Injectable hydrogel microbeads for fluorescence-based in vivo continuous glucose monitoring

Abstract

Fluorescent microbeads hold great promise for in vivo continuous glucose monitoring with wireless transdermal transmission and long-lasting activity. The full potential of fluorescent microbeads has yet to be realized due to insufficient intensity for transdermal transmission and material toxicity. This paper illustrates the highlysensitive, biostable, long-lasting, and injectable fluorescent microbeads for in vivo continuous glucose monitoring. We synthesized a fluorescent monomer composed of glucose-recognition sites, a fluorogenic site, spacers, and polymerization sites. The spacers are designed to be long and hydrophilic for increasing opportunities to bind glucose molecules; consequently, the fluorescent monomers enable high-intensive responsiveness to glucose. We then fabricated injectable-sized fluorescent polyacrylamide hydrogel beads with high uniformity and high throughput. We found that our fluorescent beads provide sufficient intensity to transdermally monitor glucose concentrations in vivo. The fluorescence intensity successfully traced the blood glucose concentration fluctuation, indicating our method has potential uses in highly-sensitive and minimally invasive continuous blood glucose monitoring.iabetes is a global pandemic affecting over 200 million people (1, 2). Maintaining normal blood glucose concentrations is crucial for preventing diabetic complications in the heart, kidney, retina, and neural system (3-6). The fingertip prick method for collecting a blood sample is used at present to accurately analyze blood glucose concentrations. However, the method provides intermittent information concerning glucose concentrations, which is not suitable to predict the trend of blood glucose change. In contrast, continuous glucose monitoring (CGM) allows diabetic patients to effortlessly recognize changes in blood glucose concentrations and signals a warning in the case of hypoand hyperglycemia patients; even when diabetic patients are sleeping (7,8).Fully-implantable glucose sensors, embedded in the body, are ideal for CGM. Previously, microdialysis and enzyme-tipped catheters have been developed as fully-implantable glucose sensors for CGM. Although these sensors are capable of providing the sequential information of blood glucose concentrations to diabetic patients, they need to have external links for continuously collecting samples or transmitting signals; thereby these methods cause discomfort and the risk of infection. Recently, an optical method using fluorescent beads (9-12) was proposed for CGM. This method provides wireless transmission through the skin, and long-lasting activity in vivo compared to enzymebased methods (13-16) that require an electrochemical reaction. However, fully-implantable glucose sensors based on the fluorescent principle have not yet been developed mainly due to the insufficient fluorescent intensity required for transdermal detection and the toxicity of the material (17).Here, we developed the highly-sensitive, biostable, longlasting, and injectable fluorescent micro...

Ultrasensitive microchip based on smart microgel for real-time online detection of trace threat analytes

“…The strategy of the ultrasensitive microchip integrated with smart microgel presented here circumvents the difficulties in simultaneously reducing the detection limit and improving the easy-to-operate property of detection techniques for trace analytes. It can be used to construct versatile new detection platforms for real-time detection of various kinds of trace analyte signals just by incorporating other stimuliresponsive microgels (6,(24)(25)(26)(27)(28), which might be a fertile area of research. Due to the excellent ultrasensitive, fast, and easy-tooperate properties, the detection platforms equipped with microchips incorporating smart microgel will provide ever-better performances in myriad applications including environmental protection, disease diagnosis and epidemic prevention, and may open up new areas of application for hydrogel-based detection techniques.…”

CMOS image sensor-based implantable glucose sensor using glucose-responsive fluorescent hydrogel

“…The hydrogel shows fluorescence in the blue-green light region. Since the hydrogel has a phenylboronic acid structure that selectively interacts with glucose, the fluorescence intensity increases with increase in the glucose concentration [8]. They implanted the hydrogel in the ears of a rat and experimentally verified the fluorescence-based glucose sensing with an external light source and an external photosensor [8].…”

“…Using the glucose-responsive fluorescent dye [7], Takeuchi et al developed implantable hydrogel microbeads [8] and a hydrogel fiber [9]. The hydrogel shows fluorescence in the blue-green light region.…”

Preparation and Characterization of a Novel Injectable Hydrogel

“…Currently, there is an increasing interest in the development of novel hydrogel systems, one of which is aqueous injectable, in situ gel-forming system. This injectable matrix could be directly delivered into voids or cavities through a needle or a catheter and does not require surgical implantation [5][6][7]. Due to its viscous behavior, the system could fit a cavity or a defect easily (e.g.…”