Biochemical sensors are analytical devices that detect specific targets by converting the biochemical molecular recognition process into amplified and measurable physicochemical signals ^[1]. Biochemical sensors serve dual functions as receivers and converters. They are composed of immobilized sensitive materials as recognition elements, appropriate physicochemical transducers, and signal amplification devices. The recognition elements include enzymes, antibodies, antigens, micro-organisms, cells, nucleic acids, and metabolites [2,3,4,5,6,7]^{[2][3][4][5][6][7]}. The physicochemical transducers include electrodes, photoelectric converters, field-effect transistors, and piezoelectric crystals [8,9,10,11,12,13]^{[8][9][10][11][12][13]}. The recognition element of a biochemical sensor responds to target materials that generate a detectable electrical signal. This signal depends on the analyte concentration and biomedical solution properties. The advantages of using biochemical sensors to detect target biomolecules include rapid response, easy operation, accurate results, relatively low cost, and so on. These advantages and continuous innovation in biochemical sensor technology have attracted researchers’ interest in developing biochemical sensors for target analyte detection under various physiological conditions. Wearable and implantable sensors can monitor various human health indicators and offer insight into kidney, cardiovascular, and respiratory system diseases. These technologies help facilitate early prevention and proper treatment [14,15,16]^[14][15][16].

Point-of-care testing (POCT) is an emerging medical care field that analyzes and diagnoses in vitro with quick results. POCT does not require specialized personnel to perform and is not limited by the environment. It can be performed on the spot, at home, in ambulances, or in hospitals [17,18]^[17][18]. With the large-scale outbreak of infectious diseases such as COVID-19, POCT plays an essential role in the rapid diagnosis and timely screening of diseases, especially in areas with limited resources ^[19]. In this case, biochemical sensors are convenient for POCT due to their high selectivity and specificity. For these reasons, portable biochemical sensors for POCT can significantly improve medical detection efficiency.

In addition to their high sensitivity, rapid response, and reasonable specificity, transistor-based biochemical sensors have been used to detect different biochemical molecular targets because they are portable, simple to operate, and do not require the pretreatment of analytes. In recent years, transistor-based biochemical sensors have also been used to detect human physiological markers, such as ECG signals, body temperature, etc., due to their superior signal amplification capability at low voltage and power consumption. As highly sensitive sensor devices, transistor-based biochemical sensors have great potential when combined with artificial intelligence (AI). Using machine learning (ML) methods to design devices and quantitatively analyze biological signals measured by transistor-based biochemical sensors may greatly improve detection accuracy and efficiency [20,21,22,23,24]^{[20][21][22][23][24]}. These developments will help transistor-based biochemical sensors pave the way for the next generation of point-of-care testing ^[25].

2. Principles of Transistor-Based Biosensors

Biochemical sensors based on transistors consist of two parts: (1) signal transduction and amplification elements and (2) signal recognition elements, which convert biochemical signals into measurable and observable electrical signals. The transistor-based biochemical sensors structure contains a substrate, insulation layer, semiconductor layer, gate electrode, and source/drain (S/D) electrode. Gate electrodes can be divided into two types based on their position: top electrode and bottom electrode structures. They include bottom-gate/bottom-contact, bottom-gate/top-contact, top-gate/bottom-contact, and top-gate/top-contact (Figure 1a–d). Bottom-gate refers to the gate deposited below the insulation layer, and the top-gate refers to the gate deposited above the semiconductor and insulation layers. Top-contact and bottom-contact are divided according to the semiconductor and source/drain electrode positions. In top-contact, the semiconductor grows on the insulation layer where the S/D electrodes are deposited. In contrast, bottom-contact refers to S/D electrodes above the semiconductor layers. When target molecules are detected by transistor-based biochemical sensors, the gate’s voltage changes and is conducted through the bottom- or top-gate. In a transistor-based biochemical sensor, the gate metal film can be replaced by a biochemical-sensitive film. When analytes act on the transistor component or interface, the biochemical-sensitive film’s composition, stacking mode, or charge density will change. This reaction affects the sensor’s electrical signal output and ultimately achieves higher detection sensitivity. Transistor-based biochemical sensors can be divided into FET, OFET, and OECT biochemical sensors based on their modified materials and specific structures. FET’s versatility arises from inorganic semiconductor materials (metal oxides and ion-selective membranes) or biomolecules directly related to the species being examined. OFET’s versatility is derived from organic semiconductor materials (OSC). While OECT’s versatility mainly depends on the material synthesis and functionalization of organic mixed ionic/electronic conductors (OMIECs) (Figure 1e).

3. Electrodes of Transistor-Based Biosensors

Electrodes are important components of transistor-based biochemical sensors. Conductivity, resolution, thinness, and smoothness are the key factors that determine whether sensors detect targets accurately. Therefore, the fabrication and processing technology of electrodes has become a critical step in producing transistor-based biochemical sensors. Common transistor electrode manufacturing processes include inkjet printing, screen printing, laser ablation, and lithography [33,34,35,36,37]^{[26][27][28][29][30]}. Some examples of these methods are described below. In 2019, Alshammari et al. proposed drop-on-demand (DOD) printing to cure silver nano-particle inks and produce highly conductive silver patterns, which were also sintered with an excimer laser and heat treatment [38]^[31]. Sintering conditions optimized for high conductivity produced patterns similar to heat treatment patterns. In the paper, inkjet printing technology was used to print conductive Ag nano-particles (AgNPs), and processed S/D silver electrodes were used to fabricate organic thin film transistors. Screen printing is a popular and straightforward coating technology that uses mesh fabric screens to mask metal interconnects on printed circuit boards. Compared with traditional vacuum deposition technology, screen printing reduces manufacturing costs. Fabricating thin and smooth electrodes by printing methods is not difficult, especially for those with high resolution and conductivity. However, to achieve better performance, the size and thickness of electrodes must be small. In addition, the overlap degree between the gate and S/D must be minimized. Therefore, electrodes are usually fabricated by photolithography or other non-printing methods.

4. Applications of Transistor-Based Biosensors

4.1. Applications of FET Biosensor in Biomarkers

FET is a semiconductor electronic device that uses the electric field effect of controlling the input circuit to adjust the output current. Its basic structure consists of two highly doped n-type regions (i.e., source and drain) on a p-type semiconductor substrate, which covers the insulation layer between the two electrodes to form a gate. The modulation of the current in the semiconductor channel is affected by the combined effect of the gate voltage and electric field generated by the applied voltage between the S/D electrodes. Traditional FETs use metal oxides as channel layer materials, known as metal-oxide-semiconductor field-effect transistor (MOSFET) sensors, where the biorecognition surface is either an extension of the gate or the gate oxide itself [58]^[32]. However, FET performance is easily damaged by aqueous solutions, which may shorten sensor life. To overcome this shortcoming and facilitate label-free detection in body fluids, researchers have proposed extended-gate field-effect transistor (EGFET) sensors that combine ion-sensitive membranes with MOSFET sensors and replace the metal gate with an electrolyte solution and reference electrodes.

4.2. OFET Biosensor Applications in Biomarkers

OFETs refer to transistors that use organic semiconductors as channel modifiers for FET. They are flexible, light, soluble, and biocompatible. Compared with inorganic materials, OFET has many advantages, such as low manufacturing costs, large coverage area, good flexibility, and easy performance adjustment. It has strong application potential in skin electronics, such as software robots, implanted devices, wearable devices, and so on. Similar to FET, OFET consists of five parts: source, drain, gate, semiconductor layer, and insulation layer. There is also a solid dielectric material between the channel semiconductor and the gate. Organic semiconductor molecules bind through weak interactions, such as the π–π interaction or van der Waals force. The basic principle of OFET is that when the source electrode is grounded, two potentials are applied to the gate and drain electrodes. This process results in two voltages: the gate-source voltage (V_GS) and the drain-source voltage (V_DS). The S/D electrodes contact the semiconductor layer, and the insulation layer separates the semiconductor layer from the gate. Therefore, OFET acts as a parallel-plate capacitor with the semiconductor layer and the gate as bipolar plates. Organic semiconductors have low carrier mass, high resistivity, and high intrinsic resistance when no voltage is applied to the gate. Electrostatic induction occurs when a voltage is applied to the gate. Induced charges are generated near the surface of the semiconductor and insulating layers, forming a conductive channel.

4.3. Applications of OECT Biosensors in Biomarkers

Wrighton et al. proposed a new electrochemical device, the OECT, in 1984, inspired by the wide application of conjugated materials in OFET [65]^[33]. If the organic semiconductor material between the source and drain allows ion infiltration, charge accumulation may occur not only at the channel/electrolyte interface but also at the conjugated polymer. The operating principle of OECT is to apply a gate voltage to the electrolyte and inject ions into the organic semiconductor channel. The drain current reflects changes in the analyte concentration when the oxidation state of the mixed conductor and conductivity of the active layer are altered. OECTs can directly sense ions and small molecular species, have a low operating voltage, simple structure, are functional in water environments, and are biocompatible. It can convert chemical signals into electrical signals and detect biochemical markers in body fluids. Typical OECT semiconductor polymer channel materials are PEDOT and its derivatives. In recent years, scientists have found that the conductive polymer PEDOT and its complex with PSS have high conductivity, flexibility, and transparency. They have been increasingly applied to wearable and implantable devices, electronic skins, OECTs, and neural interfaces [66]^[34].

4.4. Applications of Transistor-Based Sensors in Detecting Electrophysiology and Other Aspects

Flexible transistor-based sensors can detect pressure and electrophysiological signals due to their high transductivity, low operating voltage, mechanical durability, and flexibility. They have broad application prospects in wearable electronics, intelligent sensing, and human motion monitoring. Researchers are also focused on integrating biochemical markers and electrophysiology signals into the same device for simultaneous detection. In 2017, Nakata et al. developed a wearable, flexible sweat chemical sensor chip for pH measurement, including an ISFET integrated with a flexible temperature sensor [30]^[35]. Sweat pH and skin temperature were measured simultaneously in real time through skin contact. This technology has the potential to be developed as a sweat chemical sensor for healthcare and sports. OFETs perform similarly to amorphous silicon devices, with good stretchability and flexibility. These properties have great advantages for wearable temperature and pressure sensors. For example, in 2016, Ren et al. designed a flexible organic temperature sensor array OFET, which can provide two-dimensional temperature information for objects in contact with the human body [31]^[36]. During surgery, attaching temperature sensor arrays to the outside of the human body or its organs can provide valuable information on heat distribution for diagnosis and treatment. Polyelectrolyte-gated wearable OFET sensors are limited by severe hysteresis, poor stability, and low sensitivity in practical applications.

4.5. Applications of Transistor-Based Sensors Combined with AI

AI has already been integrated into various scientific fields. ML algorithms have also been used to optimize biomedical sensor design and data analysis. AI algorithms make it possible for POCT to develop into intelligent, precise, automated, and cloud-based iPOCT. Transistor-based biochemical sensors integrated with iPOCT can achieve accurate detection, fast response, and cloud sharing. They will surely play an important role in smart medicine. In 2019, Min Hsuan Lee proposed a method for predicting OFET charge mobility using machine learning [69]^[37]. He optimized the energy levels of the highest occupied molecular orbital and lowest unoccupied molecular orbital of n-type semiconductor materials using gradient enhancement and random forest regression algorithms to model experimental datasets. In 2021, Ma et al. proposed the first MoS₂ artificial neural network (ANN) chip, which produced hundreds of wafer-level FETs and high-uniformity MoS₂ thin films. They also implemented a top-gate structure FET using a gate-last process ^[20].