For the first time, medicine released from depots under the skin can be tracked in real time – without a single incision. Behind the breakthrough is a research team from Denmark and Australia whose new optical method can document whether treatment works as intended and open the way for gentler, more precise medication in the future.
A doctor places a needle against the skin and injects a liquid. Within moments, the fluid solidifies into a small depot beneath the surface, which then gradually releases medicine into the body.
Until now, there had been no way to observe how the implant actually formed or to monitor the release of the medicine. Ultrasound can show the implant as a structure under the skin but not what happens to the drug inside. A research team now seems to have found the answer: an optical technique that measures scattered light and can track both the formation of the implant and the release of the medicine in real time.
The study was led by Andrea Heinz, Associate Professor at the Department of Pharmacy, University of Copenhagen, Denmark, where she heads research on skin medicines at the University’s LEO Foundation Center for Cutaneous Drug Delivery. Her project student Maximilian Rath carried out all the experimental work. Heinz is pleased that she and her team can now show that the method accurately and painlessly determines whether the implant works as intended.
“For the first time, we have demonstrated that two key processes can be followed in real time – how the implant forms and how the medicine is released,” says Andrea Heinz, continuing: “This means that we can document the behaviour of medicines under the skin without damaging the tissue, which opens opportunities for better research, better and safer treatment and, ultimately, better documentation of efficacy.”
Old methods destroyed the tissue – the new one can see through it
Andrea Heinz has spent years studying drug formulations that act on or through the skin – from innovative gels applied to the surface to patches that release medicine over time. In this work, she has constantly sought better ways to measure how medicine penetrates the skin.
But again and again, she ran into the same problem: existing methods were either too shallow or too invasive. They cannot reveal what happens deeper in the tissue without damaging it – a limitation that, as she explains, brought many ideas to a halt.
In addition, several research groups and pharmaceutical companies began looking into a new type of depot formulation: a liquid that is injected into tissue and then solidifies into an implant. Such depots can release medicine over a longer period and in a highly controlled way. They promise gentler treatment – sparing patients from daily doses. Ultrasound could visualise the depot itself but not what happened to the drug inside. To find out, researchers still had to use uncomfortable procedures.
That challenge became the spark for Andrea Heinz and her team. They wanted a method that could reveal biological processes beneath the skin without causing any harm. Their answer was an optical technique: spatially offset Raman spectroscopy (SORS). In practice, it works like a camera that can see through the skin without cutting it. The method itself was not new – but applying it to follow how a drug depot forms and releases medicine in the body was. The aim was clear: to show that monitoring could be done in real time without surgical intervention.
How pig skin paved the way for the breakthrough
The first experiments were carried out on pig skin, which in structure and thickness closely resembles human skin. The researchers tested two model drugs, 4-cyanophenol and retinoic acid, embedded in a liquid polymer that solidifies on contact with tissue. Once injected, the liquids immediately began forming solid depots under the skin.
To probe the deeper layers of the skin, the team turned to their new technique. They used a laser tuned to 785 nanometres – in the red part of the visible spectrum. The wavelength is gentle on tissue yet strong enough to give a clear signal. Light was sent into the skin at one point and collected at another, enabling researchers to shift the focus to different depths – like adjusting a camera lens. In this way, the researchers could measure precisely in the area where the depot formed and the drug was released.
Laser light has a key advantage: at 785 nanometres it is both mild and powerful enough to provide clear data. As it travels through tissue, molecules scatter it, and some of the scattered light can be captured and analysed for information from the tissue layers through which it has passed.
Conventional Raman measurement measures only the light reflected straight back from the surface – giving information only from the top layer. By contrast, the new method collects scattered light from deeper inside the tissue. This enables researchers to detect signals from layers that were previously out of reach.
The hidden fingerprints of molecules are revealed in the light
When laser light hits a molecule, it sets the atoms vibrating in their own specific way. This shifts the light slightly and creates a unique spectrum – a molecular fingerprint known as the Raman effect. By reading these fingerprints, researchers can distinguish between skin molecules, the implant and the drug. It is similar to scanning a supermarket barcode – only at the molecular level.
Using this approach, Andrea Heinz and colleagues separated signals from skin, depot and drug. This meant that they could follow two crucial processes: how the depot took shape and how the medicine was released.
To test the method, they used two model drugs: 4-cyanophenol, which spread quickly through the tissue, and retinoic acid, which lingered in the depot. With SORS, they could track these differences in real time – without any intervention.
The method proved sensitive enough to pick up even subtle differences in how quickly drugs were released from the depot. It also enabled the team to follow how the implant slowly changed shape and density over time.
“Such changes influence how the drug is distributed in the body. By measuring continuously for 14 days, we could document the entire course – from liquid to fully formed depot and right through to complete release,” explains Andrea Heinz.
Next step: From the laboratory to the patient
For now, the team has shown that the approach works in the laboratory. The next step will be to test it in living tissue, likely in collaboration with clinicians. This will require making the equipment more user-friendly and suitable for clinical use. Heinz stresses that her group’s role was to demonstrate feasibility. Others will have to develop and commercialise the technology.
In the longer term, the aim is to make the equipment handheld so doctors can use it directly in treatment. That would, for instance, enable them to check on the spot whether a depot has formed correctly right after injection – with real patients and not just in pig skin samples in the laboratory.
But technical questions still need to be resolved. How precise are the measurements under different conditions? Can the method separate even more substances in complex formulations? What happens when the tissue is living and moving? And which drugs and formulations are best suited to this approach? The answers will determine whether the method can make its way into everyday clinical use.
For now, the experiment shows for the first time that what happens beneath the skin can be tracked without a single incision. This could open the door to more precise treatment in which medication is tailored to each patient while sparing the body as much as possible. It also gives researchers and drug developers a new way to understand and refine how medicines act in the body – not through guesswork or indirect tests but by watching the process unfold in real time.
