Self-Assembling Nanofibers Prevent Damage from Inflammation

Biomedical engineers at Duke University have developed a self-assembling nanomaterial that can help limit damage caused by inflammatory diseases by activating key cells in the immune system. In mouse models of psoriasis, the nanofiber-based drug has been shown to mitigate damaging inflammation as effectively as a gold-standard therapy. One of the hallmarks of inflammatory diseases, like rheumatoid arthritis, Crohn’s disease and psoriasis, is the overproduction of signaling proteins, called cytokines, that cause inflammation. One of the most significant inflammatory cytokines is a protein called TNF. Currently, the best treatment for these diseases involves the use of manufactured antibodies, called monoclonal antibodies, which are designed to target and destroy TNF and reduce inflammation.

Although monoclonal antibodies have enabled better treatment of inflammatory diseases, the therapy is not without its drawbacks, including a high cost and the need for patients to regularly inject themselves. Most significantly, the drugs also have uneven efficacy, as they may sometimes not work at all or eventually stop working as the body learns to make antibodies that can destroy the manufactured drug. To circumvent these issues, researchers have been exploring how immunotherapies can help teach the immune system how to generate its own therapeutic antibodies that can specifically limit inflammation.

The graphic shows the peptide nanofiber bearing complement protein C3dg (blue) and key components of the TNF protein, which include B-cell epitopes (green), and T-cell epitopes (purple)

We’re essentially looking for ways to use nanomaterials to induce the body’s immune system to become an anti-inflammatory antibody factory,” said Joel Collier, a professor of biomedical engineering at Duke University. “If these therapies are successful, patients need fewer doses of the therapy, which would ideally improve patient compliance and tolerance. It would be a whole new way of treating inflammatory disease.”

In their new paper, which appeared online in the Proceedings of the National Academy of Sciences (PNAS), Collier and Kelly Hainline, a graduate student in the Collier lab, describe how novel nanomaterials could assemble into long nanofibers that include a specialized protein, called C3dg. These fibers then were able to activate immune system B-cells to generate antibodies. “C3dg is a protein that you’d normally find in your body,” said Hainline. “The protein helps the innate immune system and the adaptive immune system communicate, so it can activate specific white blood cells and antibodies to clear out damaged cells and destroy antigens.”

Due to the protein’s ability to interface between different cells in the immune system and activate the creation of antibodies without causing inflammation, researchers have been exploring how C3dg could be used as a vaccine adjuvant, which is a protein that can help boost the immune response to a desired target or pathogen.

Source: https://pratt.duke.edu/

How The Coronavirus Infects Human Cells

Tiny artificial lungs grown in a lab from adult stem cells have allowed scientists to watch how coronavirus infects the lungs in a new ‘major breakthrough‘. Researchers from Duke University and Cambridge University produced artificial lungs in two independent and separate studies to examine the spread of Covid-19. The ‘living lung‘ models minimic the tiny air sacs that take up the oxygen we breathe, known to be where most serious lung damage from the deadly virus takes place.   Having access to the models to test the spread of SAS-CoV-2, the virus responsible for Covid-19, will allow researchers to test potential drugs and gain a better understanding of why some people suffer from the disease worse than others.

In both studies the 3D min-lung models were grown from stem cells that repair the deepest portions of the lungs when SARS-CoV-2 attacks – known as alveolar cells. To date, there have been more than 40 million cases of COVID-19 and almost 1.13 million deaths worldwide. The main target tissues of SARS-CoV-2, especially in patients that develop pneumonia, appear to be alveoli, according to the Cambridge team. They extracted the alveoli cells from donated tissue and reprogrammed them back to their earlierstem cell‘ stage and forced them to grow into self-organising alveolar-like 3D structures that mimic the behaviour of key lung tissue. Dr Joo-Hyeon Lee, co-senior author of the Cambridge paper, said we still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease.

Representative image of three – dimensional human lung alveolar organoid produced by the Cambridge and Korean researchers to better understand SARS-CoV-2

Our approach has allowed us to grow 3D models of key lung tissue – in a sense, “mini-lungs” – in the lab and study what happens when they become infected.’

Duke researchers took a similar approach. The team, led by Duke cell biologist Purushothama Rao Tata, say their model will allow for hundreds of experiments to be run simultaneously to screen for new drug candidates. ‘This is a versatile model system that allows us to study not only SARS-CoV-2, but any respiratory virus that targets these cells, including influenza,‘ Tata said.

Both teams infected models with a strain of SARS-CoV-2 to better understand who the virus spreads and what happens in the lung cells in response to the disease. The Cambridge team worked with researchers from South Korea to take a sample of the virus from a patient who was infected in January after travelling to Wuhan. Using a combination of fluorescence imaging and single cell genetic analysis, they were able to study how the cells responded to the virus.

When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly, reaching full cellular infection just six hours after infectionReplication enables the virus to spread throughout the body, infecting other cells and tissue, explained the Cambridge research team. Around the same time, the cells began to produce interferonsproteins that act as warning signals to neighbouring cells, telling them to activate their defences. After 48 hours, the interferons triggered the innate immune response – its first line of defence – and the cells started fighting back against infectionSixty hours after infection, a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.

Source: https://today.duke.edu/

Devices Made Of DNA Detect Cancer

A new cancer-detecting tool uses tiny circuits made of DNA to identify cancer cells by the molecular signatures on their surfaceDuke University researchers fashioned the simple circuits from interacting strands of synthetic DNA that are tens of thousands of times finer than a human hair. Unlike the circuits in a computer, these circuits work by attaching to the outside of a cell and analyzing it for proteins found in greater numbers on some cell types than others. If a circuit finds its targets, it labels the cell with a tiny light-up tag. Because the devices distinguish cell types with higher specificity than previous methods, the researchers hope their work might improve diagnosis, and give cancer therapies better aim.

A team led by Duke computer scientist John Reif and his former Ph.D. student Tianqi Song described their approach in a recent issue of the Journal of the American Chemical Society.

The cell membrane is studded with proteins that researchers can use to discriminate between tumor cells and normal cells, or among cancer cells of different types or disease stages.

Similar techniques have been used previously to detect cancer, but they’re more prone to false alarmsmisidentifications that occur when mixtures of cells sport one or more of the proteins a DNA circuit is designed to screen for, but no single cell type has them all. For every cancer cell that is correctly detected using current methods, some fraction of healthy cells also get mislabeled as possibly cancerous when they’re not. Each type of cancer cell has a characteristic set of cell membrane proteins on its cell surface. To cut down on cases of mistaken identity, the Duke team designed a DNA circuit that must latch onto that specific combination of proteins on the same cell to work. As a result they’re much less likely to flag the wrong cells, Reif said.

The technology could be used as a screening tool to help rule out cancer, which could mean fewer unnecessary follow-ups, or to develop more targeted cancer treatments with fewer side effects.

Source: https://today.duke.edu/

Electrified Tattoos and Personalized Biosensors

Electrical engineers at Duke University have devised a fully print-in-place technique for electronics that is gentle enough to work on delicate surfaces including paper and human skin. The advance could enable technologies such as high-adhesion, embedded electronic tattoos and bandages tricked out with patient-specific biosensors.

Two electronically active leads directly printed along the underside of Duke graduate student Nick Williams’s pinky successfully light up an LED when a voltage is applied

When people hear the term ‘printed electronics,’ the expectation is that a person loads a substrate and the designs for an electronic circuit into a printer and, some reasonable time later, removes a fully functional electronic circuit,” said Aaron Franklin, Associate Professor at Duke.

“Over the years there have been a slew of research papers promising these kinds of ‘fully printed electronics,’ but the reality is that the process actually involves taking the sample out multiple times to bake it, wash it or spin-coat materials onto it,” Franklin said. “Ours is the first where the reality matches the public perception.

The concept of so-called electronic tattoos were first developed in the late 2000s at the University of Illinois by John A. Rogers, who is now Professor of Materials Science and Engineering at Northwestern University. Rather than a true tattoo that is injected permanently into the skin, Rogers’s electronic tattoos are thin, flexible patches of rubber that contain equally flexible electrical components.

The thin film sticks to skin much like a temporary tattoo, and early versions of the flexible electronics were made to contain heart and brain activity monitors and muscle stimulators. While these types of devices are on their way to commercialization and large-scale manufacturing, there are some arenas in which they’re not well suited, such as when direct modification of a surface by adding custom electronics is needed. “For direct or additive printing to ever really be useful, you’re going to need to be able to print the entirety of whatever you’re printing in one step,” said Franklin. “Some of the more exotic applications include intimately connected electronic tattoos that could be used for biological tagging or unique detection mechanisms, rapid prototyping for on-the-fly custom electronics, and paper-based diagnostics that could be integrated readily into customized bandages.”

The techniques are described in a series of papers published in the journal Nanoscale and in the journal ACS Nano.

Source: https://pratt.duke.edu/

How To Arrange Nanoparticules With a Vinaigrette

Materials scientists at Duke University have theorized a new “oil-and-vinegar” approach to engineering self-assembling materials of unusual architectures made out of spherical nanoparticles. The resulting structures could prove useful to applications in optics, plasmonics, electronics and multi-stage chemical catalysis. Left to their own tendencies, a system of suspended spherical nanoparticles designed to clump together will try to maximize their points of contact by packing themselves as tightly as possible. This results in the formation of either random clusters or a three-dimensional, crystalline structure.

But materials scientists often want to build more open structures of lower dimensions, such as strings or sheets, to take advantage of certain phenomena that can occur in the spaces between different types of particles.  In the new study, Gaurav Arya, associate professor of mechanical engineering and materials science at Duke, proposes a method that takes advantage of the layers formed by liquids that, like a bottle of vinaigrette left on the shelf for too long, refuse to mix together.

When spherical nanoparticles are placed into such a system, they tend to form a single layer at the interface of the opposing liquids. But they don’t have to stay there. By attachingoil” or “vinegarmolecules to the particles’ surfaces, researchers can make them float more on one side of the dividing line than the other.

The particles want to maximize their number of contacts and form bulk-like structures, but at the same time, the interface of the different liquids is trying to force them into two layers,” said Arya. “So you have a competition of forces, and you can use that to form different kinds of unique and interesting structures.”

Arya’s idea is to precisely control the amount that each spherical nanoparticle is repelled by one liquid or the other. And according to his calculations, by altering this property along with others such as the nanoparticles’ composition and size, materials scientists can make all sorts of interesting shapes, from spindly molecule-like structures to zig-zag structures where only two nanoparticles touch at a time. One could even imagine several different layers working together to arrange a system of nanoparticles.

In the proof-of-concept paper, the nanoparticles could be made out of anything. Gold or semiconductors could be useful for plasmonic and electrical devices, while other metallic elements could catalyze various chemical reactions. The opposing substrates that form the interface, meanwhile, are modeled after various types of polymers that could also be used in such applications.

The novel approach appeared online on March 25 in the journal ACS Nano.

Source: https://pratt.duke.edu/