Tag Archives: Jonathan Rivnay

Implantable living pharmacy

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I stumbled across a very interesting US Defense Advanced Research Projects Agency (DARPA) project (from an August 30, 2021 posting on Northwestern University’s Rivnay Lab [a laboratory for organic bioelectronics] blog),

Our lab has received a cooperative agreement with DARPA to develop a wireless, fully implantable ‘living pharmacy’ device that could help regulate human sleep patterns. The project is through DARPA’s BTO (biotechnology office)’s Advanced Acclimation and Protection Tool for Environmental Readiness (ADAPTER) program, meant to address physical challenges of travel, such as jetlag and fatigue.

The device, called NTRAIN (Normalizing Timing of Rhythms Across Internal Networks of Circadian Clocks), would control the body’s circadian clock, reducing the time it takes for a person to recover from disrupted sleep/wake cycles by as much as half the usual time.

The project spans 5 institutions including Northwestern, Rice University, Carnegie Mellon, University of Minnesota, and Blackrock Neurotech.

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Prior to the Aug. 30, 2021 posting, Amanda Morris wrote a May 13, 2021 article for Northwestern NOW (university magazine), which provides more details about the project, Note: A link has been removed,

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The first phase of the highly interdisciplinary program will focus on developing the implant. The second phase, contingent on the first, will validate the device. If that milestone is met, then researchers will test the device in human trials, as part of the third phase. The full funding corresponds to $33 million over four-and-a-half years. 

Nicknamed the “living pharmacy,” the device could be a powerful tool for military personnel, who frequently travel across multiple time zones, and shift workers including first responders, who vacillate between overnight and daytime shifts.

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Combining synthetic biology with bioelectronics, the team will engineer cells to produce the same peptides that the body makes to regulate sleep cycles, precisely adjusting timing and dose with bioelectronic controls. When the engineered cells are exposed to light, they will generate precisely dosed peptide therapies. 

“This control system allows us to deliver a peptide of interest on demand, directly into the bloodstream,” said Northwestern’s Jonathan Rivnay, principal investigator of the project. “No need to carry drugs, no need to inject therapeutics and — depending on how long we can make the device last — no need to refill the device. It’s like an implantable pharmacy on a chip that never runs out.” 

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Beyond controlling circadian rhythms, the researchers believe this technology could be modified to release other types of therapies with precise timing and dosing for potentially treating pain and disease. The DARPA program also will help researchers better understand sleep/wake cycles, in general.

“The experiments carried out in these studies will enable new insights into how internal circadian organization is maintained,” said Turek [Fred W. Turek], who co-leads the sleep team with Vitaterna [Martha Hotz Vitaterna]. “These insights will lead to new therapeutic approaches for sleep disorders as well as many other physiological and mental disorders, including those associated with aging where there is often a spontaneous breakdown in temporal organization.” 

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For those who like to dig even deeper, Dieynaba Young’s June 17, 2021 article for Smithsonian Magazine (GetPocket.com link to article) provides greater context and greater satisfaction, Note: Links have been removed,

In 1926, Fritz Kahn completed Man as Industrial Palace, the preeminent lithograph in his five-volume publication The Life of Man. The illustration shows a human body bustling with tiny factory workers. They cheerily operate a brain filled with switchboards, circuits and manometers. Below their feet, an ingenious network of pipes, chutes and conveyer belts make up the blood circulatory system. The image epitomizes a central motif in Kahn’s oeuvre: the parallel between human physiology and manufacturing, or the human body as a marvel of engineering.

An apparatus in the embryonic stage of development at the time of this writing in June of 2021—the so-called “implantable living pharmacy”—could have easily originated in Kahn’s fervid imagination. The concept is being developed by the Defense Advanced Research Projects Agency (DARPA) in conjunction with several universities, notably Northwestern and Rice. Researchers envision a miniaturized factory, tucked inside a microchip, that will manufacture pharmaceuticals from inside the body. The drugs will then be delivered to precise targets at the command of a mobile application. …

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The implantable living pharmacy, which is still in the “proof of concept” stage of development, is actually envisioned as two separate devices—a microchip implant and an armband. The implant will contain a layer of living synthetic cells, along with a sensor that measures temperature, a short-range wireless transmitter and a photo detector. The cells are sourced from a human donor and reengineered to perform specific functions. They’ll be mass produced in the lab, and slathered onto a layer of tiny LED lights.

The microchip will be set with a unique identification number and encryption key, then implanted under the skin in an outpatient procedure. The chip will be controlled by a battery-powered hub attached to an armband. That hub will receive signals transmitted from a mobile app.

If a soldier wishes to reset their internal clock, they’ll simply grab their phone, log onto the app and enter their upcoming itinerary—say, a flight departing at 5:30 a.m. from Arlington, Virginia, and arriving 16 hours later at Fort Buckner in Okinawa, Japan. Using short-range wireless communications, the hub will receive the signal and activate the LED lights inside the chip. The lights will shine on the synthetic cells, stimulating them to generate two compounds that are naturally produced in the body. The compounds will be released directly into the bloodstream, heading towards targeted locations, such as a tiny, centrally-located structure in the brain called the suprachiasmatic nucleus (SCN) that serves as master pacemaker of the circadian rhythm. Whatever the target location, the flow of biomolecules will alter the natural clock. When the solider arrives in Okinawa, their body will be perfectly in tune with local time.

The synthetic cells will be kept isolated from the host’s immune system by a membrane constructed of novel biomaterials, allowing only nutrients and oxygen in and only the compounds out. Should anything go wrong, they would swallow a pill that would kill the cells inside the chip only, leaving the rest of their body unaffected.

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If you have the time, I recommend reading Young’s June 17, 2021 Smithsonian Magazine article (GetPocket.com link to article) in its entirety. Young goes on to discuss, hacking, malware, and ethical/societal issues and more.

There is an animation of Kahn’s original poster in a June 23, 2011 posting on openculture.com (also found on Vimeo; Der Mensch als Industriepalast [Man as Industrial Palace])

Credits: Idea & Animation: Henning M. Lederer / led-r-r.net; Sound-Design: David Indge; and original poster art: Fritz Kahn.

Synaptic transistor better then memristor when it comes to brainlike learning for computers

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An April 30, 2021 news item on Nanowerk announced research from a joint team at Northwestern University (located in Chicago, Illinois, US) and University of Hong Kong of researchers in the field of neuromorphic (brainlike) computing,

Researchers have developed a brain-like computing device that is capable of learning by association.

Similar to how famed physiologist Ivan Pavlov conditioned dogs to associate a bell with food, researchers at Northwestern University and the University of Hong Kong successfully conditioned their circuit to associate light with pressure.

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The device’s secret lies within its novel organic, electrochemical “synaptic transistors,” which simultaneously process and store information just like the human brain. The researchers demonstrated that the transistor can mimic the short-term and long-term plasticity of synapses in the human brain, building on memories to learn over time.

With its brain-like ability, the novel transistor and circuit could potentially overcome the limitations of traditional computing, including their energy-sapping hardware and limited ability to perform multiple tasks at the same time. The brain-like device also has higher fault tolerance, continuing to operate smoothly even when some components fail.

“Although the modern computer is outstanding, the human brain can easily outperform it in some complex and unstructured tasks, such as pattern recognition, motor control and multisensory integration,” said Northwestern’s Jonathan Rivnay, a senior author of the study. “This is thanks to the plasticity of the synapse, which is the basic building block of the brain’s computational power. These synapses enable the brain to work in a highly parallel, fault tolerant and energy-efficient manner. In our work, we demonstrate an organic, plastic transistor that mimics key functions of a biological synapse.”

Rivnay is an assistant professor of biomedical engineering at Northwestern’s McCormick School of Engineering. He co-led the study with Paddy Chan, an associate professor of mechanical engineering at the University of Hong Kong. Xudong Ji, a postdoctoral researcher in Rivnay’s group, is the paper’s first author.

Caption: By connecting single synaptic transistors into a neuromorphic circuit, researchers demonstrated that their device could simulate associative learning. Credit: Northwestern University

An April 30, 2021 Northwestern University news release (also on EurekAlert), which originated the news item, includes a good explanation about brainlike computing and information about how synaptic transistors work along with some suggestions for future applications,

Conventional, digital computing systems have separate processing and storage units, causing data-intensive tasks to consume large amounts of energy. Inspired by the combined computing and storage process in the human brain, researchers, in recent years, have sought to develop computers that operate more like the human brain, with arrays of devices that function like a network of neurons.

“The way our current computer systems work is that memory and logic are physically separated,” Ji said. “You perform computation and send that information to a memory unit. Then every time you want to retrieve that information, you have to recall it. If we can bring those two separate functions together, we can save space and save on energy costs.”

Currently, the memory resistor, or “memristor,” is the most well-developed technology that can perform combined processing and memory function, but memristors suffer from energy-costly switching and less biocompatibility. These drawbacks led researchers to the synaptic transistor — especially the organic electrochemical synaptic transistor, which operates with low voltages, continuously tunable memory and high compatibility for biological applications. Still, challenges exist.

“Even high-performing organic electrochemical synaptic transistors require the write operation to be decoupled from the read operation,” Rivnay said. “So if you want to retain memory, you have to disconnect it from the write process, which can further complicate integration into circuits or systems.”

How the synaptic transistor works

To overcome these challenges, the Northwestern and University of Hong Kong team optimized a conductive, plastic material within the organic, electrochemical transistor that can trap ions. In the brain, a synapse is a structure through which a neuron can transmit signals to another neuron, using small molecules called neurotransmitters. In the synaptic transistor, ions behave similarly to neurotransmitters, sending signals between terminals to form an artificial synapse. By retaining stored data from trapped ions, the transistor remembers previous activities, developing long-term plasticity.

The researchers demonstrated their device’s synaptic behavior by connecting single synaptic transistors into a neuromorphic circuit to simulate associative learning. They integrated pressure and light sensors into the circuit and trained the circuit to associate the two unrelated physical inputs (pressure and light) with one another.

Perhaps the most famous example of associative learning is Pavlov’s dog, which naturally drooled when it encountered food. After conditioning the dog to associate a bell ring with food, the dog also began drooling when it heard the sound of a bell. For the neuromorphic circuit, the researchers activated a voltage by applying pressure with a finger press. To condition the circuit to associate light with pressure, the researchers first applied pulsed light from an LED lightbulb and then immediately applied pressure. In this scenario, the pressure is the food and the light is the bell. The device’s corresponding sensors detected both inputs.

After one training cycle, the circuit made an initial connection between light and pressure. After five training cycles, the circuit significantly associated light with pressure. Light, alone, was able to trigger a signal, or “unconditioned response.”

Future applications

Because the synaptic circuit is made of soft polymers, like a plastic, it can be readily fabricated on flexible sheets and easily integrated into soft, wearable electronics, smart robotics and implantable devices that directly interface with living tissue and even the brain [emphasis mine].

“While our application is a proof of concept, our proposed circuit can be further extended to include more sensory inputs and integrated with other electronics to enable on-site, low-power computation,” Rivnay said. “Because it is compatible with biological environments, the device can directly interface with living tissue, which is critical for next-generation bioelectronics.”

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

Mimicking associative learning using an ion-trapping non-volatile synaptic organic electrochemical transistor by Xudong Ji, Bryan D. Paulsen, Gary K. K. Chik, Ruiheng Wu, Yuyang Yin, Paddy K. L. Chan & Jonathan Rivnay . Nature Communications volume 12, Article number: 2480 (2021) DOI: https://doi.org/10.1038/s41467-021-22680-5 Published: 30 April 2021

This paper is open access.

“… devices that directly interface with living tissue and even the brain,” would I be the only one thinking about cyborgs?

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.