Scientists at the University of Bath, U.K., have developed a non-invasive adhesive patch that can measure blood glucose levels directly through the skin without the need to draw blood by finger-prick sampling for calibration. The patch, based on a miniaturized pixel array platform, pulls glucose out from fluid between cells across hair follicles, and can monitor blood glucose levels over several hours.

The multidisciplinary research team tested their prototype patch on pig skin and on healthy human volunteers, and confirmed its ability to monitor blood sugar variations throughout the day. They further suggest that the patch technology lends itself to low-cost, high-volume production, which could address the need to develop a non-invasive, patient-friendly and affordable glucose monitoring platform for the growing global population of patients with type 1 and type 2 diabetes. Feasibly, the technology could be developed as an affordable, wearable sensor that sends clinically relevant glucose measurements to the diabetes patient's phone or smartwatch, wirelessly. 

“The specific architecture of our array permits calibration-free operation, and it has the further benefit of allowing realization with a variety of materials in combination,” states Adelina Ilie, Ph.D., at the University of Bath Department of Physics, who is corresponding author of the team’s published paper in Nature Nanotechnology. “We utilized graphene as one of the components as it brings important advantages: specifically, it is strong, conductive, flexible, and potentially low-cost and environmentally friendly. In addition, our design can be implemented using high-throughput fabrication techniques like screen printing, which we hope will ultimately support a disposable, widely affordable device.”

The team reports on the glucose monitoring patch in a paper entitled, “Non-invasive, transdermal, path-selective and specific glucose monitoring via a graphene-based platform.”

The World Health Organization predicts that the number of people with diabetes will rise from 171 million in 2000 to 366 million by 2030. Blood glucose monitoring is a critical part of diabetes care, and is usually carried out by testing blood drawn using a finger-stick procedure, which can be painful, and so results in “significant user resistance,” the authors state. Implantable and microneedle-based sensors have been developed as alternatives for glucose monitoring in patients with type 1 diabetes, but these technologies aren’t suitable or economically viable for use by the rapidly growing population of patients with type 2 diabetes, the team states. Other proposed non-invasive methods for detecting glucose in sweat, tears of saliva, also have limitations, which mean that they must be calibrated against a finger-stick blood draw.

The only technological approach that offers non-invasive, continuous glucose monitoring is based on reverse iontophoresis (RI), a technique through which a small electric field is applied to the skin to extract interstitial fluid (ISF) through the skin via electroosmosis, the Nature Nanotechnology authors comment. This technique formed the basis of the GlucoWatch Biographer, a glucose monitoring device that received FDA approval in 2001, but which also required finger-stick calibration.

The University of Bath researchers have now harnessed electroosmotic extraction to develop a non-invasive, patch-based glucose monitoring approach that exploits the fact that most of the electroosmotic flow during RI follows low-resistance pathways associated primarily with the hair follicles. Using the new pixel array, ISF drawn through the skin electroosmotically along each hair follicle pathway is captured into a separate, small-volume pixel, where it reacts with glucose oxidase to produce hydrogen peroxide, which is detected by electrochemical sensors. Each sensor of the array can operate on a small area over an individual hair follicle, which significantly reduces inter- and intra-skin variability in glucose extraction and increases the accuracy of the measurements taken, which means that calibration via a blood sample is not required.

“ISF-borne glucose is extracted via individual, privileged follicular pathways across the skin and detected, producing ‘quantized’ readouts of subdermal glucose,” the authors explain. “With a sufficiently dense pixel array and the correct pixel size, a number of such pathways are sampled randomly and individually…In this way, the concentration of glucose extracted via the hair follicles is in a fixed relationship with that in the ISF.”

The initial prototype device developed by the researchers relied on thin-film technology, using graphene as the preferred material, and was used for ex vivo testing on porcine skin, to demonstrate that the array could track glucose levels across the range seen in human diabetes patients. Tests on two healthy human volunteers using a second-generation prototype, constructed using commercially available screen printing technology and ink-based electrodes, confirmed that the device could monitor blood glucose over a 6-hour period and track changes in blood glucose after the participants ate lunch and a later snack. “The ISF glucose profile closely follows that of the blood glucose, with a lag of about 15 min, as expected,” the authors note.

Encouragingly, control experiments showed that without RI no glucose was detected, “confirming that, under normal transdermal monitoring conditions (that is, when the user is not actively perspiring, for example, due to strenuous exercise or high ambient temperatures), there is no contamination of the ISF-borne glucose by that in the sweat,” they continue.

The team claims that their technology could enable the development of technologies for monitoring blood glucose in diabetes patients without the need for invasive, finger-stick blood sampling. “Unlike other wearable approaches for glucose monitoring, the technology described here should ensure that the relationship between measurements made by the device and the actual blood glucose concentrations is not subject to inter- and intra-individual fluctuations in skin characteristics,” the team states

Commenting on the new device, co-author Richard Guy, Ph.D., at the University of Bath’s Department of Pharmacy & Pharmacology, concluded, “A non-invasive—that is, needle-less—method to monitor blood sugar has proven a difficult goal to attain. The closest that has been achieved has required either at least a single-point calibration with a classic 'finger-stick', or the implantation of a pre-calibrated sensor via a single needle insertion. The monitor developed at Bath promises a truly calibration-free approach, an essential contribution in the fight to combat the ever-increasing global incidence of diabetes.”

Next stages in development of the technology will be to develop a patch that can continuously record over a 24 hour period, and to optimize the number of sensors in the array, prior to undertaking clinical trials.

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