The art of engineering in miniature

Storing medications in a fine film and releasing them with electricity - This technique, developed by the BioEPIC junior research group at the University of Freiburg's Institute of Microsystems Engineering (IMTEK), has attracted a lot of attention. The research group is part of the excellence cluster BrainLinks-BrainTools. Such a drug-delivering layer on implants could make it easier in the future to research and treat brain malfunctions.

Electrodes and connections
Photo: Christian Böhler

"We tune electrodes to make neuro-implants to make them more efficient," says Christian Böhler, a doctoral candidate in the BioEPIC project, by way of introducing his work. You tune them? But the microsystems engineer doesn't mean Formula 1 engines, nor is he talking about musical instruments. "We are talking about dimensions here in the low micrometer area. That is key for understanding microsystems technologies." Big things have many problems which can be solved in simple, mechanical ways. But it's a different story with the electrodes developed at IMTEK. They not only have to be extremely small - they serve as an interface to the brain's neural tissue. That means that they have to be adapted to their biological surroundings. But why is BioEPIC making such electrodes?

Brain sections on slides.
Photo: Christian Böhler

The junior research group headed by Dr. Maria Asplund is just one of many projects in BrainLinks-BrainTools which seek to develop bi-directional neural interfaces. These are systems which can be used both for stimulating and reading brain signals. They are based on the role played by electrical processes in the communication between nerve cells alongside the chemical ones. Because many neurological diseases remain incurable, doctors and medical researchers have long sought new ways of treating them other than using drugs. For example, since the late 1990s electrical stimulation methods have been used to treat Parkinson's disease, with some success. The medical premise is - if the patient gets better, you were right.

The materials are key

No-one knows exactly how stimulation works. To find out more about the process and what causes the diseases in the first place, numerous research groups from around the world are trying to decode the patterns of behavior in malformed and diseased tissue. Information from the nervous system can be read, ideally using the same devices used to stimulate it. And that is the special service performed by bi-directional neural interfaces. Putting them into application is often difficult. "How well they work depends strongly on how the biology responds to the materials used - or put another way - on the materials we use," Asplund explains.

The main problem the researchers see is the body rejecting the implants. Immune cells attack the foreign body, setting off an inflammation. The cells needed to pass on or to receive the signal die in the inflammation - and soon no more measurements can be taken. From the medical point of view, it is useful for patients receiving such implants to take drugs to suppress such an immune reaction. High doses of the usual cortisone are required to prevent inflammations in the brain. That in turn has undesirable effects and can affect the whole body - such that in practise it is rarely used. However, if you could apply cortisone directly around the implant, far less would be needed and the effect would be in the right place. That raises the question of how the substance can be stored, put in place, and released in a controlled manner.

Storing and releasing medication

Böhler and Asplund address this in their latest study https://www.pr.uni-freiburg.de/pm/2017/schichtarbeit: PEDOT is a polymer which can store drugs and release them again when placed under an electrical voltage. A fine layer of it is applied to the electrodes on the implants. "This way we can regulate the size and timing of the dosage," says Böhler. Previously www.pr.uni-freiburg.de/pm/2016/pm.2016-02-19.22 the team had shown, that PEDOT has characteristics which make it an ideal drug deliverer.
The electrodes are made and tested in many small steps. First, a disc of semiconducting material is given a layer of polyimide and an adhesive layer of silicon carbide. Electrical contacts of platinum and iridium oxide are precipitated onto the electrode. In order to protect the electrodes, another layer of polyimide is applied. The drug is stored directly using a process like electroplating during the synthesis of PEDOT as the electrodes are covered.

After the electrode implants were cleaned, the researchers tested their electrochemical properties in 45-day long in vitro experiments. Only then were the implants placed into the brains of twelve rats. Over a period of 12 weeks, the researchers were able to conduct 320 recording and stimulation sessions of the conscious animals' brains by releasing small amounts of the drug by applying a small electrical voltage. The in vivo measurements yielded impressive results, the researchers say. The animals had none of the undesirable reactions and there were no signs of inflammation. The film of PEDOT remained stable, there were no harmful byproducts, the implants were in perfect condition after the twelve weeks, and their conductivity and resistance were unchanged.

Longer periods of use

The researchers will now look to see how the electrodes can be used over a longer period. "It should be clear that we cannot deliver a large volume," Böhler says, "However it may be that inflammation suppressants are no longer required once the probe has grown together with the nervous tissue." Yet he lists a number of options. Using the methods available, the researchers could make the film thick enough to double or triple the capacity. Another possibility is to combine it with a hydrogel with additional storage capacity. Or PEDOT serves merely as a "porter" to a bigger storage on the basis of other materials.
Böhler will finish his doctorate this year. If BrainLinks-BrainTools gets further funding approval, he has a good chance of further pursuing his drug-delivery research as a postdoc in Freiburg. If that doesn't work out, he may work for a sports car manufacturer or create sound systems for concerts. Because microsystems engineering is needed in all kinds of technical fields.

Levin Sottru