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Fundamentals of Biomedical Sensors

1.1 Introduction

The use of sensors, education, communication, computers in daily routines, and development of technology over the years has played a significant part in simplifying the human lifestyle [1-3]. Figure 1.1 shows the schematic of a sensor that involve input signal, sensing unit, and output signal. A sensing unit transforms the input signal to an output signal that can be measured using diverse principles, structures, and geometry. Consequently, a sensor converts a physical parameter (temperature, humidity, index of refraction) into a signal that may be processed (e.g. optical, electrochemical (ECL), electrical, and mechanical) [4-7]. Fluorescence, absorbance, scattering, polarization, interference, color change, and luminescence are among the phenomena utilized in the development of sensors.

Sensors have been explored in the numerous sectors that include biomedicine, electronics, military applications, biochemical sensing, and environmental monitoring [8]. A wide variety of research articles on diverse sensing applications has been published in the recent few years due to advancement in various technologies. A biosensor structure is designed using a transducer, light source, and bioreceptor to detect an analyte. Clark reported a glucose oxidase solution encased in a semipermeable membrane as an electrode sensor for measuring the oxygen level in the blood in 1962 [9]. Updike and Hicks reported a sensor that entraps glucose oxidase solution within polyacrylamide gel in 1967 [10]. Guilbault and Montalvo reported a potentiometric sensor to detect the urease [11]. Then in 1972, 1975, 1976, and 1984, the ion-selective field effect transistor, immunosensor utilizing a potentiometric transducer, ECL glucose sensor, and fiberoptic sensor utilizing polymerization techniques were reported [12-15].

Figure 1.1 An illustration of components of a sensor structure.

Optical biosensors have been explored to detect the neurotransmitters that convey intercellular chemical messages within the nervous system [16, 17]. These neurotransmitters are generated by nerve cells that move to another part of the body and convey information in the form of chemicals such as acetylcholine, dopamine, serotonin, norepinephrine, gamma-aminobutyric acid, glutamate, endorphins, histamine, oxytocin, serotonin, and melatonin. Imbalances of these neurotransmitters are responsible for various neurological disorders such as Parkinson's disease, Alzheimer's, schizophrenia, depression, acetylcholine dysfunction, and altered levels of dopamine serotonin, and norepinephrine [18-25].

The emergence of the surface plasmon resonance (SPR) phenomenon advanced this research even more. Wood observed that reflected spectrum of light is associated with bright and dark bands as light passes through diffraction grating and become polarized [26]. Rayleigh and Fano explained this effect on the basis of the wave scattering from the diffraction grating [27]. Zenneck confirmed the existence of radio frequency waves at the metal-dielectric interface and presented the corresponding Maxwell's equation solution [28]. Otto offered a comprehensive and exact comprehension of the SPR phenomenon using experimental methods in 1968 [29]. Liedberg et al. demonstrated the first SPR-based sensor for measuring bimolecular interactions in 1983 [30]. In 1993, Jorgenson and Yee described a silver plasmonic metal-based fiberoptic sensor, in which the prism is replaced with fiber core to detect the sucrose solution [31]. Later, numerous biosensor designs, including an ECL glucose sensor, the utilization of various enzymes, antibodies, and aptamers for glucose and other biochemical detection, were reported [32, 33]. Technological advances have led to a diversity of biosensor designs [34, 35]. Before they may be used, enzymes must undergo a number of processes, including isolation and purification [36].

Figure 1.2 is a timeline of the development of various biosensor design and milestones. Researchers have studied transducer systems to detect air, soil, and water pollution, as well as numerous infections, toxins, and diseases [37-40]. Identifying ultrasensitive biosensors with sensitivities in the nano, femto, and Pico range is vital to detect diseases at the initial stages - including cancer, tuberculosis infection, cardiovascular disease, and Alzheimer's disease, which are responsible for so many deaths worldwide.

Figure 1.2 A schematic illustration of year-wise progress made in the field of biosensors.

In order to investigate plasmonic, ECL, surface-enhanced Raman scattering (SERS), chemiluminescence, and mass-based biosensors, researchers have investigated numerous methodologies [41-44]. The biosensors market, which includes thermal, ECL, piezoelectric, and optical sensors with applications in medical, food toxicity, bioreactors, agriculture, environment, home healthcare diagnostics, and point-of-care testing, was valued at US$24.9 billion in 2021 globally. It will reach up to US$49.6 billion through 2030 - an indication of an annual growth rate of 8.0% in the years 2022-2030 [45, 46].

Diabetes and cancer-related diseases have increased due to several factors, including environment, food habits, and daily lifestyle. In recent years, the demand for biosensors has rapidly increased due to their wide medical applications, their potential for early diagnosis, and the number of patients affected by diabetes [47]. Of all types of optical sensor designs, ECL glucose biosensors and lateral flow assay-based test for pregnancy have been commercialized most successfully in the global market. Fluorescence-based polymerase chain reactions (PCR) are used in nucleic acid-based tests due to its high specificity and sensitivity. Colorimetric biosensors are commonly used in serological tests that include lateral flow assays and enzyme-linked immunosorbent assays (ELISA) to detect different type of antibodies. Colorimetric methods have the drawback of low sensitivity values. Most plasmonic and refractive-index-based biosensors are still limited to lab research use only [48]. Figure 1.3 illustrates the market demand of different types of biosensors; the sizes of slices indicate the estimated share for each type of biosensor.

Figure 1.3 Commercialization and market pull of different types of biosensor platforms.

1.2 Classification of Biosensors

Biosensors can be classified on the basis of bio-recognition elements (BREs), different types of transducers, and physical phenomenon. The enzymes, molecular imprinted polymers (MIP), antibodies, nucleic acids, cells, and aptamers have been explored as a biological recognition element to detect numerous analytes [49]. Types of transducers include ECL, optical, piezoelectric, thermal, and magnetic transducers that changes the form of signal. Various optical sensing techniques, such as the evanescent wave (EW) technique [50], fiber grating, SPR-based sensing, and SERS spectroscopy, are available for different applications [51]. ECL biosensors operate in potentiometric, amperometric, and conductometric mode while mass-based sensors can be magnetoelectric and piezoelectric.

1.3 Elements of Biosensors

Figures 1.4a and b show the necessary components of a biosensor, including BRE and transducers to process the signal and output display [52].

1.4 Bio-recognition Elements

BREs consist of nucleic acid (NA), lectins, enzymes, entire cells, antibodies, aptamers, bacteriophages, peptides, and molecularly imprinted polymers, as illustrated in Figure 1.4c [53]. Figure 1.4d depicts the many types of transducers. Bacteriophages are a type of pathogen that infects and replicates within bacteria by selectively attaching to tail-spike proteins. Peptides consist of a short segment of 12-15 amino acid residues that are stable in harsh environments, inexpensive, and simple to produce on a large scale. NA utilize genetic materials such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) as bioreceptors and aptamers are single-stranded DNA or RNA molecules [54]. Aptamers have a lower molecular weight, are readily produced at a low cost, and have excellent chemical stability [55]. Whole cells include microorganisms or cultivated tissues of multicellular organisms used in numerous biosensing applications due to its lower expenditures [56]. MIPs are artificial bioreceptors that are synthesized in the laboratory with binding sites designed corresponding to the target molecule [57].

1.4.1 Nucleic Acids

NAs are chains of linear polymers that consist of five nucleotides called bases: guanine, adenine, cytosine, uracil, and thymine. DNA is made up of a thymine base, while RNA uses uracil as a base. DNA is a unique genetic component of each individual organism. Due to its unique sequence and properties, NAs are used to design bioreceptors that match the complementary DNA of the concerned individual. The matching strand can be detected with...