Tag Archives: Magnus Berggren

Growing electrodes in your brain?

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.

Artificial organic neuron mimics characteristics of biological nerve cells

There’s a possibility that in the future, artificial neurons could be used for medical treatment according to a January 12, 2023 news item on phys.org,

Researchers at Linköping University (LiU), Sweden, have created an artificial organic neuron that closely mimics the characteristics of biological nerve cells. This artificial neuron can stimulate natural nerves, making it a promising technology for various medical treatments in the future.

Work to develop increasingly functional artificial nerve cells continues at the Laboratory for Organic Electronics, LOE. In 2022, a team of scientists led by associate professor Simone Fabiano demonstrated how an artificial organic neuron could be integrated into a living carnivorous plant [emphasis mine] to control the opening and closing of its maw. This synthetic nerve cell met two of the 20 characteristics that differentiate it from a biological nerve cell.

I wasn’t expecting a carnivorous plant, living or otherwise. Sadly, they don’t seem to have been able to include it in this image although the ‘green mitts’ are evocative,

Caption: Artificial neurons created by the researchers at Linköping University. Credit: Thor Balkhed

A January 13, 2023 Linköping University (LiU) press release by Mikael Sönne (also on EurkeAlert but published January 12, 2023), which originated the news item, delves further into the work,

In their latest study, published in the journal Nature Materials, the same researchers at LiU have developed a new artificial nerve cell called “conductance-based organic electrochemical neuron” or c-OECN, which closely mimics 15 out of the 20 neural features that characterise biological nerve cells, making its functioning much more similar to natural nerve cells.

“One of the key challenges in creating artificial neurons that effectively mimic real biological neurons is the ability to incorporate ion modulation. Traditional artificial neurons made of silicon can emulate many neural features but cannot communicate through ions. In contrast, c-OECNs use ions to demonstrate several key features of real biological neurons”, says Simone Fabiano, principal investigator of the Organic Nanoelectronics group at LOE.

In 2018, this research group at Linköping University was one of the first to develop organic electrochemical transistors based on n-type conducting polymers, which are materials that can conduct negative charges. This made it possible to build printable complementary organic electrochemical circuits. Since then, the group has been working to optimise these transistors so that they can be printed in a printing press on a thin plastic foil. As a result, it is now possible to print thousands of transistors on a flexible substrate and use them to develop artificial nerve cells.

In the newly developed artificial neuron, ions are used to control the flow of electronic current through an n-type conducting polymer, leading to spikes in the device’s voltage. This process is similar to that which occurs in biological nerve cells. The unique material in the artificial nerve cell also allows the current to be increased and decreased in an almost perfect bell-shaped curve that resembles the activation and inactivation of sodium ion channels found in biology.

“Several other polymers show this behaviour, but only rigid polymers are resilient to disorder, enabling stable device operation”, says Simone Fabiano

In experiments carried out in collaboration with Karolinska Institute (KI), the new c-OECN neurons were connected to the vagus nerve of mice. The results show that the artificial neuron could stimulate the mice’s nerves, causing a 4.5% change in their heart rate.

The fact that the artificial neuron can stimulate the vagus nerve itself could, in the long run, pave the way for essential applications in various forms of medical treatment. In general, organic semiconductors have the advantage of being biocompatible, soft, and malleable, while the vagus nerve plays a key role, for example, in the body’s immune system and metabolism.

The next step for the researchers will be to reduce the energy consumption of the artificial neurons, which is still much higher than that of human nerve cells. Much work remains to be done to replicate nature artificially.

“There is much we still don’t fully understand about the human brain and nerve cells. In fact, we don’t know how the nerve cell makes use of many of these 15 demonstrated features. Mimicking the nerve cells can enable us to understand the brain better and build circuits capable of performing intelligent tasks. We’ve got a long road ahead, but this study is a good start,” says Padinhare Cholakkal Harikesh, postdoc and main author of the scientific paper.

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

Ion-tunable antiambipolarity in mixed ion–electron conducting polymers enables biorealistic organic electrochemical neurons by Padinhare Cholakkal Harikesh, Chi-Yuan Yang, Han-Yan Wu, Silan Zhang, Mary J. Donahue, April S. Caravaca, Jun-Da Huang, Peder S. Olofsson, Magnus Berggren, Deyu Tu & Simone Fabiano. Nature Materials volume 22, pages 242–248 (2023) DOI: https://doi.org/10.1038/s41563-022-01450-8 Published online: 12 January 2023 Issue Date: February 2023

This paper is open access.

Mimicking the brain with an evolvable organic electrochemical transistor

Simone Fabiano and Jennifer Gerasimov have developed a learning transistor that mimics the way synapses function. Credit: Thor Balkhed

At a guess, this was originally a photograph which has been passed through some sort of programme to give it a paintinglike quality.

Moving onto the research, I don’t see any reference to memristors (another of the ‘devices’ that mimics the human brain) so perhaps this is an entirely different way to mimic human brains? A February 5, 2019 news item on ScienceDaily announces the work from Linkoping University (Sweden),

A new transistor based on organic materials has been developed by scientists at Linköping University. It has the ability to learn, and is equipped with both short-term and long-term memory. The work is a major step on the way to creating technology that mimics the human brain.

A February 5, 2019 Linkoping University press release (also on EurekAlert), which originated the news item, describes this ‘nonmemristor’ research into brainlike computing in more detail,

Until now, brains have been unique in being able to create connections where there were none before. In a scientific article in Advanced Science, researchers from Linköping University describe a transistor that can create a new connection between an input and an output. They have incorporated the transistor into an electronic circuit that learns how to link a certain stimulus with an output signal, in the same way that a dog learns that the sound of a food bowl being prepared means that dinner is on the way.

A normal transistor acts as a valve that amplifies or dampens the output signal, depending on the characteristics of the input signal. In the organic electrochemical transistor that the researchers have developed, the channel in the transistor consists of an electropolymerised conducting polymer. The channel can be formed, grown or shrunk, or completely eliminated during operation. It can also be trained to react to a certain stimulus, a certain input signal, such that the transistor channel becomes more conductive and the output signal larger.

“It is the first time that real time formation of new electronic components is shown in neuromorphic devices”, says Simone Fabiano, principal investigator in organic nanoelectronics at the Laboratory of Organic Electronics, Campus Norrköping.

The channel is grown by increasing the degree of polymerisation of the material in the transistor channel, thereby increasing the number of polymer chains that conduct the signal. Alternatively, the material may be overoxidised (by applying a high voltage) and the channel becomes inactive. Temporary changes of the conductivity can also be achieved by doping or dedoping the material.

“We have shown that we can induce both short-term and permanent changes to how the transistor processes information, which is vital if one wants to mimic the ways that brain cells communicate with each other”, says Jennifer Gerasimov, postdoc in organic nanoelectronics and one of the authors of the article.

By changing the input signal, the strength of the transistor response can be modulated across a wide range, and connections can be created where none previously existed. This gives the transistor a behaviour that is comparable with that of the synapse, or the communication interface between two brain cells.

It is also a major step towards machine learning using organic electronics. Software-based artificial neural networks are currently used in machine learning to achieve what is known as “deep learning”. Software requires that the signals are transmitted between a huge number of nodes to simulate a single synapse, which takes considerable computing power and thus consumes considerable energy.

“We have developed hardware that does the same thing, using a single electronic component”, says Jennifer Gerasimov.

“Our organic electrochemical transistor can therefore carry out the work of thousands of normal transistors with an energy consumption that approaches the energy consumed when a human brain transmits signals between two cells”, confirms Simone Fabiano.

The transistor channel has not been constructed using the most common polymer used in organic electronics, PEDOT, but instead using a polymer of a newly-developed monomer, ETE-S, produced by Roger Gabrielsson, who also works at the Laboratory of Organic Electronics and is one of the authors of the article. ETE-S has several unique properties that make it perfectly suited for this application – it forms sufficiently long polymer chains, is water-soluble while the polymer form is not, and it produces polymers with an intermediate level of doping. The polymer PETE-S is produced in its doped form with an intrinsic negative charge to balance the positive charge carriers (it is p-doped).

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

An Evolvable Organic Electrochemical Transistor for Neuromorphic Applications by Jennifer Y. Gerasimov, Roger Gabrielsson, Robert Forchheimer, Eleni Stavrinidou, Daniel T. Simon, Magnus Berggren, Simone Fabiano. Advanced Science DOI: https://doi.org/10.1002/advs.201801339 First published: 04 February 2019

This paper is open access.

There’s one other image associated this work that I want to include here,

Synaptic transistor. Sketch of the organic electrochemical transistor, formed by electropolymerization of ETE‐S in the transistor channel. The electrolyte solution is confined by a PDMS well (not shown). In this work, we define the input at the gate as the presynaptic signal and the response at the drain as the postsynaptic terminal. During operation, the drain voltage is kept constant while the gate is pulsed. Synaptic weight is defined as the amplitude of the current response to a standard gate voltage characterization pulse of −0.1 V. Different memory functionalities are accessible by applying gate voltage Courtesy: Linkoping University Researchers

Organic nanoelectronics in water

Researchers in Sweden have developed organic electronics that are stable in water according to a January 11, 2018 news item on ScienceDaily,

Researchers at the Laboratory of Organic Electronics, Linköping University [Sweden], have developed the world’s first complementary electrochemical logic circuits that can function stably for long periods in water. This is a highly significant breakthrough in the development of bioelectronics.

A January 11, 2018 Linköping University press release, which originated the news item, notes this latest advance is based on work that started in 2002,

Complementary logic circuitComplementary logic circuit Photo credit: Thor Balkhed

The first printable organic electrochemical transistors were presented by researchers at LiU as early as 2002, and research since then has progressed rapidly. Several organic electronic components, such as light-emitting diodes and electrochromic displays, are already commercially available.

The dominating material used until now has been PEDOT:PSS, which is a p-type material, in which the charge carriers are holes. In order to construct effective electron components, a complementary material, n-type, is required, in which the charge carriers are electrons.
It has been difficult to find a sufficiently stable polymer material, one that can operate in water media and in which the long polymer chains can sustain high current when the material is doped.

N-type material

In an article in the prestigious scientific journal Advanced Materials, Simone Fabiano, head of research in the Organic Nanoelectronics group at the Laboratory of Organic Electronics, presents, together with his colleagues, results from an n-type conducting material in which the ladder-type structure of the polymer backbone favours ambient stability and high current when doped. One example is BBL, poly(benzimidazobenzophenanthroline), a material often used in solar cell research.

Postdoctoral researcher Hengda Sun has found a method to create thick films of the material. The thicker the film, the greater the conductivity.

“We have used spray-coating to produce films up to 200 nm thick. These can reach extremely high conductivities,” says Simone Fabiano.

The method can also be successfully used together with printed electronics across large surfaces.

Hengda Sun has also shown that the circuits function for long periods, both in the presence of oxygen and water.

Moist surroundings

“This may appear at first glance to be a small advance in a specialised field, but what is great about it is that it has major consequences for many applications. We can now construct complementary logic circuits – inverters, sensors and other components – that function in moist surroundings,” says Simone Fabiano.

“Resistors are needed in logical circuits that are based solely on p-type electrochemical transistors. These are rather bulky, and this limits the applications that can be achieved. With an n-type material in our toolbox, we can produce complementary circuits that occupy the available space much more efficiently, since resistors are no longer required in the logical circuits,” says Magnus Berggren, professor of organic electronics and head of the Laboratory for Organic Electronics.

Applications of the organic components include logic circuits that can be printed on textile or paper, various types of cheap sensor, non-rigid and flexible displays, and – not least – the huge field of bioelectronics. Polymers that conduct both ions and electrons are the bridge needed between the ion-conducting systems in the body and the electronic components of, for example, sensors.

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

Complementary Logic Circuits Based on High-Performance n-Type Organic Electrochemical Transistors by Hengda Sun, Mikhail Vagin, Suhao Wang, Xavier Crispin, Robert Forchheimer, Magnus Berggren, and Simone Fabiano. Advanced Materials Vol. 30 Issue 3 Version of Record online: 10 JAN 2018 DOI: 10.1002/adma.201704916

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Bioelectronics: creating components that speak the body’s own language

This is work is still in its early stages but the idea that the body could be stimulated to release more of its own pain relievers is exciting. From a Nov. 2, 2016 news item on ScienceDaily,

With a microfabricated ion pump built from organic electronic components, ions can be sent to nerve or muscle cells at the speed of the nervous system and with a precision of a single cell. “Now we can start to develop components that speak the body’s own language,” says Daniel Simon, head of bioelectronics research at the Laboratory of Organic Electronics, Linköping University, Campus Norrköping.

A Nov. 2, 2016 Linköping University press release (also on EurekAlert), which originated the news item, discusses the research in more detail,

Our nerve and muscle cells send signals to each other using ions and molecules. Certain substances, such as the neurotransmitter GABA (gamma aminobutyric acid), are important signal substances throughout the central nervous system. Eighteen months ago, researchers at the Laboratory of Organic Electronics demonstrated an ion pump which researchers at the Karolinska Institutet could use to reduce the sensation of pain in awake, freely-moving rats. The ion pump delivered GABA directly to the rat´s spinal cord. The news that researchers could deliver the body’s own neurotransmitters was published in Science Advances and garnered intense interest all over the world.

The research group at the Laboratory of Organic Electronics has now achieved another major advance and developed a significantly smaller and more rapid ion pump that transmits signals nearly as rapidly as the cells themselves, and with a precision on the scale of an individual cell. …

“Our skilled doctoral students, Amanda Jonsson and Theresia Arbring Sjöström, have succeeded with the last important part of the puzzle in the development of the ion pump. When a signal passes between two synapses it takes 1-10 milliseconds, and we are now very close to the nervous system’s own speed,” says Magnus Berggren, professor of organic electronics and director of the Laboratory of Organic Electronics.

“We conclude that we have produced artificial nerves that can communicate seamlessly with the nervous system. After more than 10 years’ research we have finally got all the parts of the puzzle in place,” he says.

Amanda Jonsson, who together with Theresia Arbring Sjöström is principal author of the article in Science Advances, has developed the pain-alleviating ion pump as part of her doctoral studies. She proudly presents a glass disk with many of the new miniaturized ion pumps. Some pumps have only a single outlet, but others have six tiny point outlets.

“We can make them with several outlets, it’s just as easy as making one. And all of the outlets can be individually controlled. Previously we could only transport ions horizontally and from all outputs at the same time. Now, however, we can deliver the ions vertically, which makes the distance they have to be transported as short as a micrometre,” she explains.

All of the outputs of the ion pump can also be rapidly switched on or off with the aid of micrometre-sized ion diodes.

“The ions are released rapidly by an electrical signal, in the same way that the neurotransmitter is released in a synapse,” says Theresia Arbring Sjöström.

Organic electronic components have a major advantage here: they can conduct both ions and electricity. In this case, the material PEDOT:PSS enables the electrical signals to be converted to chemical signals that the body understands.

The ion diode has recently been developed, as has the material that forms the basis of the new rapid ion pump.

“The new material makes it possible to build with a precision and reliability not possible in previous versions of the ion pump,” says Daniel Simon.

The new ion pump has so far only been tested in the laboratory. The next step will be to test it with live cells and the researchers hope eventually to, for example alleviate pain, stop epileptic seizures, and reduce the symptoms of Parkinsons disease, using exactly the required dose at exactly the affected cells. Communication using the cell´s own language, and the cell´s own speed.

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

Chemical delivery array with millisecond neurotransmitter release by Amanda Jonsson, Theresia Arbring Sjöström, Klas Tybrandt, Magnus Berggren, and Daniel T. Simon. Science Advances  02 Nov 2016: Vol. 2, no. 11, e1601340 DOI: 10.1126/sciadv.1601340

This paper is open access.

Paper as good at storing electrical energy as commercial supercapacitors

This is another potential nanocellulose application according to a Dec. 3, 2015 news item on ScienceDaily,

Researchers at Linköping University’s Laboratory of Organic Electronics, Sweden, have developed power paper — a new material with an outstanding ability to store energy. The material consists of nanocellulose and a conductive polymer. …

One sheet, 15 centimetres in diameter and a few tenths of a millimetre thick can store as much as 1 F, which is similar to the supercapacitors currently on the market. The material can be recharged hundreds of times and each charge only takes a few seconds.

A Dec. 3, 2015 Linköping University press release (also on EurekAlert), which originated the news item, provides more detail,

It’s a dream product in a world where the increased use of renewable energy requires new methods for energy storage — from summer to winter, from a windy day to a calm one, from a sunny day to one with heavy cloud cover.

“Thin films that function as capacitors have existed for some time. What we have done is to produce the material in three dimensions. We can produce thick sheets,” says Xavier Crispin, professor of organic electronics and co-author to the article just published in Advanced Science.

Other co-authors are researchers from KTH Royal Institute of Technology, Innventia, Technical University of Denmark and the University of Kentucky.

The material, power paper, looks and feels like a slightly plasticky paper and the researchers have amused themselves by using one piece to make an origami swan — which gives an indication of its strength.

The structural foundation of the material is nanocellulose, which is cellulose fibres which, using high-pressure water, are broken down into fibres as thin as 20 nm in diameter. With the cellulose fibres in a solution of water, an electrically charged polymer (PEDOT:PSS), also in a water solution, is added. The polymer then forms a thin coating around the fibres.

“The covered fibres are in tangles, where the liquid in the spaces between them functions as an electrolyte,” explains Jesper Edberg, doctoral student, who conducted the experiments together with Abdellah Malti, who recently completed his doctorate.

The new cellulose-polymer material has set a new world record in simultaneous conductivity for ions and electrons, which explains its exceptional capacity for energy storage. It also opens the door to continued development toward even higher capacity. Unlike the batteries and capacitors currently on the market, power paper is produced from simple materials – renewable cellulose and an easily available polymer. It is light in weight, it requires no dangerous chemicals or heavy metals and it is waterproof.

This press release also offers insight into funding and how scientists view requests for reports and oversight,

The Power Papers project has been financed by the Knut and Alice Wallenberg Foundation since 2012.

“They leave us to our research, without demanding lengthy reports, and they trust us. We have a lot of pressure on us to deliver, but it’s ok if it takes time, and we’re grateful for that,” says Professor Magnus Berggren, director of the Laboratory of Organic Electronics at Linköping University.

Naturally, commercialization efforts are already in the works. (Canadian nanocellulose community watch out! The Swedes are coming!),

The new power paper is just like regular pulp, which has to be dehydrated when making paper. The challenge is to develop an industrial-scale process for this.

“Together with KTH, Acreo and Innventia we just received SEK 34 million from the Swedish Foundation for Strategic Research to continue our efforts to develop a rational production method, a paper machine for power paper,” says Professor Berggren.

Here’s a link to and a citation for the team’s study,

An Organic Mixed Ion–Electron Conductor for Power Electronics by Abdellah Malti, Jesper Edberg, Hjalmar Granberg, Zia Ullah Khan, Jens W. Andreasen, Xianjie Liu, Dan Zhao, Hao Zhang, Yulong Yao, Joseph W. Brill, Isak Engquist, Mats Fahlman, Lars Wågberg, Xavier Crispin, and Magnus Berggren. Advanced Science DOI: 10.1002/advs.201500305 Article first published online: 2 DEC 2015

© 2015 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is open access.

Researchers at Karolinska Institute (Sweden) build an artificial neuron

Unlike my post earlier today (June 26, 2015) about BrainChip, this is not about neuromorphic engineering (artificial brain), although I imagine this new research from the Karolinska Institute (Institutet) will be of some interest to that community. This research was done in the interest of developing* therapeutic interventions for brain diseases. One aspect of this news item/press release I find particularly interesting is the insistence that “no living parts” were used to create the artificial neuron,

A June 24, 2015 news item on ScienceDaily describes what the artificial neuron can do,

Scientists have managed to build a fully functional neuron by using organic bioelectronics. This artificial neuron contain [sic] no ‘living’ parts, but is capable of mimicking the function of a human nerve cell and communicate in the same way as our own neurons do. [emphasis mine]

A June 24, 2015 Karolinska Institute press release (also on EurekAlert), which originated the news item, describes how neurons communicate in the brain, standard techniques for stimulating neuronal cells, and the scientists’ work on a technique to improve stimulation,

Neurons are isolated from each other and communicate with the help of chemical signals, commonly called neurotransmitters or signal substances. Inside a neuron, these chemical signals are converted to an electrical action potential, which travels along the axon of the neuron until it reaches the end. Here at the synapse, the electrical signal is converted to the release of chemical signals, which via diffusion can relay the signal to the next nerve cell.

To date, the primary technique for neuronal stimulation in human cells is based on electrical stimulation. However, scientists at the Swedish Medical Nanoscience Centre (SMNC) at Karolinska Institutet in collaboration with collegues at Linköping University, have now created an organic bioelectronic device that is capable of receiving chemical signals, which it can then relay to human cells.

“Our artificial neuron is made of conductive polymers and it functions like a human neuron,” says lead investigator Agneta Richter-Dahlfors, professor of cellular microbiology. “The sensing component of the artificial neuron senses a change in chemical signals in one dish, and translates this into an electrical signal. This electrical signal is next translated into the release of the neurotransmitter acetylcholine in a second dish, whose effect on living human cells can be monitored.”

The research team hope that their innovation, presented in the journal Biosensors & Bioelectronics, will improve treatments for neurologial disorders which currently rely on traditional electrical stimulation. The new technique makes it possible to stimulate neurons based on specific chemical signals received from different parts of the body. In the future, this may help physicians to bypass damaged nerve cells and restore neural function.

“Next, we would like to miniaturize this device to enable implantation into the human body,” says Agneta Richer-Dahlfors. “We foresee that in the future, by adding the concept of wireless communication, the biosensor could be placed in one part of the body, and trigger release of neurotransmitters at distant locations. Using such auto-regulated sensing and delivery, or possibly a remote control, new and exciting opportunities for future research and treatment of neurological disorders can be envisaged.”

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

An organic electronic biomimetic neuron enables auto-regulated neuromodulation by Daniel T. Simon, Karin C. Larsson, David Nilsson, Gustav Burström, b, Dagmar Galter, Magnus Berggren, and Agneta Richter-Dahlfors. Biosensors and Bioelectronics Volume 71, 15 September 2015, Pages 359–364         doi:10.1016/j.bios.2015.04.058

This paper is behind a paywall.

As to anyone (other than myself) who may be curious about exactly what they used (other than “living parts”) to create an artificial neuron, there’s the paper’s abstract,

Current therapies for neurological disorders are based on traditional medication and electric stimulation. Here, we present an organic electronic biomimetic neuron, with the capacity to precisely intervene with the underlying malfunctioning signalling pathway using endogenous substances. The fundamental function of neurons, defined as chemical-to-electrical-to-chemical signal transduction, is achieved by connecting enzyme-based amperometric biosensors and organic electronic ion pumps. Selective biosensors transduce chemical signals into an electric current, which regulates electrophoretic delivery of chemical substances without necessitating liquid flow. Biosensors detected neurotransmitters in physiologically relevant ranges of 5–80 µM, showing linear response above 20 µm with approx. 0.1 nA/µM slope. When exceeding defined threshold concentrations, biosensor output signals, connected via custom hardware/software, activated local or distant neurotransmitter delivery from the organic electronic ion pump. Changes of 20 µM glutamate or acetylcholine triggered diffusive delivery of acetylcholine, which activated cells via receptor-mediated signalling. This was observed in real-time by single-cell ratiometric Ca2+ imaging. The results demonstrate the potential of the organic electronic biomimetic neuron in therapies involving long-range neuronal signalling by mimicking the function of projection neurons. Alternatively, conversion of glutamate-induced descending neuromuscular signals into acetylcholine-mediated muscular activation signals may be obtained, applicable for bridging injured sites and active prosthetics.

While it’s true neither are “living parts,” I believe both enzymes and organic electronic ion pumps can be found in biological organisms. The insistence on ‘nonliving’ in the press release suggests that scientists in Europe, if nowhere else, are still quite concerned about any hint that they are working on genetically modified organisms (GMO). It’s ironic when you consider that people blithely use enzyme-based cleaning and beauty products but one can appreciate the* scientists’ caution.

* ‘develop’ changed to ‘developing’ and ‘the’ added on July 3, 2015.

Electronic organic micropump for direct drug delivery to the brain

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.

###

[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.