Sensing devices detect physical or composition variations in signals, and sensors act as transducers that transmit signals from one energy form into another form [1]. Microelectromechanical system (MEMS) based-sensing devices comprise three parts: a sensing element, a transducer, and a readout platform that interprets the converted signal. Sensor performance can be assessed using variables such as sensitivity, resolution, accuracy, response time, and limit of detection. MEMS-based sensing devices translate alternating signals into a distinct form that can be used to control measured variables [2]. MEMS sensors integrate mechanical constituents, detectors, and electrical components on a silicon substrate, ranging in size from a few microns to a few millimeters, and are produced using semiconductor materials [3]. This technology combines microelectronics and micromachining on a silicon wafer to create a conventional semiconducting device [4]. Recently, metal oxide-based sensors (e.g., zinc oxide, titanium dioxide, and tin dioxide) have received attention for the detection of gases [5]. However, high sensitivity can only be attained at high operating temperatures, and selectivity concerns exist. To overcome these limitations, alternative techniques are required that combine different sensing elements, particularly the use of novel metal nanoparticles (e.g., plutonium, gold, silver, and lead) [6–8].

MEMS technology emerged from the distinct semiconductor device fabrication method comprising material layer deposition, patterning, and etching [9]. Industrial and domestic applications have been widely adopted to address human comfort issues, and various MEMS sensors have been developed in many fields (from internal to exterior uses) using a variety of operating principles and sensor materials. Such sensors offer major benefits, for example in gas detection systems (e.g., moisture content and poisonous gas) and disease diagnosis [5]. The predicted contribution of microelectronics-derived technologies (i.e., microsystems, microfluidics, and nanotechnologies) to the field of molecular analysis is twofold: first, system miniaturization and possible device cost reduction, and second, the development of new detection principles to improve sensitivities and lower detection thresholds. The vast majority of biosensors, which convert biological signal into a measurable physical signal, are based on electrochemical and optical transductions but many other techniques, such as those requiring electrical and mechanical, e.g., MEMS, transducers, have also been developed. As a result, the literature on this subject is extensive, and even though only a few products have made it to market in terms of research volume [we can cite the surface plasmon resonance (SPR), quartz crystal microbalance (QCM), gold nanoparticles and graphene field-effect transistor (GFET) technologies as examples], the expected impact of these technologies on the world of molecular analysis is enormous [10].

From the past 20 years, MEMS and especially resonators of all shapes and sizes were revolutionizing the biological detection market. Several studies were reported that demonstrate the potential of MEMS-based biosensor to ultrahigh sensitivity to mass loading [11–13]. Besides this, various researches demonstrated the ability of immobilizing enzymes [14], aptamer [15], antibodies [16], and DNA probes [17] on the surface of sensor to specifically capture biological targets of interest-including viruses [18] and bacteria within a sampled liquid volume. MEMS constitute a broad field that shows potential for applications in most areas of life, and the quickly evolving field of electronic microsystems has experienced rapid development in sensing mechanisms for fabrication and integration processes. However, the efficiency of these sensors is dependent on appropriate sensor selection. This review offers a summary of MEMS fabrication, sensing technologies, and their functional applications, emphasizing common examples in daily life, and with a focus on healthcare applications. The article is organized as follows: Section 1.1 introduces MEMS technology; Section 1.2 outlines MEMS fabrication methods; Section 1.3 describes MEMS outputs; Section 2 reviews of MEMS applications, with a focus on healthcare applications such as biosensors; and Section 3 provides conclusions and future perspectives.

1.1. MEMS

The first demonstration of what is now considered MEMS technology was published in a Physical Review paper in the Bell Telephone Laboratory, which revealed some of the stress-sensitive effects of the piezoresistors silicon and germanium [19]. Although MEMS is not the best umbrella term, due to the large variety of instruments in this field, in the United States MEMS refers to the entire field of MEMS (i.e., any device originating from microfabrication other than integrated circuits); it is also known as microelectronics. Other terms for this broad area of microfabrication include microsystems technology in Europe and micromachines in Asia.

To measure ambient signals and convert them into meaningful electrical signals, MEMS sensors use a wide range of domains [20]. Six domains are most commonly used: the chemical domain (e.g., composition, concentration, oxidation or reduction, or pH), electrical domain (e.g., electric field, voltage, capacity, current, resistance, polarization, and frequency), radiative domain (e.g., frequency, wavelength, polarization, transmittance, reflection, and refraction index), magnetic domain (e.g., magnetic flux, penetrable coefficient, magnetic induction, and magnetic moment), thermostatic domain (e.g., flow, heat, and matter state), and mechanical domain (e.g., length, width, area, velocity pressure, torque force, volume, acceleration, acoustic wavelength, and intensity).

MEMS can be classified into several categories based on chip operation. MEMS devices can perform sensing for gas measurement, monitoring, detection, bodily material measurement, and medicine delivery. As shown in Fig. 1, MEMS have been classified into different categories based on application. Today, MEMS devices are used widely in technologies ranging from consumer products to satellites. Finally, the sensor can be categorized into two groups based on the operating principle: static and dynamic modes of operation.

Figure 1. Categorization of MEMS on the basis of their applications.

1.2. MEMS device fabrication methods

MEMS devices are produced via the addition and deletion of twodimensional (2D) silicon layers on a silicon substrate in high-volume batch processing to yield a 3D device; manufacturing procedures include chemical vapor deposition (CVD), photolithography, and etching. Design engineers have examined some of the secondary elements of these sensors based on their application, such as power, delay, size, and stimulated area of the micrometer. Three commonly used MEMS fabrication processes include surface micromachining, bulk micromachining, and LIGA (lithography, electroplating, and molding, from the German Lithographie, Galvanoformung, Abformung) [21]. In addition to this base process, additional layers are added using thin-film deposition and bonding, as well as etching, with spacer layers. The flow diagram in Fig. 2 depicts the procedures involved in MEMS sensor production [22, 23].

Figure 2. Fabrication design flow of MEMS sensor. Reproduced with the permission from [23], Copyright 2019, Blue Eyes Intelligence Engineering & Sciences Publication.

Photolithography: This is a graphic technique for duplicating the main design on a silicon wafer. A circuit design is created on an integrated circuit, usually on the exterior of silicon wafers.

Etching: Silicon etching is a key step in the bulk and surface micromachining design process. It is used not only to build trenches and cavities for the base structures but also to release cantilevers and membranes. Ultimately, release etching is applied to undercut the structural material and remove the sacrificial layer [24, 25].

CVD: CVD is used to create solid materials with high purity and performance. In this process, the substrate is exposed to volatile compounds, which react and degrade on the substrate’s surface, resulting in the desired deposition.

1.3. Sensor output signal

MEMS output signals are based on the sensing mechanism. The sensing mechanism is based on the use of a polymer deposited on the sensing layer that absorbs a specific chemical, which causes variations in the beam’s stress, mass, electrical or chemical and mechanical characteristics. As shown in Fig. 3, optical, capacitive, and piezoresistive mechanisms may be employed to measure the output signals of MEMS sensors [9]. Different sensing techniques have various benefits and limitations. For example, optical sensors have high practicality but are relatively expensive compared to capacitive and piezoresistive sensors [26]. Thus, capacitive and piezoresistive techniques are commonly employed to sense output signals.

Figure 3. The sensing mechanism of MEMS.

A wide variety of MEMS sensors have been used to enhance functionality in the healthcare industry, with the aim of increasing health monitoring and disease detection. MEMS devices accept input information (chemical or physical) and then convert it into electronic signals. Numerous MEMS sensors can be found in applications in various fields, as outlined in Fig. 4.

Figure 4. MEMS application in the real world.

2.1. Biosensors

Biosensors analyze chemical or biological reactions by generating the response proportional to the concentration of an analyte in the reaction. For instance, diagnostic technologies based on nanomaterials provide a feasible alternative to real-time polymerase chain reaction (PCR) for rapid and accurate viral detection. Magnetic nanoparticles can facilitate this complex viral extraction via coprecipitation for easy and rapid RNA extraction, and have been used in more than 50,000 diagnostic tests [27]. Biosensors have been fabricated for the diagnosis of cancer, human immunodeficiency virus (HIV), influenza virus, and other viral diseases. Moreover, biosensors have various applications, aimed at improving quality of life, including food safety, disease detection, and environmental monitoring. A major application of biosensors is the detection of biomolecule indicators of a disease or drug target. Several MEMS-based biosensors are discussed here.

2.2. MEMS applications in healthcare

Traditional diagnostic methods

Quantitative PCR and sequencing have been used widely for nucleic acid-based diagnostics. The high sensitivity, robustness, and versatility of PCR assays have made this technique the gold standard for diagnosing nucleic acid biomarkers; however, the reagents and equipment are expensive, and processing requires highly trained personnel [28]. Meanwhile, isothermal nucleic acid amplification evades the thermal cycle process, which results in lower detection specificity due to non-specific amplification [29]. The specificity of nucleic acidbased diagnostics can be increased by application of additional readout methods, specifically using MEMS sensors, fluorophore probes, oligonucleotide probes, or molecular beacons. There is high demand for new technology that merges usability and cost efficiency for accurate diagnosis.

CRISPR-based biosensors

The fast-evolving field of CRISPR-based sensors is aimed at producing nucleic acid-based point-of-care diagnostic assays for routine healthcare monitoring, based on the programmability, selectivity, and convenience of CRISPR technology (Fig. 5). CRISPR has several distinguishing characteristics, including a strong signal amplification efficiency, low reaction temperature, and high recognition specificity [30, 31], which are favorable for the advancement of nextgeneration technologies. However, past CRISPR-based diagnostics, such as HOLMES, SHERLOCK [32], and DETECTOR, were not optimized because they involved multiple pre-operation steps (e.g., nucleic acid extraction, amplification), increasing the probability of crosscontamination and complication [33,34]. Furthermore, most CRISPR diagnostics are based on qualitative detection [33].

Figure 5. Applications of MEMS sensors in the health sector. Reproduced with the permission from [30], Copyright 2018, The European Biotechnology Thematic Network Association.

Amplification-based diagnostic approaches have several drawbacks, including cross-contamination-induced false positives, amplification errors, and quantification challenges. Thus, nanoprobe-based approaches that do not require nucleic acid amplification may facilitate advancements in diagnostics. However, this novel strategy is difficult to implement using standard probes. The development of ultrasensitive probes that can be used in CRISPR-based diagnostic procedures without the need for nucleic acid amplification shows great potential for lowering detection limits. For instance, surface-enhanced Raman scattering (SERS) is a highly sensitive spectroscopic system for diagnosing single molecules [35]. The substrate is adsorbed onto silver and gold nanoparticles, resulting in a significant increase in Raman scattering (up to or 10⁸ or more). For instance, Kim et al. [36] developed a SERS-based approach to quantify multidrug-resistant microorganisms, combining the high specificity of CRISPR–Cas9 with the high sensitivity of SERS to identify genomic DNA with femtomolar sensitivity. The Raman reporter molecule with DNA insertion characteristics, CRISPR–Cas9, coated on gold-coated magnetic nanoparticles, was attracted to the magnetic particles for SERS detection. The researchers demonstrated the effectiveness of this technique for testing clinical samples of multidrug-resistant bacteria in intensive care unit patients without any pre-amplifiers [Fig. 6(a)] [36].

Figure 6. Nanoprobe-based, ultrasensitive CRISPR biosensor. (a) CRISPR-dCas9-mediated gold magnetic nanoparticle, ultra-sensitive SERS based detection for superbug infection. Reproduced with the permission from [36], Copyright 2020, American Chemical Society. (b) Coupling gold nanoparticle-mediated metalenhanced fluorescence (MEF) and CRISPR-Cas12a for nucleic acid detection without amplification. Reproduced with the permission from [37], Copyright 2021, American Chemical Society.

Metal-enhanced fluorescence (MEF) mechanisms have also been shown to enhance the detection efficiency of CRISPR diagnostics. For example, Choi et al. [37] developed smart MEF probes that connected 20-nm gold nanoparticles to 60-nm gold nanoparticles via fluorescein isothiocyanate-modified double-stranded DNA and single-stranded DNA; the linked single-stranded DNA was degraded by CRISPR– Cas12a-based trans-cleavage activity. This Cas12a-based detection method exhibited sub-femtomolar sensitivity, and the researchers confirmed amplification-free DNA readings in human serum samples and buffer solutions [Fig. 6(b)] [37].

Biosensors have been used widely to diagnose influenza, HIV, and other viral diseases [38,39]. Diagnostic methods that combine microand nano-sensing devices with CRISPR can attain high diagnostic efficiency with very high sensitivity. For instance, the CRISPR–Chip is a graphene field-effect transistor (gFET) that used nucleic acid hybridization connected to graphene, which operates as a graphene surface with the source and drain electrode for the gFET device [40]. This chip manifests various electronic signals for complementary and mutant DNA sequences, to regulate the electronic characteristics of the gFET and manifest the electrical signal when diagnosing DNA samples. The system is highly sensitive, and can detect at the femtomolar level. This technique was used to design a graphene-based biosensor to detect SARS-CoV-2. The S antibody was conjugated on the graphene surface using 1-pyrene butyric acid N-hydroxy succinimide ester linkers, and the device diagnosed the antibody or nucleic acid concentrations in the femtogram per milliliter concentration range [Fig. 7(a)]. Moreover, toroidal plasmonic metal sensors were fabricated with the ability to detect concentrations as low as 4.2 fM. Such meta-sensors could be used in point-of-care testing, where a fast and accurate detection method is needed [41]. In another recent application to SARS-CoV-2 detection, SARS-CoV-2 antibodies were conjugated on the nano-sensor chip surface, onto which the whole SARSCoV- 2 could bind, leading to a change in intensity measured via optical sensing devices. With a limit of detection of 30 virus particles, and detection complete in 15 min, this method quantify the viral concentration below standard nasopharyngeal swabs and saliva viral concentration [42]. A cheap and portable sensor controlled by a smartphone application could detect SARS-CoV-2 in a single step, with a detection time of 15 min; this assay quantified the virus concentrations of 0–107 particles/mL and could be used at home, in clinics, and for emergency screening [43]. A clinical diagnostic assay was established to merge a dual-functional plasmonic resonance effect with the surface plasmon resonance sensing transduction pathway, with detection assays performed on 2D gold nano-islands [Fig. 7(b)] [44]. The gold nanoislands comprised complementary DNA receptors that conjugated to the genetic material of SARS-CoV-2. This device used two incidence angles, and could be stimulated by two wavelengths, one for local surface plasmon resonance and the other from a plasmonic photothermal biosensor. Thus, the detection system could be used for the detection of envelope, RdRp-COVID, and F1ab-COVID. This biosensor had a limit of detection of 0.22 pM and allowed for selective detection in a multigene mixture. Moreover, using a plasmon resonance-based sensor decreased the likelihood of false-positive results [45].

Figure 7. SARS-CoV-2 detection based on nanomaterial-based sensors. (a) gFET based SARS-CoV-2 detection. (b) The plasmonic photothermal biosensor with localized plasmon resonance based on 2-D gold nanoparticles. Reproduced with the permission of [44], Copyright 2021, MDPI.

This review examined strategies used in MEMS design, fabrication, production, and function. MEMS sensors, fabricated using photolithography, etching, and CVD, can be classified based on the sensing domain, clinical data, and other factors, and applications based on temperature and sensitivity have also been described. MEMS technology simplifies diagnostic applications by reducing power consumption through the design, fabrication, and management of micron-sized systems, and allows electronic and mechanical elements to be combined onto one chip to create a microscopic device. Microscopic devices combine sensors, actuators, signal processors, communication systems, and other components to form intelligent systems, and MEMS integrated sensors may help improve system performance and efficiency. Research is underway to enhance MEMS sensor technology to support a wider range of applications in the electronics, healthcare, automotive, communication, and material science fields. MEMS sensors are appealing to various industries, particularly healthcare, and their development shows major potential from a multidisciplinary perspective.

This research was supported by the Technology Innovation Program (Project No. 20012362) funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea); Smart Farm Innovation Technology Development Program(421020-03); the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (NRF- 2021M3A9I5021439); the Research Program to Solve Urgent Safety Issues of the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Science and ICT(MSIT)) (NRF- 2020M3E9A1111636); the National R&D Program of National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (NRF-2021M3H4A4079276, NRF-2021M3H4A4079381); the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (1711134045).

The authors declare no conflicts of interest.