Category Archives: medicine

Coelacanth (a living fish fossil) may provide clue to making artificial organs for transplantation

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An ancient fish called a ‘living fossil’ has helped researchers understand the basics of stem cells. This will further stem cell research and be a step in the direction of creating artificial organs. The coelacanth fish is 400 million years old. Photo: Canva. Courtesy: university of Copenhagen

A December 12, 2022 University of Copenhagen press release (also on EurekAlert) describes work which may have an impact on organ transplants,

A beating heart. A complicated organ that pumps blood around the body of animals and humans. Not exactly something you associate with a Petri dish in a laboratory.

But that may change in the future, and save the lives of people whose own organs fail. And the research is now one step closer to that.

To design artificial organs you first have to understand stem cells and the genetic instructions that govern their remarkable properties.

Professor Joshua Mark Brickman at the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) has unearthed the evolutionary origins of a master gene that acts on a network of genes instructing stem cells.

“The first step in stem cell research is to understand the gene regulatory network that supports so-called pluripotent stem cells. Understanding how their function was perfected in evolution can help provide knowledge about how to construct better stem cells,” says Joshua Mark Brickman.

Pluripotent stem cells are stem cells that can develop into all other cells. For example, heart cells. If we understand how the pluripotent stem cells develop into a heart, then we are one step closer to replicating this process in a laboratory.

What are stem cells?

Stem cells are non-specialized cells found in all multicellular organisms. Stem cells have two properties that distinguish them from other cell types. On the one hand, stem cells can undergo an unlimited number of cell divisions (mitoses), and on the other hand, stem cells have the ability to mature (differentiate) into several cell types.

A pluripotent stem cell is a cell that can develop into any other cell, such as a heart cell, hair cell or eye cell.

A ‘living fossil’ is the key to understanding stem cells

The pluripotent property of stem cells – meaning that the cells can develop into any other cell – is something that has traditionally been associated with mammals.

Now Joshua Mark Brickman and his colleagues have found that the master gene that controls stem cells and supports pluripotency also exists in a fish called coelacanth. In humans and mice this gene is called OCT4 and they found that the coelacanth version could replace the mammalian one in mouse stem cells.

In addition to the fact that the coelacanth is in a different class from mammals, it has also been called a ‘living fossil,’ since approximately 400 million years ago it developed into the form it has today. It has fins shaped like limbs and is therefore thought to resemble the first animals to move from the sea onto land.

“By studying its cells, you can go back in evolution, so to speak,” explains Assistant Professor Molly Lowndes.

Assistant Professor Woranop Sukparangsi continues: “The central factor controlling the gene network in stem cells is found in the coelacanth. This shows that the network already existed early in evolution, potentially as far back as 400 million years ago.”

And by studying the network in other species, such as this fish, the researchers can distill what the basic concepts that support a stem cell are.

“The beauty of moving back in evolution is that the organisms become simpler. For example, they have only one copy of some essential genes instead of many versions. That way, you can start to separate what is really important for stem cells and use that to improve how you grow stem cells in a dish,” says PhD student Elena Morganti.

Sharks, mice and kangaroos

In addition to the researchers finding out that the network around stem cells is much older than previously thought, and found in ancient species, they also learned how exactly evolution has modified the network of genes to support pluripotent stem cells.

The researchers looked at the stem cell genes from over 40 animals. For example sharks, mice and kangaroos. The animals were selected to provide a good sampling of the main branch points in evolution.

The researchers used artificial intelligence to build three-dimensional models of the different OCT4 proteins. The researchers could see that the general structure of the protein is maintained across evolution. While the regions of these proteins known to be important for stem cells do not change, species-specific differences in apparently unrelated regions of these proteins alter their orientation, potentially affecting how well it supports pluripotency.

“This a very exciting finding about evolution that would not have been possible prior to the advent of new technologies. You can see it as evolution cleverly thinking, we don not tinker with the ‘engine in the car’, but we can move the engine around and improve the drive train to see if it makes the car go faster,” says Joshua Mark Brickman.

…

The study is a collaborative project spanning Australia, Japan and Europe, with vital strategic partnerships with the groups of Sylvie Mazan at the Oceanological Observatory of Banyuls-sur-Mer in France and professor Guillermo Montoya at Novo Nordisk Foundation Center for Protein Research at University of Copenhagen.

Caption: Coelacanth-fish and other animals. Credit: By Woranop Sukparangsi Courtesy: University of Copenhagen

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

Evolutionary origin of vertebrate OCT4/POU5 functions in supporting pluripotency by Woranop Sukparangsi, Elena Morganti, Molly Lowndes, Hélène Mayeur, Melanie Weisser, Fella Hammachi, Hanna Peradziryi, Fabian Roske, Jurriaan Hölzenspies, Alessandra Livigni, Benoit Gilbert Godard, Fumiaki Sugahara, Shigeru Kuratani, Guillermo Montoya, Stephen R. Frankenberg, Sylvie Mazan & Joshua M. Brickman. Nature Communications volume 13, Article number: 5537 (2022) DOI: https://doi.org/10.1038/s41467-022-32481-z Published: 21 September 2022

This paper is open access.

Powered by light: a battery-free pacemaker

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I think it looks more like a potato than a heart but it does illustrate how this new battery-free pacemaker would wrap around a heart,

Caption: An artist’s rendering shows how a new pacemaker, designed by a UArizona-led team of researchers, is able to envelop the heart. The wireless, battery-free pacemaker could be implanted with a less invasive procedure than currently possible and would cause patients less pain. Credit: Philipp Gutruff

An October 27, 2022 news item on ScienceDaily announces a technology that could make life much easier for people with pacemakers (Comment: In the image, that looks more like a potato than a heart, to me),

University of Arizona engineers lead a research team that is developing a new kind of pacemaker, which envelops the heart and uses precise targeting capabilities to bypass pain receptors and reduce patient discomfort.

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An October 27, 2022 University of Arizona news release (also on EurekAlert) by Emily Dieckman, which originated the news item, explains the reasons for the research and provides some technical details (Note: Links have been removed),

Pacemakers are lifesaving devices that regulate the heartbeats of people with chronic heart diseases like atrial fibrillation and other forms of arrhythmia. However, pacemaker implantation is an invasive procedure, and the lifesaving pacing the devices provide can be extremely painful. Additionally, pacemakers can only be used to treat a few specific types of disease.

In a paper published Wednesday [October 26, 2022] in Science Advances, a University of Arizona-led team of researchers detail the workings of a wireless, battery-free pacemaker they designed that could be implanted with a less invasive procedure than currently possible and would cause patients less pain. The study was helmed by researchers in the Gutruf Lab, led by biomedical engineering assistant professor and Craig M. Berge Faculty Fellow Philipp Gutruf.

Currently available pacemakers work by implanting one or two leads, or points of contact, into the heart with hooks or screws. If the sensors on these leads detect a dangerous irregularity, they send an electrical shock through the heart to reset the beat.

“All of the cells inside the heart get hit at one time, including the pain receptors, and that’s what makes pacing or defibrillation painful,” Gutruf said. “It affects the heart muscle as a whole.”

The device Gutruf’s team has developed, which has not yet been tested in humans, would allow pacemakers to send much more targeted signals using a new digitally manufactured mesh design that encompasses the entire heart. The device uses light and a technique called optogenetics.

Optogenetics modifies cells, usually neurons, sensitive to light, then uses light to affect the behavior of those cells. This technique only targets cardiomyocytes, the cells of the muscle that trigger contraction and make up the beat of the heart. This precision will not only reduce pain for pacemaker patients by bypassing the heart’s pain receptors, it will also allow the pacemaker to respond to different kinds of irregularities in more appropriate ways. For example, during atrial fibrillation, the upper and lower chambers of the heart beat asynchronously, and a pacemaker’s role is to get the two parts back in line.

“Whereas right now, we have to shock the whole heart to do this, these new devices can do much more precise targeting, making defibrillation both more effective and less painful,” said Igor Efimov, professor of biomedical engineering and medicine at Northwestern University, where the devices were lab-tested. “This technology could make life easier for patients all over the world, while also helping scientists and physicians learn more about how to monitor and treat the disease.”

Flexible mesh encompasses the heart

To ensure the light signals can reach many different parts of the heart, the team created a design that involves encompassing the organ, rather than implanting leads that provide limited points of contact.

The new pacemaker model consists of four petallike structures made of thin, flexible film, which contain light sources and a recording electrode. The petals, specially designed to accommodate the way the heart changes shape as it beats, fold up around the sides of the organ to envelop it, like a flower closing up at night.

“Current pacemakers record basically a simple threshold, and they will tell you, ‘This is going into arrhythmia, now shock!'” Gutruf said. “But this device has a computer on board where you can input different algorithms that allow you to pace in a more sophisticated way. It’s made for research.”

Because the system uses light to affect the heart, rather than electrical signals, the device can continue recording information even when the pacemaker needs to defibrillate. In current pacemakers, the electrical signal from the defibrillation can interfere with recording capabilities, leaving physicians with an incomplete picture of cardiac episodes. Additionally, the device does not require a battery, which could save pacemaker patients from needing to replace the battery in their device every five to seven years, as is currently the norm.

Gutruf’s team collaborated with researchers at Northwestern University on the project. While the current version of the device has been successfully demonstrated in animal models, the researchers look forward to furthering their work, which could improve the quality of life for millions of people.

The prototype looks like this,

Caption: The device uses light and a technique called optogenetics, which modifies cells that are sensitive to light, then uses light to affect the behavior of those cells.. Credit: Philipp Gutruff

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

Wireless, fully implantable cardiac stimulation and recording with on-device computation for closed-loop pacing and defibrillation by Jokubas Ausra, Micah Madrid, Rose T. Yin, Jessica Hanna, Suzanne Arnott, Jaclyn A. Brennan, Roberto Peralta, David Clausen, Jakob A. Bakall, Igor R. Efimov, and Philipp Gutruf. Science Advances 26 Oct 2022 Vol 8, Issue 43 DOI: 10.1126/sciadv.abq7469

This paper is open access.

Even a ‘good’ gene edit can go wrong

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An October 24, 2022 news item on ScienceDaily highlights research into better understanding problems with ‘good’ CRISPR (clustered regularly interspaced short palindromic repeats) gene editing,

A Rice University lab is leading the effort to reveal potential threats to the efficacy and safety of therapies based on CRISPR-Cas9, the Nobel Prize-winning gene editing technique, even when it appears to be working as planned.

Bioengineer Gang Bao of Rice’s George R. Brown School of Engineering and his team point out in a paper published in Science Advances that while off-target edits to DNA have long been a cause for concern, unseen changes that accompany on-target edits also need to be recognized — and quantified.

Bao noted a 2018 Nature Biotechnology paper indicated the presence of large deletions. “That’s when we started looking into what we can do to quantify them, due to CRISPR-Cas9 systems designed for treating sickle cell disease,” he said.

…

An October 24, 2022 Rice University news release (also on EurekAlert), which originated the news item, details the concerns (Note: Links have been removed),

Bao has been a strong proponent of CRISPR-Cas9 as a tool to treat sickle cell disease, a quest that has brought him and his colleagues ever closer to a cure. Now the researchers fear that large deletions or other undetected changes due to gene editing could persist in stem cells as they divide and differentiate, thus have long-term implications for health.

“We do not have a good understanding of why a few thousand bases of DNA at the Cas9 cut site can go missing and the DNA double-strand breaks can still be rejoined efficiently,” Bao said. “That’s the first question, and we have some hypotheses. The second is, what are the biological consequences? Large deletions (LDs) can reach to nearby genes and disrupt the expression of both the target gene and the nearby genes. It is unclear if LDs could result in the expression of truncated proteins. 

“You could also have proteins that misfold, or proteins with an extra domain because of large insertions,” he said. “All kinds of things could happen, and the cells could die or have abnormal functions.”

His lab developed a procedure that uses single-molecule, real-time (SMRT) sequencing with dual unique molecular identifiers (UMI) to find and quantify unintended LDs along with large insertions and local chromosomal rearrangements that accompany small insertions/deletions (INDELs) at a Cas9 on-target cut site. 

“To quantify large gene modifications, we need to perform long-range PCR, but that could induce artifacts during DNA amplification,” Bao said. “So we used UMIs of 18 bases as a kind of barcode.”

“We add them to the DNA molecules we want to amplify to identify specific DNA molecules as a way to reduce or eliminate artifacts due to long-range PCR,” he said. “We also developed a bioinformatics pipeline to analyze SMRT sequencing data and quantified the LDs and large insertions.”

The Bao lab’s tool, called LongAmp-seq (for long-amplicon sequencing), accurately quantifies both small INDELs and large LDs. Unlike SMRT-seq, which requires the use of a long-read sequencer often only available at a core facility, LongAmp-seq can be performed using a short-read sequencer.

To test the strategy, the lab team led by Rice alumna Julie Park, now an assistant research professor of bioengineering, used Streptococcus pyogenes Cas9 to edit beta-globin (HBB), gamma-globin (HBG) and B-cell lymphoma/leukemia 11A (BCL11A) enhancers in hematopoietic stem and progenitor cells (HSPC) from patients with sickle cell disease, and the PD-1 gene in primary T-cells.  

They found large deletions of up to several thousand bases occurred at high frequency in HSPCs: up to 35.4% in HBB, 14.3% in HBG and 15.2% in BCL11A genes, as well as on the PD-1 (15.2%) gene in T-cells. 

Since two of the specific CRISPR guide RNAs tested by the Bao lab are being used in clinical trials to treat sickle cell disease, he said it’s important to determine the biological consequences of large gene modifications due to Cas9-induced double-strand breaks. 

Bao said the Rice team is currently looking downstream to analyze the consequences of long deletions on messenger RNA, the mediator that carries code for ribosomes to make proteins. “Then we’ll move on to the protein level,” Bao said. “We want to know if these large deletions and insertions persist after the gene-edited HSPCs are transplantation into mice and patients.”  

Co-authors of the study from Rice are graduate students Mingming Cao and Yilei Fu, alumni Yidan Pan and Timothy Davis, research specialist Lavanya Saxena, microscopist/bioinstrumentation specialist Harshavardhan Deshmukh and Todd Treangen, an assistant professor of computer science, and Emory University’s Vivien Sheehan, an associate professor of pediatrics. 

Bao is the department chair and Foyt Family Professor of Bioengineering, a professor of chemistry, materials science and nanoengineering, and mechanical engineering, and a CPRIT Scholar in Cancer Research.

The National Institutes of Health (R01HL152314, OT2HL154977) supported the research.

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

Comprehensive analysis and accurate quantification of unintended large gene modifications induced by CRISPR-Cas9 gene editing by So Hyun Park, Mingming Cao, Yidan Pan, Timothy H. Davis, Lavanya Saxena, Harshavardhan Deshmukh, Yilei Fu, Todd Treangen, Vivien A. Sheehan, and Gang Bao. Science Advances Vol 8, Issue 42 DOI: 10.1126/sciadv.abo7676 First published online: 21 Oct 2022 Published in print: March 3, 2023

This paper is behind a paywall.

Brain stimulation combined with a nose spray containing nanoparticles can improve stroke recovery (in an animal model)

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A September 28, 2022 news item on Nanowerk announces research into combining nasal sprays and brain stimulation in efforts to improve stroke recovery (Note: A link has been removed),

In a recent study (Materials Today Chemistry, “Enhancing non-invasive brain stimulation with non-invasively delivered nanoparticles for improving stroke recovery”), researchers from Xi’an Jiaotong-Liverpool University and other universities in China have reported that brain stimulation combined with a nose spray containing nanoparticles can improve recovery after ischemic stroke in an animal model.

The nasal spray is a non-invasive method for delivering magnetic nanoparticles into the brain that the study finds can increase the benefits of transcranial magnetic stimulation (TMS). TMS is a method of non-invasive brain stimulation already used clinically or in clinical trials to treat neurological conditions like stroke, Parkinson’s disease, Alzheimer’s disease, depression, and addiction.

…

I have two previous posts about nasal sprays and nanoparticles (links to previous posts follow at the end) but this item is the first to include brain stimulation. From a September 27, 2022 Xi’an Jiaotong-Liverpool University press release (also on EurekAlert but published on September 28, 2022), which originated the news item,

Rats that were given combined nanoparticle and TMS treatment every 24 hours for 14 days after an ischemic stroke had better overall health, put on weight more quickly and had improved cognitive and motor functions compared to those treated with TMS alone.

During TMS treatment, an electrical current runs through an electric coil placed outside the skull, producing a magnetic field that stimulates brain cells by inducing a further electrical current inside the brain. However, the stimulation is often not intense enough to penetrate far enough into the brain to reach the areas needing treatment. 

In this new study, the researchers show that magnetic nanoparticles, administered intranasally, can make neurons more responsive and amplify the magnetic signal from TMS to reach deeper brain tissue, aiding recovery. The finding offers new opportunities for treating neurological disorders. 

From impossible to possible

The research answers a key question in nanomedicine – whether it is possible to enhance TMS by using nanoparticles that are non-invasively delivered into the brain. Leading figures in the field previously stated that it was almost impossible because of the blood-brain barrier. This physical barrier separates the brain from the rest of the body’s bloodstream.

However, the team of researchers overcame this by guiding the magnetic nanoparticles closer to the correct area with a large magnet near the head. 

Dr Gang Ruan, a corresponding author of the study, says: “We were able to overcome the blood-brain barrier and send enough nanoparticles into the brain to use in combination with TMS simulation to improve recovery from stroke. 

“TMS devices are already used for the clinical treatment of neurological disorders but have severe limitations in terms of stimulation strength and depths of the brain they can penetrate. 

“By non-invasively putting magnetic nanoparticles into the brain, we can amplify and enhance the TMS stimulation effects on neurons, making the treatment more effective,” Dr Ruan adds.

“Showing it is possible to use nanoparticles in this way paves the way for medical applications of nanoparticles for other neurological disorders.”

Crossing barriers 

The iron oxide nanoparticles used in the study are already prescribed to treat iron deficiency as they are non-toxic and biodegradable. The team also modified the nanoparticles by coating them with various non-toxic substances. 

Dr Ruan says: “The coating causes the nanoparticles to stick to the blood-brain barrier, increasing their chances of passing through it. Without this coating, the particles just bounce back from the barrier instead of crossing it.

“The modifications of the iron oxide particles also ensure that the nanoparticles can stick to the neurons and increase their responsiveness to TMS stimulation.”

The safety of using the modified nanoparticles needs to be assessed in clinical trials but has the potential to be used in combination with TMS, and other methods such as brain imaging, to gain more insight into how the brain works and improve the treatment of neurological disorders. 

“Many scientists still think it is impossible to non-invasively send enough nanoparticles into the brain to affect brain function. Yet we have shown that it is possible,” says Dr Ruan.

“We combined the expertise on our team in four different disciplines, materials science, biophysics, neuroscience, and medical science, to push the boundaries of our knowledge and challenge what is currently thought in the field.”

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

Enhancing non-invasive brain stimulation with non-invasively delivered nanoparticles for improving stroke recovery by Y. Hong, J. Wang, J. Li, Z. Xu, X. Yang, M. Bai, P. Gong, Y. Xi, X. Zhang, P. Xu, X. Chen, R. Li, X. Liu, G. Ruan, G. Xua. Materials Today Chemistry Volume 26, December 2022, 101104 DOI: https://doi.org/10.1016/j.mtchem.2022.101104 First available online: 19 August 2022

This paper is behind a paywall.

As promised, here are the links to the other posts about nasal sprays and nanoparticles:

One final note, “Xi’an Jiaotong-Liverpool University (XJTLU) is an international university formed in partnership between the University of Liverpool and Xi’an Jiaotong University in China. Find out more about XJTLU“

Tattoo yourself painlessly

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This is all at the microscale (for those who don’t know what micro means in this context, it’s one-millionth; specifically, the needles are measured in miilionths of a meter).

Caption: A magnified view of a microneedle patch with green tattoo ink. Credit: Georgia Tech

From a September 14, 2022 Georgia Institute of Technology (Georgia Tech) news release (also on EurekAlert),

Instead of sitting in a tattoo chair for hours enduring painful punctures, imagine getting tattooed by a skin patch containing microscopic needles. Researchers at the Georgia Institute of Technology have developed low-cost, painless, and bloodless tattoos that can be self-administered and have many applications, from medical alerts to tracking neutered animals to cosmetics.

“We’ve miniaturized the needle so that it’s painless, but still effectively deposits tattoo ink in the skin,” said Mark Prausnitz, principal investigator on the paper. “This could be a way not only to make medical tattoos more accessible, but also to create new opportunities for cosmetic tattoos because of the ease of administration.”

Prausnitz, Regents’ Professor and J. Erskine Love Jr. Chair in the School of Chemical and Biomolecular Engineering, presented the research in the journal iScience, with former Georgia Tech postdoctoral fellow Song Li as co-author.

Tattoos are used in medicine to cover up scars, guide repeated cancer radiation treatments, or restore nipples after breast surgery. Tattoos also can be used instead of bracelets as medical alerts to communicate serious medical conditions such as diabetes, epilepsy, or allergies.

Various cosmetic products using microneedles are already on the market — mostly for anti-aging — but developing microneedle technology for tattoos is new. Prausnitz, a veteran in this area, has studied microneedle patches for years to painlessly administer drugs and vaccines to the skin without the need for hypodermic needles.

“We saw this as an opportunity to leverage our work on microneedle technology to make tattoos more accessible,” Prausnitz said. “While some people are willing to accept the pain and time required for a tattoo, we thought others might prefer a tattoo that is simply pressed onto the skin and does not hurt.” 

Transforming Tattooing

Tattoos typically use large needles to puncture repeatedly into the skin to get a good image, a time-consuming and painful process. The Georgia Tech team has developed microneedles that are smaller than a grain of sand and are made of tattoo ink encased in a dissolvable matrix.

“Because the microneedles are made of tattoo ink, they deposit the ink in the skin very efficiently,” said Li, the lead author of the study.

In this way, the microneedles can be pressed into the skin just once and then dissolve, leaving the ink in the skin after a few minutes without bleeding.  

Tattooing Technique

Although most microneedle patches for pharmaceuticals or cosmetics have dozens or hundreds of microneedles arranged in a square or circle, microneedle patch tattoos imprint a design that can include letters, numbers, symbols, and images. By arranging the microneedles in a specific pattern, each microneedle acts like a pixel to create a tattoo image in any shape or pattern.

The researchers start with a mold containing microneedles in a pattern that forms an image. They fill the microneedles in the mold with tattoo ink and add a patch backing for convenient handling. The resulting patch is then applied to the skin for a few minutes, during which time the microneedles dissolve and release the tattoo ink. Tattoo inks of various colors can be incorporated into the microneedles, including black-light ink that can only be seen when illuminated with ultraviolet light.

Prausnitz’s lab has been researching microneedles for vaccine delivery for years and realized they could be equally applicable to tattoos. With support from the Alliance for Contraception in Cats and Dogs, Prausnitz’s team started working on tattoos to identify spayed and neutered pets, but then realized the technology could be effective for people, too.

The tattoos were also designed with privacy in mind. The researchers even created patches sensitive to environmental factors such as light or temperature changes, where the tattoo will only appear with ultraviolet light or higher temperatures. This provides patients with privacy, revealing the tattoo only when desired.

The study showed that the tattoos could last for at least a year and are likely to be permanent, which also makes them viable cosmetic options for people who want an aesthetic tattoo without risk of infection or the pain associated with traditional tattoos. Microneedle tattoos could alternatively be loaded with temporary tattoo ink to address short-term needs in medicine and cosmetics.

Microneedle patch tattoos can also be used to encode information in the skin of animals. Rather than clipping the ear or applying an ear tag to animals to indicate sterilization status, a painless and discreet tattoo can be applied instead.

“The goal isn’t to replace all tattoos, which are often works of beauty created by tattoo artists,” Prausnitz said. “Our goal is to create new opportunities for patients, pets, and people who want a painless tattoo that can be easily administered.”

Prausnitz has co-founded a company called Micron Biomedical that is developing microneedle patch technology, bringing it further into clinical trials, commercializing it, and ultimately making it available to patients. 

Prausnitz and several other Georgia Tech researchers are inventors of the microneedle patch technology used in this study and have ownership interest in Micron Biomedical. They are entitled to royalties derived from Micron Biomedical’s future sales of products related to the research. These potential conflicts of interest have been disclosed and are overseen by Georgia Institute of Technology. 

You can see what they mean when they claim this is not competitive with the work you’ll see from a tattoo artist,

Heart tattoo: microneedle patch (above) and tattoo on skin (below).Credit: Song Li, Georgia Tech

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

Microneedle patch tattoos by Song Li, Youngeun Kim, Jeong Woo Lee, Mark R. Prausnitz. iScience DOI:https://doi.org/10.1016/j.isci.2022.105014 Published: September 14, 2022

This paper is open access.

The company mentioned in the news release, Micron Biomedical can be found here.

Skin-like computing device analyzes health data with brain-mimicking artificial intelligence (a neuromorphic chip)

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The wearable neuromorphic chip, made of stretchy semiconductors, can implement artificial intelligence (AI) to process massive amounts of health information in real time. Above, Asst. Prof. Sihong Wang shows a single neuromorphic device with three electrodes. (Photo by John Zich)

Does everything have to be ‘brainy’? Read on for the latest on ‘brainy’ devices.

An August 4, 2022 University of Chicago news release (also on EurekAlert) describes work on a stretchable neuromorphic chip, Note: Links have been removed,

It’s a brainy Band-Aid, a smart watch without the watch, and a leap forward for wearable health technologies. Researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have developed a flexible, stretchable computing chip that processes information by mimicking the human brain. The device, described in the journal Matter, aims to change the way health data is processed.

“With this work we’ve bridged wearable technology with artificial intelligence and machine learning to create a powerful device which can analyze health data right on our own bodies,” said Sihong Wang, a materials scientist and Assistant Professor of Molecular Engineering.

Today, getting an in-depth profile about your health requires a visit to a hospital or clinic. In the future, Wang said, people’s health could be tracked continuously by wearable electronics that can detect disease even before symptoms appear. Unobtrusive, wearable computing devices are one step toward making this vision a reality. 

A Data Deluge
The future of healthcare that Wang—and many others—envision includes wearable biosensors to track complex indicators of health including levels of oxygen, sugar, metabolites and immune molecules in people’s blood. One of the keys to making these sensors feasible is their ability to conform to the skin. As such skin-like wearable biosensors emerge and begin collecting more and more information in real-time, the analysis becomes exponentially more complex. A single piece of data must be put into the broader perspective of a patient’s history and other health parameters.

Today’s smart phones are not capable of the kind of complex analysis required to learn a patient’s baseline health measurements and pick out important signals of disease. However, cutting-edge artificial intelligence platforms that integrate machine learning to identify patterns in extremely complex datasets can do a better job. But sending information from a device to a centralized AI location is not ideal.

“Sending health data wirelessly is slow and presents a number of privacy concerns,” he said. “It is also incredibly energy inefficient; the more data we start collecting, the more energy these transmissions will start using.”

Skin and Brains
Wang’s team set out to design a chip that could collect data from multiple biosensors and draw conclusions about a person’s health using cutting-edge machine learning approaches. Importantly, they wanted it to be wearable on the body and integrate seamlessly with skin.

“With a smart watch, there’s always a gap,” said Wang. “We wanted something that can achieve very intimate contact and accommodate the movement of skin.”

Wang and his colleagues turned to polymers, which can be used to build semiconductors and electrochemical transistors but also have the ability to stretch and bend. They assembled polymers into a device that allowed the artificial-intelligence-based analysis of health data. Rather than work like a typical computer, the chip— called a neuromorphic computing chip—functions more like a human brain, able to both store and analyze data in an integrated way.

Testing the Technology
To test the utility of their new device, Wang’s group used it to analyze electrocardiogram (ECG) data representing the electrical activity of the human heart. They trained the device to classify ECGs into five categories—healthy or four types of abnormal signals. Then, they tested it on new ECGs. Whether or not the chip was stretched or bent, they showed, it could accurately classify the heartbeats.

More work is needed to test the power of the device in deducing patterns of health and disease. But eventually, it could be used either to send patients or clinicians alerts, or to automatically tweak medications.

“If you can get real-time information on blood pressure, for instance, this device could very intelligently make decisions about when to adjust the patient’s blood pressure medication levels,” said Wang. That kind of automatic feedback loop is already used by some implantable insulin pumps, he added.

He already is planning new iterations of the device to both expand the type of devices with which it can integrate and the types of machine learning algorithms it uses.

“Integration of artificial intelligence with wearable electronics is becoming a very active landscape,” said Wang. “This is not finished research, it’s just a starting point.”

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

Intrinsically stretchable neuromorphic devices for on-body processing of health data with artificial intelligence by Shilei Dai, Yahao Dai, Zixuan Zhao, Jie Xu, Jia Huang, Sihong Wang. Matter DOI:https://doi.org/10.1016/j.matt.2022.07.016 Published: August 04, 2022

This paper is behind a paywall.

Lab-made cartilage gel for stiff, achy knees

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Researchers claim their lab-made cartilage is better than the real thing in an August 11, 2022 news item on phys.org, Note: Links have been removed,

Over-the-counter pain relievers, physical therapy, steroid injections—some people have tried it all and are still dealing with knee pain.

Often knee pain comes from the progressive wear and tear of cartilage known as osteoarthritis, which affects nearly one in six adults—867 million people—worldwide. For those who want to avoid replacing the entire knee joint, there may soon be another option that could help patients get back on their feet fast, pain-free, and stay that way.

Writing in the journal Advanced Functional Materials, a Duke University-led team says they have created the first gel-based cartilage substitute that is even stronger and more durable than the real thing.

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Caption: Duke researchers have developed a gel-based cartilage substitute to relieve achy knees that’s even stronger and more durable than the real thing. Clinical trials to start next year. Credit: Canva Credit: Benjamin Wiley, Duke University

Here’s the August 11, 2022 Duke University news release (also on EurekAlert), which originated the news item, where you’ll find more details about the research, Note: Links have been removed,

Mechanical testing reveals that the Duke team’s hydrogel — a material made of water-absorbing polymers — can be pressed and pulled with more force than natural cartilage, and is three times more resistant to wear and tear.

Implants made of the material are currently being developed by Sparta Biomedical and tested in sheep. Researchers are gearing up to begin clinical trials in humans next year.

“If everything goes according to plan, the clinical trial should start as soon as April 2023,” said Duke chemistry professor Benjamin Wiley, who led the research along with Duke mechanical engineering and materials science professor Ken Gall.

To make this material, the Duke team took thin sheets of cellulose fibers and infused them with a polymer called polyvinyl alcohol — a viscous goo consisting of stringy chains of repeating molecules — to form a gel.

The cellulose fibers act like the collagen fibers in natural cartilage, Wiley said — they give the gel strength when stretched. The polyvinyl alcohol helps it return to its original shape. The result is a Jello-like material, 60% water, which is supple yet surprisingly strong.

Natural cartilage can withstand a whopping 5,800 to 8,500 pounds per inch of tugging and squishing, respectively, before reaching its breaking point. Their lab-made version is the first hydrogel that can handle even more. It is 26% stronger than natural cartilage in tension, something like suspending seven grand pianos from a key ring, and 66% stronger in compression — which would be like parking a car on a postage stamp.

“It’s really off the charts in terms of hydrogel strength,” Wiley said.

The team has already made hydrogels with remarkable properties. In 2020, they reported that they had created the first hydrogel strong enough for knees, which feel the force of two to three times body weight with each step.

Putting the gel to practical use as a cartilage replacement, however, presented additional design challenges. One was achieving the upper limits of cartilage’s strength. Activities like hopping, lunging, or climbing stairs put some 10 Megapascals of pressure on the cartilage in the knee, or about 1,400 pounds per square inch. But the tissue can take up to four times that before it breaks.

“We knew there was room for improvement,” Wiley said.

In the past, researchers attempting to create stronger hydrogels used a freeze-thaw process to produce crystals within the gel, which drive out water and help hold the polymer chains together. In the new study, instead of freezing and thawing the hydrogel, the researchers used a heat treatment called annealing to coax even more crystals to form within the polymer network.

By increasing the crystal content, the researchers were able to produce a gel that can withstand five times as much stress from pulling and nearly twice as much squeezing relative to freeze-thaw methods.

The improved strength of the annealed gel also helped solve a second design challenge: securing it to the joint and getting it to stay put.

Cartilage forms a thin layer that covers the ends of bones so they don’t grind against one another. Previous studies haven’t been able to attach hydrogels directly to bone or cartilage with sufficient strength to keep them from breaking loose or sliding off. So the Duke team came up with a different approach.

Their method of attachment involves cementing and clamping the hydrogel to a titanium base. This is then pressed and anchored into a hole where the damaged cartilage used to be. Tests show the design stays fastened 68% more firmly than natural cartilage on bone.

“Another concern for knee implants is wear over time, both of the implant itself and the opposing cartilage,” Wiley said.

Other researchers have tried replacing damaged cartilage with knee implants made of metal or polyethylene, but because these materials are stiffer than cartilage they can chafe against other parts of the knee.

In wear tests, the researchers took artificial cartilage and natural cartilage and spun them against each other a million times, with a pressure similar to what the knee experiences during walking. Using a high-resolution X-ray scanning technique called micro-computed tomography (micro-CT), the scientists found that the surface of their lab-made version held up three times better than the real thing. Yet because the hydrogel mimics the smooth, slippery, cushiony nature of real cartilage, it protects other joint surfaces from friction as they slide against the implant.

Natural cartilage is remarkably durable stuff. But once damaged, it has limited ability to heal because it doesn’t have any blood vessels, Wiley said.

In the United States, osteoarthritis is twice as common today than it was a century ago. Surgery is an option when conservative treatments fail. Over the decades surgeons have developed a number of minimally invasive approaches, such as removing loose cartilage, or making holes to stimulate new growth, or transplanting healthy cartilage from a donor. But all of these methods require months of rehab, and some percentage of them fail over time.

Generally considered a last resort, total knee replacement is a proven way to relieve pain. But artificial joints don’t last forever, either. Particularly for younger patients who want to avoid major surgery for a device that will only need to be replaced again down the line, Wiley said, “there’s just not very good options out there.”

“I think this will be a dramatic change in treatment for people at this stage,” Wiley said.

This work was supported in part by Sparta Biomedical and by the Shared Materials Instrumentation Facility at Duke University. Wiley and Gall are shareholders in Sparta Biomedical.

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

A Synthetic Hydrogel Composite with a Strength and Wear Resistance Greater than Cartilage by Jiacheng Zhao, Huayu Tong, Alina Kirillova, William J. Koshut, Andrew Malek, Natasha C. Brigham, Matthew L. Becker, Ken Gall, Benjamin J. Wiley. Advanced Functional Materials DOI: https://doi.org/10.1002/adfm.202205662 First published: 04 August 2022

This paper is behind a paywall.

You can find Sparta Biomedical here.

Making longer lasting bandages with sound and bubbles

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This research into longer lasting bandages described in an August 12, 2022 news item on phys.org comes from McGill University (Montréal, Canada)

Researchers have discovered that they can control the stickiness of adhesive bandages using ultrasound waves and bubbles. This breakthrough could lead to new advances in medical adhesives, especially in cases where adhesives are difficult to apply such as on wet skin.

“Bandages, glues, and stickers are common bioadhesives that are used at home or in clinics. However, they don’t usually adhere well on wet skin. It’s also challenging to control where they are applied and the strength and duration of the formed adhesion,” says McGill University Professor Jianyu Li, who led the research team of engineers, physicists, chemists, and clinicians.

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Caption: Adhesive hydrogel applied on skin under ultrasound probe. Credit: Ran Huo and Jianyu Li

An August 12, 2022 McGill University news release (also on EurekAlert), which originated the news item, delves further into the work,

“We were surprised to find that by simply playing around with ultrasonic intensity, we can control very precisely the stickiness of adhesive bandages on many tissues,” says lead author Zhenwei Ma, a former student of Professor Li and now a Killam Postdoctoral Fellow at the University of British Columbia.

Ultrasound induced bubbles control stickiness

In collaboration with physicists Professor Outi Supponen and Claire Bourquard from the Institute of Fluid Dynamics at ETH Zurich, the team experimented with ultrasound induced microbubbles to make adhesives stickier. “The ultrasound induces many microbubbles, which transiently push the adhesives into the skin for stronger bioadhesion,” says Professor Supponen. “We can even use theoretical modeling to estimate exactly where the adhesion will happen.”

Their study, published in the journal Science, shows that the adhesives are compatible with living tissue in rats. The adhesives can also potentially be used to deliver drugs through the skin. “This paradigm-shifting technology will have great implications in many branches of medicine,” says University of British Columbia Professor Zu-hua Gao. “We’re very excited to translate this technology for applications in clinics for tissue repair, cancer therapy, and precision medicine.”

“By merging mechanics, materials and biomedical engineering, we envision the broad impact of our bioadhesive technology in wearable devices, wound management, and regenerative medicine,” says Professor Li, who is also a Canada Research Chair in Biomaterials and Musculoskeletal Health.

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

Controlled tough bioadhesion mediated by ultrasound by Zhenwei Ma, Claire Bourquard, Qiman Gao, Shuaibing Jiang, Tristan De Iure-Grimmel, Ran Huo, Xuan Li, Zixin He, Zhen Yang, Galen Yang, Yixiang Wang, Edmond Lam, Zu-hua Gao, Outi Supponen and Jianyu Li. Science 11 Aug 2022 Vol 377, Issue 6607 pp. 751-755 DOI: 10.1126/science.abn8699

This paper is behind a paywall.

I haven’t seen this before but it seems that one of the journal’s editors decided to add a standalone paragraph to hype some of the other papers about adhesives in the issue,

A sound way to make it stick

Tissue adhesives play a role in temporary or permanent tissue repair, wound management, and the attachment of wearable electronics. However, it can be challenging to tailor the adhesive strength to ensure reversibility when desired and to maintain permeability. Ma et al. designed hydrogels made of polyacrylamide or poly(N-isopropylacrylamide) combined with alginate that are primed using a solution containing nanoparticles of chitosan, gelatin, or cellulose nanocrystals (see the Perspective by Es Sayed and Kamperman). The application of ultrasound causes cavitation that pushes the primer molecules into the tissue. The mechanical interlocking of the anchors eventually results in strong adhesion between hydrogel and tissue without the need for chemical bonding. Tests on porcine or rat skin showed enhanced adhesion energy and interfacial fatigue resistance with on-demand detachment. —MSL

I like the wordplay and am guessing that MSL is:

Marc S. Lavine
Senior Editor
Education: BASc, University of Toronto; PhD, University of Cambridge
Areas of responsibility: Reviews; materials science, biomaterials, engineering

Diagnosing diseases by using nanomembranes to isolate biomarkers in tears

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How are they planning to make people cry on command or use a swab on your eyeball? In general, I like the idea of using tears instead of other bodily secretions but it’s the practicalities that have me questioning how this kind of diagnostic test could be implemented. In any event, here’s more from a July 20, 2022 news item on phys.org,

Going to the doctor might make you want to cry, and according to a new study, doctors could someday put those tears to good use. In ACS Nano, researchers report a nanomembrane system that harvests and purifies tiny blobs called exosomes from tears, allowing researchers to quickly analyze them for disease biomarkers. Dubbed iTEARS, the platform could enable more efficient and less invasive molecular diagnoses for many diseases and conditions, without relying solely on symptoms.

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A July 20, 2022 American Chemical Society (ACS) news release (also on EurekAlert), which originated the news item, explains the work in more detail,

Diagnosing diseases often hinges on assessing a patient’s symptoms, which can be unobservable at early stages, or unreliably reported. Identifying molecular clues in samples from patients, such as specific proteins or genes from vesicular structures called exosomes, could improve the accuracy of diagnoses. However, current methods for isolating exosomes from these samples require long, complicated processing steps or large sample volumes. Tears are well-suited for sample collection because the fluid can be collected quickly and non-invasively, though only tiny amounts can be harvested at a time. So, Luke Lee, Fei Liu and colleagues wondered if a nanomembrane system, which they originally developed for isolating exosomes from urine and plasma, could allow them to quickly obtain these vesicles from tears and then analyze them for disease biomarkers.

The team modified their original system to handle the low volume of tears. The new system, called “Incorporated Tear Exosomes Analysis via Rapid-isolation System” (iTEARS), separated out exosomes in just 5 minutes by filtering tear solutions over nanoporous membranes with an oscillating pressure flow to reduce clogging. Proteins from the exosomes could be tagged with fluorescent probes while they were still on the device and then transferred to other instruments for further analysis. Nucleic acids were also extracted from the exosomes and analyzed. The researchers successfully distinguished between healthy controls and patients with various types of dry eye disease based on a proteomic assessment of extracted proteins. Similarly, iTEARS enabled researchers to observe differences in microRNAs between patients with diabetic retinopathy and those that didn’t have the eye condition, suggesting that the system could help track disease progression. The team says that this work could lead to a more sensitive, faster and less invasive molecular diagnosis of various diseases — using only tears.

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

Discovering the Secret of Diseases by Incorporated Tear Exosomes Analysis via Rapid-Isolation System: iTEARS by Liang Hu, Ting Zhang, Huixiang Ma, Youjin Pan, Siyao Wang, Xiaoling Liu, Xiaodan Dai, Yuyang Zheng, Luke P. Lee, and Fei Liu. ACS Nano 2022, XXXX, XXX, XXX-XXX DOI: https://doi.org/10.1021/acsnano.2c02531 Publication Date:July 20, 2022 © 2022 American Chemical Society

This paper appears to be open access.

A CRISPR (clustered regularly interspaced short palindromic repeats) anniversary

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June 2022 was the 10th anniversary of the publication of a study the paved the way for CRISPR-Cas9 gene editing and Sophie Fessl’s June 28, 2022 article for The Scientist offers a brief history (Note: Links have been removed),

Ten years ago, Emmanuelle Charpentier and Jennifer Doudna published the study that paved the way for a new kind of genome editing: the suite of technologies now known as CRISPR. Writing in [the journal] Science, they adapted an RNA-mediated bacterial immune defense into a targeted DNA-altering system. “Our study . . . highlights the potential to exploit the system for RNA-programmable genome editing,” they conclude in the abstract of their paper—a potential that, in the intervening years, transformed the life sciences. 

From gene drives to screens, and diagnostics to therapeutics, CRISPR nucleic acids and the Cas enzymes with which they’re frequently paired have revolutionized how scientists tinker with DNA and RNA. … altering the code of life with CRISPR has been marred by ethical concerns. Perhaps the most prominent example was when Chinese scientist He Jiankui created the first gene edited babies using CRISPR/Cas9 genome editing. Doudna condemned Jiankui’s work, for which he was jailed, as “risky and medically unnecessary” and a “shocking reminder of the scientific and ethical challenges raised by this powerful technology.” 

There’s also the fact that legal battles over who gets to claim ownership of the system’s many applications have persisted almost as long as the technology has been around. Both Doudna and Charpentier’s teams from the University of California, Berkeley, and the University of Vienna and a team led by the Broad Institute’s Feng Zhang claim to be the first to have adapted CRISPR-Cas9 for gene editing in complex cells (eukaryotes). Patent offices in different countries have reached varying decisions, but in the US, the latest rulings say that the Broad Institute of MIT [Massachusetts Institute of Technology] and Harvard retains intellectual property of using CRISPR-Cas9 in eukaryotes, while Emmanuelle Charpentier, the University of California, and the University of Vienna maintain their original patent over using CRISPR-Cas9 for editing in vitro and in prokaryotes. 

Still, despite the controversies, the technique continues to be explored academically and commercially for everything from gene therapy to crop improvement. Here’s a look at seven different ways scientists have utilized CRISPR.

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Fessl goes on to give a brief overview of CRISPR and gene drives, genetic screens, diagnostics, including COVID-19 tests, gene therapy, therapeutics, crop and livestock improvement, and basic research.

For anyone interested in the ethical issues (with an in depth look at the Dr. He Jiankui story), I suggest reading either or both Eben Kirksey’s 2020 book, “The Mutant Project; Inside the Global Race to Genetically Modify Humans,”

An anthropologist visits the frontiers of genetics, medicine, and technology to ask: Whose values are guiding gene editing experiments? And what does this new era of scientific inquiry mean for the future of the human species?

“That rare kind of scholarship that is also a page-turner.”
—Britt Wray, author of Rise of the Necrofauna

At a conference in Hong Kong in November 2018, Dr. He Jiankui announced that he had created the first genetically modified babies—twin girls named Lulu and Nana—sending shockwaves around the world. A year later, a Chinese court sentenced Dr. He to three years in prison for “illegal medical practice.”

As scientists elsewhere start to catch up with China’s vast genetic research program, gene editing is fueling an innovation economy that threatens to widen racial and economic inequality. Fundamental questions about science, health, and social justice are at stake: Who gets access to gene editing technologies? As countries loosen regulations around the globe, from the U.S. to Indonesia, can we shape research agendas to promote an ethical and fair society?

Eben Kirksey takes us on a groundbreaking journey to meet the key scientists, lobbyists, and entrepreneurs who are bringing cutting-edge genetic engineering tools like CRISPR—created by Nobel Prize-winning biochemists Jennifer Doudna and Emmanuelle Charpentier—to your local clinic. He also ventures beyond the scientific echo chamber, talking to disabled scholars, doctors, hackers, chronically-ill patients, and activists who have alternative visions of a genetically modified future for humanity.

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and/or Kevin Davies’s 2020 book, “Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing,”

One of the world’s leading experts on genetics unravels one of the most important breakthroughs in modern science and medicine. 

If our genes are, to a great extent, our destiny, then what would happen if mankind could engineer and alter the very essence of our DNA coding? Millions might be spared the devastating effects of hereditary disease or the challenges of disability, whether it was the pain of sickle-cell anemia to the ravages of Huntington’s disease.

But this power to “play God” also raises major ethical questions and poses threats for potential misuse. For decades, these questions have lived exclusively in the realm of science fiction, but as Kevin Davies powerfully reveals in his new book, this is all about to change.

Engrossing and page-turning, Editing Humanity takes readers inside the fascinating world of a new gene editing technology called CRISPR, a high-powered genetic toolkit that enables scientists to not only engineer but to edit the DNA of any organism down to the individual building blocks of the genetic code.

Davies introduces readers to arguably the most profound scientific breakthrough of our time. He tracks the scientists on the front lines of its research to the patients whose powerful stories bring the narrative movingly to human scale.

Though the birth of the “CRISPR babies” in China made international news, there is much more to the story of CRISPR than headlines seemingly ripped from science fiction. In Editing Humanity, Davies sheds light on the implications that this new technology can have on our everyday lives and in the lives of generations to come.

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Kevin Davies is the executive editor of The CRISPR Journal and the founding editor of Nature Genetics. He holds an MA in biochemistry from the University of Oxford and a PhD in molecular genetics from the University of London. He is the author of Cracking the Genome, The $1,000 Genome, and co-authored a new edition of DNA: The Story of the Genetic Revolution with Nobel Laureate James D. Watson and Andrew Berry. In 2017, Kevin was selected for a Guggenheim Fellowship in science writing.

I’ve read both books and while some of the same ground is covered, the perspectives diverge somewhat. Both authors offer a more nuanced discussion of the issues than was the case in the original reporting about Dr. He’s work.