Category Archives: medicine

Xenobots (living robots) that can reproduce

Xenobots (living robots made from African frog (Xenopus laevis) frog cells) can now self-replicate. First mentioned here in a June 21, 2021 posting, xenobots have captured the imagination of various media outlets including the Canadian Broadcasting Corporation’s (CBC) Quirks and Quarks radio programme and blog where Amanda Buckiewicz posted a December 3, 2021 article about the latest xenobot development (Note: Links have been removed),

In a new study, Bongard [Joshua Bongard, a computer scientist at the University of Vermont] and his colleagues from Tufts University and Harvard’s Wyss Institute for Biologically Inspired Engineering found that the xenobots would autonomously collect loose single cells in their environment, gathering hundreds of cells together until new xenobots had formed.

“This took a little bit for us to wrap our minds around,” he said. “There’s no programming here. Instead, we’re designing or shaping these xenobots, and what they do, the way they behave, is based on shape.”

“We take a couple of thousand of those frog cells and we squish them together into a ball and put that in the bottom of a petri dish,” Bongard told Quirks & Quarks host Bob McDonald. 

“If you were to look into the dish, you would see some very small, what look like specks of pepper, moving about in the bottom of the petri dish.”

The xenobots initially received no instruction from humans on how to replicate. But when researchers added extra cells to the dish containing xenobots, they observed that the xenobots would assemble them into piles.

“Cells early in development are sticky,” said Bongard. “If the pile is large enough and the cells stick together, the outer ones on the surface will grow very small hairs, which are called cilia. And eventually, after four days, those cilia will start to beat back and forth like flexible oars, and the pile will start moving.”

“And that’s a child xenobot.” 

A November 29, 2021 Wyss Institute news release by Joshua Brown describes the process a little differently,

To persist, life must reproduce. Over billions of years, organisms have evolved many ways of replicating, from budding plants to sexual animals to invading viruses.

Now scientists at the University of Vermont, Tufts University, and the Wyss Institute for Biologically Inspired Engineering at Harvard University have discovered an entirely new form of biological reproduction—and applied their discovery to create the first-ever, self-replicating living robots.

The same team that built the first living robots (“Xenobots,” assembled from frog cells—reported in 2020) has discovered that these computer-designed and hand-assembled organisms can swim out into their tiny dish, find single cells, gather hundreds of them together, and assemble “baby” Xenobots inside their Pac-Man-shaped “mouth”—that, a few days later, become new Xenobots that look and move just like themselves.

And then these new Xenobots can go out, find cells, and build copies of themselves. Again and again.

In a Xenopus laevis frog, these embryonic cells would develop into skin. “They would be sitting on the outside of a tadpole, keeping out pathogens and redistributing mucus,” says Michael Levin, Ph.D., a professor of biology and director of the Allen Discovery Center at Tufts University and co-leader of the new research. “But we’re putting them into a novel context. We’re giving them a chance to reimagine their multicellularity.” Levin is also an Associate Faculty member at the Wyss Institute.

And what they imagine is something far different than skin. “People have thought for quite a long time that we’ve worked out all the ways that life can reproduce or replicate. But this is something that’s never been observed before,” says co-author Douglas Blackiston, Ph.D., the senior scientist at Tufts University and the Wyss Institute who assembled the Xenobot “parents” and developed the biological portion of the new study.

“This is profound,” says Levin. “These cells have the genome of a frog, but, freed from becoming tadpoles, they use their collective intelligence, a plasticity, to do something astounding.” In earlier experiments, the scientists were amazed that Xenobots could be designed to achieve simple tasks. Now they are stunned that these biological objects—a computer-designed collection of cells—will spontaneously replicate. “We have the full, unaltered frog genome,” says Levin, “but it gave no hint that these cells can work together on this new task,” of gathering and then compressing separated cells into working self-copies.

“These are frog cells replicating in a way that is very different from how frogs do it. No animal or plant known to science replicates in this way,” says Sam Kriegman, Ph.D.,  the lead author on the new study, who completed his Ph.D. in Bongard’s lab at UVM and is now a post-doctoral researcher at Tuft’s Allen Center and Harvard University’s Wyss Institute for Biologically Inspired Engineering.

Both Buckiewicz’s December 3, 2021 article and Brown’s November 29, 2021 Wyss Institute news release are good reads with liberal used of embedded images. If you have time, start with Buckiewicz as she provides a good introduction and follow up with Brown who gives more detail and has an embedded video of a December 1, 2021 panel discussion with the scientists behind the xenobots.

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

Kinematic self-replication in reconfigurable organisms by Sam Kriegman, Douglas Blackiston, Michael Levin, and Josh Bongard. PNAS [Proceedings of the National Academy of Sciences] December 7, 2021 118 (49) e2112672118; https://doi.org/10.1073/pnas.2112672118

This paper appears to be open access.

Optimizing mRNA nanoparticles

The process of continuously working on scientific improvements is not always appreciated by outsiders such as myself. A December 28, 2021 news item on Nanowerk highlights research published (from 2019 and 2020) on improving delivery of mRNA used in vaccines (Note: A link has been removed),

The research neutron source Hein Maier-Leibnitz (FRM II) at the Technical University of Munich (TUM) is playing an important role in the investigation of mRNA nanoparticles similar to the ones used in the Covid-19 vaccines from vendors BioNTech and Moderna. Researchers at the Heinz Maier-Leibnitz Zentrum (MLZ) used the high neutron flux available in Garching to characterize various formulations for the mRNA vaccine and thus to lay the groundwork for improving the vaccine’s efficacy.

A December 27, 2021 TUM press release, which originated the news item, delves further into the science of improving something that already works well,

The idea of using messenger RNA (mRNA) as an active ingredient is a brilliant one: The molecule contains the specific blueprint for proteins which are then synthesize by the cell. This makes it generally possible to provide a very wide spectrum of different therapeutically effective proteins.

In the case of the Covid-19 vaccine, these are the proteins of the characteristic spikes on the surface of the Corona virus which are used for vaccination. The proteins are presented on the surface of immune cells; then the human immune system triggers defenses against these foreign proteins and thus against the Corona virus. The mRNA itself is completely broken down after only a few hours, a fact which is advantageous to the safety of these vaccines.

The road to the best packaging

The mRNA has to be packaged appropriately in order to keep it from being broken down on the way to the cell by the ubiquitous enzymes of the human body. This is done using nanoparticles which can consist of a mixture of lipids or polymers.

The lipids are fat molecules similar to the molecules of the cell membrane and help deposit the mRNA in the interior of the cell. Lipids and biopolymers are then broken down or excreted by the body.

To this ends, the BioNTech formulation team led by Dr. Heinrich Haas worked together with the group led by Prof. Peter Langguth of the Pharmaceutical Technology department at the Johannes Gutenberg University Mainz’s Institute of Pharmaceutical and Biomedical Sciences. They developed a series of formulations in which the nanoparticles consisted of various mixtures of lipids and biopolymers already proved in pharmaceuticals.

In the light of neutrons

In order to compare the properties of variously composed nanoparticles with one another, the researchers subjected the nanoparticles to a wide range of investigations. In addition to x-ray and microscopic analyses, these investigations included radiation with neutrons using the instrument KWS-2, operated by the Forschungszentrum Jülich at the FRM II of the Technical University of Munich in Garching.

The neutrons are scattered in the interior of the nanoparticles, inter alia, on the hydrogen nuclei and are deflected from their paths in a characteristic way. This is the basis for conclusions about their distribution. If the hydrogen atoms of certain components – for example of the lipids only – are exchanged with heavy hydrogen, the chemical properties and the pharmaceutical efficacy do not change, but the scattering pattern of the neutrons does.

“This method makes it possible to selectively highlight parts of a complex multi-component morphology without changing the physical chemistry of the sample,” says Dr. Aurel Radulescu of the Jülich Centre for Neutron Science (JCNS), who is responsible for the instrument KWS-2 and who led the evaluation of the measurement results. “This makes it possible to depict structural properties which other methods can only barely render visible, if at all.”

The right degree of order is the key

In these analyses the research teams were interested in how efficiently the various formulations were able to transmit the mRNA into the cell, referred to as transfection. The researchers thus found out that the highest transfection rates were achieved with nanoparticles that are characterized by a certain type of internal arrangement.

“High levels of biological activity were registered whenever ordered and less ordered areas alternated in the interior of the nanoparticles in a characteristic manner. This could be a generally valid concept of structure-activity relationship which can be applied independently of the systems investigated here,” Dr. Heinrich Haas of BioNTech points out. A similarly low degree of order had also been found previously by the research teams using x-ray radiation in other lipid nanoparticles.

An improved procedure

In order to receive the desired structural properties lipids and biopolymers had to be combined with the mRNA using exactly defined procedures. Here the research team was able to show that the nanoparticles for packaging the mRNA could be produced in a single step, which means a significant simplification compared to the two-step procedure which was originally also investigated.

Thus a simplified method for the creation of mRNA nanoparticles with improved activity was ultimately found. “Such questions of practical producibility represent an important prerequisite for the possibility of developing pharmaceutical products,” says Prof. Langguth. In the future such concepts could be taken into account in the development of new mRNA-based therapeutic agents.

Here are links to and citations for the papers (Note: This is not my usual way of setting the links),

Hybrid Biopolymer and Lipid Nanoparticles with Improved Transfection Efficacy for mRNA by Christian D. Siewert, Heinrich Haas, Vera Cornet, Sara S. Nogueira, Thomas Nawroth, Lukas Uebbing, Antje Ziller, Jozef Al-Gousous, Aurel Radulescu, Martin A. Schroer, Clement E. Blanchet, Dmitri I. Svergun, Markus P. Radsak, Ugur Sahin and Peter Langguth. Cells 2020, 9(9), 2034 – DOI: 10.3390/cells9092034

This paper appears to be open access.

Investigation of charge ratio variation in mRNA – DEAE-dextran polyplex delivery systems by C. Siewert, H. Haas, T. Nawroth, A. Ziller, S. S. Nogueira, M. A. Schroer, C. E. Blanchet, D. I. Svergun, A. Radulescu, F. Bates, Y. Huesemann, M. P. Radsak, U. Sahin, P. Langguth. Biomaterials, 2019; DOI: 10.1016/j.biomaterials.2018.10.020

This paper is open access.

Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery by S S. Nogueira, A. Schlegel, K. Maxeiner, B. Weber, M. Barz, M. A. Schroer, C. E. Blanchet, D. I. Svergun, S. Ramishetti, D. Peer, P. Langguth, U. Sahin, H. Haas. ACS Appl. Nano Mater. 2020, 3, 11, 10634–10645 – DOI: 10.1021/acsanm.0c01834

This paper is behind a paywall.

Whimsy and nanoscienists

Mohsen Hosseini and William Ducker’s contest-winning image, titled “Lotus on Anti-SARS-CoV-2 Coating.” [downloaded from https://vtx.vt.edu/articles/2021/12/nnci-image-contest.html]

Not everything is as it seems in this image according to a January 5, 2022 news item on phys.org (Note: Links have been removed),

At extremely small scales, looks can be deceiving. While at first glance you might see lily pads floating on a tranquil pond, this image is actually a clever adaptation of a snapshot taken on a scanning electron microscope.

In reality, the green spots are only a few micrometers across—smaller than width of a human hair. They make up a surface coating that was developed to limit the transmission of SARS-CoV-2, the virus that causes COVID-19. The coating is composed of a silver-based material applied to a glass surface. The lotus flower, though, was some added artistic flair courtesy of image-editing software.

A January 4, 2022 Virginia Tech news release, which originated the news item, provides more details about the ‘whimsical’ researchers, the image contest, and the research that led to their entry,

Mohsen Hosseini, Ph.D. candidate in chemical engineering, and William Ducker, professor of chemical engineering, recently won an award in the National Nanotechnology Coordinated Infrastructure (NNCI) image contest with this image. Both Hosseini and Ducker are affiliated with the Macromolecules Innovation Institute (MII).

Their win was in the category “most whimsical.”

“As part of the rigor involved in scientific research, I am always careful to maintain the accuracy of my original results,” said Hosseini. “However, this competition was very freeing. It gave me a chance to take my scanning electron microscopy results and legitimately alter it in any way that I chose. It was liberating and fun to express my artistic style. The result isn’t a Monet, but I am glad people liked it.”

The image contest, titled “Plenty of Beauty at the Bottom,” is hosted annually by NNCI in celebration of National Nano Day, which occurred on Oct. 9, 2021. Funded by the National Science Foundation, the NNCI is a network of 16 sites around the country that are dedicated to supporting nanoscience and nanotechnology research and development. Virginia Tech’s NanoEarth center is part of that network, working to advance earth and environmental nanotechnology infrastructure. This image was captured using a scanning electron microscope (SEM) that is part of the Nanoscale Characterization and Fabrication Laboratory (NCFL) in the Virginia Tech Corporate Research Center. This SEM is the latest addition to the instrument suite at the NCFL, which is an initiative of the Institute for Critical Technology and Applied Science. The NCFL gives researchers across the University access to advanced instrumentation including state-of-the-art electron microscopes, optical microscopes, and several spectroscopic techniques.

The development of the protective surface coating began more than a year ago, when the coronavirus pandemic was in its early stages. Working on a team that included another doctoral student, Saeed Behzadinasab, the researchers’ goal was to find a way to prevent the spread of COVID-19 via contaminated surfaces. The coating they produced can successfully inactivate the virus (SARS-CoV-2) when it lands on a solid surface, so that when a person later touches the surface, the virus is unable to infect them.

In studying how their surface coating behaves and performs, the researchers captured images of it at the micro scale. Hosseini explained, “The NNCI contest invitation motivated me to select one of the scanning electron microscope images of my coatings, and edit it according to the contest’s criteria. My brain was filled with ideas since I had recently designed a front cover that was awarded to our paper published in ACS Biomaterials Science & Engineering. I came up with a lotus idea in minutes and that worked very well.”

Interestingly, the researchers had originally developed a brown coating that showed a great deal of promise. However, after conducting tests with consumers, it became clear that the public would be more likely to use a coating that was clear, instead of brown. Ducker’s research group was inspired to produce another coating, which this time would be transparent. As Hosseini put it, “It’s ironic that the invisible coating ended up being the subject of visual art, and even got an award for it.”

Ducker and Hosseini teamed up with Joseph Falkinham and Myra Williams from the Department of Biological Sciences to test the coating on a variety of other illness-causing microorganisms. It proved particularly effective against several bacteria including MRSA, a troublesome antibiotic-resistant bacterium that plagues hospitals.

With its transparent appearance and its broad antimicrobial effectiveness, the coating is now a strong candidate for commercialization. Indeed, Ducker has founded a company dedicated to pursuing the production of this surface coating on a larger scale.

Hosseini and Ducker are proud to have their image shared with the national nanoscience community. The recognition shows an appreciation for their hard work, in addition to their whimsical perspective. According to NanoEarth assistant director Tonya Pruitt, “Virginia Tech has had some excellent submissions to the NNCI image contest over the years, but this is the first year we’ve had a winner!”

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

Reduction of Infectivity of SARS-CoV-2 by Zinc Oxide Coatings by Mohsen Hosseini, Saeed Behzadinasab, Alex W.H. Chin, Leo L.M. Poon, and William A. Ducker. ACS Biomater. Sci. Eng. 2021, 7, 11, 5022–5027 DOI: https://doi.org/10.1021/acsbiomaterials.1c01076 Publication Date:October 6, 2021 Copyright © 2021 American Chemical Society

This paper is behind a paywall.

You can find the other winners and honorable mentions of the NNCI Image Contest 2021 here. The contest is also known as “Plenty of Beauty at the Bottom” in honour of Richard Feynman and his 1959 lecture, “There’s plenty of room at the bottom.”

The NNCI website can be found here.

Transformational machine learning (TML)

It seems machine learning is getting a tune-up. A November 29, 2021 news item on ScienceDaily describes research into improving machine learning from an international team of researchers,

Researchers have developed a new approach to machine learning that ‘learns how to learn’ and out-performs current machine learning methods for drug design, which in turn could accelerate the search for new disease treatments.

The method, called transformational machine learning (TML), was developed by a team from the UK, Sweden, India and Netherlands. It learns from multiple problems and improves performance while it learns.

A November 29, 2021 University of Cambridge press release (also on EurekAlert), which originated the news item, describes the potential this new technique may have on drug discovery and more,

TML could accelerate the identification and production of new drugs by improving the machine learning systems which are used to identify them. The results are reported in the Proceedings of the National Academy of Sciences.

Most types of machine learning (ML) use labelled examples, and these examples are almost always represented in the computer using intrinsic features, such as the colour or shape of an object. The computer then forms general rules that relate the features to the labels.

“It’s sort of like teaching a child to identify different animals: this is a rabbit, this is a donkey and so on,” said Professor Ross King from Cambridge’s Department of Chemical Engineering and Biotechnology, who led the research. “If you teach a machine learning algorithm what a rabbit looks like, it will be able to tell whether an animal is or isn’t a rabbit. This is the way that most machine learning works – it deals with problems one at a time.”

However, this is not the way that human learning works: instead of dealing with a single issue at a time, we get better at learning because we have learned things in the past.

“To develop TML, we applied this approach to machine learning, and developed a system that learns information from previous problems it has encountered in order to better learn new problems,” said King, who is also a Fellow at The Alan Turing Institute. “Where a typical ML system has to start from scratch when learning to identify a new type of animal – say a kitten – TML can use the similarity to existing animals: kittens are cute like rabbits, but don’t have long ears like rabbits and donkeys. This makes TML a much more powerful approach to machine learning.”

The researchers demonstrated the effectiveness of their idea on thousands of problems from across science and engineering. They say it shows particular promise in the area of drug discovery, where this approach speeds up the process by checking what other ML models say about a particular molecule. A typical ML approach will search for drug molecules of a particular shape, for example. TML instead uses the connection of the drugs to other drug discovery problems.

“I was surprised how well it works – better than anything else we know for drug design,” said King. “It’s better at choosing drugs than humans are – and without the best science, we won’t get the best results.”

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

Transformational machine learning: Learning how to learn from many related scientific problems by Ivan Olier, Oghenejokpeme I. Orhobor, Tirtharaj Dash, Andy M. Davis, Larisa N. Soldatova, Joaquin Vanschoren, and Ross D. King. PNAS December 7, 2021 118 (49) e2108013118; DOI: https://doi.org/10.1073/pnas.2108013118

This paper appears to be open access.

Brain surgery with no scalpel or incisions

A December 3, 2021 news item on ScienceDaily announces some very exciting work from the University of Virginia UVA) and Stanford University,

University of Virginia School of Medicine researchers have developed a noninvasive way to remove faulty brain circuits that could allow doctors to treat debilitating neurological diseases without the need for conventional brain surgery.

The UVA team, together with colleagues at Stanford University, indicate that the approach, if successfully translated to the operating room, could revolutionize the treatment of some of the most challenging and complex neurological diseases, including epilepsy, movement disorders and more. The approach uses low-intensity focused ultrasound waves combined with microbubbles to briefly penetrate the brain’s natural defenses and allow the targeted delivery of a neurotoxin. This neurotoxin kills the culprit brain cells while sparing other healthy cells and preserving the surrounding brain architecture.

A November 22, 2021 University of Virginia news release (also on EurekAlert but published on December 3, 2021), which originated the news item, offers technical details (Note: Links have been removed),

“This novel surgical strategy has the potential to supplant existing neurosurgical procedures used for the treatment of neurological disorders that don’t respond to medication,” said researcher Kevin S. Lee of UVA’s Departments of Neuroscience and Neurosurgery and the Center for Brain Immunology and Glia, or BIG. “This unique approach eliminates the diseased brain cells, spares adjacent healthy cells and achieves these outcomes without even having to cut into the scalp.”

The Power of PING

The new approach, called “PING,” has already demonstrated exciting potential in laboratory studies. For instance, one of the promising applications for PING could be for the surgical treatment of epilepsies that do not respond to medication. Approximately a third of patients with epilepsy do not respond to anti-seizure drugs, and surgery can reduce or eliminate seizures for some of them. Lee and his team, along with their collaborators at Stanford, have shown that PING can reduce or eliminate seizures in two research models of epilepsy. The findings raise the possibility of treating epilepsy in a carefully targeted and noninvasive manner without the need for traditional brain surgery. 

Another important potential advantage of PING is that it could encourage the surgical treatment of appropriate patients with epilepsy who are reluctant to undergo conventional invasive or ablative surgery.

In a scientific paper newly published in the Journal of Neurosurgery, Lee and his collaborators detail the ability of PING to focally eliminate neurons in a brain region, while sparing non-target cells in the same area. In contrast, currently available surgical approaches damage all cells in a treated brain region. 

A key advantage of the approach is its incredible precision. PING harnesses the power of magnetic-resonance imaging to let scientists peer inside the skull so that they can precisely guide sound waves to open the body’s natural blood-brain barrier exactly where needed. This barrier is designed to keep harmful cells and molecules out of the brain, but it also prevents the delivery of potentially beneficial treatments.

The UVA group’s new paper concludes that PING allows the delivery of a highly targeted neurotoxin, cleanly wiping out problematic neurons, a type of brain cell, without causing collateral damage. 

Another key advantage of the precision of this approach is that it can be used on irregularly shaped targets in areas that would be extremely difficult or impossible to reach through regular brain surgery. “If this strategy translates to the clinic,” the researchers write in their new paper, “the noninvasive nature and specificity of the procedure could positively influence both physician referrals for, and patient confidence in, surgery for medically intractable neurological disorders.”

“Our hope is that the PING strategy will become a key element in the next generation of very precise, noninvasive, neurosurgical approaches to treat major neurological disorders,” said Lee, who is part of the UVA Brain Institute.

About the Research

Lee’s groundbreaking research has been supported by the National Institutes of Health, the Chester Fund and the Charlottesville-based Focused Ultrasound Foundation. The work is part of an expansive effort at UVA Health to explore the potential of scalpel-free focused ultrasound to treat complex diseases throughout the body.

UVA’s pioneering research has already paved the way for the federal Food and Drug Administration to approve focused ultrasound for the treatment of essential tremor, a common movement disorder, and Parkinson’s disease symptoms. Research is underway on its potential applications for many more conditions, including breast cancer and glioblastoma, a deadly form of brain tumor. Learn more about UVA’s focused ultrasound research.

The research team included Yi Wang, Matthew J. Anzivino, Yanrong Zhang, Edward H. Bertram, James Woznak, Alexander L. Klibanov, Erik Dumont and Max Wintermark. 

An application to patent the PING procedure has been submitted by members of the research group. 

The research was funded by the National Institutes of Health, grants R01 NS102194 and R01 CA217953-01; the Chester Fund; and the Focused Ultrasound Foundation.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

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

Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells by Yi Wang, Matthew J. Anzivino, Yanrong Zhang, Edward H. Bertram, James Woznak, Alexander L. Klibanov, Erik Dumont, Max Wintermark, and Kevin S. Lee. Journal of Neurosurgery DOI: https://doi.org/10.3171/2021.7.JNS21123 Online Publication Date: 19 Nov 2021

This paper is behind a paywall.

Wound healing without sutures

Whoever wrote this Technion-Israel Institute of Technology November 28, 2021 press release (also on EurekAlert) they seem to have had a lot of fun doing it,

“Sutures? That’s practically medieval!”

It is a staple of science fiction to mock sutures as outdated. The technique has, after all, been in use for at least 5,000 years. Surely medicine should have advanced since ancient Egypt. Professor Hossam Haick from the Wolfson Department of Chemical Engineering at the Technion has finally turned science fiction into reality. His lab succeeded in creating a smart sutureless dressing that binds the wound together, wards off infection, and reports on the wound’s condition directly to the doctors’ computers. Their study was published in Advanced Materials.

Current surgical procedures entail the surgeon cutting the human body, doing what needs to be done, and sewing the wound shut – an invasive procedure that damages surrounding healthy tissue. Some sutures degrade by themselves – or should degrade – as the wound heals. Others need to be manually removed. Dressing is then applied over the wound and medical personnel monitor the wound by removing the dressing to allow observation for signs of infection like swelling, redness, and heat. This procedure is painful to the patient, and disruptive to healing, but it is unavoidable. Working with these methods also mean that infection is often discovered late, since it takes time for visible signs to appear, and more time for the inspection to come round and see them. In developed countries, with good sanitation available, about 20% of patients develop infections post-surgery, necessitating additional treatment and extending the time to recovery. The figure and consequences are much worse in developing countries.

How will it work with Prof. Haick’s new dressing?

Prior to beginning a procedure, the dressing – which is very much like a smart band-aid – developed by Prof. Haick’s lab will be applied to the site of the planned incision. The incision will then be made through it. Following the surgery, the two ends of the wound will be brought together, and within three seconds the dressing will bind itself together, holding the wound closed, similarly to sutures. From then, the dressing will be continuously monitoring the wound, tracking the healing process, checking for signs of infection like changes in temperature, pH, and glucose levels, and report to the medical personnel’s smartphones or other devices. The dressing will also itself release antibiotics onto the wound area, preventing infection.

“I was watching a movie on futuristic robotics with my kids late one night,” said Prof. Haick, “and I thought, what if we could really make self-repairing sensors?”

Most people discard their late-night cinema-inspired ideas. Not Prof. Haick, who, the very next day after his Eureka moment, was researching and making plans. The first publication about a self-healing sensor came in 2015 (read more about it on the Technion website here). At that time, the sensor needed almost 24 hours to repair itself. By 2020, sensors were healing in under a minute (read about the study by Muhammad Khatib, a student in Prof. Haick’s lab here), but while it had multiple applications, it was not yet biocompatible, that is, not usable in contact with skin and blood. Creating a polymer that would be both biocompatible and self-healing was the next step, and one that was achieved by postdoctoral fellow Dr. Ning Tang.

The new polymer is structured like a molecular zipper, made from sulfur and nitrogen: the surgeon’s scalpel opens it; then pressed together, it closes and holds fast. Integrated carbon nanotubes provide electric conductivity and the integration of the sensor array. In experiments, wounds closed with the smart dressing healed as fast as those closed with sutures and showed reduced rates of infection.

“It’s a new approach to wound treatment,” said Prof. Haick. “We introduce the advances of the fourth industrial revolution – smart interconnected devices, into the day-to-day treatment of patients.”

Prof. Haick is the head of the Laboratory for Nanomaterial-based Devices (LNBD) and the Dean of Undergraduate Studies at the Technion. Dr. Ning Tang was a postdoctoral fellow in Prof. Haick’s laboratory and conducted this study as part of his fellowship. He has now been appointed an associate professor in Shanghai Jiao Tong University.

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

Highly Efficient Self-Healing Multifunctional Dressing with Antibacterial Activity for Sutureless Wound Closure and Infected Wound Monitoring by Ning Tang, Rongjun Zhang, Youbin Zheng, Jing Wang, Muhammad Khatib, Xue Jiang, Cheng Zhou, Rawan Omar, Walaa Saliba, Weiwei Wu, Miaomiao Yuan, Daxiang Cui, Hossam Haick. DOI: https://doi.org/10.1002/adma.202106842 First published: 05 November 2021

This paper is behind a paywall.

I usually like to have three links to a news/press release and in my searches for a third source for this press release, I stumbled onto the technioncanada.org website. They seemed to have scooped everyone including Technion as they have a November 25, 2021posting of the press release.

Osseosurface (bone) electronics

A November 19, 2021 news item on ScienceDaily announced a class of electronic devices that can grow on bone surfaces,

A team of University of Arizona researchers has developed an ultra-thin wireless device that grows to the surface of bone and could someday help physicians monitor bone health and healing over long periods. The devices, called osseosurface electronics, are described in a paper published Thursday [November 18, 2021] in Nature Communication

Caption: Osseosurface electronic devices, which attach directly to the bone, could one day help physicians monitor bone health. One is show here applied to a synthetic bone in the Gutruf Lab at the University of Arizona. Credit: Gutruf Lab

A November 18, 2021 University of Arizona (UArizona) news release, also on EurekAlert, by Emily Dieckman, which originated the news release, delves further into the work (Note: Links have been removed),

“As a surgeon, I am most excited about using measurements collected with osseosurface electronics to someday provide my patients with individualized orthopedic care – with the goal of accelerating rehabilitation and maximizing function after traumatic injuries,” said study co-senior author Dr. David Margolis, an assistant professor of orthopedic surgery in the UArizona College of Medicine – Tucson and orthopedic surgeon at Banner – University Medical Center Tucson.

Fragility fractures associated with conditions like osteoporosis account for more days spent in the hospital than heart attacks, breast cancer or prostate cancer. Although not yet tested or approved for use in humans, the wireless bone devices could one day be used not only to monitor health, but to improve it, said study co-senior author Philipp Gutruf, an assistant professor of biomedical engineering and Craig M. Berge faculty fellow in the College of Engineering.

“Being able to monitor the health of the musculoskeletal system is super important,” said Gutruf, who is also a member of the university’s BIO5 Institute. “With this interface, you basically have a computer on the bone. This technology platform allows us to create investigative tools for scientists to discover how the musculoskeletal system works and to use the information gathered to benefit recovery and therapy.”

Because muscles are so close to bones and move so frequently, it is important that the device be thin enough to avoid irritating surrounding tissue or becoming dislodged, Gutruf explained.

“The device’s thin structure, roughly as thick as a sheet of paper, means it can conform to the curvature of the bone, forming a tight interface,” said Alex Burton, a doctoral student in biomedical engineering and co-first author of the study. “They also do not need a battery. This is possible using a power casting and communication method called near-field communication, or NFC, which is also used in smartphones for contactless pay.”

Ceramic Adhesive Grows to Bone

The outer layers of bones shed and renew just like the outer layers of skin. So, if a traditional adhesive was used to attach something to the bone, it would fall off after just a few months. To address this challenge, study co-author and BIO5 Institute member John Szivek – a professor of orthopedic surgery and biomedical engineering – developed an adhesive that contains calcium particles with an atomic structure similar to bone cells, which is used as to secure osseosurface electronics to the bone.

“The bone basically thinks the device is part of it, and grows to the sensor itself,” Gutruf said. “This allows it to form a permanent bond to the bone and take measurements over long periods of time.”

For instance, a doctor could attach the device to a broken or fractured bone to monitor the healing process. This could be particularly helpful in patients with conditions such as osteoporosis, since they frequently suffer refractures. Knowing how quickly and how well the bone is healing could also inform clinical treatment decisions, such as when to remove temporary hardware like plates, rods or screws.

Some patients are prescribed drugs designed to speed up bone healing or improve bone density, but these prescriptions can have side effects. Close bone monitoring would allow physicians to make more informed decisions about drug dosage levels.

To give you an idea of the device’s scale,

The device is as thin as a sheet of paper and roughly the size of a penny. Courtesy of Gutruf Lab

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

Osseosurface electronics—thin, wireless, battery-free and multimodal musculoskeletal biointerfaces by Le Cai, Alex Burton, David A. Gonzales, Kevin Albert Kasper, Amirhossein Azami, Roberto Peralta, Megan Johnson, Jakob A. Bakall, Efren Barron Villalobos, Ethan C. Ross, John A. Szivek, David S. Margolis & Philipp Gutruf. Nature Communications volume 12, Article number: 6707 (2021) DOI: https://doi.org/10.1038/s41467-021-27003-2 Published: 18 November 2021

This paper is open access.

3D-printed ‘smart helmets’ for the military

Caption: The Rice University-designed smart helmet is intended to modernize standard-issue military helmets by 3D-printing a nanomaterial-enhanced exoskeleton with embedded sensors to actively protect the brain against kinetic or directed-energy effects. Credit: Rice University

Hopefully this will limit the number of head injuries suffered by soldiers.

Some years ago I was at dinner with friends when one of them, a doctor at the local hospital, told me that the Canadian military, which was in Afghanistan at the time, was dealing with a high number of head injury cases, in part due to the soldiers’ own protective gear.

For example, the protective helmet meant you were less likely to receive a catastrophic injury to your cranium (e.g., metal cracking through bone) but your head would be shaken and that isn’t good for anyone’s brain.

It would seem this project at Rice University (Texas, US) is designed to limit the problem of your own protective gear causing injury, from a November 10, 2021 Rice University news release (also on EurekAlert), Note: Links have been removed,

Rice University researchers have received $1.3 million from the Office of Naval Research through the Defense Research University Instrumentation Program to create the world’s first printable military “smart helmet” using industrial-grade 3D printers. 

Led by principal investigator Paul Cherukuri, executive director of Rice’s Institute of Biosciences and Bioengineering, the Smart Helmet program aims to modernize standard-issue military helmets by 3D-printing a nanomaterial-enhanced exoskeleton with embedded sensors to actively protect the brain against kinetic or directed-energy effects. 

Rice will utilize Carbon Inc.’s L1 printer to develop a strong-but-light military-grade helmet that incorporates advances in materials, image processing, artificial intelligence, haptic feedback and energy storage. The printer enables rapid prototyping that in turn simplifies the process of incorporating the sensors, cameras, batteries and wiring harnesses the program requires, Cherukuri said. 

“Current helmets have evolved little since the last century and are still heavy, bulky, passive devices,” he said. “Because of advances in sensors and additive manufacturing, we’re now reimagining the helmet as a 3D-printed, AI-enabled, ‘always-on’ wearable that detects threats near or far and is capable of launching countermeasures to protect soldiers, sailors, airmen and Marines. Essentially, we’re building J.A.R.V.I.S.”

The Smart Helmet program will use technology drawn from projects like the FlatCam, a system developed by co-investigator and electrical and computer engineer Ashok Veeraraghavan and his colleagues that incorporates sophisticated image processing to eliminate the need for bulky lenses, as well as Cherukuri’s Teslaphoresis, a kind of tractor beam for nanomaterials that could help create physical and electromagnetic shields inside the helmets. 

“A smart helmet task force has been assembled from some of the finest minds at Rice to tackle the challenge of creating a self-contained, intelligent system that protects the warfighter at all times,” Cherukuri said. The task force includes the labs of materials scientist Pulickel Ajayan, civil and environmental engineer and Rice Provost Reginald DesRoches, mechanical engineer Marcia O’Malley, chemist James Tour and Veeraraghavan.

While the location of the L1 has yet to be determined, a Carbon M2 printer will be located at the Oshman Engineering Design Kitchen (OEDK), where it will be available for projects other than the helmet. Rice undergraduates who design and build their mandated capstone projects at the OEDK are taking part in the helmet project, working alongside graduate students and postdoctoral researchers to develop the heads-up display.   

“We’ve got a lot of innovative tech in university labs that has never seen the light of day,” Cherukuri said. “We’re simply developing that technology into a device that gives the men and women protecting our country a real chance at coming home safe and sound. This is for them.”

Self-assembling salt-crystal nanoscale ‘origami’ balls

This November 4, 2021 news item on Nanowerk features research from the Korea Advanced Institute of Science and Technology (KAIST),

Researchers have developed a technique whereby they can spontaneously encapsulate microscopic droplets of water and oil emulsion in a tiny sphere made of salt crystals—sort of like a minute, self-constructing origami soccer ball filled with liquid. The process, which they are calling ‘crystal capillary origami,’could be used in a range of fields from more precise drug delivery to nanoscale medical devices.

A November 4, 2021 KAIST press release (also on EurekAlert), which originated the news item, goes on to provide technical detail,

Capillary action, or ‘capillarity,’ will be familiar to most people as the way that water or other liquids can move up narrow tubes or other porous materials seemingly in defiance of gravity (for example within the vascular systems of plants, or even more simply, the drawing up of paint between the hairs of a paintbrush). This effect is due to the forces of cohesion (the tendency of a liquid’s molecules to stick together), which results in surface tension, and adhesion (their tendency to stick to the surface of other substances). The strength of the capillarity depends on the chemistry of the liquid, the chemistry of the porous material, and on the other forces acting on them both. For example, a liquid with lower surface tension than water would not be able to hold up a water strider insect. 

Less well known is a related phenomenon, elasto-capillarity, that takes advantage of the relationship between capillarity and the elasticity of a very tiny flat sheet of a solid material. In certain circumstances, the capillary forces can overcome the elastic bending resistance of the sheet. 

This relationship can be exploited to create ‘capillary origami,’ or three-dimensional structures. When a liquid droplet is placed on the flat sheet, the latter can spontaneously encapsulate the former due to surface tension. Capillary origami can take on other forms including wrinkling, buckling, or self-folding into other shapes. The specific geometrical shape that the 3D capillary origami structure ends up taking is determined by both the chemistry of the flat sheet and that of the liquid, and by carefully designing the shape and size of the sheet.

There is one big problem with these small devices, however. “These conventional self-assembled origami structures cannot be completely spherical and will always have discontinuous boundaries, or what you might call ‘edges,’ as a result of the original two-dimensional shape of the sheet,” said Kwangseok Park, a lead researcher on the project. He added, “These edges could turn out to be future defects with the potential for failure in the face of increased stress.” Non-spherical particles are also known to be more disadvantageous than spherical particles in terms of cellular uptake. 

Professor Hyoungsoo Kim from the Department of Mechanical Engineering explained, “This is why researchers have long been on the hunt for substances that could produce a fully spherical capillary origami structure.” 

The authors of the study have demonstrated such an origami sphere for the first time. They showed how instead of a flat sheet, the growth of salt-crystals can perform capillary origami action in a similar manner. What they call ‘crystal capillary origami’ spontaneously constructs a smooth spherical shell capsule from these same surface tension effects, but now the spontaneous encapsulation of a liquid is determined by the elasto-capillary conditions of growing crystals.

Here, the term ‘salt’ refers to a compound of one positively charged ion and another negatively charged. Table salt, or sodium chloride, is just one example of a salt. The researchers used four other salts: calcium propionate, sodium salicylate, calcium nitrate tetrahydrate, and sodium bicarbonate to envelop a water-oil emulsion. Normally, a salt such as sodium chloride has a cubical crystal structure, but these four salts form plate-like structures as crystallites or ‘grains’ (the microscopic shape that forms when a crystal first starts to grow) instead. These plates then self-assemble into perfect spheres.

Using scanning electron microscopy and X-ray diffraction analysis, they investigated the mechanism of such formation and concluded that it was ‘Laplace pressure’ that drives the crystallite plates to cover the emulsion surface. Laplace pressure describes the pressure difference between the interior and exterior of a curved surface caused by the surface tension at the interface between the two substances, in this case between the salt water and the oil.

The researchers hope that these self-assembling nanostructures can be used for encapsulation applications in a range of sectors, from the food industry and cosmetics to drug delivery and even tiny medical devices.

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

Crystal capillary origami capsule with self-assembled nanostructures by
Kwangseok Park and Hyoungsoo Kim. Nanoscale, 2021, 13, 14656-14665 DOI: https://doi.org/10.1039/D1NR02456F First published 19 Jul 2021

This paper is behind a paywall.

Living optical fibers

The word ‘living’ isn’t usually associated with optical fibers and the addition had me thinking that this October 11, 2021 Nanowerk Spotlight story by Michael Berger would be a synthetic biology story. Well, not exactly. Do read on for a good introduction describing glass, fiber optics, and optogenetics,

Glass is one of the oldest manufactured materials used by humans and glass making dates back at least 6000 years, long before humans had discovered how to smelt iron. Glasses have been based on the chemical compound silica – silicon dioxide, or quartz – the primary constituent of sand. Soda-lime glass, containing around 70% silica, accounts for around 90% of manufactured glass.

Historically, we are familiar with glasses’ decorative use or as window panes, household items, and in optics such as eyeglasses, microscopes and telescopes. More recently, starting in the 1950s, glass has been used in the manufacture of fiber optic cables, a technology that has revolutionized the communications industry and helped ring in the digital revolution.

Fiber optic cables propagate a signal as a pulse of light along a transparent medium, usually glass. This is not only used to transmit information but, for instance in many healthcare and biomedical applications, scientists use optical fibers for sensing applications by shining light into a sample and evaluating the absorbed or transmitted light.

A recent development in this field is optogenetics, a neuromodulation method that uses activation or deactivation of brain cells by illumination with different colors of light in order to treat brain disorders.

Berger goes on to explain the latest work and reveals what ‘living’ means where this work is concerned,

This work represents a simple and low-cost approach to fabricating optical fibers made from biological materials. These fibers can be easily modified for specific applications and don’t require sophisticated equipment to generate relevant information. This method could be used for many practical sensing and biological modeling applications.

“We use a natural, ionic, and biologically compatible crosslinking approach, which enables us to produce flexible hydrogel fibers in continuous multi-layered architectures, meaning they are easy to produce and can be modified after fabrication,” explains Guimarães [Carlos Guimarães, the paper’s first author]. “Similarly to silica fibers, the core hydrogel of our structures can be exposed, fused to another fiber or reassembled if they break, and efficiently guide light through the established connection.”

These flexible hydrogel fibers are made from sugars and work just like solid-state optical fibers used to transmit data. However, they are biocompatible so they can be easily integrated with biological systems.

“We could even consider them to be alive [emphasis mine] since we can use them to grow living cells inside the fiber,” says Guimarães. “As these embedded cells grow over time, we can then use light to inform on living dynamic events, for example to track cancer invasive proliferation into optical information.” [emphasis mine]

As to what constitutes optical information in this context,

Another intriguing aspect of these hydrogel fibers is that their permeable mesh enables the inclusion of biological targets of interest for detection. For example, the scientists observed that fibers were able to soak SARS-CoV-2 viruses, and by integrating nanoparticles for their binding and detection, shifts in visible light could be observed for detecting the accumulation of viral particles within the fiber.

“When light moving through the fiber encounters living cells, it changes its characteristics depending on cellular density, invasive proliferation, expression of molecules, etc.” Guimarães notes. “This light-cell interaction can digitize complex biological events, converting responses such as cancer cell progression in 3D environments and susceptibility to drugs into numbers and data, very fast and without the need for sample destruction.”

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

Engineering Polysaccharide-Based Hydrogel Photonic Constructs: From Multiscale Detection to the Biofabrication of Living Optical Fibers by Carlos F. Guimarães, Rajib Ahmed, Amideddin Mataji-Kojouri, Fernando Soto, Jie Wang, Shiqin Liu, Tanya Stoyanova, Alexandra P. Marques, Rui L. Reis, Utkan Demirci. Advanced Materials DOI: https://doi.org/10.1002/adma.202105361 First published: 07 October 2021

This paper is behind a paywall.