clinical and clinical research fields including medication delivery, customised medicine, and diagnostic potential, a field now known as “nanodiagnostics”. Upcoming version nanoparticles (UCNPs), which display photon upconversion phenomena when activated by incident near-infrared (NIR) light with emission in the visible region of the electromagnetic spectrum, are other prominent types of NMs in biosensing. It has been reported that biocompatible UCNP composites based on fluorescence resonance energy transfer (FRET) may detect OSCC biomarkers using energy changes in the red and blue wavelength ranges. The expression of matrix metalloproteinase 2 (MMP2) in tumour models and OC tissues could be detected by the emission of blue fluorescence when irradiated44,64,65. Dr. Rajalekshmi M P, et al. International Journal of Dental Science and Innovative Research (IJDSIR) ©2025 IJDSIR, All Rights Reserved Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Page92 Conclusion This review provides an overview of the most advanced biosensing strategies that have been developed to perform early-stage diagnosis of OC. The importance of saliva as a readily available and continuously renovated biofluid has been stressed in order to stimulate further research on salivary biomarkers, whose timely detection could improve patients’ quality of life and their survival. All these materials and process should be thoroughly studied for its applicability to clinical practice. Welldesigned clinical trials on diagnostic, predictive and prognostic performance of saliva biomarkers will complete the path to their application in clinical practice. Wearable intraoral bioelectronic platforms and portable POC devices are expected to see an increasing clinical applicability in the near future, as they offer substantial advantages compared to traditional laboratory equipment and procedures. Given that the concentration of salivary biomarkers is typically lower than that in other biofluids, extremely sensitivite biosensors are needed to reliably detect the analyte of interest. Limit of detection and sensitivity matches mostly overcome the limits that can be reached with traditional techniques. The integration of miniaturized wireless communication units within these integrated bioelectronic devices is also a key enabler for the future of smart interconnected systems. This would in turn enable the opportunity to share clinical data with clinicians could enable better predictions based on innovative algorithms based on big data ultimately better diagnosis, prognosis, and treatment for the patient. We expect intraoral biosensors to play a pivotal role in continuous real-time data acquisition for the detection of potentially malignant biomarkers related to oral cancer. Among the various types of malignancies, oral cancer is best suited to be tackled with wearable sensors placed in the oral cavity due to the direct contact of saliva with premalignant or malignant lesions. Therefore, the aim of this review is that of stimulating research in this direction, while considering the requirements of a translational research that should not only offer interesting new research avenues to pursue inside a laboratory, but also find a sustainable and effective way of developing devices that can have a wide applicability in clinical settings. References 1. 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