Scientists have developed a groundbreaking multichemical image sensor that can simultaneously detect lactate and proton (H+) dynamics in real-time—without the need for labeling.
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Published in Biosensors and Bioelectronics, this innovation could significantly enhance biochemical monitoring, opening new possibilities in biomedical research and clinical diagnostics. By providing a clearer and more dynamic view of chemical changes, the sensor could improve the detection and analysis of physiological conditions and biochemical signaling in biological samples.
Background
Understanding how multiple chemical signals interact in real-time is essential for advancing medical and biological research. Traditional sensing methods often face challenges in sensitivity and specificity, particularly when detecting low concentrations of analytes in complex biological fluids. While existing biosensors can analyze lactate and H+ dynamics separately, few technologies allow for their simultaneous monitoring—an advancement that could offer deeper insights into metabolic processes and disease mechanisms.
Potentiometric sensors, which measure voltage changes in response to ion concentrations, have been promising tools for detecting biochemical markers like lactate and H+. However, most previous studies have focused on single-analyte detection.
This research bridges the gap by integrating gold electrode patterns with complementary metal-oxide-semiconductor (CMOS) technology, significantly enhancing spatial resolution and detection sensitivity—both crucial for biological applications.
The Study
To create the multichemical image sensor, the research team employed advanced semiconductor processing techniques. The sensor was built on CMOS technology with a 0.15-μm process and a 256 × 256-pixel array featuring a 2-μm pitch. The gold electrode patterns were created using photolithography, beginning with UV irradiation to clean the Ta2O5 substrate.
A positive photoresist was then applied, followed by controlled light exposure and development to define electrode regions. Thin layers of gold and titanium were deposited using electron-beam physical vapor deposition, forming the functional lactate and pH-sensing areas. The sensor was encapsulated in epoxy resin for protection, leaving exposed pixels to facilitate biochemical interactions.
The sensor relies on potentiometric detection. Lactate is measured through enzymatic reactions involving lactate oxidase (LOx) and horseradish peroxidase (HRP), which catalyze oxidation processes. This setup allows the sensor to generate real-time voltage outputs corresponding to lactate concentrations and pH levels—key for analyzing biological systems.
Results and Discussion
The sensor demonstrated high sensitivity, detecting pH changes with a response of 65 mV per unit and identifying lactate concentrations as low as 1 μM. These capabilities enable precise real-time monitoring of biochemical fluctuations.
By capturing both lactate and H+ dynamics simultaneously, the sensor provides a more comprehensive understanding of their roles and interactions in physiological processes. Its high spatial resolution and rapid response make it particularly useful for analyzing localized biochemical events, offering deeper insights into metabolic functions and cellular behavior.
Another notable advantage is the sensor’s stability across varying environmental conditions, ensuring consistent performance in different biological applications. Unlike traditional sensors, which often struggle with stability and specificity, this multichemical sensor offers a more efficient and reliable approach to real-time multi-analyte detection.
Conclusion
This study presents a CMOS-based multichemical image sensor that enables real-time visualization of lactate and pH distributions with high sensitivity and precision. The integration of gold electrode patterns on a potentiometric sensor array marks a significant step forward in biosensing technology.
The findings lay the groundwork for future advancements in chemical sensing and bioimaging. By allowing the simultaneous monitoring of multiple biochemical markers, this sensor has the potential to enhance diagnostic tools and health monitoring systems. As the demand for high-resolution, accurate biosensors grows, this innovation represents a major breakthrough in real-time biochemical imaging.
Journal Reference
Doi H., Muraguchi 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, 268, 116898. DOI: 10.1016/j.bios.2024.116898, https://www.sciencedirect.com/science/article/pii/S0956566324009059?via%3Dihub