National Project “Co-Creation Initiative Support Program (COI-NEXT)” Kawasaki Hub (Project CHANGE: Project Leader, Prof. Takanori Ichiki) is operated by Innovation Center of NanoMedicine (iCONM: Center Director, Prof. Kazunori Kataoka). It has established “Nursing Engineering” as one of its three core pillars, aiming to use engineering to address the anticipated shortage of care workers due to the accelerating aging and declining birthrate. For example, “blood sampling” is considered as one of the most critical nursing procedures. However, cases where venous puncture is difficult due to aging, disease, or treatment are not uncommon. A needs survey conducted by the Kawasaki Nursing Association also revealed numerous requests asking, “Is there a way for anyone to perform blood sampling easily and without causing pain to the patient?” Consequently, Project CHANGE is advancing research on engineering solutions for this problem. Wearable biosensors, which have gained attention in recent years for enabling easy health monitoring, are one such example. We are pleased to share groundbreaking results achieved in the development of a microneedle device (an extremely fine and short needle) using polylactic acid, a biodegradable polymer, and incorporating microfabrication techniques to reduce invasiveness.
Professor Takanori Ichiki of the Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo (iCONM Research Director / Principal Investigator / CHANGE Project Leader) and Associate Professor Hiroaki Takehara (iCONM Visiting Researcher) led a team including Dr. Yukihiro Kanda (CHANGE R&D Theme 3 Sub-leader) from the iCONM Ichiki Lab, Professor Akira Matsumoto (CHANGE R&D Theme 1 Leader) from the Institute for Bio-Materials and Bio-Engineering, Institute of Science Tokyo, and this technology is expected to enable blood glucose level prediction using interstitial fluid (ISF) from the skin. While less physically burdensome than venous blood sampling, ISF sampling is limited to very small quantities.
Novelty of the Research
To enable “clinical testing without blood sampling,” we must consider what biological sample could replace blood. Among these, ISF within the skin—rich in biological components useful for disease diagnosis—emerges as a strong candidate. However, collecting and analyzing ISF is more challenging than blood, requiring either extraction technology for ultra-trace amounts (sub-nanoliters) or the integration of ultra-miniature sensors directly into micro-syringes. The research described in this paper aims to achieve high-precision quantification of glucose in ultra-trace samples. The enzyme-based methods currently used for blood glucose measurement convert the target glucose molecule into another substance via an enzymatic reaction, consuming it. This consumption affects the accuracy of quantification when sample quantities are minute. Therefore, we devised and demonstrated an optical microneedle device-based blood glucose measurement method that does not consume glucose during testing. Furthermore, it does not use unstable biological substances like enzymes, contributing to a longer device lifespan.
Research Findings
The research group has previously reported a technique for manufacturing highly transparent 2-mm-long polylactic acid microneedles and imparting functionality to their tips via hydrogel photopolymerization. This enables effective collection of interstitial fluid (ISF) from the dermal reticular layer, where capillaries are densely distributed and plasma components are abundant. The paper now published describes the development of an optical microneedle device with a tip functionalized using a fluorescent hydrogel containing boronic acid, which quantitatively and reversibly binds to glucose. This device successfully achieved high-precision quantification of glucose in ultra-micro samples at the sub-nanoliter level.
The tip of the microneedle features a pocket measuring 100 μm in diameter × 100 μm in depth (volume: 0.79 nL). The boronic acid-containing hydrogel block embedded at its contact point emits fluorescence upon light irradiation when glucose is detected. Fluorescence obtained from samples of various concentrations was collected using a GRIN lens3. Analysis of its intensity confirmed quantitative correlation with the amount of glucose incorporated into the boronic acid within the hydrogel. The error range at this time was 0.0% to 9.6%, which falls well within the error range standard for commercially available self-monitoring blood glucose meters4.
Future Prospects and Social Contribution
Optical microneedle devices featuring functional hydrogels at their tips enable quantitative analysis without consuming the target compound, making them an effective method for testing ultra-micro samples. By replacing blood draws—which impose physical and psychological burdens on both patients and healthcare providers—with clinical testing using interstitial fluid (ISF) from the dermal reticular layer, this approach is expected to enhance the quality and efficiency of home healthcare, a field projected to grow significantly.
Notes
1) Hydrogel: When polymers in a liquid form a network structure that traps the liquid, causing it to lose fluidity (gel), it is called a “hydrogel” if the liquid is water. Examples include konjac, jelly, and slime.
2) Journal of Materials Chemistry B: An academic journal launched by the Royal Society of Chemistry in 1991, focusing on theoretical or experimental research reporting new insights, applications, properties, and synthesis related to materials. Since 2013, it has been divided into three sections: A, B, and C. Section B handles papers related to medicine and biology. Its 2024 impact factor is 5.8.
https://www.rsc.org/publishing/journals/journal-of-materials-chemistry-b
3) GRIN lens: A cylindrical glass element with a continuously varying refractive index from the central axis toward the periphery. Even with flat ends, it functions as a lens.
4) Measurement Error: Glucose concentration errors were 4.9% at 6.1 mM, 9.6% at 12.9 mM, 0.0% at 21.5 mM, and 7.9% at 37.5 mM. For commercially available self-monitoring blood glucose meters, the quality standard requires that at least 95% of readings at 5.6 mM or higher fall within a 15% error margin.
Papers
Journal: Journal of Materials Chemistry B
Title: Development of an optical microneedle device embedding sub-nanoliter volumes of boronic acid-based fluorescent hydrogel
Authors: Masahiro Fukuhara, Hiroaki Takehara*, Kevin Berthelmes, Benjamin Kersch-Hunt, Jordan E. Gardiner, Yukihiro Kanda, Akira Matsumoto, Tony D. James and Takanori Ichiki
DOI: 10.1039/D5TB00385G
*A graphic illustrating the content of this paper was featured on the cover of the journal.
