Developed by Masahiro Fukuhara and colleagues, the system combines transparent polymer microneedles with a fluorescent hydrogel sensor embedded at the needle tip.
Demonstrated in glucose solutions in the study, the work is designed to support future sensing in interstitial fluid, the liquid that surrounds cells beneath the skin.
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Interstitial fluid contains a wide range of biomarkers relevant to disease monitoring, including glucose. It is already used in clinical continuous glucose monitoring systems, but collecting diagnostically meaningful samples remains difficult.
Extracting interstitial fluid disrupts local pressure balance in blood vessels, and available sample volumes are extremely small.
Conventional enzymatic glucose sensors add another complication: They consume glucose during measurement. In sub-nanoliter volumes, readings are easily distorted and therefore have limited reliability.
Creating a Fluorescence-Based Alternative
To overcome these limits, the researchers developed a fluorescence-based sensing approach that does not consume target molecules.
Their design uses optically transparent poly-L-lactide (PLLA) microneedles that act as waveguides, delivering excitation light to a sensing region at the needle tip and collecting emitted fluorescence in return.
Each microneedle is 2 mm long - long enough to reach the reticular layer near the vascular plexus - and features a pocket structure at its tip. This pocket holds a fluorescent hydrogel block measuring 100 µm in diameter and 100 µm in depth, with a total volume of just 0.79 nanoliters.
The hydrogel is functionalized with a mono-boronic acid-based anthracene probe that reversibly binds to D-glucose.
Changes in glucose concentration alter the hydrogel’s fluorescence intensity, enabling optical readout without consuming the analyte.
The microneedles were made using vacuum-assisted molding and intentionally kept fully amorphous. The study shows that increasing crystallinity in PLLA sharply reduces optical transparency, making crystallinity control essential for waveguiding performance.
A gradient-index (GRIN) lens was integrated at the base of each microneedle for precise focus of excitation light at the tip.
Hydrogel embedding was achieved through localized photopolymerization, with ultraviolet light delivered through the microneedle itself to form the sensing region only where needed.
Proof-of-Concept Glucose Measurements
To evaluate the system, the researchers tested glucose sensing in buffered aqueous solutions rather than in vivo.
Measurements were performed across concentrations ranging from 6.1 to 37.5 mM under weakly alkaline conditions (pH 8.5), which are required for the boronic acid probe used in this study.
The device achieved individual measurement errors of 4.9 %, 9.6 %, 0.0 %, and 7.9 % at increasing glucose concentrations, corresponding to an average error of 5.6 % across the tested range.
What the Study Revealed About Interstitial Fluid
Beyond solution experiments, the team used finite-element diffusion modeling to examine how glucose would behave at the microneedle tip in an interstitial fluid-like environment.
The simulations suggest that glucose concentrations could be resolved within approximately 180-200 seconds and that sensing remains localized to within about 200 micrometers of the needle tip.
These results support the device’s potential for highly localized, short-term measurements without bulk fluid extraction.
The authors emphasize that glucose sensing in this study was only demonstrated at pH 8.5, not under physiological conditions. However, they note that the optical probe embedded in the hydrogel can be replaced, allowing the same microneedle platform to be adapted for different biomarkers or operating environments.
While not presenting a ready-to-use clinical sensor, the study establishes a platform for non-consumptive molecular sensing at the sub-nanoliter scale, an important step toward minimally invasive diagnostics based on interstitial fluid.
Journal Reference
Fukuhara, M. et al. (2025). Development of an optical microneedle device embedding sub-nanoliter volumes of boronic acid-based fluorescent hydrogel. Journal of Materials Chemistry B, 13(47), 15273-15281. DOI: 10.1039/D5TB00385G
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