Category Archives: medicine

Biobots (also known as biohybrid robots) occupy a third state between life and death?

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I got a bit of a jolt from this September 12, 2024 essay by Peter A Noble, affiliate professor of microbiology at the University of Washington, and Alex Pozhitkov, senior technical lead of bioinformatics, Irell & Manella Graduate School of Biological Sciences at City of Hope, for The Conversation (h/t Sept. 12, 2024 item on phys.org), Note: Links have been removed,

Life and death are traditionally viewed as opposites. But the emergence of new multicellular life-forms from the cells of a dead organism introduces a “third state” that lies beyond the traditional boundaries of life and death.

Usually, scientists consider death to be the irreversible halt of functioning of an organism as a whole. However, practices such as organ donation highlight how organs, tissues and cells can continue to function even after an organism’s demise. This resilience raises the question: What mechanisms allow certain cells to keep working after an organism has died?

We are researchers who investigate what happens within organisms after they die. In our recently published review, we describe how certain cells – when provided with nutrients, oxygen, bioelectricity or biochemical cues – have the capacity to transform into multicellular organisms with new functions after death.

Life, death and emergence of something new

The third state challenges how scientists typically understand cell behavior. While caterpillars metamorphosing into butterflies, or tadpoles evolving into frogs, may be familiar developmental transformations, there are few instances where organisms change in ways that are not predetermined. Tumors, organoids and cell lines that can indefinitely divide in a petri dish, like HeLa cells [cervical cancer cells taken from Henrietta Lacks without her knowledge], are not considered part of the third state because they do not develop new functions.

However, researchers found that skin cells extracted from deceased frog embryos were able to adapt to the new conditions of a petri dish in a lab, spontaneously reorganizing into multicellular organisms called xenobots [emphasis mine]. These organisms exhibited behaviors that extend far beyond their original biological roles. Specifically, these xenobots use their cilia – small, hair-like structures – to navigate and move through their surroundings, whereas in a living frog embryo, cilia are typically used to move mucus.

Xenobots are also able to perform kinematic self-replication, meaning they can physically replicate their structure and function without growing. This differs from more common replication processes that involve growth within or on the organism’s body.

Researchers have also found that solitary human lung cells can self-assemble into miniature multicellular organisms that can move around. These anthrobots [emphasis mine] behave and are structured in new ways. They are not only able to navigate their surroundings but also repair both themselves and injured neuron cells placed nearby.

Taken together, these findings demonstrate the inherent plasticity of cellular systems and challenge the idea that cells and organisms can evolve only in predetermined ways. The third state suggests that organismal death may play a significant role in how life transforms over time.

…

I had not realized that xenobots are derived from dead frog embryos something I missed when mentioning or featuring them in previous stories, the latest in a September 13, 2024 posting, which also mentions anthrobots. Previous stories were published in a June 21, 2021 posting about xenobots 2.0 and their ability to move and a June 8, 2022 posting about their ability to reproduce. Thank you to the authors for relieving me of some of my ignorance.

For some reason I was expecting mention, brief or otherwise, of ethical or social implications but the authors offered this instead, from their September 12, 2024 essay, Note: Links have been removed,

Implications for biology and medicine

The third state not only offers new insights into the adaptability of cells. It also offers prospects for new treatments.

For example, anthrobots could be sourced from an individual’s living tissue to deliver drugs without triggering an unwanted immune response. Engineered anthrobots injected into the body could potentially dissolve arterial plaque in atherosclerosis patients and remove excess mucus in cystic fibrosis patients.

Importantly, these multicellular organisms have a finite life span, naturally degrading after four to six weeks. This “kill switch” prevents the growth of potentially invasive cells.

A better understanding of how some cells continue to function and metamorphose into multicellular entities some time after an organism’s demise holds promise for advancing personalized and preventive medicine.

I look forward to hearing about the third state and about any ethical or social issues that may arise from it.

Painless, wearable patch for continuous smartphone monitoring of critical health data from Canadian researchers

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A June 18, 2024 McMaster University news release also on EurekAlert and on the University of Waterloo news website) by Wade Hemsworth describes the ‘Wearable Aptalyzer’, Note: A link has been removed,

Researchers at two Ontario universities have developed a pain-free, wearable sensor that can continuously monitor levels of blood sugar, lactates and other critical health indicators for weeks at a time, sending results to a smartphone or other device.

The Wearable Aptalyzer, created by a team featuring researchers from McMaster University and the University of Waterloo, uses an array of tiny hydrogel needles that penetrate just deeply enough to reach the interstitial fluid beneath the skin, but not far enough to reach the blood vessels or nerves.

The patch gathers and sends information about markers in the fluid to an electronic device such as a smart phone, creating an ongoing record of patterns in the rise and fall of critical biomarkers.

Once developed for clinical use, it will allow health professionals to access current medical information that today is available only retrospectively after blood tests and lab work.

The new technology could make monitoring the markers of specific diseases and conditions as simple as tracking pulse, blood pressure and other vital signs. The researchers describe the work in a new paper published today [version of record published May 16, 2024] in the journal Advanced Materials.

“This technology can provide real-time information about both chronic and acute health conditions, allowing caregivers to act more quickly and with greater certainty when they see trouble,” says one of the paper’s two corresponding authors, McMaster’s Leyla Soleymani,  professor of Engineering Physics who holds the Canada Research Chair in Miniaturized Biomedical Devices.

“The Wearable Aptalyzer is a general platform, meaning it can measure any biomarkers of interest, ranging from diabetes to cardiac biomarkers,” says corresponding author Mahla Poudineh, an assistant professor and director of the IDEATION Lab in the Department of Electrical and Computer Engineering at Waterloo. “Continuous health monitoring doesn’t just help catch diseases early and track how treatments are working. It also helps us understand how diseases happen, filling in important gaps in our knowledge that need attention.”

A user would apply and remove the patch much like a small bandage held in place with barely visible, soft hooks. The convenience is likely to appeal to diabetics and others who test themselves by drawing samples of blood or by using solid monitoring patches with metal needles that penetrate deeper and rely on less specific electrodes.

The greatest promise of the technology, though, may lie in its ability to produce weeks’ worth of meaningful results at a time, and to transmit data to electronic devices experts can read without sophisticated equipment.

Among the other potential applications, the Wearable Aptalyzer can make it possible to read and send data that signals cardiac events in real time, making it a potentially valuable tool for monitoring patients in ambulances and emergency rooms, and during treatment. The same technology can readily be adapted to monitor the progress and treatment of many chronic illnesses, including cancers, the researchers say.

The technology holds promise for improving care use in remote care settings, such as northern Indigenous communities set far from hospitals, or on space flights. Data from the Wearable Aptalyzer can signal trouble before symptoms become apparent, making it more likely patients can receive timely care.

The next steps in developing the technology for broad use include human trials and regulatory approvals. The researchers are seeking partners to help commercialize the technology.

The paper’s lead authors are Fatemeh Bakhshandeh of McMaster and Hanjia Zheng of Waterloo. Together with Soleymani and Poudineh, their co-authors are Waterloo’s Sadegh Sadeghzadeh, Irfani Ausri, Fatemeh Keyvani, Fasih Rahman, Joe Quadrilatero, and Juewen Liu, and McMaster’s Nicole Barra, Payel Sen, and Jonathan Schertzer.

Caption: The monitoring patch as compared to a 25-cent coin for scale. Credit: University of Waterloo

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

Wearable Aptalyzer Integrates Microneedle and Electrochemical Sensing for In Vivo Monitoring of Glucose and Lactate in Live Animals by Fatemeh Bakhshandeh, Hanjia Zheng, Nicole G. Barra, Sadegh Sadeghzadeh, Irfani Ausri, Payel Sen, Fatemeh Keyvani, Fasih Rahman, Joe Quadrilatero, Juewen Liu, Jonathan D. Schertzer, Leyla Soleymani, Mahla Poudineh. Advanced Materials 2313743 DOI: https://doi.org/10.1002/adma.202313743 First online version of record published: 16 May 2024

This paper is open access.

New approach to cartilage regeneration

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Not long after announcing their new work on cartilage and ‘dancing molecules’, Samuel I. Stupp and his team at Northwestern University (Chicago, Illinois) have announced work with a new material that does not have dancing molecules in a study using animal models. It’s here in an August 5, 02024 Northwestern University news release (also on EurekAlert and on SciTechDaily and received by email) by Amanda Morris, Note: Links have been removed,

Northwestern University scientists have developed a new bioactive material that successfully regenerated high-quality cartilage in the knee joints of a large-animal model.

Although it looks like a rubbery goo, the material is actually a complex network of molecular components, which work together to mimic cartilage’s natural environment in the body. 

In the new study, the researchers applied the material to damaged cartilage in the animals’ knee joints. Within just six months, the researchers observed evidence of enhanced repair, including the growth of new cartilage containing the natural biopolymers (collagen II and proteoglycans), which enable pain-free mechanical resilience in joints.

With more work, the researchers say the new material someday could potentially be used to prevent full knee replacement surgeries, treat degenerative diseases like osteoarthritis and repair sports-related injuries like ACL [anterior cruciate ligament] tears.

The study will be published during the week of August 5 [2024] in the Proceedings of the National Academy of Sciences.

“Cartilage is a critical component in our joints,” said Northwestern’s Samuel I. Stupp, who led the study. “When cartilage becomes damaged or breaks down over time, it can have a great impact on people’s overall health and mobility. The problem is that, in adult humans, cartilage does not have an inherent ability to heal. Our new therapy can induce repair in a tissue that does not naturally regenerate. We think our treatment could help address a serious, unmet clinical need.”

A pioneer of regenerative nanomedicine, Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology and its affiliated center, the Center for Regenerative Nanomedicine. Stupp has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine. Jacob Lewis, a former Ph.D. student in Stupp’s laboratory, is the paper’s first author.

What’s in the material?

The new study follows recently published work from the Stupp laboratory, in which the team used “dancing molecules” to activate human cartilage cells to boost the production of proteins that build the tissue matrix. Instead of using dancing molecules, the new study evaluates a hybrid biomaterial also developed in Stupp’s lab. The new biomaterial comprises two components: a bioactive peptide that binds to transforming growth factor beta-1 (TGFb-1) — an essential protein for cartilage growth and maintenance — and modified hyaluronic acid, a natural polysaccharide present in cartilage and the lubricating synovial fluid in joints. 

“Many people are familiar with hyaluronic acid because it’s a popular ingredient in skincare products,” Stupp said. “It’s also naturally found in many tissues throughout the human body, including the joints and brain. We chose it because it resembles the natural polymers found in cartilage.”

Stupp’s team integrated the bioactive peptide and chemically modified hyaluronic acid particles to drive the self-organization of nanoscale fibers into bundles that mimic the natural architecture of cartilage. The goal was to create an attractive scaffold for the body’s own cells to regenerate cartilage tissue. Using bioactive signals in the nanoscale fibers, the material encourages cartilage repair by the cells, which populate the scaffold.

Clinically relevant to humans

To evaluate the material’s effectiveness in promoting cartilage growth, the researchers tested it in sheep with cartilage defects in the stifle joint, a complex joint in the hind limbs similar to the human knee. This work was carried out in the laboratory of Mark Markel in the School of Veterinary Medicine at the University of Wisconsin–Madison. 

According to Stupp, testing in a sheep model was vital. Much like humans, sheep cartilage is stubborn and incredibly difficult to regenerate. Sheep stifles and human knees also have similarities in weight bearing, size and mechanical loads.

“A study on a sheep model is more predictive of how the treatment will work in humans,” Stupp said. “In other smaller animals, cartilage regeneration occurs much more readily.”

In the study, researchers injected the thick, paste-like material into cartilage defects, where it transformed into a rubbery matrix. Not only did new cartilage grow to fill the defect as the scaffold degraded, but the repaired tissue was consistently higher quality compared to the control.

A lasting solution

In the future, Stupp imagines the new material could be applied to joints during open-joint or arthroscopic surgeries. The current standard of care is microfracture surgery, during which surgeons create tiny fractures in the underlying bone to induce new cartilage growth.

“The main issue with the microfracture approach is that it often results in the formation of fibrocartilage — the same cartilage in our ears — as opposed to hyaline cartilage, which is the one we need to have functional joints,” Stupp said. “By regenerating hyaline cartilage, our approach should be more resistant to wear and tear, fixing the problem of poor mobility and joint pain for the long term while also avoiding the need for joint reconstruction with large pieces of hardware.”

The study, “A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model,” was supported by the Mike and Mary Sue Shannon Family Fund for Bio-Inspired and Bioactive Materials Systems for Musculoskeletal Regeneration.

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

A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model by Jacob A. Lewis, Brett Nemke, Yan Lu, Nicholas A. Sather, Mark T. McClendon, Michael Mullen, Shelby C. Yuan, Sudheer K. Ravuri, Jason A. Bleedorn, Marc J. Philippon, Johnny Huard, Mark D. Markel, and Samuel I. Stupp. Proceedings ot the National Academy of Sciences (PNAS) 121 (33) e2405454121 DOI: https://doi.org/10.1073/pnas.2405454121 August 6, 2024

This paper is behind a paywall.

Healing cartilage damage with ‘dancing molecules’

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A July 26, 2024 Northwestern University (Chicago, Illinois) news release (also on EurekAlert) by Amanda Morris describes a new application for ‘dancing molecules’, Note 1: Links have been removed; Note 2: These are ‘in vitro’ (petri dish) experiments ,

In November 2021, Northwestern University researchers introduced an injectable new therapy, which harnessed fast-moving “dancing molecules,” to repair tissues and reverse paralysis after severe spinal cord injuries.

Now, the same research group has applied the therapeutic strategy to damaged human cartilage cells. In the new study, the treatment activated the gene expression necessary to regenerate cartilage within just four hours. And, after only three days, the human cells produced protein components needed for cartilage regeneration.

The researchers also found that, as the molecular motion increased, the treatment’s effectiveness also increased. In other words, the molecules’ “dancing” motions were crucial for triggering the cartilage growth process.

…

“When we first observed therapeutic effects of dancing molecules, we did not see any reason why it should only apply to the spinal cord,” said Northwestern’s Samuel I. Stupp, who led the study. “Now, we observe the effects in two cell types that are completely disconnected from one another — cartilage cells in our joints and neurons in our brain and spinal cord. This makes me more confident that we might have discovered a universal phenomenon. It could apply to many other tissues.”

An expert in regenerative nanomedicine, Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology and its affiliated center, the Center for Regenerative Nanomedicine. Stupp has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine. Shelby Yuan, a graduate student in the Stupp laboratory, was primary author of the study.

Big problem, few solutions

As of 2019, nearly 530 million people around the globe were living with osteoarthritis, according to the World Health Organization. A degenerative disease in which tissues in joints break down over time, osteoarthritis is a common health problem and leading cause of disability.

In patients with severe osteoarthritis, cartilage can wear so thin that joints essentially transform into bone on bone — without a cushion between. Not only is this incredibly painful, patients’ joints also can no longer properly function. At that point, the only effective treatment is a joint replacement surgery, which is expensive and invasive.

“Current treatments aim to slow disease progression or postpone inevitable joint replacement,” Stupp said. “There are no regenerative options because humans do not have an inherent capacity to regenerate cartilage in adulthood.”

What are ‘dancing molecules’?

Stupp and his team posited that “dancing molecules” might encourage the stubborn tissue to regenerate. Previously invented in Stupp’s laboratory, dancing molecules are assemblies that form synthetic nanofibers comprising tens to hundreds of thousands of molecules with potent signals for cells. By tuning their collective motions through their chemical structure, Stupp discovered the moving molecules could rapidly find and properly engage with cellular receptors, which also are in constant motion and extremely crowded on cell membranes.

“We are beginning to see the tremendous breadth of conditions that this fundamental discovery on ‘dancing molecules’ could apply to.” — Samuel I. Stupp, materials scientist

Once inside the body, the nanofibers mimic the extracellular matrix of the surrounding tissue. By matching the matrix’s structure, mimicking the motion of biological molecules and incorporating bioactive signals for the receptors, the synthetic materials are able to communicate with cells.

“Cellular receptors constantly move around,” Stupp said. “By making our molecules move, ‘dance’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”

Motion matters

In the new study, Stupp and his team looked to the receptors for a specific protein critical for cartilage formation and maintenance. To target this receptor, the team developed a new circular peptide that mimics the bioactive signal of the protein, which is called transforming growth factor beta-1 (TGFb-1).

Then, the researchers incorporated this peptide into two different molecules that interact to form supramolecular polymers in water, each with the same ability to mimic TGFb-1. The researchers designed one supramolecular polymer with a special structure that enabled its molecules to move more freely within the large assemblies. The other supramolecular polymer, however, restricted molecular movement.

“We wanted to modify the structure in order to compare two systems that differ in the extent of their motion,” Stupp said. “The intensity of supramolecular motion in one is much greater than the motion in the other one.”

Although both polymers mimicked the signal to activate the TGFb-1 receptor, the polymer with rapidly moving molecules was much more effective. In some ways, they were even more effective than the protein that activates the TGFb-1 receptor in nature.

“After three days, the human cells exposed to the long assemblies of more mobile molecules produced greater amounts of the protein components necessary for cartilage regeneration,” Stupp said. “For the production of one of the components in cartilage matrix, known as collagen II, the dancing molecules containing the cyclic peptide that activates the TGF-beta1 receptor were even more effective than the natural protein that has this function in biological systems.”

What’s next?

Stupp’s team is currently testing these systems in animal studies and adding additional signals to create highly bioactive therapies.

“With the success of the study in human cartilage cells, we predict that cartilage regeneration will be greatly enhanced when used in highly translational pre-clinical models,” Stupp said. “It should develop into a novel bioactive material for regeneration of cartilage tissue in joints.”

Stupp’s lab is also testing the ability of dancing molecules to regenerate bone — and already has promising early results, which likely will be published later this year. Simultaneously, he is testing the molecules in human organoids to accelerate the process of discovering and optimizing therapeutic materials.  

Stupp’s team also continues to build its case to the Food and Drug Administration, aiming to gain approval for clinical trials to test the therapy for spinal cord repair.

“We are beginning to see the tremendous breadth of conditions that this fundamental discovery on ‘dancing molecules’ could apply to,” Stupp said. “Controlling supramolecular motion through chemical design appears to be a powerful tool to increase efficacy for a range of regenerative therapies.”

The study, “Supramolecular motion enables chondrogenic bioactivity of a cyclic peptide mimetic of transforming growth factor-β1,” was supported by a gift from Mike and Mary Sue Shannon to Northwestern University for research on musculoskeletal regeneration at the Center for Regenerative Nanomedicine of the Simpson Querrey Institute for BioNanotechnology.

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

Supramolecular Motion Enables Chondrogenic Bioactivity of a Cyclic Peptide Mimetic of Transforming Growth Factor-β1 by Shelby C. Yuan, Zaida Álvarez, Sieun Ruth Lee, Radoslav Z. Pavlović, Chunhua Yuan, Ethan Singer, Steven J. Weigand, Liam C. Palmer, Samuel I. Stupp. Journal of the American Chemical Society Vol 146/Issue 31 (or J. Am. Chem. Soc. 2024, 146, 31, 21555–21567) DOI: https://doi.org/10.1021/jacs.4c05170 Published July 25, 2024 Copyright © 2024 American Chemical Society

This paper is behind a paywall.

Regenerate damaged skin, cartilage, and bone with help from silkworms?

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A July 24, 2024 news item on phys.org highlights research into regenerating bone and skin, Note: A link has been removed,

Researchers are exploring new nature-based solutions to stimulate skin and bone repair.

In the cities of Trento and Rovereto in northern Italy and Bangkok in Thailand, scientists are busy rearing silkworms in nurseries. They’re hoping that the caterpillars’ silk can regenerate human tissue. For such a delicate medical procedure, only thoroughbreds will do.

“By changing the silkworm, you can change the chemistry,” said Professor Antonella Motta, a researcher in bioengineering at the University of Trento in Italy. That could, in turn, affect clinical outcomes. “This means the quality control should be very strict.”

Silk has been used in surgical sutures for hundreds of years and is now emerging as a promising nature-based option for triggering human tissue to self-regenerate. Researchers are also studying crab, shrimp and mussel shells and squid skin and bone for methods of restoring skin, bone and cartilage. This is particularly relevant as populations age.

…

A July 23, 2024 article by Gareth Willmer for Horizon Magazine, the EU (European Union) research & innovation magazine, which originated the news item, provides more details,

‘Tissue engineering is a new strategy to solve problems caused by pathologies or trauma to the organs, as an alternative to transplants or artificial device implantations,’ said Motta, noting that these interventions can often fail or expire. ‘The idea is to use the natural ability of our bodies to rebuild the tissue.’

The research forms part of the five-year EU-funded SHIFT [Shaping Innovative Designs for Sustainable Tissue Engineering Products] project that Motta coordinates, which includes universities in Europe, as well as partners in Asia and Australia. Running until 2026, the research team aim to scale up methods for regenerating skin, bone and cartilage using bio-based polymers and to get them ready for clinical trials. The goal is to make them capable of repairing larger wounds and tissue damage.

The research builds on work carried out under the earlier REMIX [Regenerative Medicine Innovation Crossing – Research and Innovation Staff Exchange in Regenerative Medicine] project, also funded by the EU, which made important advances in understanding the different ways in which these biomaterials could be used. 

Building a scaffold

Silk, for instance, can be used to form a “scaffold” in damaged tissue that then activates cells to form new tissue and blood vessels. The process could be used to treat conditions such as diabetic ulcers and lower back pain caused by spinal disc degeneration. The SHIFT team have been exploring minimally invasive procedures for treatment, such as hydrogels that can be applied directly to the skin, or injected into bone or cartilage.

The approaches using both silkworms and some of the marine organisms have great potential, said Motta. 

‘We have three or four systems with different materials that are really promising,’ she said. By the end of SHIFT, the goal is to have two or three prototypes that can be developed together with start-up and spin-off companies created in collaboration with the project. 

One of the principles of the SHIFT team has been been exploring how best to harness the concept of a circular economy. For example, they are looking into how waste products from the textile and food industries can be reused in these treatments.

Yet with complicated interactions at a microscale, and the need to prevent the body from rejecting foreign materials, such tissue engineering is a big challenge. 

‘The complexity is high because the nature of biology is not easy,’ said Motta. ‘We cannot change the language of the cells, but instead have to learn to speak the same language as them.’

But she firmly believes the nature-based rather than synthetic approach is the way to go and thinks treatments harnessing SHIFT’s methods could become available in the early 2030s. 

‘I believe in this approach,’ said Motta. ‘Bone designed by nature is the best bone we can have.’

Skin care

Another EU-funded project known as SkinTERM [Skin Tissue Engineering and Regenerative Medicine: From skin repair to regeneration], which runs for almost five years until mid-2025, is also looking at novel ways to get tissue to self-regenerate, focusing on skin. To treat burns and other surface wounds today, a thin layer of skin is sometimes grafted from another part of the body. This can cause the appearance of disfiguring scars and the patient’s mobility may be impacted when the tissue contracts as it heals. Current skin-grafting methods can also be painful.

The SkinTERM team are therefore investigating how inducing the healing process in the networks of cells surrounding a wound might enable skin to repair itself. 

‘We could do much better if we move towards regeneration,’ said Dr Willeke Daamen, who coordinates SkinTERM as a researcher in soft tissue regeneration at Radboud University in Nijmegen, the Netherlands. ‘The ultimate goal would be to get the same situation before and after being wounded.’

Researchers are studying a particular mammal – the spiny mouse – which has a remarkable ability to heal without scarring. It is able to self-repair damage to other tissues like the heart and spinal cord too. This is also true of early foetal skin.

The team are examining these systems to learn more about how they work and the processes occurring in the area around cells, known as the extracellular matrix. They hope to identify factors that might have a role in the regenerative process, and test how it might be induced in humans. 

Kick-start

‘We’ve been trying to learn from those systems on how to kick-start such processes,’ said Daamen. ‘We’ve made progress in what kinds of compounds seem at least in part to be responsible for a regenerative response.’

Many lines of research are being carried out among a new generation of multidisciplinary scientists being trained in this area, and a lot has already been achieved, said Daamen.

They have managed to create scaffolds using different components related to skin regeneration, such as the proteins collagen and elastin. They have also collected a vast amount of data on genes and proteins with potential roles in regeneration. Their role will be further tested by using them on scar-prone cells cultured on collagen scaffolds.

‘The mechanisms are complex,’ said Dr Bouke Boekema, a senior researcher at the Association of Dutch Burn Centres in Beverwijk, the Netherlands, and vice-coordinator of SkinTERM. 

‘If you find a mechanism, the idea is that maybe you can tune it so that you can stimulate it. But there’s not necessarily one magic bullet.’

By the end of the project next year, Boekema hopes the research could result in some medical biomaterial options to test for clinical use. ‘It would be nice if several prototypes were available for testing to see if they improve outcomes in patients.’

Research in this article was funded by the Marie Skłodowska-Curie Actions (MSCA). The views of the interviewees don’t necessarily reflect those of the European Commission. If you liked this article, please consider sharing it on social media.

Interesting. Over these last few months, I’ve been stumbling across more than my usual number of regenerative medicine stories.

Grow better organ-like tissues by using silkworms

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A June 6, 2024 news item on ScienceDaily describes a technique, which could lead to better organ-on-a-chip (OOC) systems,

Biomedical engineers at Duke University [North Carolina, US] have developed a silk-based, ultrathin membrane that can be used in organ-on-a-chip models to better mimic the natural environment of cells and tissues within the body. When used in a kidney organ-on-a-chip platform, the membrane helped tissues grow to recreate the functionality of both healthy and diseased kidneys.

By allowing the cells to grow closer together, this new membrane helps researchers to better control the growth and function of the key cells and tissues of any organ, enabling them to more accurately model a wide range of diseases and test therapeutics.

…

A June 6, 2024 Duke University news release (also on EurekAlert), which originated the news item, describes the OOC system and the problem these researchers are seeking to solve,

Often no larger than a USB flash drive, organ-on-a-chip (OOC) systems have revolutionized how researchers study the underlying biology of the human body, whether it’s creating dynamic models of tissue structures, studying organ functions or modeling diseases. These platforms are designed to stimulate cell growth and differentiation in a way that best mimics the organ of interest. Researchers can even populate these tools with human stem cells to generate patient-specific organ models for pre-clinical studies.

But as the technology has evolved, problems in the chip’s design have also emerged –– most notably with the materials used to create the membranes that form the support structure for the specialized cells to grow on. These membranes are typically composed of polymers that don’t degrade, creating a permanent barrier between cells and tissues. While the extracellular membranes in human organs are often less than one micron thick, these polymer membranes are anywhere from 30 to 50 microns, hindering communication between cells and limiting cell growth.

“We want to handle the tissues in these chips just like a pathologist would handle biopsy samples or even living tissues from a patient, but this wasn’t possible with the standard polymer membranes because the extra thickness prevented the cells from forming structures that more closely resemble tissues in the human body,” said Samira Musah, an assistant professor of biomedical engineering and medicine at Duke. “We thought, ‘Wouldn’t it be nice if we could get a protein-based material that mimics the structure of these natural membranes and is thin enough for us to slice and study?’”

This question led Musah and George (Xingrui) Mou, a PhD student in Musah’s lab and first author on the paper, to silk fibroin, a protein created by silkworms that can be electronically spun into a membrane. When examined under a microscope, silk fibroin looks like spaghetti or a Jackson Pollock painting. Made out of long, intertwining fibers, the porous material better mimics the structure of the extracellular matrix found in human organs, and it has previously been used to create scaffolds for purposes like wound healing.

“The silk fibroin allowed us to bring the membrane thickness down from 50 microns to five or fewer, which gets us an order of magnitude closer to what you’d see in a living organism,” explained Mao.

To test this new membrane, Musah and Mao applied the material to their kidney chip models. Made out of a clear plastic and roughly the size of a quarter, this OOC platform is meant to resemble a cross section of a human kidney––specifically the glomerular capillary wall, a key structure in the organ made from clusters of blood vessels that is responsible for filtering blood.

Once the membrane was in place, the team added human induced pluripotent stem cell derivatives into the chip. They observed that these cells were able to send signals across the ultrathin membrane, which helped the cells differentiate into glomerular cells, podocytes and vascular endothelial cells. The platform also triggered the development of endothelial fenestrations in the growing tissue, which are holes that allow for the passage of fluid between the cellular layers.

By the end of the test, these different kidney cell types had assembled into a glomerular capillary wall and could efficiently filter molecules by size.

“The new microfluidic chip system’s ability to simulate in vivo-like tissue-tissue interfaces and induce the formation of specialized cells, such as fenestrated endothelium and mature glomerular podocytes from stem cells, holds significant potential for advancing our understanding of human organ development, disease progression, and therapeutic development,” said Musah.

As they continue to optimize their model, Musah and colleagues are hoping to use this technology to better understand the mechanisms behind kidney disease. Despite affecting more than 15 percent of American adults, researchers lack effective models for the disease. Patients are also often not diagnosed until the kidneys have been substantially damaged, and they are often required to undergo dialysis or receive a kidney transplant.

“Using this platform to develop kidney disease models could help us discover new biomarkers of the disease,” said Mao. “This could also be used to help us screen for drug candidates for several kidney disease models. The possibilities are very exciting.”

“This technology has implications for all organ-on-a-chip models,” said Musah. “Our tissues are made up of membranes and interfaces, so you can imagine using this membrane to improve models of other organs, like the brain, liver, and lungs, or other disease states. That’s where the power of our platform really lies.”

This work was supported by a Whitehead Scholarship in Biomedical Research, Chair’s Research Award from the Department of Medicine at Duke University, MEDx Pilot Grant on Biomechanics in Injury or Injury Repair, Burroughs Wellcome Fund PDEP Career Transition Ad Hoc Award, Duke Incubation Fund from the Duke Innovation & Entrepreneurship Initiative, Genetech Research Award, a George M. O’Brien Kidney Center Pilot Grant (P30 DK081943), an NIH [National Institutes of Health] Director’s New Innovator Grant (DP2DK138544).

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

An Ultrathin Membrane Mediates Tissue-Specific Morphogenesis and Barrier Function in a Human Kidney Chip by Xingrui Mou, Jessica Shah, Yasmin Roye, Carolyn Du, Samira Musah. Science Advances. June 4, 2024 Vol 10, Issue 23 DOI: https://doi.org/10.1126/sciadv.adn2689

This paper is open access.

A new strategy for creating hybrid bacteria and incorporatiing nanoparticles into living nanomedicine

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A May 27, 2024 Nanowerk Spotlight article by Michael Berger features research into using bacteria as a delivery device for medical treatment, Note: Links have been removed,

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Researchers have long sought to harness bacteria as a Trojan horse to deliver therapeutic payloads deep into tumors. Certain species of bacteria preferentially grow in the hypoxic cores of solid tumors, enabling much deeper penetration than possible with standard nanomedicine drug delivery approaches that rely on passive accumulation. Additionally, some bacteria naturally produce substances toxic to cancer cells. However, maintaining control over bacterial replication and toxicity while achieving a meaningful anti-tumor effect has proven challenging.

Now, scientists from Shanghai University in China report (Advanced Functional Materials, “Engineering Photothermal and H2S-Producing Living Nanomedicine by Bacteria-Enabled Self-Mineralization”) an innovative strategy to engineer a hybrid bacterial-nanoparticle system dubbed “Sa@FeS” to launch a multi-pronged attack against tumors from within.

They start with an attenuated strain of Salmonella typhimurium bacteria, which is drawn to the hypoxic regions in tumors. By feeding the Salmonella specific nutrients, they coax it to biomineralize its cell surface with photothermal iron sulfide nanoparticles without impairing bacterial viability and mobility.

The resulting nanomedicine platform enables three distinct but synergistic therapeutic mechanisms. First, the Salmonella bacteria naturally produce hydrogen sulfide gas, which recent studies show can be directly toxic to cancer cells by damaging DNA, disrupting mitochondrial function, and inhibiting cellular metabolism. Second, upon exposure to near-infrared laser light, the iron sulfide nanoparticles efficiently convert the light to heat, subjecting tumor cells to photothermal ablation.

Most powerfully, the released hydrogen sulfide gas, mildly acidic tumor microenvironment, and photothermal heating work in concert to dramatically amplify the effectiveness of chemodynamic therapy. In this therapy, iron-based nanoparticles convert hydrogen peroxide into highly toxic hydroxyl radicals.

While promising, chemodynamic therapy is often limited by insufficient hydrogen peroxide in tumors. The Sa@FeS therapy overcomes this by using the released hydrogen sulfide to suppress tumor cells’ enzymes that break down hydrogen peroxide, causing its levels to build up. Simultaneously, the heating and acidosis accelerate the iron-catalyzed conversion of hydrogen peroxide to hydroxyl radicals.

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Berger’s May 27, 2024 article goes on to describe this new treatment’s advantages and finishes the article with scientists’ hopes that other microorganisms could be harnessed for treatments in the future, Note: Links have been removed,

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Moreover, the researchers suggest that beyond bacteria, other diverse microorganisms such as fungi and viruses could potentially be engineered for similar therapeutic applications, opening up an even broader horizon for ‘living medicines’. Nevertheless, this impressive study lights the way for a new generation of bio-inspired therapies that merge the tools of synthetic biology and nanotechnology to open new fronts in the war against cancer.

On that note, my July 2, 2024 post about a new approach to ending the global amphibian pandemic, features the proposed use of a virus to kill off the fungal infection affecting frogs.

Getting back to nanomedicine and synthetic biology, here’s a link to and a citation for the paper featured in Berger’s article.,

Engineering Photothermal and H2S-Producing Living Nanomedicine by Bacteria-Enabled Self-Mineralization by Weiyi Wang, Jun Song, Weijie Yu, Meng Chen, Guangru Li, Jinli Chen, Liang Chen, Luodan Yu, Yu Chen. Advanced Functional Materials DOI: https://doi.org/10.1002/adfm.202400929 First published: 14 May 2024

This paper is behind a paywall.

Novel probiotic for eczema from US National Institute of Allergy and Infectious Diseases (NIAID)

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This treatment relieves symptoms; it doesn’t cure. As for whether or not it’s currently available to the public, it’s a little complicated.

I am not endorsing or recommending the treatment. That said, it does look promising.

Now, here’s the latest news about the treatment.

Novel probiotic for eczema

A June 26, 2024 (US National Institutes of Health) NIH/National Institute of Allergy and Infectious Diseases news release (also on EurekAlert) announces the availability of a new treatment for rrelief of eczema,

WHAT:
NIAID research has led to the availability of a new over-the-counter topical eczema probiotic. The probiotic is based on the discovery by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, that bacteria present on healthy skin called Roseomonas mucosa can safely relieve eczema symptoms in adults and children. R. mucosa-based topical interventions could simplify or complement current eczema management, when used in consultation with an individual’s healthcare provider. A milestone for eczema sufferers, the availability of an R. mucosa-based probiotic is the result of seven years of scientific discovery and research in NIAID’s Laboratory of Clinical Immunology and Microbiology (LCIM).

Eczema—also known as atopic dermatitis—is a chronic inflammatory skin condition that affects approximately 20% of children and 10% of adults worldwide. The condition is characterized by dry, itchy skin that can compromise the skin’s barrier, which functions to retain moisture and keep out allergens. This can make people with eczema more vulnerable to bacterial, viral and fungal skin infections. R. mucosa is a commensal bacterium, meaning it occurs naturally as part of a typical skin microbiome. Individuals with eczema experience imbalances in the microbiome and are deficient in certain skin lipids (oils). NIAID researchers demonstrated that R. mucosa can help restore those lipids.

Scientists led by Ian Myles, M.D., M.P.H., chief of the LCIM Epithelial Research Unit, found specific strains of R. mucosa reduced eczema-related skin inflammation and enhanced the skin’s natural barrier function in both adults and children. To arrive at this finding, Dr. Myles and colleagues spearheaded a spectrum of translational research on R. mucosa. They isolated and cultured R. mucosa in the laboratory, conducted preclinical (laboratory/animal) and clinical (human) studies, and made the bacteria available for commercial, non-therapeutic development [emphasis mine]. The R. mucosa-based probiotic released this week is formulated by Skinesa and called Defensin. [emphasis mine]

In Phase 1/2 open-label and Phase 2 blinded, placebo-controlled clinical studies, most people experienced greater than 75% improvement in eczema severity following application of R. mucosa. Improvement was seen on all treated skin sites, including the inner elbows, inner knees, hands, trunk and neck. The researchers also observed improvement in skin barrier function. Additionally, most participants needed fewer corticosteroids to manage their eczema, experienced less itching, and reported a better quality of life following R. mucosa therapy. These benefits persisted after treatment ended: therapeutic R. mucosa strains remained on the skin for up to eight months in study participants who were observed for that duration.

To expand the potential use of R. mucosa, NIAID will conduct an additional clinical trial to generate further evidence on its efficacy in reducing eczema symptoms [emphasis mine]. Those data could form the basis of an application to the Food and Drug Administration to enable the product to be regulated as a nonprescription drug and made accessible to a broader population of people with eczema. Study results are expected in 2024 [?] [emphasis mine].

WHO: 
Ian Myles, M.D., M.P.H, chief of the Epithelial Research Unit in NIAID’s Laboratory of Clinical Immunology and Microbiology, …

Not mentioned for some reason, is that there are no side effects of the treatment. There also appears to be an error in the news release/business announcement regarding the date for the next study results. There is currently a clinical trial which is due to begin August 20, 2024 and to be completed in 2026. There are no other trials listed on the ClinicalTrials.govwebsite after the trial results reported in 2020.

Non-therapeutic product? Nonprescription drug?

There is now a non-therapeutic product based on the R. mucosa-based probiotic that was tested by Ian Myles and his team. In short, it’s being sold as a skin product for people with itchy, dry skin and with no mention of eczema or any other skin condition. Sold as Defensin™ by Skinesa, they have this to say about their product,

Improves the look and feel of your skin in 90 days or less.

A skin health breakthrough from over 7 years of research, Defensin™ was created by a team of doctors to promote healthy skin.

*Probiotic strain Roseomonas mucosa RSM 2015 clinically shown to improve skin health.(1),(2)

*9 out of 10 patients achieved clearer, healthier skin in the clinical trial.(1)

*Innovated and studied by doctors at the NIH.(1),(2)

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SPECIAL NOTICE: NIH RESEARCH SHOWS THIS PRODUCT IS NOT COMPATIBLE WITH:

Aveeno Eczema Therapy
Eucerin Eczema Relief
Aquafor Healing Ointment
Curel Hydrotherapy

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(1) Myles, Ian A et al. Sci Transl Med 2020 Sep 9;12(560):eaaz8631. doi: 10.1126/scitranslmed.aaz8631.
(2) Myles, Ian A, et al. JCI Insight. 2018 May 3;3(9):e120608. doi: 10.1172/jci.insight.120608.

FAQs (frequently asked questions) by Skinesa

Keep scrolling down the Defensin™ by Skinesa webpage and you will find these questions and answers amongst others,

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What makes Defensin different from other products?

Probiotics are live microorganisms that provide health benefits when administered in adequate amounts. By definition, probiotics must have a scientifically demonstrated health effect.

In the case of Defensin™ Topical Skin Probiotic, our probiotic ingredient can be matched to two randomized controlled clinical trials that show safety and efficacy in promoting clear, healthy skin. Our probiotic is a one-of-a-kind probiotic strain that is not available generically.

Note: 99% of the “probiotic” topical skincare products are not probiotics at all, rather they are lysates, or probiotic byproducts which are not living.

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Are there any side effects of using Defensin?

There are no known side effects based on the 2 successful clinical trials.

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Getting picky

At this point, the treatment has no side effects but there have been adverse events. Like a lot of people, I assumed these two terms were synonymous. Wrong. The difference is largely but no exclusively one of degree. Here’s how the Association of Health Care Journalists explains it, from their Adverse event vs. side effect webpage,

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Adverse events and side effects are often conflated in news stories, blogs, social media, everyday discussion and even in conversations with medical professionals. However, when writing about research studies, there is a key difference that journalists must understand to avoid inadvertently misleading readers. An adverse event refers to any event that affects a person’s health that occurs after they have received a treatment, whether that treatment is a medication, a surgery, a therapy or another intervention. The adverse event may or may not be caused by the intervention [emphasis mine].

A side effect is an adverse effect that has been determined as a direct result [emphasis mine] of the intervention. In other words, the person who took a certain medication experiences an adverse event, such as a dry mouth or an increased blood pressure, that the medication definitely caused. Side effects are determined by comparing adverse events [emphasis mine] in randomized controlled trials where one group receives the intervention and one group does not. If the proportion of a certain adverse event is much higher in the group receiving the drug or intervention than in the control group, then the drug or intervention is the cause of that adverse event, which then becomes a side effect.

For example [emphasis mine], say 100 people receive the flu vaccine. Then 90 of them have sore arms, 10 have fevers, two have muscle cramps, two of them get into car accidents later that day, and one of them has a heart attack [emphasis mine] that night. All of those events are adverse effects [emphasis mine]— including the car accidents and heart attack — even though there is no biological way the flu vaccine could have caused the car accidents and there is no evidence that flu vaccines increase the risk of a heart attack. The sore arms, fevers and muscle cramps, however, very well could have been side effects [emphasis mine]. It’s not a guarantee that all the fevers were caused by the flu vaccine, but fever is a known possible side effect of the vaccine. The muscle cramps depend on where they occurred. If the cramps are in the arms where the person got the shot, it probably is a side effect. If it’s a Charley horse cramp in the leg, it’s an adverse event that’s probably unrelated to the flu vaccine. If it’s general achiness for a day that feels similar to what the flu feels like, then it likely was caused by the vaccine since that’s a known side effect. This is why reading the list of adverse events in a vaccine package insert tells the reader nothing about actual possible side effects of the vaccine.

Thank you to the Association of Health Care Journalists (AHCJ)! One last flower, if you have time, check out Mary Chris Jaklevic’s August 13, 2024 article, “How a class reporting project exposed ethical problems with a pioneering brain study” on the AHCJ website. The study, by the way, was being conducted at the Mount Sinai Medical Center in New York. As Mount Sinai notes on its About Us webpage,

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Encompassing the Icahn School of Medicine at Mount Sinai and eight hospital campuses in the New York metropolitan area, as well as a large, regional ambulatory footprint, Mount Sinai is internationally acclaimed for its excellence in research, patient care, and education [emphasis mine] across a range of specialties.

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Thankfully, no one appears to have suffered harm from the research but the ethical issues are troubling.

Getting back to the eczema treatment and adverse events vs. side effects

The 2020 study cited on the Skinesa’s Defensin webpage notes this in the study’s abstract,

Dysbiosis of the skin microbiota is increasingly implicated as a contributor to the pathogenesis of atopic dermatitis (AD). We previously reported first-in-human safety and clinical activity results from topical application of the commensal skin bacterium Roseomonas mucosa for the treatment of AD in 10 adults and 5 children older than 9 years of age. Here, we examined the potential mechanism of action of R. mucosa treatment and its impact on children with AD less than 7 years of age, the most common age group for children with AD. In 15 children with AD, R. mucosa treatment was associated with amelioration of disease severity, improvement in epithelial barrier function, reduced Staphylococcus aureus burden on the skin, and a reduction in topical steroid requirements without severe adverse events [emphasis mine]. Our observed response rates to R. mucosa treatment were greater than those seen in historical placebo control groups in prior AD studies. Skin improvements and colonization by R. mucosa persisted for up to 8 months after cessation of treatment. Analyses of cellular scratch assays and the MC903 mouse model of AD suggested that production of sphingolipids by R. mucosa, cholinergic signaling, and flagellin expression may have contributed to therapeutic impact through induction of a TNFR2-mediated epithelial-to-mesenchymal transition. These results suggest that a randomized, placebo-controlled trial of R. mucosa treatment in individuals with AD is warranted and implicate commensals in the maintenance of the skin epithelial barrier.

Fro anyone who wants to see the 2020 study, here’s a link to and a citation for it,

Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair by Ian A. Myles, Carlo R. Castillo, Kent D. Barbian, Kishore Kanakabandi, Kimmo Virtaneva, Emily Fitzmeyer, Monica Paneru, Francisco Otaizo-Carrasquero, Timothy G. Myers, Tovah E. Markowitz, Ian N. Moore, Xue Liu, Marc Ferrer, Yosuke Sakamachi, Stavros Garantziotis, Muthulekha Swamydas, Michail S. Lionakis, Erik D. Anderson, Noah J. Earland, Sundar Ganesan, Ashleigh A. Sun, Jenna R.E. Bergerson, Robert A. Silverman, Maureen Petersen, Craig A. Martens, and Sandip K. Datta . Science Translational Medicine 9 Sep 2020 Vol 12, Issue 560 DOI: 10.1126/scitranslmed.aaz8631

This paper appears to be open access.

Moving on to ‘nonprescription drug’

If I understand the news release/business announcement correctly, this latest clinical trial is designed with FDA (US Food and Drug Administration) approval in mind. This will allow marketing of the treatment or product as an nonprescription drug for eczema. Right now, Defensin is being sold as a ‘topical skin probiotic’.

Here’s more about the latest trial, from the Cardamom and Topical Roseomonas in Atopic Dermatitis webpage on clinicaltrials.gov,

Study Overview

Brief Summary

Background:

Atopic dermatitis (AD), also called eczema, is a chronic skin condition. AD can make skin dry and itchy, and sometimes it can lead to serious health problems, such as asthma, food allergies, eye infections, and sleep problems. No cure exists for AD. Researchers know that people with AD have different kinds of harmless bacteria on their skin than do people without AD. They want to see if adding a harmless bacteria (Roseomonas mucosa) to the skin can help people with AD.

Objective:

To test a skin treatment that contains R. mucosa and ground cardamom seeds in people with AD.

Eligibility:

People aged 2 years and older with AD.

Design:

All study visits will be remote. Participants will have 5 visits over about 7 months.

Participants will be screened. Researchers will review their AD and medical history.

Participants will receive a study product in the mail. The product comes as a powder in single-use packets. Participants will be shown how to mix the powder with water in a single-use spray vial. They will spray the solution onto their skin 2 to 3 times per week for 14 weeks.

Half of participants will receive the study powder. Half will receive a placebo; the placebo looks just like the study powder but contains no bacteria. They will not know which one they have.

During 3 study visits, participants will take a skin swab. They will receive supplies in the mail to rub a cotton swab on their skin and mail it back to the researchers.

Participants may opt to have pictures taken of their AD.

Participants will fill out 4 online questionnaires.Show less

Detailed Description

Study Description:

This is a double-blind, randomized, phase 2b clinical trial for a topical formulation of a live biotherapeutic containing Roseomonas mucosa combined with ground cardamom seeds in a sucrose solution for patients with atopic dermatitis (AD). Participants will reconstitute the dried product in water and apply topically 2 or 3 times per week for 14 weeks. After 14 weeks, all interventions will cease, and participants will be followed for an additional 14 weeks to assess how long treatment effects last. During the course of study, we will assess disease severity (eg, itch, rash, and quality of life [QOL]) using a variety of AD assessments, ease of compliance with treatment, and changes in the microbiome profile of the skin. We hypothesize that topical treatment with Roseomonas mucosa, combined with ground cardamom seeds, will provide significantly more alleviation in AD symptoms than placebo, and that these effects will last beyond active treatment (due to the ability of the bacteria to colonize the patients’ skin).

Primary Objective:

To determine if R mucosa combined with ground cardamom seeds can improve symptoms of AD in patients aged 2 and older, 14 weeks after treatment discontinuation.

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Primary Endpoint:

Proportion of participants achieving a 90% improvement in Eczema Area and Severity Index (EASI90; a measure of eczema rash) from baseline(week 0) to study completion (week 28).

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Official Title

A Phase 2b, Double-Blind, Randomized, Placebo-Controlled Trial of Cardamom and Topical Roseomonas in Atopic Dermatitis

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Eligibility criteria [emphasis mine]

Ages Eligible for Study 2 Years to 100 Years (Child,  Adult,  Older Adult )

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I’ve read eligibility criteria for lots and lots of studies and this is the first time I’ve seen this range of ages. Usually children, youth and older adults (over 55) are excluded.

To sum up, you can buy a product from Skinesa (it’s not cheap), which doesn’t make any promises about eczema. There’s also a clinical trial where final results won’t be published until at least 2026.

Again,this post is neither an endorsement nor a recommendation. If you are interested in the currently available product, I’d suggest consulting with your doctor.

Component of cinnamon essential oil for bacteria ‘nanokiller’

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A May 23, 2024 news item on phys.org features an ‘intelligent nanokiller’,

A team of researchers from the Universitat Politècnica de València (UPV) and the CIBER de Bioingeniería, Biomaterials y Nanomedicine (CIBER-BBN) has developed an intelligent “nanokiller” based on a component of cinnamon essential oil (cinnamaldehyde) for use as an antimicrobial agent.

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So far, the new nanodevice has shown significant efficacy against pathogenic microorganisms such as Escherichia coli, Staphylococcus aureus, and Candida albicans. It could be applied for the elimination of pathogens that may be present in food, wastewater and in the treatment of nosocomial infections, which are those acquired during hospital stays.

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A May 24, 2024 Universitat Politècnica de València (UPV) press release (also on EurekAlert but published May 23, 2024), which originated the news item, further details the effects of this ‘nanokller’,

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In the case of Escherichia coli, most strains are harmless, although some can cause severe abdominal cramping or acute diarrhea and vomiting. In the case of Staphylococcus aureus bacteria, its effects can be skin infections, bloodstream infections, osteomyelitis, or pneumonia. Meanwhile, Candida albicans is a fungus found in different biological fluids, causing diseases such as candidemia or invasive candidiasis.

Easy application

According to the team of the IDM-CIBER NanoSens group, applying this ” nanokiller ” would be very simple. “For example, we could create a spray, make a formulation based on water and other compounds, and apply it directly. We could make a water-based formulation in the field and spray it directly, like any pesticide today. And in hospitals, it could be applied on bandages, and we could even try to make a capsule that could be taken orally,” explains Andrea Bernardos, a researcher in the NanoSens group at the Inter-University Institute for Molecular Recognition Research and Technological Development (IDM).

High efficacy

The new nanodevice improves the efficacy of encapsulated cinnamaldehyde compared to the free compound: about 52-fold for Escherichia coli, about 60-fold for Staphylococcus aureus, and about 7-fold for Candida albicans.

“The increase in the antimicrobial activity of the essential oil component is possible thanks to the decrease in its volatility due to its encapsulation in a porous silica matrix and the increase in its local concentration when released due to the presence of the microorganisms,” highlights Andrea Bernardos, a researcher at the Inter-University Research Institute for Molecular Recognition and Technological Development (IDM).

It stands out for its high antimicrobial activity at very low doses, among its advantages. In addition, it enhances the antimicrobial properties of free cinnamaldehyde with a reduction of the biocidal dose of around 98% for bacterial strains (Escherichia coli and Staphylococcus aureus) and 72% for the yeast strain (Candida albicans) when the nanodevice is applied.

“Moreover, this type of device containing natural biocides (such as essential oil components) whose release is controlled by the presence of pathogens could also be applied in fields such as biomedicine, food technology, agriculture, and many others,” concludes Ángela Morellá-Aucejo, also an IDM researcher at the Universitat Politècnica de València.

The results of this study have been published in the journal Biomaterials Advances.

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

Remarkable enhancement of cinnamaldehyde antimicrobial activity encapsulated in capped mesoporous nanoparticles: A new “nanokiller” approach in the era of antimicrobial resistance by Ángela Morellá-Aucejo, Serena Medaglia, María Ruiz-Rico, Ramón Martínez-Máñez, María Dolores Marcos, Andrea Bernardos. Biomaterials Advances Volume 160, June 2024, 213840 DOI: https://doi.org/10.1016/j.bioadv.2024.213840 Available online: 26 March 2024, Version of Record: 4 April 2024. Under a Creative Commons license

This paper is open access.

Listening to a protein fold itself

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This May 20, 2024 news item on ScienceDaily announces new work on protein folding that can be heard,

By converting their data into sounds, scientists discovered how hydrogen bonds contribute to the lightning-fast gyrations that transform a string of amino acids into a functional, folded protein. Their report, in the Proceedings of the National Academy of Sciences [PNAS], offers an unprecedented view of the sequence of hydrogen-bonding events that occur when a protein morphs from an unfolded to a folded state.

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This video (courtesy of the University of Illinois at Urbana-Champaign) is “A sonification and animation of a state machine based on a simple lattice model used by Martin Gruebele to teach concepts of protein-folding dynamics,” Note: Also embedded in April 1, 2022 posting, “Sonifying the protein folding process,”

The latest work is in a May 20, 2024 University of Illinois at Urbana-Champaign news release (also on EurekAlert) by Diana Yates, which originated the news item. It provides more information about the researchers’ work and about the use of data sonification, Note: Links have been removed,

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“A protein must fold properly to become an enzyme or signaling molecule or whatever its function may be — all the many things that proteins do in our bodies,” said University of Illinois Urbana-Champaign chemistry professor Martin Gruebele, who led the new research with composer and software developer Carla Scaletti.  

Misfolded proteins contribute to Alzheimer’s disease, Parkinson’s disease, cystic fibrosis and other disorders. To better understand how this process goes awry, scientists must first determine how a string of amino acids shape-shifts into its final form in the watery environment of the cell. The actual transformations occur very fast, “somewhere between 70 nanoseconds and two microseconds,” Gruebele said.

Hydrogen bonds are relatively weak attractions that align atoms located on different amino acids in the protein. A folding protein will form a series of hydrogen bonds internally and with the water molecules that surround it. In the process, the protein wiggles into countless potential intermediate conformations, sometimes hitting a dead-end and backtracking until it stumbles onto a different path.

See video: Protein Sonification: Hairpin in a trap

The researchers wanted to map the time sequence of hydrogen bonds that occur as the protein folds. But their visualizations could not capture these complex events.

“There are literally tens of thousands of these interactions with water molecules during the short passage between the unfolded and folded state,” Gruebele said.

So the researchers turned to data sonification, a method for converting their molecular data into sounds so that they could “hear” the hydrogen bonds forming. To accomplish this, Scaletti wrote a software program that assigned each hydrogen bond a unique pitch. Molecular simulations generated the essential data, showing where and when two atoms were in the right position in space — and close enough to one another — to hydrogen bond. If the correct conditions for bonding occurred, the software program played a pitch corresponding to that bond. Altogether, the program tracked hundreds of thousands of individual hydrogen-bonding events in sequence.

See video: Using sound to explore hydrogen bond dynamics during protein folding [embedded just above this excerpt]

Numerous studies suggest that audio is processed roughly twice as fast as visual data in the human brain, and humans are better able to detect and remember subtle differences in a sequence of sounds than if the same sequence is represented visually, Scaletti said.

“In our auditory system, we’re really very attuned to small differences in frequency,” she said. “We use frequencies and combinations of frequencies to understand speech, for example.”

A protein spends most of its time in the folded state, so the researchers also came up with a “rarity” function to identify when the rare, fleeting moments of folding or unfolding took place.

The resulting sounds gave them insight into the process, revealing how some hydrogen bonds seem to speed up folding while others appear to slow it. They characterized these transitions, calling the fastest “highway,” the slowest “meander,” and the intermediate ones “ambiguous.”

Including the water molecules in the simulations and hydrogen-bonding analysis was essential to understanding the process, Gruebele said.

“Half of the energy from a protein-folding reaction comes from the water and not from the protein,” he said. “We really learned by doing sonification how water molecules settle into the right place on the protein and how they help the protein conformation change so that it finally becomes folded.”

While hydrogen bonds are not the only factor contributing to protein folding, these bonds often stabilize a transition from one folded state to another, Gruebele said. Other hydrogen bonds may temporarily impede proper folding. For example, a protein may get hung up in a repeating loop that involves one or more hydrogen bonds forming, breaking and forming again — until the protein eventually escapes from this cul de sac to continue its journey to its most stable folded state.

“Unlike the visualization, which looks like a total random mess, you actually hear patterns when you listen to this,” Gruebele said. “This is the stuff that was impossible to visualize but it’s easy to hear.”

The National Science Foundation, National Institutes of Health and Symbolic Sound Corporation supported this research.

Gruebele also is a professor in the Beckman Institute for Advanced Science and Technology and an affiliate of the Carl R. Woese Institute for Genomic Biology at the U. of I.

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

Hydrogen bonding heterogeneity correlates with protein folding transition state passage time as revealed by data sonification by Carla Scaletti, Premila P. Samuel Russell, Kurt J. Hebel, Meredith M. Rickard, Mayank Boob, Franz Danksagmüller, Stephen A. Taylor, Taras V. Pogorelov, and Martin Gruebele. PNAS 121 (22) e2319094121 DOI: https://doi.org/10.1073/pnas.2319094121 Published: May 20, 2024

This paper is behind a paywall.