The rise in biosensor device innovation has shifted scientific attention toward the creation of advanced biosensor technologies and tools. Presently, these devices have gained significant traction across critical sectors, including biomedicine, drug development, food quality assurance, and environmental assessment. Despite the relative simplicity of diagnostic tests, challenges persist in achieving reliable early detection and monitoring of cancer, as well as in evaluating anticancer chemotherapeutic agents. This review focuses on showcasing the application of biosensors as diagnostic tools and exploring their prospective future roles. Historical advancements in biosensor development have paved the way for researchers to refine biosensing components, aiming to enhance their sensitivity and specificity—particularly crucial in cancer diagnostics, where continuous efforts are needed to identify and validate new biomarkers, engineer ligands targeting them, and improve sample processing techniques. Furthermore, there is a growing demand for multichannel biosensors capable of simultaneously detecting multiple cancer markers. Looking ahead, the future landscape for biosensor technology appears highly promising, but realizing its full potential will depend on a concerted, multi-disciplinary strategy that emphasizes cost-effective innovations to transition biosensor systems from experimental settings to widespread commercial use.
Following the groundbreaking invention of the first glucose biosensor by Clark Jr and Lyons [1], the demand for biosensor technology in medicine and nanotechnology has grown considerably. Researchers are increasingly focusing on creating rapid, efficient, user-friendly, and cost-effective diagnostic tools. It is anticipated that these objectives can be achieved by integrating chemistry, biological sciences, and nanotechnology into the design of emerging biosensor systems. While biosensor technology has already found extensive use across various sectors—including medical diagnostics, food and beverage industries, environmental monitoring, agriculture, and numerous biotechnology-related industries [2]—the biosensor for blood glucose monitoring has achieved widespread commercial success due to its reliable precision in detecting disease-specific biomarkers in both in-vitro and in-vivo settings [3]. The term “sensor,” originating from the Latin word “sentire,” meaning “to perceive,” was first introduced by Cammann [4]. Biosensors operate through a receptor-transducer mechanism, allowing them to detect and interpret biochemical or biophysical properties within a given medium. Their key strengths lie in their exceptional selectivity and sensitivity, enabling the precise identification of specific biological molecules [5].
A wide variety of biosensors are currently available, including enzyme-based, electrochemical, immune-sensor, protein, genetically encoded (DNA-based), tissue-based, microbial or cell-based, magnetic, optical, piezoelectric, and thermal biosensors. Each type is distinguished by its unique manufacturing process and field of application, though they all fundamentally rely on sample recognition, transduction, and signal amplification. These innovations have revolutionized the medical sciences by offering devices capable of detecting even the smallest amounts of biological samples, significantly increasing demand for them [6].
Today, biosensor technologies have been adopted across multiple sectors. In healthcare, they are instrumental for detecting and diagnosing tumors, identifying a range of pathogens and their toxins, and monitoring blood glucose levels in diabetic patients. Additional applications include quantitative assessment of cardiac markers in undiluted serum samples, immune-sensor-based detection of leukemias, and rapid identification of cancer biomarkers through the integration of biochip technologies. Recent advancements also include the use of diamond micro-needle electrodes for neurochemical sensing [7].
In the food industry, biosensors play a crucial role in detecting gases from spoiled food, identifying contamination, and monitoring bacterial and fungal growth in perishable products [8]. Against the backdrop of global concerns over bioterrorism—where biological agents like Bacillus anthracis, hepatitis C virus, Ebola virus, and SARS virus are deliberately used for harm—biosensor technology has proven effective in early detection of such threats [9]. Ongoing research aims to enhance the selectivity, detection thresholds further, and ultra-sensitivity of biosensors, transitioning them from classical electrochemical devices to systems based on optical, visual, glass, silica, and nanomaterials [10]. These advancements promise to enable continuous real-time monitoring and improved process control, replacing traditional, time-intensive laboratory diagnostics with bedside monitoring of critical health parameters. This review focuses on showcasing the application of biosensors as diagnostic tools and exploring their prospective future roles.
Extensive research has been conducted in biosensor technology. This review presents a modest attempt to organize scattered information into a resource that could serve as a helpful guide for future investigations. The effort aims to offer valuable insights and guidelines to researchers in Physics, Biomedicine, and Chemistry, helping them address future challenges and advance biosensing technologies.
Structural analysis of biosensor
Designing and mechanism of biosensor devices
The earliest use of a biosensor dates back to the development of a potentiometric enzyme-based electrode for monitoring blood glucose levels [1]. With recent technological advances, significant time and energy have been invested in developing biosensors that are smaller, multifunctional, and user-friendly [11]. To meet these goals, various biological sensing elements have been utilized, including enzymes, tissues, microbial cells, organelles, and whole cells, which either function via catalytic reactions or via affinity interactions involving antibodies, receptors, or nucleic acids [12].
Biosensor operation is based on coupling mechanisms that can vary in nature. In some cases, biological elements are attached to sensors via physical adsorption or encapsulation, with non-covalent intermolecular forces maintaining the bond [13]. Another technique, matrix immobilization, involves embedding biological components within porous media such as gel matrices, which serve as a bridge between the biological entity and the sensor [14]. Alternatively, covalent coupling creates direct chemical bonds between the biosensor and biological molecules [15]. Another mechanism is physical entrapment, in which biological molecules are confined within a semipermeable membrane that separates the analyte from the sensor element while maintaining essential contact [16].
Technical approaches for bio-transducer elements
The functional strategy of biosensors varies based on whether the detection system is labeled or label-free. Labeled detection strategies depend heavily on specific markers that attach to the target, requiring the immobilization of target proteins onto the sensing platform to ensure accurate and reliable detection.
In contrast, label-free detection methods focus on identifying target molecules without chemical tagging, even for challenging targets. This approach paves the way for cross-disciplinary innovation, merging expertise from biotechnology, electrical engineering, bioengineering, and electronics to engineer label-free biosensors with broad applicability across environmental monitoring and medical diagnostics [17-19].
Types of biosensors
Among the various classes of biosensors, electrochemical, optical, and piezoelectrical types are the most widely adopted. Despite their differences in construction and application, all share a common operational concept: the detection of a stimulus resulting from the interaction between the analyte and the biosensing element, followed by its conversion into a measurable signal (Figure 1).
Figure 1. Schematic of a biosensor (Source: https://yildizuludag.wordpress.com/2009).
Classical or electrochemical biosensors
Electrochemical biosensors emerged initially through the pioneering work of Clark Jr and Lyons [1], who introduced a glucose oxidase-based system. These glucose biosensors have become essential tools for routine blood sugar monitoring in diabetic patients, especially within hospital and clinical settings. However, issues such as enzyme instability and sample inconsistency often require frequent recalibration [20]. Modern advancements have enabled the enhancement of metal and carbon electrode surfaces with various biomaterials, such as enzymes, antibodies, and DNA, which facilitate signal generation upon specific catalytic or binding events. Innovations based on the electrode’s selectivity and stability have given rise to a variety of electrochemical biosensor designs. The glucose biosensor, in particular, has seen significant evolutionary improvements [21].
The foundational principle of electrochemical biosensors has been applied to monitor antioxidants and reactive oxygen species in biological systems, notably by detecting uric acid. Yet, due to interference from ascorbic acid oxidation, the original designs faced limitations, prompting a shift toward amperometric biosensors capable of simultaneously assessing oxidation and reduction reactions [22]. To achieve greater cost-effectiveness and reproducibility, enzymes have been immobilized on both traditional and nanomaterial-based electrodes, yielding highly selective and sensitive uric acid biosensors suitable for routine diagnostic applications. In a similar vein, researchers have developed a wireless mouthguard biosensor that detects uric acid levels in saliva [23]. Electrochemical biosensors have also been utilized for hormone detection, although this application still demands further technological refinements [24]. Furthermore, electrochemical biosensing techniques have expanded to include nucleic acid detection, which holds tremendous promise for gene therapy applications targeting genetic disorders [25]. Continued innovations in bio-fabrication have further diversified electrochemical biosensor technology, broadening its relevance within biomedicine.
Optical/visual biosensors
Optical/visual biosensors detect wavelength variations in response to analyte interactions. Despite their considerable potential, especially in biomedicine and environmental applications, there remains a need to refine these biosensors to achieve higher simplicity and ultra-sensitivity. The incorporation of gold, silica, quartz, glass, and carbon-based nanomaterials via microfabrication techniques has significantly improved performance. Using this technology, highly sensitive, portable biosensors based on Cytochrome P450 enzymes have been developed. Additionally, fiber-optic chemical biosensors have been successfully integrated into applications such as drug discovery, biosensing, and broader biomedical applications.
Currently, hydrogels have gained popularity as matrix materials for immobilizing sensing elements, offering benefits such as enhanced analyte entrapment, controlled release, and protection of immobilized DNA. Furthermore, the excellent optical transparency of hydrogels enables clear visual detection, thereby improving the efficiency of biosensor platforms [26-34].
Silica/quartz/crystal and glass biosensors
In recent years, the unique properties of silica, quartz, crystal, and glass have made them increasingly popular in biosensor development. Among these, silicone stands out for its favorable optical and mechanical properties, biocompatibility, electronic properties, and, importantly, its non-toxic nature. Silicone nanomaterials have found widespread applications in bioimaging, biosensing, and cancer therapy [33, 34]. Table 1 highlights key biomarkers essential for cancer detection.
Table 1. Common biomarkers for cancer detection [35].
Types of cancer | Biomarker for detection |
Breast | BRCA1, BRCA2, CA 15-3, CA 125, CA 27.29, CeA, NY-BR-1, iNG-1, HeR2/NeU, eR/PR |
Colon | CeA, eGF, p53 |
Esophageal | SCC |
Liver | AFP, CeA |
Lung | CeA, CA 19-9, SCC, NSe, NY-eSO-1 |
Melonama | Tyrosinase, NY-eSO-1 |
Ovarian | CA 125, HCG, p53, CeA, CA 549, CASA, CA 19-9, CA 15-3, MCA, MOv-1, TAG72 |
Prostate | PSA |
While silicone nanoparticles offer numerous benefits, several critical challenges remain before their widespread application, including strategies for large-scale manufacturing, ensuring comprehensive biocompatibility, and achieving economically viable production costs for commercialization. Successfully overcoming these hurdles will pave the way for silicone nanomaterials to revolutionize their role as a preferred biosensor material [26, 28-30, 34].
Bio-sensors based on nanomaterials
A wide range of nanoparticles, including gold, silicone, silver, copper, and carbon-based structures such as graphite, graphene, and carbon nanotubes, are utilized for biosensor immobilization [18, 27, 34-40]. Owing to their remarkable specificity and sensitivity, nanomaterials have significantly enhanced the performance of biosensor devices. Among them, gold nanoparticles are particularly notable for their exceptional resistance to oxidation and internal biocompatibility [41]. In contrast, silver nanoparticles, despite their utility, are prone to oxidative degradation and may be toxic when introduced into biological systems [42]. Nevertheless, nanomaterials remain pivotal for improving detection limits, enabling biosensors to achieve single-molecule sensitivity [19]. For instance, platinum-based nanoparticles have been effectively used to detect low concentrations of DNA [30], and quantum dots and iron oxide nanoparticles have shown efficacy in targeting tumor-associated antigens [43].
Synthetic fluorescent / genetically encoded biosensors
This category of biosensors has revolutionized the exploration of cellular biological processes and molecular signaling pathways [44-46]. Originally, fluorescent-labeled antibodies were designed to visualize structures within fixed cells, laying the groundwork for the development of sensors that detect the binding of second messengers, small molecules, and biomolecules [46]. Present-day fluorescent biosensors are sophisticated enough to study motor proteins at the single-molecule level [45], although significant technical challenges remain. Genetically encoded biosensors targeting mitochondrial processes, such as monitoring reactive oxygen species and cAMP levels, have offered deeper insights into energy metabolism [47]. Similarly, FRET-based biosensors (Förster resonance energy transfer) have been engineered to image intracellular signaling molecules such as cAMP, cGMP, and calcium, with cGMP being particularly crucial in cardiovascular physiology [48]. These innovations, combined with optimized methodologies, have led to the development of biosensors based on microbes and cellular organelles, each directed toward specific biological targets [42, 46]. Despite their advantages, electrochemical, electromechanical, and optical biosensors still outperform traditional molecular detection techniques [49]. Future directions aim to develop whole-genome optical biosensors that combine fluorescence techniques with small molecules or nanomaterials to expand their applications.
Microbial biosensors
Recent advancements have enabled the application of microbial biosensors in environmental surveillance and bioremediation. Using genetic engineering, protein engineering, and synthetic biology, microorganisms can now be programmed for high specificity and sensitivity, delivering measurable outputs for detection tasks. These biosensors have proven highly effective for biodegradation of xenobiotic compounds, utilizing live cells that exhibit enzymatic degradation activity [50]. Furthermore, microbial fuel cell-based biosensors now enable the monitoring of biochemical oxygen demand and environmental toxicity by converting organic substrates into electrical energy through microbial fermentation. Such bio-electrochemical devices harness microbial respiration to drive energy conversion processes. Despite these innovations, challenges such as low power density and production costs persist. Ongoing efforts focus on integrating systemic approaches to enhance the efficiency and affordability of microbial biosensors [10]. In addition to environmental applications, microbial biosensors are increasingly used to detect pesticides and heavy metals, with higher eukaryotic microorganisms preferred over prokaryotic systems due to their broader sensitivity to environmental toxins and relevance to higher-order animals [51]. With continued advancements, microbial biosensors are poised to play a vital role in environmental pollution monitoring and sustainable energy generation [10, 52].
Earlier sections provided an overview of various biosensor types and their respective applications. Here, the focus shifts to evaluating biosensors based on selectivity, specificity, sensitivity, response time, cost-efficiency, and portability.
The advent of electrochemical sensors greatly expanded their reach into the mainstream market, particularly for glucose monitoring and pregnancy testing, due to their affordability, rapid response, portability, and low detection thresholds [19]. Enhancements in detection limits and sensitivity were enabled by integrating polymers and nanomaterials for analyte immobilization. This advancement led to the emergence of bio-fabrication strategies that utilize both contact- and non-contact-based patterning techniques. Using lateral flow technology, biological samples can be directed directly to specific targets, enabling efficient interactions. Materials such as gold, silver, and silicone have significantly advanced electrochemical biosensors, offering high sensitivity and specificity for real-time applications. Nevertheless, their limited regeneration capacity remains a drawback for extended use.
Single-analyte detection through contact-based methods has proven particularly effective, using FRET, fluorescent-based, surface plasmon resonance, and bioluminescent resonance energy transfer transducers [28]. However, these methods have not yet been successfully adapted for simultaneous multi-analyte detection. For multiplexed detection, micro- and nano-cantilever transducers integrated into electrochemical sensor platforms have shown considerable promise. Non-contact-based techniques, including laser direct writing and 3D bioprinting, have also achieved notable milestones; however, their widespread application is hindered by high costs and the need for extensive customization. Despite these challenges, some progress has been made in developing amperometric electrochemical biosensors capable of diagnosing diseases by analyzing body fluids [23].
A major breakthrough in biosensor innovation has been the development of fiber-optic, chemistry-based optical biosensors, offering exceptional sensitivity for detecting single molecules, such as DNA and peptides. These sensors are widely used in biomedicine and forensic science. Merging elements such as enzyme/substrate systems, antigen/antibody complexes, and nucleic acid interactions has dramatically advanced optical biosensor technology. Moreover, biosensing systems can incorporate biological components like tissue sections, plant or animal cells, or microorganisms. In practical terms, molecular optoelectronics has enabled the development of optical biometric recognition platforms.
Recent enhancements in optical biosensor performance have been enabled by advances in surface morphology analysis, particularly through advanced electron microscopy and atomic force microscopy. However, achieving femtomolar detection limits remains a challenge. With modern optical technologies, innovations such as nanomechanical biosensors leveraging surface resonance phenomena and microcantilevers have paved the way for the creation of DNA chips capable of sensitive, real-time, specific analysis [53-55]. Optical biosensors offer clear benefits, including rapid and comprehensive data acquisition, yet high production costs and technical hurdles, such as complex biofabrication processes and stringent sterilization requirements, constrain their adoption. Addressing these challenges is crucial for optimizing the full potential of optical biosensor technology.
Bio-fabrication has proven to be a crucial approach for developing mass-produced biosensors. With advancements in micro and nanofabrication, mechanical devices featuring nano-sized moving components have been successfully created. This fabrication technique merges biophysics with bioengineering to create effective micro- and nano-electromechanical biosensors. However, challenges persist in scaling up mass-based sensors, particularly in capturing agents for nano-scale fabrication, where microelectronic techniques play an essential role. Notably, semiconductor materials and quantum dot technology have significant potential applications in this field. Despite progress, there is still room for enhancement in biosensor technologies, especially in developing large-scale arrays for real-time, quantitative assays. The fabrication of micro- and nano-scale cantilevers appears promising in this regard [35].
Genetically encoded and synthetic fluorescent biosensors represent a major technological leap, allowing for the analysis of molecular biological mechanisms [44-46]. Although these biosensors are expected to play a pivotal role in single-molecule detection, they require advanced instrumentation, intricate probe preparation, and precise detection methodology, all of which pose substantial practical challenges. Microbial fuel-based biosensors, due to their high sensitivity and selectivity, show considerable promise in bioremediation; however, they are hindered by high costs and complex procedures required for microbial strain development. This involves rigorous genetic engineering, large-scale microbial strain production, adherence to ethical and regulatory standards, and the management of production costs. Despite these hurdles, microbial biosensors remain effective tools for environmental monitoring.
The combination of optical, bio-electronic, and electrochemical principles, biological materials, biomolecules, nanomaterials, and polymers has driven the development of integrated technologies for creating advanced micro- and nano-biosensor platforms. These innovations aim to produce highly sensitive biosensors [55]. Modern biosensor development incorporates a diverse array of technologies, including electrochemical, electromechanical, fluorescence-based optical, and genetically engineered microorganism technologies. In the realm of disease diagnosis and therapy, these technologies have proven highly valuable. Presently, there is an increasing demand for biofabrication that emphasizes rapid analysis while maintaining cost-effectiveness, bridging the gap from cellular to whole-animal detection with high single-molecule accuracy. In environments where biosensors are used under multiplex conditions, advanced 2D and 3D detection methods, coupled with sophisticated transducers, are employed to identify and measure small analytes of interest [28].
Considerable strides have been made in this area, with several key innovations at various stages of development. Moving forward, the goal is to create more durable, regenerative biosensors suitable for long-term use. Achieving this will significantly benefit clinicians and patients by enhancing diagnostic and therapeutic applications of biosensors. Nanomaterials, especially quantum dots, are pivotal to nanotechnology applications, contributing not only to tumor detection but also to drug-delivery systems targeting cancer cells. While challenges remain, overcoming these barriers would mark a significant milestone in medical science. The future of biosensors in cancer diagnosis hinges on achieving high specificity, selectivity, low cost, and rapid detection. Previous accomplishments in biosensor development have paved the way for further advances, particularly in enhancing cancer detection capabilities. This ongoing development focuses on refining biomarkers, developing ligands specific to those biomarkers, and enhancing multichannel biosensors that simultaneously analyze multiple cancer markers.
The outlook for biosensors is highly promising, though it demands a committed, cost-efficient, and interdisciplinary approach to transition these systems from the research and development stage to the commercial market. A critical factor in developing an effective biosensor is the optimal integration of biosensing and biofabrication technologies, combined with synthetic biology techniques, using electrochemical, bioelectronic, or optical principles. Ongoing research is essential to address the challenges in deploying biosensors, particularly in cancer applications.
I extend my gratitude to my co-authors for their significant contributions in completing this review.
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