Introduction
People have felt that their mind controls the body. Advances in immunology and neuroscience are scientifically elucidating this experience. For example, it has been clarified that the mechanism by which changes in the activity of the central nervous system due to stress regulate the immune response through sympathetic nerves. If these latest medical knowledge and electronic advances can be used to provide a simple monitoring system for stress-related substances, it is hoped that it will help prevent mental and physical diseases. Nevertheless, performing a blood draw to detect the stress hormones cortisol and catecholamine has the challenge that the act of drawing blood itself causes stress. Instead, cortisol concentration measurement from saliva has been developed as a non-invasive detection, but catecholamines cannot be detected from saliva. Salivary cortisol concentration measurements have been developed as an alternative non-invasive detection method, but catecholamines are unable to obtain the necessary information from saliva. Salivary -amylase and chromogranin A (CgA) have also been studied and used in part as alternatives to catecholamines. Secretary immunoglobulin A (s-IgA) in saliva is also a good stress marker that reflects suppression of the immune system by stress. Simultaneous monitoring of the time-dependence of these stress markers of different origins is expected to help elucidate the complex mental stress mechanisms [1].

Sensor module platform
Accurate and inexpensive biomaterial detectors are required for IoT biosensing systems and monitoring over time has not been realized until now. Field-effect transistor (FET) biosensors are small devices that detect various types of biomarkers at low power consumption without disturbing the system under test [2]. The biggest challenge of FET biosensors when used in electronics systems is instability due to current drift. We have succeeded in developing a method that minimizes drift using only the normal silicon fab process. This manufacturing process does not use tantalum pentoxide or other special materials.
Figure 1 shows a picture of a newly developed four element FET sensor chip with extremely low instability. The electronics part of the developed biosensor module consists of this chip and a Bluetooth Low Energy (BLE)-type communication circuit. We selected four types of aptamers as sensor receptors on the gate insulator on the chip [3]. The aptamers can be stored and used at room temperature for a long period of time. They also have the advantages of being reversible to thermal denaturation and can be produced inexpensively and industrially. Finally, as a technique for producing biosensors with less variation, such as commercial physical sensors, we developed a tool for uniformly immobilizing the receptor monolayer in a narrow range of fixed positions on the chip.

Simultaneous detection of multiple stress markers in saliva
When n types of receptors are immobilized on n FET elements, n-1 types of independent signals can be extracted. The effects of non-specifically adsorbed substances and pH in saliva, temperature fluctuation, optical noise, and crosstalk between elements can be eliminated from the original signals of multiple FET elements. Using this technique, we succeeded in obtaining multiple stress marker concentrations such as cortisol, a-amylase, s-IgA, and CgA [4], at the same time just by dropping saliva on the sensor. The signal time constant is less than 1 minute, which indicates that a continuous monitor is realized substantially.

Operability equivalent to physical sensor
Internet of Things (IoT) systems require many low-cost sensors. FET sensor chips manufactured using only the conventional silicon fab process can achieve a low cost of about $1 per chip. However, even with such cheap biosensors, if they are disposable, the cost burden on the user will increase significantly in the long run. As a result, it becomes difficult to secure good customers as fixed users. In addition, disposable chips are not suitable for continuous monitoring required for medically important data. We are developing biosensors that are as easy to operate as conventional physical sensors by introducing reusable cleaning methods and recycled precision cleaning methods.

References
[1] L. Steinman, Annu. Rev. Immunol., 32, 257-281, (2014).
[2] K. Ohashi, T. Osaka, ECS Transactions, 75, 39, 1-9, (2017).
[3] N Kaneko, H Minagawa, J Akitomi, K Ohashi, S Kuroiwa, S Wustoni, S Hideshima, T Osaka, K Horii, I Waga, The 43rd International Symposium on Nucleic Acids Chemistry, 2P-55, (2016).
[4] S. Kuroiwa, R. Takibuchi, A. Matsuzaka, S. Hideshima, N. Kaneko, H. Minagawa, K. Horii, I. Waga, T. Nakanishi, K. Ohashi, T. Momma, T. Osaka, 232nd ECS Meeting, 2115, (2017).