Long-term in vivo glucose monitoring using fluorescent hydrogel fibers

Abstract

The use of fluorescence-based sensors holds great promise for continuous glucose monitoring (CGM) in vivo, allowing wireless transdermal transmission and long-lasting functionality in vivo. The ability to monitor glucose concentrations in vivo over the long term enables the sensors to be implanted and replaced less often, thereby bringing CGM closer to practical implementation. However, the full potential of long-term in vivo glucose monitoring has yet to be realized because current fluorescence-based sensors cannot remain at an implantation site and respond to blood glucose concentrations over an extended period. Here, we present a long-term in vivo glucose monitoring method using glucose-responsive fluorescent hydrogel fibers. We fabricated glucose-responsive fluorescent hydrogels in a fibrous structure because this structure enables the sensors to remain at the implantation site for a long period. Moreover, these fibers allow easy control of the amount of fluorescent sensors implanted, simply by cutting the fibers to the desired length, and facilitate sensor removal from the implantation site after use. We found that the polyethylene glycol (PEG)-bonded polyacrylamide (PAM) hydrogel fibers reduced inflammation compared with PAM hydrogel fibers, transdermally glowed, and continuously responded to blood glucose concentration changes for up to 140 days, showing their potential application for long-term in vivo continuous glucose monitoring.glucose-responsive fluorescence | long-lasting implantable sensor | biocompatible interface | implantable glucose sensor | diabetes mellitus I n vivo glucose monitoring allows continuous glucose monitoring (CGM) and facilitates intensive control of blood glucose concentrations in diabetic patients. Long-lasting implantable sensors can reduce the frequency of implantation and replacement, resulting in long-term in vivo glucose monitoring with less effort by patients and less tissue damage. For decades, implantable sensors for long-term use have been developed using enzyme electrodes. However, these methods have several drawbacks for long-term use because these enzyme based sensors are insufficiently stable in vivo (1), they are poorly accurate in low glucose concentrations (2), and their activity is oxygen-dependent (3). In contrast, glucose-responsive fluorescence is a promising approach that maintains long-lasting functionality in vivo due to its enzyme-free and reversible reaction (4-9). We recently developed fluorescent hydrogel microbeads that are transdermally detectable, injectable, minimally invasive, and biocompatible (10). To bring this technology closer to long-term application, the fluorescent hydrogel sensors need to remain at the implantation site for a long period (over 3 mo) and be easily removable after use; despite their great potential for continuous glucose monitoring, the microbeads were not suitable for long-term monitoring in vivo because they dispersed from the implantation site and were difficult to remove. In addition, the biointerface of the fluoresce...

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

“…The matrix of MNs was made from cross-linked HA to improve the stiffness of MNs and restrict the loss of GRVs from needles. With transcutaneous administration, the GRVs loaded in MNs disassembled when exposed to high interstitial fluid glucose in vascular and lymph capillary networks (35), thereby promoting the release of insulin, which was then taken up quickly through the regional lymph and capillary vessels (36). We demonstrated that this "smart insulin patch" with a novel glucoseresponsive mechanism displayed rapid responsiveness for glucose regulation and reliable avoidance of hypoglycemia in a mouse model of type 1 diabetes.…”

Glucose‐Sensitive Hydrogel Optical Fibers Functionalized with Phenylboronic Acid

“…[1b, 5] Optical sensors offer advantages over electrochemical assays since they can be constructed to be label-free, provide real-time continuous monitoring for long periods of time, are immune to electromagnetic interference, and can be calibrated internally. [6] One of the promising approaches for optical glucose sensors is to covalently incorporate glucose-sensitive chelating agents such as phenylboronic acid (PBA) derivatives [7] into matrixes such as or micro- and nanostructures including holographic thin films, [8] crystalline colloidal arrays, [9] plasmonic nanoantennas, [10] Fabry-Perot cavities, [11] fluorescent dyes, [12] and quantum dots (QDs). [13] Optical monitoring systems have also been developed in the form of solid-state optodes that report on the glucose concentration via refractive index (RI) changes.…”

“…[19] For instance, optical polymer fibers based on fluorescent sensing have been reported for quantitative glucose measurements. [12] However, photobleaching of the fluorophore, and variations in the illumination source and output caused over/underestimation of the glucose concentration in vivo . Additionally, this technology was not applicable to individuals with skin pigmentation, light scattering from the tissue, and was affected by epidermal thickness.…”

Opening windows on new biology and disease mechanisms: development of real-time in vivo sensors

“…For high spatial resolution, these detectors require complex imaging modalities, such as two-photon confocal imaging, for reliable temporal and spatial resolution. Feasible use of such sensors in human patients will probably sacrifice spatial resolution for broad in vivo accuracy, as in embedded optical glucose sensors [4]. Positron emission tomography sensors are well established, with a growing list of increasingly validated substrates for in vivo sensing including glucose metabolism, oxygenation, neurotransmitters and proteases.…”

“…Recent refinements of implantable optical detectors are a particularly promising development that will have major implications for the use of fluorescence-based biosensors [22]. These implantable optical sensors have recently been applied to great effect to subcutaneously assay glucose concentrations using a fluorescent hydrogel-based glucose sensor [4].…”