If you found yourself with a cough or cold in 19th century England, you might have been offered a mustard plaster – a mustard powder poultice contained within a protective dressing typically applied to the chest. Supposedly, this could help break up phlegm. Fast forward a few centuries and today’s wearable drug delivery devices still broadly follow the same rationale: you put them on and they administer medicine. Yet science and technology have advanced in leaps and bounds since the Victorian era, and we can now deliver drugs with the precision and comfort our ancestors couldn’t have imagined.
The skin can now be penetrated without causing pain, for instance. We can control exactly when a dose is given; a device can even be programmed to do this automatically. Complex electronic components can be made very small, allowing us to build devices that are discreet and lightweight. With these capabilities, research labs and device makers around the world are working on new and improved wearables: skin patches, microneedle devices, injectors, and more. One key area of interest here is creating ‘smart’ devices, which trigger drug release in response to a stimulus – like an electronic signal or change in physiology.
These systems promise precise control over dosing along with greater ease of use. The idea is to make it as frictionless as possible for patients to take their medicine correctly.
Smart sensors
When we talk about ‘smart’ devices, we mostly mean electronically-controlled systems that collect information from the body or environment and feed it into a backend control, says associate professor in bioelectronics at the University of Oxford, Christopher Proctor. The system then processes that information to determine whether to trigger drug release.
This way, the dose can be given at precisely the moment that the patient needs it. Here’s an example of how it works. A person with type 1 diabetes puts on an automated insulin delivery device, inserting a glucose sensor beneath their skin’s outer layer. It measures how much sugar is in the fluid between their cells (interstitial fluid) to gauge blood glucose levels. This information is sent to the system’s backend. If blood sugar is too high, more insulin is released; if it’s too low, the dose is reduced. The type of sensor you use will depend on what you’re trying to measure. “The most mature are certainly different glucose sensors,” says Proctor. “Which is partly because that’s been the greatest need and the most obvious application for some of these systems. But others are coming along.”
For instance, systems which work by picking up Wi-Fi or Bluetooth signals. Deep tech research centre Tyndall National Institute has proposed a new, smart wearable concept where signals from a smartphone release the drug through hollow microneedles.
Advanced sensors are used to monitor and control dosage, explains principal researcher at Tyndall, Dr Conor O’Mahony. “These will track exactly what you took, how much you took [and] when you took it.” There are also sensors which detect whether the device has been applied to the body properly. This information is all fed to a smartphone. Patients receive notifications letting them know when it’s time for their next dose – and they can then tell the device to administer it through the smartphone, too.
Another common technique is to look for certain biomarkers in sweat. Here, you could use a process called iontophoresis, where voltage is applied to make the patient sweat a little, Proctor explains. “[This] allows you to get a better sample of sweat, and then you can measure the concentrations of different ions in the sweat.”
Some therapeutic devices using iontophoresis are available commercially while the method is also used for monitoring and to assist with diagnosis (it’s often used to identify cystic fibrosis, for example). Though plenty of researchers are interested in the technique, Proctor isn’t currently aware of any device on the market that uses it to provide feedback to an electronic drug delivery system.
Delivering the drug
But a feedback mechanism is only one key aspect of these systems. They must also get the medicine to its target as efficiently as possible – all while ensuring the device stays small and light enough to work as a wearable. Microneedles are a popular choice here because they can penetrate far enough under the skin for the drug to enter the bloodstream (while bypassing the stomach and liver, which can reduce side-effects) but are too short to reach the nerve endings. This allows for effective delivery – the drug enters the blood fast without being metabolised elsewhere in the body – via a small patch. They’re also painless for the patient to apply. Depending on what you need your system to do, other techniques can be used in tandem with microneedles. For instance, Tyndall’s device uses micropumps to push liquid through hollow microneedles – which allows for use of higher volumes than with other microneedle-based approaches, O’Mahony explains. “You can basically push as much liquid through those needles as the skin will take.” The device is designed to deliver high-value biological drugs, which often need to be given in larger doses.
Or you could use electroporation, says Research Scientist II and associate director of the Laboratory for Drug Delivery at Georgia Institute of Technology, Gülçin Arslan Azizoglu. “You apply this really small amount of electricity [to] metal microneedles, and then that allows you to open pores within the cells for a short amount of time. You can then deliver big proteins into the cells directly.”
Electroporation makes it easier for the drug to enter the target cells, adds Proctor. “Some people have looked at it for trying to treat different skin cancers, where you really want to get the drug into a very localised, specific target.” It can be used with or without microneedles, though the needles may enhance penetration through the skin. While we’re yet to see any systems using electroporation on the market, there are plenty under development – including in Arslan Azizoglu’s lab.
There’s also been interest in other delivery methods that increase the skin’s permeability. The electric field created via iontophoresis can give drug molecules a little extra push through its outer layer, while use of heat could enhance skin penetration by causing pores to dilate. Again, this is mostly the stuff of research: only a handful of transdermal devices are currently commercially available.
Comfort, usability, compliance
Sophisticated systems are all well and good, but if a patient finds your device too uncomfortable or inconvenient, they simply won’t use it. That’s why usability should factor in throughout the entire development process. Perhaps the most significant consideration here is making delivery as smooth and painless as possible. Often, that’s why microneedles are used: you barely feel them once they’re in. Plus, at least one in ten adults worldwide are estimated to have needle phobia. Being able to avoid a jab is a “big selling point for people,” says O’Mahony. With injectors, use of smaller and thinner needles can help reduce insertion pain, too. There’s also the physical sensation of wearing the device. While you’d always want to choose forms and materials that feel as comfortable as possible, you’re limited by the requirements of what you’re building. It’s an engineering challenge: preserve the function of the system while making the device as unobtrusive as you can.
For instance, if you needed certain electronic components that couldn’t be flexible, you’d have no choice but to make a rigid device rather than a patch. Though because some electronics can now be made in very small sizes, you might still be able to make something that’s lightweight and discreet. The perceived invasiveness of a device is also about how burdensome it is for the patient, says Proctor. “How often do you have to interact with it and replace it? Those are important considerations as well.”
Automated delivery and monitoring systems would help solve this problem: the less the patient has to do, the better. Though patients also want to know whether they’re using the device correctly, says Arslan Azizoglu. “Surveys actually show that the patient wants to have a feedback mechanism. They want to understand if the application worked or not.” For example, you could have the device change colour after a dose is given. Or send a notification to their phone.
We could even create new ways for patients to interact with devices that motivate them to take their medication correctly. O’Mahony sees a future where systems could incorporate gamification – for instance, patients earning points which could be redeemed for groceries – to boost compliance. “That’s been proven to improve adherence by quite a lot,” he says.
Looking ahead
We have the science, materials, and technology to make advanced drug delivery systems — but it takes time to do. “From design phase to market is probably seven years,” says O’Mahony. “The research before that could be a decade.”
Most wearable devices available now focus on either drug delivery or monitoring health markers, says Arslan Azizoglu. Only a few smart devices that do both, like automated insulin delivery systems, have made it to market. But that’s set to change. Interest in the field is rising and much research is currently underway, both in the lab and at trial phase. “In the coming years, I would hope that a lot of these systems will be being tested at clinical stage,” says Proctor.
