Non-invasive glucose monitoring for diabetes: five strategies under development

Nearly 4 million people in the UK have been diagnosed with diabetes — about 10% with type 1, and the rest with type 2. Worldwide, about 415 million adults are living with diabetes, according to the International Diabetes Federation. People with type 1 diabetes may be advised to test their blood-sugar levels four to eight times a day; with type 2 diabetes, the recommended frequency of testing varies, but it may be once a day or more. The first blood glucose monitors came to market in the 1970s. Since then, while there have been improvements in the technology, “we’ve not had any successful alternative provided at all”, notes Richard Guy, a pharmaceutical scientist at the University of Bath.

A number of barriers exist to self-testing using current methods. “The reasons [people] don’t do it are that it’s painful, it’s messy, it’s often inconvenient, because of whatever situation they happen to be in, or perhaps they feel intimidated about doing it,” says Guy. “Whenever you talk to diabetics, particularly type 1s who have had it for years and really need to test themselves frequently, they are desperate to find an alternative that is discreet and doesn’t involve all the paraphernalia.”

Patients’ desire for something more convenient is helping to push research into ‘minimally-invasive’ or truly non-invasive glucose monitoring, with results sent wirelessly to smart devices, agrees David Pugh, a former physical chemist at AstraZeneca Pharmaceuticals, now a technology analyst at the Cambridge-based company IDTechEx.

But there is also a big drive from parents of young children with diabetes, and offspring of older people, who would like to keep easy track of their relative’s blood sugars, says Pugh. A minimally or non-invasive continuous glucose-monitoring system — ideally hooked up to an automatic drug-delivery device — could allow older people to live independently for longer, and give parents greater peace of mind.

There’s no question that diabetics would like to have a non-invasive method, and if they had it they would use it; the problem is that nobody has really come up with a way of doing it that has translated into an effective technology

In the past few years, there has been a lot of research into other ways to measure glucose, says Pugh. While the ultimate system would be truly non-invasive, “at the moment we’re moving towards continuous glucose monitoring using minimally invasive techniques”, he adds.

Guy explains: “I don’t think there’s any question that the medical world believes that better control of blood sugar is key to mitigating the terrible morbidity associated with diabetes. And there’s no question that diabetics would like to have a non-invasive method, and if they had it they would use it. The problem is that nobody has really come up with a way of doing it that has translated into an effective technology.”

But some companies may now be close.

Here we review five methods being investigated to monitor glucose levels:

• Interstitial fluid, via ‘minimally invasive’ systems
• Light-based methods
• An earlobe clip
• Smart contact lenses
• Sweat patches

Minimally invasive systems

Minimally invasive systems measure glucose in interstitial fluid — the fluid that surrounds cells and provides them with nutrients. These nutrients, including glucose, come from capillary blood. The glucose levels in interstitial fluid are not quite the same as in the blood, but it is possible to use a formula to work out blood glucose levels from interstitial fluid readings. There is a delay between peaks and troughs in blood glucose levels and interstitial fluid levels of about ten minutes. While this will not matter much for the majority of diabetes patients, says Richard Guy, a pharmaceutical scientist at the University of Bath, for people who experience rapid rises or falls in blood sugar (especially patients with ‘brittle’ type 1 diabetes), interstitial fluid testing would not be appropriate.

A few companies already market interstitial fluid glucose monitors, such as the Dexcom G5 Mobile and the Freestyle Libre, but these devices do require penetration of the skin. After being inserted, the small sensor remains in place for a number of days (which varies according to the device), and glucose readings are transmitted wirelessly to a smart device.

The next step, some companies think, is an interstitial fluid glucose monitor that does not penetrate the skin, but instead draws fluid to the surface for testing.

Back in 2000, Guy acted as a consultant on a device called the GlucoWatch, which used a small electric current to do exactly this. The US Food and Drug Administration (FDA) eventually approved GlucoWatch for use by people with diabetes. However, users complained about skin irritation, and the company struggled financially.

Loughborough-based company Nemaura has now developed a new device based on the same method for extracting glucose from interstitial fluid. The device, called SugarBEAT, could be on the market in the UK and select EU territories by the end of 2017, according to company director Faz Chowdhury. Nemaura also plans to submit for pre-market approval in the US by the end of 2017.

“It uses a similar approach for extracting glucose, though a fundamental difference is the difference in levels of skin irritation,” says Chowdhury. “In a study of more than 40 patients, over 100 patient days, there were no reports of skin irritation,” he adds, although he will not discuss the technological change behind this. The SugarBEAT is also much smaller and lighter, and worn like a patch on the arm, with sensors that are disposable daily.

One downside with this first generation device is that a user still has to do one finger-prick test every day to calibrate it. But Nemaura is working on a second-generation model that will not require this.

Wearable technologies are at the forefront of medical device development and consumers are more welcoming of the newer products

Chowdhury believes that SugarBEAT will succeed where the GlucoWatch failed, partly because of reduced skin irritation and partly because of a change in attitudes towards wearable technology. “The world has moved on radically since [the GlucoWatch]. Wearable technologies are at the forefront of medical device development and consumers are far more welcoming of such technologies.”

Guy agrees: “The GlucoWatch was ahead of its time. Everyone is talking about wearable health monitoring technologies now.”

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Light-based methods

A light-based glucose monitor would be the “absolutely ideal” way to measure glucose, since it would be truly non-invasive, discreet and very easy to use, says Richard Guy, a pharmaceutical scientist at the University of Bath. Light-based monitors would work by shining a beam of light onto someone’s skin, then measuring what fraction of the light is absorbed by glucose, and from this, calculating blood sugar levels.

Various teams around the world are working on light-based methods but there are several challenges. One of the biggest challenges “concerns unravelling the complex data to establish the accurate calibration of the method”, says Maciej Wrobel at the Gdansk University of Technology in Poland, who is working on this approach. Another is accurately evaluating glucose levels in vivo, rather than just in the laboratory. “Current attempts — although only a handful of studies — at larger-scale clinical translation show great promise in increasing the accuracy and precision to clinically-relevant levels,” says Wrobel.

FDA approval will be difficult as there are no comparable devices out in the market

Gin Jose, a specialist in functional materials and deputy director of research and innovation at the University of Leeds, is also working on a light-based glucose sensor. At the heart of the technology is a piece of nano-engineered silica glass with ions that fluoresce in infrared light when a low power laser hits them. If the glass comes into contact with the user’s skin, the extent of the fluorescence signal varies in relation to the concentration of glucose in their blood. To provide a reading, a user places their forefinger on the device for 30 seconds. Prototypes of the Glucosense Monitor have been made, but there is still work to be done.

“Improving the specificity for low concentration measurements is the important challenge,” Jose says. “Most proposed light technologies have difficulties in addressing this in a clinical trial. We are working to overcome it by combining quantum technology aspects.”

Jose hopes that new prototypes will be ready by summer 2018, and that a device could be on the market in Europe in two to three years. “FDA approval will be difficult as there are no comparable devices out in the market. Therefore, very comprehensive studies will be required,” he adds.

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Earlobe clip

The Israeli-based company Integrity Applications has developed a clip that attaches to the ear lobe to monitor glucose.

The GlucoTrack device has been approved for sale in countries that use the CE marking requirements, which includes the UK, and it is now available in a few European countries (including Spain and Italy), with plans to sell more widely in Europe.

It is intended for people with type 2 diabetes and in pre-diabetic adults. The system consists of a main unit and an ear clip, which monitors glucose using three independent technologies: ultrasonic, electromagnetic and thermal. Exactly how those signals are used and combined is proprietary, the company says. GlucoTrack is not a continuous monitor, but rather must be attached by the user each time they want to check their levels.

The combination of three different measures overcomes a lack of sensitivity or specificity that could affect just one measure alone, maintains Stefanie Saffron of Integrity Applications. Some data have been published. A recent paper in the International Journal of Diabetes & Metabolic Disorders showed “adequate accuracy” over a period of six months in 112 type 2 diabetes patients^[1]
. This was after just a single calibration using three finger pricks spaced out over 30 minutes for each individual. User satisfaction reports were “favourable”, and three quarters of patients in the trial said that they thought they would increase the frequency of glucose monitoring with the device.

Integrity Applications is now in negotiations with companies that run trials in the US to initiate clinical trials that meet FDA requirements.

David Pugh, a former physical chemist at AstraZeneca Pharmaceuticals, now a technology analyst at the Cambridge-based company IDTechEx, is cautious, however. “It looks interesting and I don’t doubt the scientific validity,” he says. “But it’s very big and clunky. If you’re going to test blood sugar, ideally you want it to be more discreet than what we have now.” With a recommended retail price for the main unit of US$2,000 and US$100 for the ear clip that must be replaced every six months, it is also expensive.

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Smart contact lenses

The concept of using contact lenses to measure glucose in tears has made a big splash in the media but the technology seems to be lagging behind the claims.

Google is one major company to have announced a plan to make a smart contact lens glucose monitor for people with diabetes. In 2014, it submitted a patent to the US Patent & Trademark Office for a contact lens made from two layers of material, with a pinhole that would admit tear fluid for testing by sensors. It would use a wireless antenna, thinner than a hair, to transmit readings to a smart device.

But “it increasingly seems like this is ‘slideware’ — the concept and design exist really in PowerPoint”, says David Pugh, a former physical chemist at AstraZeneca Pharmaceuticals, now a technology analyst at the Cambridge-based company IDTechEx. “The medical side hasn’t really come off.”

Richard Guy, a pharmaceutical scientist at the University of Bath, agrees with Pugh’s analysis. “You hear all these smart, clever ideas that people have, but if you wait a year and a half, or two years, and nothing else has come out, then you know the announcement at the start was probably premature.”

You hear all these smart, clever ideas that people have, but if you wait a year and a half, or two years, and nothing else has come out, then you know the announcement at the start was probably premature

The US-based company Verily (which was once part of Google and was tasked with developing the lens) did not reply to requests for information on the status of the research. However, in November 2016, a representative from Novartis, which had partnered on the project, told the news agency Reuters: “It is too early to say when human clinical trials for these lenses will begin… this is a very technically complex process,” and analysts were quick to note that at the eyeforpharma conference in Barcelona in March 2017, Verily did not mention the smart lens.

Some groups are still working on tear-based methods. In April 2017, a team at Oregon State University announced that it had created a prototype glucose-sensing contact lens. And a Netherlands-based company called NovioSense has announced that it is planning trials of a flexible miniature tear-based sensor that rests in the lower eyelid. But some researchers are cautious. While glucose levels in tears can be related to levels in blood, it is not clear that tear glucose concentration is a good enough measure for diabetes control, says Koji Sode, who researches biosensors at Tokyo University.

There are similar concerns over the idea of using glucose levels in saliva. Here however, there are additional potential problems: what a person eats or drinks could affect the results. “There have always been question marks over the reliability of saliva compared with other fluids,” notes Guy.

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Sweat patches

Just one millionth of a litre of sweat could be used to test for glucose, according to a team in South Korea. In March 2017, the researchers based at the University of Seoul published a paper in Science Advances showing that their flexible, sweat-based sensor can provide accurate measures, at least in the short term^[2]
.

One challenge — as with tears — is that there is less glucose in sweat than there is in blood, so it is harder to find. Other chemicals in sweat, such as lactic acid, can also disrupt the results.

The team’s disposable graphene-and-gold patch has three sensors that monitor sugar levels, four that test the acidity of sweat and a humidity sensor to analyse the amount of sweat — all designed to allow for a reliable measurement. All of this is encased in a porous layer that allows the sweat to soak through the electronics. The glucose reading is then sent wirelessly to a computer or smartphone.

The results of tests using the sweat patch before and after people sat down for a meal “agree well” with those from standard blood tests, according to the published data. But much more work will be needed to show the sensor can reliably monitor glucose in the longer term.

Richard Guy, a pharmaceutical scientist at the University of Bath, approves of the approach. “I think this is the sort of advance you need to have to push the field forward,” he says.

Other teams are also working on sweat-based methods. At the University of Texas at Dallas, researchers led by engineer Shalini Prasad first developed a flexible textile-based biosensor to monitor the stress hormone cortisol before then moving on to investigate glucose.

“Glucose is a tricky molecule to monitor because other factors can confound a signal,” notes Prasad. When people exercise or are under stress, the level of other compounds in their sweat, such as cortisol and lactic acid, change as well, and these can interfere with glucose detection.

Glucose is a tricky molecule to monitor because other factors can confound a signal

In October 2016, the team published initial data on sweat samples, showing that they could reliably quantify glucose^[3]
. “In our sensor mechanism, we use the same chemistry and enzymatic reaction that are incorporated into blood glucose testing strips,” Prasad says. But they also control for factors known to affect sweat readings: “We have shown that with our technology, we address three critical issues: low volume of ambient sweat, interference from other compounds and pH swings,” says Prasad. Eventually she envisions a sensor that could be used and discarded at the end of each day.

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