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Medical products such as ointments or syringes reach their limits when it comes to delivering medication locally – and above all in a controlled manner over a longer period of time. Empa researchers are therefore developing polymer fibers that can deliver active ingredients precisely over the long term. These "liquid core fibers" contain drugs inside and can be processed into medical textiles.

Treating a wound or an inflammation directly where it occurs has clear advantages: The active ingredient reaches its target immediately, and there are no negative side effects on uninvolved parts of the body. However, conventional local administration methods reach their limits when it comes to precisely dosing active ingredients over a longer period of time. As soon as an ointment leaves the tube or the injection fluid flows out of the syringe, it is almost impossible to control the amount of active ingredient. Edith Perret from Empa's Advanced Fibers laboratory in St. Gallen is therefore developing medical fibers with very special "inner values": The polymer fibers enclose a liquid core with therapeutic ingredients. The aim: medical products with special capabilities, e.g. surgical suture material, wound dressings and textile implants that can administer painkillers, antibiotics or insulin precisely over a longer period of time. Another aim is to achieve individual, patient-specific dosage of the drug in the sense of personalized medicine.

Biocompatible and tailor-made
A decisive factor that turns a conventional textile fiber into a medical product is the material of the fiber sheath. The team chose polycaprolactone (PCL), a biocompatible and biodegradable polymer that is already being used successfully in the medical field. The fiber sheath encloses the valuable substance, such as a painkiller or an antibacterial drug, and releases it over time. Using a unique pilot plant, the researchers produced PCL fibers with a continuous liquid core by means of melt spinning. In initial lab tests, stable and flexible liquid-core fibers were produced. What's more, the Empa team had already successfully demonstrated, together with a Swiss industrial partner, that this process not only works in the lab but also on an industrial scale.

The parameters according to which the medical fibers release an enclosed agent were first investigated using fluorescent model substances and then with various drugs. "Small molecules such as the painkiller ibuprofen move gradually through the structure of the outer sheath," says Edith Perret. Larger molecules, on the other hand, are released at the two ends of the fibers.

Precisely controllable and effective in the long term
“Thanks to a variety of parameters, the properties of the medical fibers can be precisely controlled," explains the Empa researcher. After extensive analyses using fluorescence spectroscopy, X-ray technology and electron microscopy, the researchers were able to demonstrate, for instance, the influence of the sheath thickness and crystal structure of the sheath material on the release rate of the drugs from the liquid core fibers.

Depending on the active ingredient, the manufacturing process can also be adapted: Active ingredients that are insensitive to high temperatures during melt spinning can be integrated directly into the core of the fibers in a continuous process. For temperature-sensitive drugs, on the other hand, the team was able to optimize the process so that a placeholder initially fills the liquid core, which is replaced later on by the sensitive active ingredient.

One of the advantages of liquid core fibers is the ability to release the active ingredient from a reservoir over a longer period of time. This opens up a wide range of possible applications. With diameters of 50 to 200 micrometers, the fibers are large enough to be woven or knitted into robust textiles, for example. However, the medical fibers could also be guided inside the body to deliver hormones such as insulin, says Perret. Another advantage: Fibers that have released their medication can be refilled. The range of active ingredients that can be administered easily, conveniently and precisely using liquid core fibers is large. In addition to painkillers, anti-inflammatory drugs, antibiotics and even lifestyle preparations are conceivable.

In a next step, the researchers want to equip surgical suture material with antimicrobial properties. The new process will be used to fill various liquid core materials with antibiotics in order to suture tissue during an operation in such a way that wound germs have no chance of causing an infection. Empa researcher Perret is also convinced that future collaboration with clinical partners will form the basis for further innovative clinical applications.

Aiming for clinical partnerships
Advancing a new technology? Identifying innovative applications? Empa researcher Edith Perret is looking for interested clinicians who recognize the potential of drug delivery via liquid core fibers and want to become active in this field.

A bandage that releases medication as soon as an infection starts in a wound could treat injuries more efficiently. Empa researchers are currently working on polymer fibers that soften as soon as the environment heats up due to an infection, thereby releasing antimicrobial drugs.

It is not possible to tell from the outside whether a wound will heal without problems under the dressing or whether bacteria will penetrate the injured tissue and ignite an inflammation. To be on the safe side, disinfectant ointments or antibiotics are applied to the wound before the dressing is applied. However, these preventive measures are not necessary in every case. Thus, medications are wasted and wounds are over-treated.

Even worse, the wasteful use of antibiotics promotes the emergence of multi-resistant germs, which are an immense problem in global healthcare. Empa researchers at the two Empa laboratories Biointerfaces and Biomimetic Membranes and Textiles in St. Gallen want to change this. They are developing a dressing that autonomously administers antibacterial drugs only when they are really needed.

The idea of the interdisciplinary team led by Qun Ren and Fei Pan: The dressing should be "loaded" with drugs and react to environmental stimuli. "In this way, wounds could be treated as needed at exactly the right moment," explains Fei Pan. As an environmental stimulus, the team chose a well-known effect: the rise in temperature in an infected, inflamed wound.

Now the team had to design a material that would react appropriately to this increase in temperature. For this purpose, a skin-compatible polymer composite was developed made of several components: acrylic glass (polymethyl methacrylate, or PMMA), which is used, for example, for eyeglass lenses and in the textile industry, and Eudragit, a biocompatible polymer mixture that is used, for example, to coat pills. Electrospinning was used to process the polymer mixture into a fine membrane of nanofibers. Finally, octenidine was encapsulated in the nanofibers as a medically active component. Octenidine is a disinfectant that acts quickly against bacteria, fungi and some viruses. In healthcare, it can be used on the skin, on mucous membranes and for wound disinfection.

Signs of inflammation as triggers
As early as in the ancient world, the Greek physician Galen described the signs of inflammation. The five Latin terms are still valid today: dolor (pain), calor (heat), rubor (redness), tumor (swelling) and functio laesa (impaired function) stand for the classic indications of inflammation. In an infected skin wound, local warmth can be as high as five degrees. This temperature difference can be used as a trigger: Suitable materials change their consistency in this range and can release therapeutic substances.

Shattering glove
"In order for the membrane to act as a "smart bandage" and actually release the disinfectant when the wound heats up due to an infection, we put together the polymer mixture of PMMA and Eudragit in such a way that we could adjust the glass transition temperature accordingly," says Fei Pan. This is the temperature, at which a polymer changes from a solid consistency to a rubbery, toughened state. Figuratively, the effect is often described in reverse: If you put a rubber glove in liquid nitrogen at –196 degrees, it changes its consistency and becomes so hard that you can shatter it like glass with one blow.

The desired glass transition temperature of the polymer membrane, on the other hand, was in the range of 37 degrees. When inflammation kicks in and the skin heats up above its normal temperature of 32 to 34 degrees, the polymer changes from its solid to a softer state. In laboratory experiments, the team observed the disinfectant being released from the polymer at 37 degrees – but not at 32 degrees. Another advantage: The process is reversible and can be repeated up to five times, as the process always "switches itself off" when it cools down. Following these promising initial tests, the Empa researchers now want to fine-tune the effect. Instead of a temperature range of four to five degrees, the smart bandage should already switch on and off at smaller temperature differences.

Smart and unsparing
To investigate the efficacy of the nanofiber membranes against wound germs, further laboratory experiments are now in the pipeline. Team leader Qun Ren has long been concerned with germs that nestle in the interface between surfaces and the environment, such as on a skin wound. "In this biological setting, a kind of no man's land between the body and the dressing material, bacteria find a perfect biological niche," says the Empa researcher. Infectious agents such as staphylococci or Pseudomonas bacteria can cause severe wound healing disorders. It was precisely these wound germs that the team allowed to become acquainted with the smart dressing in the Petri dish. And indeed: The number of bacteria was reduced roughly 1000-fold when octenidine was released from the smart dressing. "With octenidine, we have achieved a proof of principle for controlled drug release by an external stimulus," said Qun Ren. In future, she said, the technology could be applied to other types of drugs, increasing the efficiency and precision in their dosage.

The smart dressing
Empa researchers are working in interdisciplinary teams on various approaches to improve medical wound treatment. For example, liquid sensors on the outside of the dressing are to make it visible when a wound is healing poorly by changing their color. Critical glucose and pH values serve as biomarkers.

To enable bacterial infections to be contained directly in the wound, the researchers are also working on a polymer foam loaded with anti-inflammatory substances and on a skin-friendly membrane made of plant material. The cellulose membrane is equipped with antimicrobial protein elements and kills bacteria extremely efficiently in laboratory tests.

Moreover, digitalization can achieve more economical and efficient dosages in wound care: Empa researchers are developing digital twins of the skin that allow control and prediction of the course of a therapy using real-time modeling.

Further information:
Prof. Dr. Katharina
Maniura Biointerfaces
Phone +41 58 765 74 47
Katharina.Maniura@empa.ch

Prof. Dr. René Rossi
Biomimetic Membranes and Textiles
Phone +41 58 765 77 65
Rene.rossi@empa.ch