Tag Archives: Sahika Inal

Growing electrodes in your brain?

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This isn’t for everybody. From a February 23, 2023 news item on Nanowerk, Note: A link has been removed,

The boundaries between biology and technology are becoming blurred. Researchers at Linköping, Lund, and Gothenburg universities in Sweden have successfully grown electrodes in living tissue using the body’s molecules as triggers. The result, published in the journal Science (“Metabolite-induced in vivo fabrication of substrate-free organic bioelectronics”), paves the way for the formation of fully integrated electronic circuits in living organisms.

Caption: The injectable gel being tested on a microfabricated circuit. Credit: Thor Balkhed

I have two news releases for this research. First, the February 23, 2023 American Association for the Advancement of Science (AAAS) news release on EurekAlert,

Researchers have developed a way to make bioelectronics directly inside living tissues, an approach they tested by making electrodes in the brain, heart, and fin tissue of living zebrafish, as well as in isolated mammalian muscle tissues. According to the authors, the new method paves the way for in vivo fabrication of fully integrated electronic circuits within the nervous system and other living tissue. “Safety and stability analyses over long periods will be essential to determining whether such technology is useful for chronic implantations,” writes Sahika Inal in a related Perspective. “However, the strategy … suggests that any living tissue can turn into electronic matter and brings the field closer to generating seamless biotic-abiotic interfaces with a potentially long lifetime and minimum harm to tissues.” Implantable electronic devices that can interface with soft biological neural tissues offer a valuable approach to studying the complex electrical signaling of the nervous system and enable the therapeutic modulation of neural circuitry to prevent or treat various diseases and disorders. However, conventional bioelectronic implants often require the use of rigid electronic substrates that are incompatible with delicate living tissues and can provoke injury and inflammation that can affect a device’s electrical properties and long-term performance. Overcoming the incompatibility between static, solid-state electronic materials and dynamic, soft biological tissues has proven challenging. Here, Xenofon Strakosas and colleagues present a method to fabricate polymer-based, substrate-free electronic conducting materials directly inside a tissue. Strakosas et al. developed a complex molecular precursor cocktail that, when injected into a tissue, uses endogenous metabolites (glucose and lactate) to induce polymerization of organic precursors to form conducting polymer gels. To demonstrate the approach, the authors “grew” gel electrodes in the brain, heart, and fin tissue of living zebrafish, with no signs of tissue damage, and in isolated mammalian muscle tissues, including beef, pork and chicken. In medicinal leeches, they showed how the conducting gel could interface nervous tissue with electrodes on a tiny flexible probe.

The second is the February 23, 2023 Linköping University press release on EurekAlert, which originated the news item, and it provides further insight,

“For several decades, we have tried to create electronics that mimic biology. Now we let biology create the electronics for us,” says Professor Magnus Berggren at the Laboratory for Organic Electronics, LOE, at Linköping University.

Linking electronics to biological tissue is important to understand complex biological functions, combat diseases in the brain, and develop future interfaces between man and machine. However, conventional bioelectronics, developed in parallel with the semiconductor industry, have a fixed and static design that is difficult, if not impossible, to combine with living biological signal systems.

To bridge this gap between biology and technology, researchers have developed a method for creating soft, substrate-free, electronically conductive materials in living tissue. By injecting a gel containing enzymes as the “assembly molecules”, the researchers were able to grow electrodes in the tissue of zebrafish and medicinal leeches.

“Contact with the body’s substances changes the structure of the gel and makes it electrically conductive, which it isn’t before injection. Depending on the tissue, we can also adjust the composition of the gel to get the electrical process going,” says Xenofon Strakosas, researcher at LOE and Lund University and one of the study’s main authors.

The body’s endogenous molecules are enough to trigger the formation of electrodes. There is no need for genetic modification or external signals, such as light or electrical energy, which has been necessary in previous experiments. The Swedish researchers are the first in the world to succeed in this.

Their study paves the way for a new paradigm in bioelectronics. Where it previously took implanted physical objects to start electronic processes in the body, injection of a viscous gel will be enough in the future.

In their study, the researchers further show that the method can target the electronically conducting material to specific biological substructures and thereby create suitable interfaces for nerve stimulation. In the long term, the fabrication of fully integrated electronic circuits in living organisms may be possible.

In experiments conducted at Lund University, the team successfully achieved electrode formation in the brain, heart, and tail fins of zebrafish and around the nervous tissue of medicinal leeches. The animals were not harmed by the injected gel and were otherwise not affected by the electrode formation. One of the many challenges in these trials was to take the animals’ immune system into account.

“By making smart changes to the chemistry, we were able to develop electrodes that were accepted by the brain tissue and immune system. The zebrafish is an excellent model for the study of organic electrodes in brains,” says Professor Roger Olsson at the Medical Faculty at Lund University, who also has a chemistry laboratory at the University of Gothenburg.

It was Professor Roger Olsson who took the initiative for the study, after he read about the electronic rose developed by researchers at Linköping University in 2015. One research problem, and an important difference between plants and animals, was the difference in cell structure. Whereas plants have rigid cell walls which allow for the formation of electrodes, animal cells are more like a soft mass. Creating a gel with enough structure and the right combination of substances to form electrodes in such surroundings was a challenge that took many years to solve.

“Our results open up for completely new ways of thinking about biology and electronics. We still have a range of problems to solve, but this study is a good starting point for future research,” says Hanne Biesmans, PhD student at LOE and one of the main authors.

Here’s a link to and a citation for the paper,

Metabolite-induced in vivo fabrication of substrate-free organic bioelectronics by Xenofon Strakosas, Hanne Biesmans, Tobias Abrahamsson, Karin Hellman, Malin Silverå Ejneby, Mary J. Donahue, Peter Ekström, Fredrik Ek, Marios Savvakis, Martin Hjort, David Bliman, Mathieu Linares, Caroline Lindholm, Eleni Stavrinidou, Jennifer Y. Gerasimov, Daniel T. Simon, Roger Olsson, and Magnus Berggren. Science 23 Feb 2023 Vol 379, Issue 6634 pp. 795-802 DOI: 10.1126/science.adc9998

This paper is behind a paywall.

Electronic organic micropump for direct drug delivery to the brain

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I can understand the appeal but have some questions about this micropump in the brain concept. First, here’s more about the research from an April 16, 2015 news item on Nanowerk,

Many potentially efficient drugs have been created to treat neurological disorders, but they cannot be used in practice. Typically, for a condition such as epilepsy, it is essential to act at exactly the right time and place in the brain. For this reason, the team of researchers led by Christophe Bernard at Inserm Unit 1106, “Institute of Systems Neuroscience” (INS), with the help of scientists at the École des Mines de Saint-Étienne and Linköping University (Sweden) have developed an organic electronic micropump which, when combined with an anticonvulsant drug, enables localised inhibition of epileptic seizure in brain tissue in vitro.

An April 16, 2015 INSERM (Institut national de la santé et de la recherche médicale) press release on EurekAlert, which originated the news item, goes on to describe the problem the researchers are attempting to solve and their solution to it,

Drugs constitute the most widely used approach for treating brain disorders. However, many promising drugs failed during clinical testing for several reasons:

  • they are diluted in potentially toxic solutions,
  • they may themselves be toxic when they reach organs to which they were not initially directed,
  • the blood-brain barrier, which separates the brain from the blood circulation, prevents most drugs from reaching their targets in the brain,
  • drugs that succeed in penetrating the brain will act in a non-specific manner, i.e. on healthy regions of the brain, altering their functions.

Epilepsy is a typical example of a condition for which many drugs could not be commercialised because of their harmful effects, when they might have been effective for treating patients resistant to conventional treatments [1].

During an epileptic seizure, the nerve cells in a specific area of the brain are suddenly activated in an excessive manner. How can this phenomenon be controlled without affecting healthy brain regions? To answer this question, Christophe Bernard’s team, in collaboration with a team led by George Malliaras at the Georges Charpak-Provence Campus of the École des Mines of Saint-Étienne and Swedish scientists led by Magnus Berggren from Linköping University, have developed a biocompatible micropump that makes it possible to deliver therapeutic substances directly to the relevant areas of the brain.

The micropump (20 times thinner than a hair) is composed of a membrane known as “cation exchange,” i.e., it has negative ions attached to its surface. It thus attracts small positively charged molecules, whether these are ions or drugs. When an electrical current is applied to it, the flow of electrons generated projects the molecules of interest toward the target area.

To enable validation of this new technique, the researchers reproduced the hyperexcitability of epileptic neurons in mouse brains in vitro. They then injected GABA, a compound naturally produced in the brain and that inhibits neurons, into this hyperactive region using the micropump. The scientists then observed that the compound not only stopped this abnormal activity in the target region, but, most importantly, did not interfere with the functioning of the neighbouring regions.

This technology may thus resolve all the above-mentioned problems, by allowing very localised action, directly in the brain and without peripheral toxicity.

“By combining electrodes, such as those used to treat Parkinson’s disease, with this micropump, it may be possible to use this technology to treat patients with epilepsy who are resistant to conventional treatments, and those for whom the side-effects are too great,” explains Christophe Bernard, Inserm Research Director.

Based on these initial results, the researchers are now working to move on to an in vivo animal model and the possibility of combining this high-technology system with the microchip they previously developed in 2013. The device could be embedded and autonomous. The chip would be used to detect the imminent occurrence of a seizure, in order to activate the pump to inject the drug at just the right moment. It may therefore be possible to control brain activity where and when it is needed.

In addition to epilepsy, this state-of-the-art technology, combined with existing drugs, offers new opportunities for many brain diseases that remain difficult to treat at this time.

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[1] Epilepsy in brief

This disease, which affects nearly 50 million people in the world, is the most common neurological disorder after migraine.

The neuronal dysfunctions associated with epilepsy lead to attacks with variable symptoms, from loss of consciousness to disorders of movement, sensation or mood.

Despite advances in medicine, 30% of those affected are resistant to all treatments.

Here’s a link to and a citation for the paper,

Controlling Epileptiform Activity with Organic Electronic Ion Pumps by Adam Williamson, Jonathan Rivnay, Loïg Kergoat, Amanda Jonsson, Sahika Inal, Ilke Uguz, Marc Ferro, Anton Ivanov, Theresia Arbring-Sjöström, Daniel T. Simon, Magnus Berggren, George G. Malliaras, and Christophe Bernardi. Advanced Materials First published: 11 April 2015Full publication history DOI: 10.1002/adma.201500482

This paper is behind a paywall.

Finally, my questions. How does the pump get refilled once the drugs are used up? Do you get a warning when the drug supply is almost nil? How does that warning work? Does implanting the pump require brain surgery or is there a less intrusive fashion of placing this pump exactly where you want it to be? Once it’s been implanted, how do you find a pump  20 times thinner than a human hair?

For some reason this micropump brought back memories of working in high tech environments where developers would come up with all kinds of nifty ideas but put absolutely no thought into how these ideas might actually work once human human beings got their hands on the product. In any event, the micropump seems exciting and I hope researchers work out the kinks, implementationwise, before they’re implanted.