They hurt. Veins can burst, or even roll — like they’re trying to avoid the needle, too.

Oftentimes, doctors use blood samples to check for biomarkers of disease: antibodies that signal a viral or bacterial infection, such as SARS-CoV-2, the virus responsible for COVID-19; or cytokines indicative of inflammation seen in conditions such as rheumatoid arthritis and sepsis.

These biomarkers aren’t just in blood, though. They can also be found in the dense liquid medium that surrounds our cells, but in a low abundance that makes it difficult to be detected.

Until now.

Engineers at the McKelvey School of Engineering at Washington University in St. Louis have developed a microneedle patch that can be applied to the skin, capture a biomarker of interest and, thanks to its unprecedented sensitivity, allow clinicians to detect its presence.

The technology is low cost, easy for a clinician or patients themselves to use, and could eliminate the need for a trip to the hospital just for a blood draw.

The research, from the lab of Srikanth Singamaneni, the Lilyan & E. Lisle Hughes Professor in the Department of Mechanical Engineering & Material Sciences, was published online Jan. 22 in the journal Nature Biomedical Engineering.

In addition to the low cost and ease of use, these microneedle patches have another advantage over blood draws, perhaps the most important feature for some: “They are entirely pain-free,” Singamaneni said.

Finding a biomarker using these microneedle patches is similar to blood testing. But instead of using a solution to find and quantify the biomarker in blood, the microneedles directly capture it from the liquid that surrounds our cells in skin, which is called dermal interstitial fluid (ISF). Once the biomarkers have been captured, they’re detected in the same way — using fluorescence to indicate their presence and quantity.

ISF is a rich source of biomolecules, densely packed with everything from neurotransmitters to cellular waste. However, to analyze biomarkers in ISF, conventional method generally requires extraction of ISF from skin. This method is difficult and usually the amount of ISF that can be obtained is not sufficient for analysis. That has been a major hurdle for developing microneedle-based biosensing technology.

Another method involves direct capture of the biomarker in ISF without having to extract ISF. Like showing up to a packed concert and trying to make your way up front, the biomarker has to maneuver through a crowded, dynamic soup of ISF before reaching the microneedle in the skin tissue. Under such conditions, being able to capture enough of the biomarker to see using the traditional assay isn’t easy.

But the team has a secret weapon of sorts: “plasmonic-fluors,” an ultrabright fluorescence nanolabel. Compared with traditional fluorescent labels, when an assay was done on microneedle patch using plasmonic-fluor, the signal of target protein biomarkers shined about 1,400 times as bright and become detectable even when they are present at low concentrations.

“Previously, concentrations of a biomarker had to be on the order of a few micrograms per milliliter of fluid,” Zheyu (Ryan) Wang, a graduate student in the Singamaneni lab and one of the lead authors of the paper, said. That’s far beyond the real-world physiological range. But using plasmonic-fluor, the research team was able to detect biomarkers on the order of picograms per milliliter.

“That’s orders of magnitude more sensitive,” Ryan said.

These patches have a host of qualities that can make a real impact on medicine, patient care and research.

They would allow providers to monitor biomarkers over time, particularly important when it comes to understanding how immunity plays out in new diseases.

For example, researchers working on COVID-19 vaccines need to know if people are producing the right antibodies and for how long. “Let’s put a patch on,” Singamaneni said, “and let’s see whether the person has antibodies against COVID-19 and at what level.”

Or, in an emergency, “When someone complains of chest pain and they are being taken to the hospital in an ambulance, we’re hoping right then and there, the patch can be applied,” Jingyi Luan, a student who recently graduated from the Singamaneni lab and one of the lead authors of the paper, said. Instead of having to get to the hospital and have blood drawn, EMTs could use a microneedle patch to test for troponin, the biomarker that indicates myocardial infarction.

For people with chronic conditions that require regular monitoring, microneedle patches could eliminate unnecessary trips to the hospital, saving money, time and discomfort — a lot of discomfort.

The patches are almost pain-free. “They go about 400 microns deep into the dermal tissue,” Singamaneni said. “They don’t even touch sensory nerves.”

In the lab, using this technology could limit the number of animals needed for research. Sometimes research necessitates a lot of measurements in succession to capture the ebb and flow of biomarkers — for example, to monitor the progression of sepsis. Sometimes, that means lot of small animals.

“We could significantly lower the number of animals required for such studies,” Singamaneni said.

The implications are vast — and Singamaneni’s lab wants to make sure they are all explored.

There is a lot of work to do, he said: “We’ll have to determine clinical cutoffs,” that is, the range of biomarker in ISF that corresponds to a normal vs. abnormal level. “We’ll have to determine what levels of biomarker are normal, what levels are pathological.” And his research group is working on delivery methods for long distances and harsh conditions, providing options for improving rural healthcare.

“But we don’t have to do all of this ourselves,” Singamaneni said. Instead, the technology will be available to experts in different areas of medicine.

“We have created a platform technology that anyone can use,” he said. “And they can use it to find their own biomarker of interest.”

We don’t have to do all of this ourselves

Singamaneni and Erica L. Scheller, assistant professor of Medicine in the Division of Bone and Mineral Disease at the School of Medicine, worked together to investigate the concentration of biomarkers in local tissues.

Current approaches for such evaluation require the isolation of local tissues and do not allow successive and continuous inspection. Singamaneni and Scheller are developing a better platform to achieve long term monitoring of local biomarker concentration.

Working together

Srikanth Singamaneni, the Lilyan E. Lisle Hughes Professor in the Department of Mechanical Engineering & Materials Science, and Jai S. Rudra, assistant professor in the Department of Biomedical Engineering, worked together to look at cocaine vaccines, which work by blocking cocaine’s ability to enter the brain.

Current candidates for such a vaccine don’t confer long-lasting results; they require frequent boosting. Singamaneni and Rudra wanted a better way to determine when the effects of the vaccine had waned. “We’ve shown that we can use the patches to understand whether a person is still producing the necessary antibodies,” Singamaneni said. “No blood draw necessary.”

Kamchatka’s Shiveluch volcano has had more than 40 violent eruptions over the last 10,000 years. The last gigantic blast occurred in 1964, creating a new crater and covering an area of nearly 100 square kilometers with pyroclastic flows. But Shiveluch is actually currently erupting, as it has been for over 20 years. So why would anyone risk venturing too close?

Researchers from Washington University in St. Louis, including Michael Krawczynski, assistant professor of earth and planetary sciences in Arts & Sciences and graduate student Andrea Goltz, brave the harsh conditions on Kamchatka because understanding what makes Shiveluch tick could help scientists understand the global water cycle and gain insights into the plumbing systems of other volcanoes.

In a recent study published in the journal Contributions to Mineralogy and Petrology, researchers from the Krawczynski lab looked at small nodules of primitive magma that were erupted and preserved amid other materials.

“The minerals in these nodules retain the signatures of what was happening early in the magma’s evolution, deep in Earth’s crust,” said Goltz, the lead author of the paper.

The researchers found that the conditions inside Shiveluch include roughly 10%-14% water by weight (wt%). Most volcanoes have less than 1% water. For subduction zone volcanoes, the average is usually 4%, rarely exceeding 8 wt%, which is considered superhydrous.

Of particular interest is a mineral called amphibole, which acts as a proxy or fingerprint for high water content at known temperature and pressure. The unique chemistry of the mineral tells researchers how much water is present deep underneath Shiveluch.

“When you convert the chemistry of these two minerals, amphibole and olivine, into temperatures and water contents as we do in this paper, the results are remarkable both in terms of how much water and how low a temperature we’re recording,” Krawczynski said.

“The only way to get primitive, pristine materials at low temperatures is to add lots and lots of water,” he said. “Adding water to rock has the same effect as adding salt to ice; you’re lowering the melting point. In this case, there is so much water that the temperature is reduced to a point where amphiboles can crystallize.”

Video: https://www.youtube.com/watch?v=ebVN7PcGJbo&feature=emb_logo

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Materials provided by Washington University in St. Louis. Original written by Shawn Ballard. Note: Content may be edited for style and length.

Now, a group of Brown University researchers has found a way to customize metallic grain structures from the bottom up. In a paper published in the journal Chem, the researchers show a method for smashing individual metal nanoclusters together to form solid macro-scale hunks of solid metal. Mechanical testing of the metals manufactured using the technique showed that they were up to four times harder than naturally occurring metal structures.

“Hammering and other hardening methods are all top-down ways of altering grain structure, and it’s very hard to control the grain size you end up with,” said Ou Chen, an assistant professor of chemistry at Brown and corresponding author of the new research. “What we’ve done is create nanoparticle building blocks that fuse together when you squeeze them. This way we can have uniform grain sizes that can be precisely tuned for enhanced properties.”

For this study, the researchers made centimeter-scale “coins” using nanoparticles of gold, silver, palladium and other metals. Items of this size could be useful for making high-performance coating materials, electrodes or thermoelectric generators (devices that convert heat fluxes into electricity). But the researchers think the process could easily be scaled up to make super-hard metal coatings or larger industrial components.

The key to the process, Chen says, is the chemical treatment given to the nanoparticle building blocks. Metal nanoparticles are typically covered with organic molecules called ligands, which generally prevent the formation of metal-metal bonds between particles. Chen and his team found a way to strip those ligands away chemically, allowing the clusters to fuse together with just a bit of pressure.

The metal coins made with the technique were substantially harder than standard metal, the research showed. The gold coins, for example, were two to four times harder than normal. Other properties like electrical conduction and light reflectance were virtually identical to standard metals, the researchers found.

The optical properties of the gold coins were fascinating, Chen says, as there was a dramatic color change when the nanoparticles were compressed into bulk metal.

“Because of what’s known as the plasmonic effect, gold nanoparticles are actually purplish-black in color,” Chen said. “But when we applied pressure, we see these purplish clusters suddenly turn to a bright gold color. That’s one of the ways we knew we had actually formed bulk gold.”

In theory, Chen says, the technique could be used to make any kind of metal. In fact, Chen and his team showed that they could make an exotic form of metal known as a metallic glass. Metallic glasses are amorphous, meaning they lack the regularly repeating crystalline structure of normal metals. That gives rise to remarkable properties. Metallic glasses are more easily molded than traditional metals, can be much stronger and more crack-resistant, and exhibit superconductivity at low temperatures.

“Making metallic glass from a single component is notoriously hard to do, so most metallic glasses are alloys,” Chen said. “But we were able to start with amorphous palladium nanoparticles and use our technique to make a palladium metallic glass.”

Chen says he’s hopeful that the technique could one day be widely used for commercial products. The chemical treatment used on the nanoclusters is fairly simple, and the pressures used to squeeze them together are well within the range of standard industrial equipment. Chen has patented the technique and hopes to continue studying it.

“We think there’s a lot of potential here, both for industry and for the scientific research community,” Chen said.

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The team, which includes Thomas Danz and Professor Claus Ropers, took advantage of an unusual property of a material made up of atomically thin layers of sulphur and tantalum atoms. At room temperature, its crystal structure is distorted into tiny wavelike structures — a “charge-density wave” is formed. At higher temperatures, a phase transition occurs in which the original microscopic waves suddenly disappear. The electrical conductivity also changes drastically, an interesting effect for nano-electronics.

In their experiments, the researchers induced this phase transition with short laser pulses and recorded a film of the charge-density wave reaction. “What we observe is the rapid formation and growth of tiny regions where the material was switched to the next phase,” explains first author Thomas Danz from Göttingen University. “The Ultrafast Transmission Electron Microscope developed in Göttingen offers the highest time resolution for such imaging in the world today.” The special feature of the experiment lies in a newly developed imaging technique, which is particularly sensitive to the specific changes observed in this phase transition. The Göttingen physicists use it to take images that are composed exclusively of electrons that have been scattered by the crystal’s waviness.

Their cutting-edge approach allows the researchers to gain fundamental insights into light-induced structural changes. “We are already in a position to transfer our imaging technique to other crystal structures,” says Professor Claus Ropers, leader of Nano-Optics and Ultrafast Dynamics at Göttingen University and Director at the MPI for Biophysical Chemistry. “In this way, we not only answer fundamental questions in solid-state physics, but also open up new perspectives for optically switchable materials in future, intelligent nano-electronics.”

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The research is important because “NSAIDs are arguably the most commonly used anti-inflammatory medications,” said principal investigator Craig B. Wilen, Assistant Professor of Laboratory Medicine and Immunology, Yale University School of Medicine.

In addition to taking NSAIDs for chronic conditions such as arthritis, people take them “for shorter periods of time during infections, and [during] acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise,” said Dr. Wilen. “Our work suggests that the NSAID meloxicam dampens the immune response to SARS-CoV-2 infection.”

The research also suggests that the consequences of NSAID use during natural infection and vaccination should be evaluated in humans, said Dr. Wilen. “This data likely exists, particularly in the clinical trials for the vaccines, so it should be mined to see if it produces antibody responses in people.”

“Taking NSAIDs during COVID-19 could be harmful or beneficial, depending on the timing of administration,” said Dr.Wilen. The potent anti-inflammatory, dexamethasone (not an NSAID), is detrimental to COVID-19 sufferers when taken early in the infection, but beneficial when administered during later stages of COVID-19, said Dr. Wilen.

Similarly, NSAIDs’ anti-inflammatory activity might be detrimental early in SARS-CoV-2 infection, because at this stage, inflammation is usually helpful. That changes at later stages of COVID-19, particularly if the patient undergoes an intense inflammation known as a cytokine storm. A cytokine storm is an immune response of inflammatory compounds that often occurs in COVID-19 patients, can lead to complications, need for the intensive care unit, and even death.

A reduction in neutralizing antibodies caused by NSAIDs might be benign, or it might blunt the immune system’s ability to fight the disease during the early stages of infection. It could also reduce the magnitude and/or length of protection from either natural infection or vaccination, said Dr. Wilen.

The initial motivation to investigate NSAIDs’ effect on COVID-19 “was a twitter thread, suggesting NSAIDs should not be used during COVID-19,” said Dr. Wilen. “This seemed suspicious to us, so we wanted to investigate.”

Dr. Wilen and his team expected that there would be little to no effect of NSAIDs on viral infection, which turned out to be correct.They also thought that NSAIDs would not significantly affect the antibody response to natural infection. “In fact, we initially didn’t even carefully look at the antibody response, because we didn’t expect it to be altered by NSAIDs. This turned out to be wrong, said Dr. Wilen.

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