A research team from Toyohashi University of Technology’s Department of Electrical and Electronic Information Engineering, led by Professor Kazuaki Sawada and Project Assistant Professor Hideo Doi, created a semiconductor sensor that allows for the real-time monitoring of two different kinds of biomolecule dynamics in solutions. The study was published in Biosensors and Bioelectronics.
The developed semiconductor bioimage sensor. Image Credit: Toyohashi University of Technology
The sensor records the movement of hydrogen ions and lactate (neurotransmitters) in a solution as picture data by employing semiconductor technology to form a thin metal film that acts as a neurotransmitter-sensitive membrane on sensor pixels arrayed two-dimensionally in a 2 µm pitch.
It is anticipated that the measurement of the relationship between neurotransmitters and ion distribution, which varies both temporally and spatially between cells, will have a high spatiotemporal resolution. A time resolution of milliseconds and a spatial resolution of several microns (roughly 1/17 the size of a strand of hair) were attained.
Details
The majority of the brain consists of about 100 billion neurons and ten times as many non-neuronal cells (glial cells). Information is transferred between cells by converting action potentials neurons produce into electrical impulses. Chemical compounds known as neurotransmitters or ions move between the microscopic gaps in cell-to-cell junctions. These ions are extensively involved in the pathophysiology of the brain and play a significant role in controlling brain function as chemical signals.
The creation of a bioimaging technology that visualizes and measures the spatiotemporal dynamics of chemical substances distributed in the extracellular space from a few microns (cellular level) to a few hundred µm (cellular population level) will allow researchers to examine the intricate functions and pathology of the brain based on the clarification of the mechanism of chemical signal transmission.
However, the majority of traditional chemical signal detection devices are difficult to downsize and miniaturize because they have a single tiny electrode with a diameter of several tens of microns or electrodes spaced at intervals of several hundred microns and pass electric current. As a result, sensors that quantify the micron-level distribution of chemical information have not been developed.
Professor Sawada's group has already created a semiconductor image sensor that records ion movement similarly to a camera. This was accomplished by employing semiconductor technology to integrate and miniaturize potentiometric sensor pixel elements for hydrogen ion detection, with continuous efforts to improve the sensor’s performance.
Using a recognition element (enzyme) that selectively detects biomolecules, the researchers achieved real-time simultaneous measurement of lactate and hydrogen ions involved in memory formation. They also created an imaging device for multisensing that uses metal electrodes arranged in a lattice shape spaced 6 µm apart on the developed sensor array. It is also possible to structure the electrode array with recognition elements that match to biomolecules, which allows for the simultaneous multichemical detection of more than two different kinds of neurotransmitters.
Previously, a single-point electrode was used to measure one type of biomolecule or an electrode array sensor with the low spatial resolution was used to measure one to three types of biomolecules. Chemical signals in microscopic areas, like between cells, can be detected and spatiotemporal analysis is made possible by the recently created capability of “capturing, visualizing, and measuring” two types of chemicals on a surface with great spatial resolution.
This development provides information on chemical processes that point-based sensors were previously unable to provide. In a joint study with scientists from the University of Yamanashi's Faculty of Medicine, who are specialists in pharmacology and brain science, the reaction of hippocampal cells—which are in charge of memory—to pharmacological stimulation was noted. The researchers monitored lactate release and extracellular pH concurrently.
This innovation allows for the direct label-free implantation and measurement of cells and tissues in biological samples, allowing for the detection of spatiotemporal changes in ions and neurotransmitters. Building on this first-of-a-kind ion image sensor technology, the team hopes to further enhance it for use in medical and social settings.
Future Prospects
The team intends to continue improving sensor performance and functionality to increase the variety of compounds that may be measured. It will perform applied measurements using brain slices and solid tumor-like diseased tissue to clarify the physiological importance of temporal and spatial variations in molecular dynamics within the extracellular environment.
This method can potentially evaluate pharmacological effects and analyze chemical interactions in the complex extracellular microenvironment.
Journal Reference:
Doi, H., et. al. (2025) Real-time simultaneous visualization of lactate and proton dynamics using a 6-μm-pitch CMOS multichemical image sensor. Biosensors and Bioelectronics. doi.org/10.1016/j.bios.2024.116898