Targeted Immune Stimulation For More Effective Vaccines (Medicine)

Cutanos, a spin-off from the Max Planck Society, is developing novel vaccines and immunotherapies

In the future, it could be possible to stimulate the immune system with extremely high efficacy via the skin. Cutanos GmbH, a spin-off from the Max Planck Institute of Colloids and Interfaces, has developed a corresponding method for modulating immune cells in the skin. The LC-TDS technology makes it possible to specifically influence certain cells of the immune system and thus fight various infections and diseases. Founded in Vienna in January, the start-up has concluded an exclusive licence with the Max Planck Society for this novel procedure and is now developing innovative immunotherapies based upon it.

Bacteria and viruses are recognised by various cells of the immune system via antigens, i.e. external molecular structures that are specific to each pathogen. Antigens are therefore a popular basis for vaccines and immunotherapies designed to train the immune system to fight pathogens. However, these antigens are detected by a multitude of different receptors on different immune cells, which can sometimes result in divergent reactions within the immune system. Now, for the first time, a new method developed at the Max Planck Institute of Colloids and Interfaces in Potsdam is making it possible to supply only a specific type of immune cell with antigens in order to trigger a controlled immune response. Known as “Langerhans cells”, these cells are predominantly located in the uppermost skin layer (epidermis) and contain the Langerin receptor, which is specific to them. The technique developed at the Max Planck Institute allows exclusive access to these immune cells via an artificially produced ligand that only binds to Langerin.

LC-TDS technology elicits the desired immune response

The Langerin-specific ligand is the core of the Langerhans Cell Targeted Delivery System, (LC-TDS). In addition to the ligand, this modular system includes a transport system (vehicle) and the active substances or antigens to be delivered (cargo). The ligand is a small, synthetically produced molecule that sits on the surface of the carrier in large numbers. Due to its high binding specificity for Langerin, it ensures that the vehicle is detected and processed by the Langerhans cells just like a natural pathogen. Liposomes, proteins, LNPs (lipid nanoparticles) or other microparticles serve as the vehicles. Studies on epidermal cell suspensions as well as human skin explants have shown that the LC-TDS is taken up by 97 per cent of Langerhans cells, whereas only 0.1 percent of other, so-called off-target cells are addressed. This combination of high specificity and selectivity allows the active substances to be transported and with extreme precision. The cargo can be small molecules, peptides, proteins or mRNA. Since the addressed Langerhans cells are located in the top layer of the skin, LC-TDS can be administered via minimally invasive microneedles.

As mediators of immunity and tolerance, Langerhans cells are able to distinguish between foreign and endogenous antigens. Therefore, the LC-TDS can be applied in different areas for the purpose of immune activation and regulation. As a result, Cutanos is currently working on antiviral vaccines and therapies for autoimmune diseases. In addition, drug delivery can also be used to specifically kill cancerous Langerhans cells, as is necessary in cases of Langerhans cell histiocytosis, for example.

Funding secures development

Working principle of the Langerhans Cell Targeted Delivery System (LC-TDS). © Cutanos GmbH

Cutanos GmbH has set itself the goal of developing the LC-TDS to market maturity and marketing it internationally. For this purpose, it has rented office and laboratory space on the campus of the University of Vienna, where it has access to the institution’s research infrastructure. The two founders, Christoph Rademacher and Robert Wawrzinek together with other scientists, conceived the novel method at the Max Planck Institute of Colloids and Interfaces in the department of Peter H. Seeberger, and have now exclusively licensed it as part of their spin-off, which was founded in January. In addition, the start-up has successfully secured funds from an international consortium of investors as part of its current seed-funding round. “The successful spin-off of Cutanos is a perfect example of how breakthroughs in basic research can be implemented so that important medical challenges can be addressed,” says Peter H. Seeberger, Director of the Biomolecular Systems Department at the Max Planck Institute.

Cutanos GmbH’s business model envisages adapting the technology to the individual needs of its customers in the biotech and pharmaceutical sectors in the future. Thus, the company will present the design, formulation and preclinical in vitro and in vivo experiments with the goal of creating customised LC-TDS solutions. In addition, following successful proof of concepts (PoCs), Cutanos will advance the application of its method into clinical development for the indications of antiviral vaccines, Graves’ disease and Langerhans cell histiocytosis.

Max Planck Innovation, the technology transfer organisation of the Max Planck Society, has long supported and accompanied the startup’s establishment – and has now licensed the LC-TDS technology to the fledgling business. “We are very enthusiastic about the LC-TDS approach being developed by Cutanos. The scientists’ tireless efforts, together with the SARS-CoV2 project funded by the KHAN Technology Transfer Fund I (KHAN-I), has finally helped to get the new company off the ground and laid the foundation for the current funding round,” says Mareike Göritz, Senior Patent and Licensing Manager at Max Planck Innovation. “We are pleased that the two co-inventors Christoph Rademacher and Robert Wawrzinek continue to contribute their great expertise in this field to bring the technology to the market and thus to the patients.”

Featured image: Langerhans cell which has taken up the Langerhans Cell Targeted Delivery System (marked in red). © Cutanos GmbH

This science news has been confirmed by us from Max Planck Gesellschaft

Provided by Max Planck Gesellschaft

Developing Cancer Therapies With Stem Cells (Medicine)

The Shin Kaneko laboratory uses iPS cells to develop immune cells that attack colorectal cancer.

In recent years, adoptive cell transfer therapies have given cancer patients new hope and, in some cases, even cures. In these therapies, anti-cancer cells are processed and injected into patients. A new study by the Shin Kaneko Laboratory shows how iPS cells can be used to prepare even more potent adoptive cell transfer therapies for colorectal cancers.

In typical adoptive cell transfer therapies, the anti-cancer cells are taken directly from the patient. In all cases of cancer, the patient produces tumor-infiltrating lymphocytes that recognize and kill cancer cells. The problem is that the number of these lymphocytes is not high enough to stop the cancer from spreading.

CiRA Prof. Shin Kaneko explains that because of the recognition, most adoptive cell transfer therapies use these cells.

“The cells are collected and expanded, but the cells lose their potency. The ideal cells for the therapy would have juvenile properties. This means longer persistency and more proliferation. But these conditions are difficult to manufacture if using patient cells,” he said.

Kaneko added that along with these properties is that the lymphocytes target the cancer cells with high specificity. That is, they kill cancer cells but no healthy cells in the patient. iPS cells can provide the juvenile properties, but only certain iPS cells can also provide the specificity.

“Our hypothesis was that we could maintain the cancer specificity if we programmed tumor-infiltrating lymphocytes. Other reprogrammed cells would not have specificity,” said Takeshi Ito, the first author of the study.

Unlike other iPS cells, those made from reprogrammed tumor-infiltrating lymphocytes carried the surface receptors needed to recognize the cancer cells. To test their hypothesis, the researchers collected tumor-infiltrating lymphocytes sensitive for colorectal cancers. These cells were then reprogrammed into iPS cells and then differentiated back into tumor-infiltrating lymphocytes.

Notably, in contrast to the original tumor-infiltrating lymphocytes, those differentiated from iPS cells showed longer telomeres and persistency and more proliferation, resulting in superior cytotoxicity against the cancer cells.

“In adoptive cell transfer therapies, patient cells are safest but not always effective at killing the cancer. We are developing safe adoptive cell transfer therapies with iPS cells that have a higher killing effect,” said Kaneko.

Reference: Ito, T., Kawai, Y., Yasui, Y. et al. The therapeutic potential of multiclonal tumoricidal T cells derived from tumor infiltrating lymphocyte-derived iPS cells. Commun Biol 4, 694 (2021).

Provided by CIRA

New Microchip Sensor Measures Stress Hormones from Drop of Blood (Medicine)

A Rutgers-led team of researchers has developed a microchip that can measure stress hormones in real time from a drop of blood.

The study appears in the journal Science Advances.

Cortisol and other stress hormones regulate many aspects of our physical and mental health, including sleep quality. High levels of cortisol can result in poor sleep, which increases stress that can contribute to panic attacks, heart attacks and other ailments.

Currently, measuring cortisol takes costly and cumbersome laboratory setups, so the Rutgers-led team looked for a way to monitor its natural fluctuations in daily life and provide patients with feedback that allows them to receive the right treatment at the right time.

The researchers used the same technologies used to fabricate computer chips to build sensors thinner than a human hair that can detect biomolecules at low levels. They validated the miniaturized device’s performance on 65 blood samples from patients with rheumatoid arthritis.

“The use of nanosensors allowed us to detect cortisol molecules directly without the need for any other molecules or particles to act as labels,” said lead author Reza Mahmoodi, a postdoctoral scholar in the Department of Electrical and Computer Engineering at Rutgers University-New Brunswick.

With technologies like the team’s new microchip, patients can monitor their hormone levels and better manage chronic inflammation, stress and other conditions at a lower cost, said senior author Mehdi Javanmard, an associate professor in Rutgers’ Department of Electrical and Computer Engineering.

“Our new sensor produces an accurate and reliable response that allows a continuous readout of cortisol levels for real-time analysis,” he added. “It has great potential to be adapted to non-invasive cortisol measurement in other fluids such as saliva and urine. The fact that molecular labels are not required eliminates the need for large bulky instruments like optical microscopes and plate readers, making the readout instrumentation something you can measure ultimately in a small pocket-sized box or even fit onto a wristband one day.”

The study included Rutgers co-author Pengfei Xie, a Ph.D. student, and researchers from the University of Minnesota and University of Pennsylvania. The research was funded by the DARPA ElectRX program.

Reference: S. Reza Mahmoodi, Pengfei Xie, Daniel P. Zachs, Erik J. Peterson, Rachel S. Graham, Claire R. W. Kaiser, Hubert H. Lim, Mark G. Allen, Mehdi Javanmard, “Single-step label-free nanowell immunoassay accurately quantifies serum stress hormones within minutes”, Science Advances  30 Jun 2021: Vol. 7, no. 27, eabf4401 DOI:

Provided by Rutgers University

Belowground Microbial Solutions To Aboveground Plant Problems (Agriculture)

Researchers from the Max Planck Institute for Plant Breeding Research (MPIPZ) have discovered that signalling occurring from the response of plant leaves to light, and plant roots to microbes, is integrated along a microbiota-root-shoot axis to boost plant growth when light conditions are suboptimal.

Land plants – plants that live primarily in terrestrial habitats and form vegetation on earth – are anchored to the ground through their roots, and their performance depends on both the belowground soil conditions and the aboveground climate. Plants utilise sunlight to grow through the process of photosynthesis where light energy is converted to chemical energy in chloroplasts, the powerhouses of plant cells.  Therefore, the amount and quality of light perceived by chloroplasts through light absorbing pigments, such as chlorophyll, is a defining factor in plant growth and health. A substantial amount of the chemical compounds produced during the conversion of light energy to chemical energy, termed photoassimilates (mainly sugars), is translocated to the plant root compartment and invested in the surrounding soil to sustain microbial growth. Consequently, roots harbour complex microbial communities of bacteria and filamentous eukaryotes (i.e., fungi and oomycetes), and the composition of these communities profoundly influences plant performance. However, the extent to which plants can take advantage of belowground microbes to orchestrate aboveground stress responses remains largely unexplored. Now, in a new study published in Nature Plants, Stéphane Hacquard and his colleagues from the Department of Plant-Microbe Interactions at the MPIPZ in Cologne, Germany, shed light on these aboveground-belowground connections.

To tackle this question, the first author of the study Shiji Hou performed experiments where the aboveground light conditions and the belowground microbial conditions could be controlled.  By comparing the growth of Arabidopsis thaliana (Thale Cress) grown in the absence of root microbes (i.e., germ-free) to those colonized by a complex community of 183 bacteria, 24 fungi and 7 oomycetes, the researchers observed that the presence of microbes rescued the plant growth-deficiency observed under low light conditions. Inoculation experiments with leaf pathogens further indicated that plants colonized by microbes were also more resistant to aboveground leaf pathogens than germ-free control plants, indicating that the presence of root microbes can promote both plant growth and defence under low light.

By comparing growth and defence responses of colonized plants between the two light conditions, the scientists observed that investment in growth under low light conditions came at the cost of defence, since microbiota-induced defence responses were reduced and plants were more susceptible to leaf pathogens under low light. Based on this observation, the authors of the study then hypothesized that when light conditions are suboptimal, plants favour microbe-induced growth over microbe-induced defence responses. To test this hypothesis, the researchers screened different A. thaliana mutants to identify those that failed to invest in growth under low light. Consistent with their hypothesis, the identified mutants were better at resisting leaf pathogens instead. Furthermore, the scientists found that the presence of the host transcription factor MYC2 was crucial to tip the balance in favour of microbiota-induced growth instead of microbiota-induced defence under low light conditions.    

The researchers then went on to investigate whether the make-up of the microbial community belowground could explain aboveground investment in growth at the expense of defence under low light. To do this, they analysed the composition of the root microbiota across the different A. thaliana mutants and observed that the bacterial community composition was markedly different depending on whether the different plants invested in growth under low light. This experiment led to the identification of 67 bacterial strains that were predicted to be associated with plant growth rescue under low light. To test a potential causal link, the researchers prepared three different bacterial communities composed of either: 1) all 183 strains, 2) the 183 strains lacking the 67 strains predicted to be important for growth rescue or 3) the 67 strains alone. Remarkably, A. thaliana wild-type plants colonized with the 67-member community invested in growth under low light, whereas those colonized by the community lacking these bacterial strains did not, instead favouring better resistance to leaf infection by pathogens.

In the words of study lead Stéphane Hacquard: “Our results suggest that plant growth and defence responses are engaged in different feedback loops with the root microbiota depending on aboveground light conditions. It is likely that light-induced change in root exudation profiles is an important mechanism that stimulates the growth of particular beneficial bacterial root commensals that boost plant growth, in the expense of defence responses under low light”. The observation that microbiota-root-shoot-circuits exist in plants is reminiscent of recent results obtained in the context of the microbiota-gut-brain axis in animals, where a direct link between gut commensals and brain functions was uncovered. The results suggest that bacterial root and gut commensals have important functions in modulating stress responses not only locally, but also in distant host organs.   

These findings have important applications for utilizing belowground microbes to promote aboveground stress responses in plants. By applying the knowledge gained in this study it would now be conceivable to design synthetic microbial communities with modular functions that could be used to promote plant resistance to particular biotic or abiotic stresses, and ultimately promote plant health in nature.

Featured image: Priority to microbiota-induced plant growth over defence, under low light conditions. Image created with BioRender.

Reference: Shiji Hou, Thorsten Thiergart, Nathan Vannier, Fantin Mesny, Jörg Ziegler, Brigitte Pickel, Stéphane Hacquard, “A microbiota-root-shoot circuit favours Arabidopsis growth over defence under suboptimal light”, Nature Plants, July 5, 2021. Link to paper

Provided by MPIPBR

Discovered A Population of Large Black Holes in the Star Cluster Palomar 5 (Cosmology)

Palomar 5 is a unique star cluster. This is due, in the first place, to the fact that it is one of the “spongiest” in the Milky Way halo, with an average distance of a few light-years between the stars, comparable to the distance from the Sun to the brightest star. next. Second, because it is associated with a specular stellar current that covers more than 20 degrees in the sky. In an article published in Nature Astronomy , an international team of astronomers and astrophysicists led by the University of Barcelona shows that the two distinctive features of Palomar 5 are probably the result of a population of more than one hundred black holes in the center of the cluster.

“The number of black holes is about three times greater than would be expected from the number of stars in the cluster, which means that more than 20% of the total mass of the cluster is made up of black holes,” explains Mark Gieles . professor at the Institute of Cosmos Sciences of the University of Barcelona (ICCUB) and lead author of the work. “Each has a mass twenty times the mass of the Sun,” says the expert, “and they formed in supernova explosions at the end of the life of massive stars, when the cluster was still very young.”

Tidal currents are associations of stars that were ejected from star clusters or dwarf galaxies. In recent years, about thirty narrow stellar currents have been discovered in the halo of the Milky Way. “We don’t know how these currents form, but one idea is that they are star clusters that have suffered some disturbance,” explains Gieles. However, none of the recently discovered currents have an associated star cluster, so researchers cannot be sure of this theory. To understand how these currents formed, one must study one with an associated stellar system: “Palomar 5 is the only case, and this makes it a kind of Rosetta Stone, which will allow us to understand the formation of stellar currents. · Lars », points out Gieles. “That’s why we studied it in detail,” he explains.

CCUB researcher Mark Gieles. 
Image: ICCUB

In this study, the authors simulated the orbits and evolution of each star from cluster formation to final dissolution. Their initial properties varied until they found that the observations of the current and the cluster matched. The astronomer team believes that Palomar 5 was formed from a smaller black hole fraction, but the stars were able to escape more efficiently than the black holes, so the black hole fraction increased gradually.

The black holes dynamically inflated the cluster through gravitational assistance interactions with the stars, which caused more stars to escape and the current to form. Just before it dissolves completely — about a billion years from now — the cluster will be completely made up of black holes. “This work has helped us to understand that, although the Palomar 5 cluster has the brightest and longest tails than any other cluster in the Milky Way, it is not unique. Instead, we believe that many similarly dominated black hole clusters have already disintegrated in the tides of the Milky Way to form the first newly discovered stellar currents, “said Denis Erkal , co-author of the study. , researcher at the University of Surrey (UK).

Gieles notes that the study shows “that the presence of a large population of black holes may have been common in all groups that formed the currents.” This is important for understanding the formation of globular clusters, initial star masses, and the evolution of massive stars. This work also has important implications for gravitational waves. “A large portion of binary black hole fusions are believed to form in star clusters. A big unknown in this scenario is the number of black holes in the clusters, which is difficult to delimit observationally because we can not observe the black holes, “says Fabio Antonini, Professor at Cardiff University (Wales, UK), and also co-author of the paper. “Our method provides a way to know how many black holes there are in a star cluster by looking at the stars that are ejected from it,” he said.

Palomar 5 is a globular cluster discovered in 1950 by Walter Baade. It is located in the constellation of the Serpent, at a distance of about 65,000 light-years, and is one of approximately 150 globular clusters orbiting the Milky Way. It is over ten billion years old, like most other globular clusters, meaning it formed in the early stages of galaxy formation. It is approximately ten times less massive and five times more extensive than a typical globular cluster and in the final stages of dissolution.

Simulation showing the formation of tidal currents in the Palomar 5 star cluster and the distribution of black holes. In yellow you see the stars and in black the black holes. More than 20% of the mass of Palomar 5 is made up of black holes.

Featured image: Map of the Milky Way plan obtained from data in the Gaia catalog (eDR3). At the top is a region where the star cluster of Palomar 5 and its tidal tails are observed (data obtained thanks to the DESI Legacy Imaging Survey, DECaLS). Image: E. Balbinot, Gaia, DECaLS-DESI

Reference article :

M. Gieles et al. “A supra-massive population of Stella-massblack holes in the globular cluster Palomar 5” . Nature Astronomy , July 5, 2021. DOI: 10.1038 / s41550-021-01392-2

Provided by University of Barcelona

From Atoms To Planets, The Longest-running Space Station Experiment (Astronomy)

As Europe celebrates 20 years of ESA astronauts on the International Space Station, a Russian-European experiment has been running quietly in the weightless research centre for just as long: the Plasma Kristall (PK) suite of investigations into fundamental science.

Roscosmos cosmonaut Oleg Novitsky working on the Plasma Kristall-4 experiment in Europe’s Columbus laboratory on the International Space Station, 18 June 2021. Credit: ESA/NASA–T. Pesquet

Plasma Kristall takes a plasma and injects fine dust particles in weightlessness, turning the dust into highly charged particles that interact with each other, bouncing off each other as their charge causes the particles to attract or repel. Under the right conditions, the dust particles can arrange themselves over time to form organised structures, or plasma crystals.

Visualising the laws of physics
Visualising the laws of physics © ESA

These interactions and forming of three-dimensional structures resemble the workings of our world on the atomic scale, a world so small that we cannot see move even with an electron microscope. Add a laser to the mix and the dust particles can be seen and recorded for observation by scientists on Earth for a sneak peak of the world beyond our eyes.

These surrogate atoms are a way for researchers to simulate how materials form on an atomic scale, and to test and visualise theories. The experiment cannot be run on Earth because gravity only makes sagging, flattened recreations possible; if you want to see how a crystal is constituted you need to remove the force pulling downwards – gravity.

Sergei with original PK-3 experiment on the Space Station in 2001
Sergei with original PK-3 experiment on the Space Station in 2001 © ESA

On 3 March 2001, “PK-3 Plus” was turned on in the Zvezda module, the first physical experiment to run on the Space Station. Led by the German aerospace centre DLR and Russian space agency Roscosmos the experiment was a success and later followed up by a fourth version, installed in 2014 in ESA’s Columbus laboratory, this time as an ESA-Roscosmos collaboration.

Elena installing PK-4 in 2014
Roscosmos cosmonaut Elena Serove installing the Plasma Kristall-4 experiment in Europe’s Columbus laboratory on the International Space Station in 2014. Credit: ESA/NASA
Plasma Kristall-4
Plasma Kristall-4. Credit: Michael Kretschmer

Planet conceptions

By changing the parameters in PK-4, such as adjusting voltage or using larger dust particles, the atom doppelgangers can simulate different interactions. Complex phenomena such as phase transitions, for example from gas to liquid, microscopic motions, the onset of turbulence and shear forces are well known in physics, but not fully understood at the atomic level.

Using PK-4, researchers across the world can follow how an object melts, how waves spread in fluids and how currents change at the atomic level.  

Around 100 papers have been published based on the Plasma Kristall experiments and the knowledge gained is helping understand how planets form too. At its origin our planet Earth was probably two dust particles that met in space and grew and grew into our world. PK-4 can model these origin moments as they are during the conception of planets.

CADMOS during PK-4 operations
CADMOS during PK-4 operations © ESA

The huge amount of data that PK-4 creates is so vast it cannot be downloaded through the Space Station’s communication network, so hard disks are physically shipped to space and back with terabytes of information. The experiment is run from Toulouse, France, at the CNES space agency operating centre Cadmos.

Astrid Orr, ESA’s physical sciences coordinator notes “PK-4 is a great example of fundamental science done on the Space Station; through international collaboration and long-term investment we are learning more about the world around us, on the minute scale as well as on the cosmic scale.

“The knowledge from the PK experiments can be directly applied to research on fusion physics – where dust needs to be removed – and the processing of electronic chips, for example in plasma processes in the semiconductor and solar cell industry. In addition, the miniaturisation of the technology required when developing Plasma Kristal is already being applied in plasma-based medical equipment for hospitals.

“The PK experiments address a large range of physical phenomena, so ground-breaking discoveries can happen at any moment.”

This science news has been confirmed by us from ESA

Provided by ESA

How 3D-printed Scaffolds Promotes Tissue Regeneration? (Medicine)

Research published today has demonstrated the viability of 3D-printed tissue scaffolds that harmlessly degrade while promoting tissue regeneration following implantation.

The scaffolds showed highly promising tissue-healing performance, including the ability to support cell migration, the ‘ingrowth’ of tissues, and revascularisation (blood vessel growth).

Professor Andrew Dove, from the University of Birmingham’s School of Chemistry, led the research group and is the lead author on the paper published in Nature Communications, which characterises the physical properties of the scaffolds, and explains how their ‘shape memory’ is key to promoting tissue regeneration.

Professor Dove commented: “The scaffolds have evenly distributed and interconnected pores that allow diffusion of nutrients from surrounding tissues. The shape memory means this structure is retained when the scaffold is implanted into tissues, and this supports the infiltration of cells into the scaffold while encouraging tissue regeneration and revascularisation.”

The scaffolds were created using 3D printing resin ‘inks’ developed during a major programme of biomaterials research led by Professor Andrew Dove at the University of Birmingham and Warwick University. The resins are being commercialised under the tradename 4Degra™ by 4D Biomaterials, a spinout from University of Birmingham Enterprise and Warwick Innovations that was launched in May 2020.

The scaffolds showed several major advantages over current approaches used to fill soft tissue voids that remain after trauma or surgery, including sufficient elasticity to conform to irregular spaces, the ability to undergo compression of up to 85% before returning to their original geometry, compatibility with tissues, and non-toxic biodegradation.

The paper describes several compositions for the 4Degra™ resins that enable materials of a wide range of strengths to be manufactured. All of the compositions include a photoinitiator and a photoinhibitor to ensure the resins rapidly turn into gel on exposure to light in the visible spectrum to enable their 3D printing into a range of scaffold geometries.

The researchers showed that the materials were non toxic to cells and they also performed mechanical testing to ensure the scaffolds could regain their shape, geometry and pore size after compression, and performed tests that showed the scaffolds can fill an irregular shaped void in alginate gel which was used as a mimic of soft tissue.

Laboratory studies demonstrated that the scaffold degrades by surface erosion into non-acidic products, which means the scaffold structure allows for slow, continuous tissue infiltration.

The findings were confirmed in a mouse model that simulates implantation into adipose (fat) tissue. These studies showed infiltration of adipocytes and fibroblasts and vascularisation at two months, and a tissue arrangement and macrophage presence that was indicative of normal tissue restoration rather than damaged, scarred tissue or an inflammatory response.

At four months, the researchers found small, mature blood vessels in the surrounding tissue. The scaffolds also demonstrated excellent biocompatibility. The collagen capsule formed around implants was less than 200 µm thick, which is well below the 500 µm threshold used for biocompatibility in other studies, and there was no calcification or necrosis.

Also at four months, 80% of the scaffold was still present, demonstrating the slow degradation predicted by the laboratory studies, and indicating the scaffolds would provide support for more than a year, allowing sufficient time for mature tissue ingrowth. The controls, which used poly(L-lactic acid) (PLLA) as a comparator, did not show a significant reduction over the four month period.

Professor Dove comments: “3D printed materials have received a lot of attention in the tissue engineering world. However void-filling materials to provide mechanical support, biocompatibility, and surface erosion characteristics that ensure consistent tissue support during the healing process, and this means a fourth dimension (time) needs to be considered in material design.

“We have demonstrated that it’s possible to produce highly porous scaffolds with shape memory, and our processes and materials will enable production of self-fitting scaffolds that take on soft tissue void geometry in a minimally invasive surgery without deforming or applying pressure to the surrounding tissues. Over time, the scaffold erodes with minimal swelling, allowing slow continuous tissue infiltration without mechanical degradation.”

4D Biomaterials has made fast progress in scaling up production of the 4Degra™ resin-inks at its laboratory in MediCity, Nottingham (UK) and is now offering technical grade material for commercial supply to 3D printing companies and medical device manufacturers.

CEO Phil Smith said “We are looking to collaborate with innovative companies in Europe and North America to develop a new generation of 3D-printed medical devices that translate the unique advantages of the 4Degra™ resin-ink platform into improved treatment outcomes for patients”. With the first customer shipments dispatched and a funding round about to close, Phil added “We will be making further announcements shortly.” 

Featured image: Bioresorbable tissue scaffolds © University of Birmingham

This science news has been confirmed by us from University of Birmingham

Provided by University of Birmingham

What Happens In the Brain Of Flies and Maybe, People when They Choose Their Food? (Neuroscience)

Flies have discriminating taste. Like a gourmet perusing a menu, they spend much of their time seeking sweet nutritious calories and avoiding bitter, potentially toxic food. But what happens in their brains when they make these food choices?

Yale researchers discovered an interesting way to find out. They tricked them.

In a study that could also help illuminate how people make food choices, the researchers gave hungry fruit flies the choice between sweet, nutritious food laced with bitter quinine and a less sweet, but not bitter, food containing fewer calories. Then, using neuroimaging, they tracked neural activity in their brains as they made these tough choices.

So which won? Calories or better taste?

“It depends on how hungry they are,” said Michael Nitabach, professor of cellular and molecular physiology, genetics, and neuroscience at Yale School of Medicine and senior author of the study. “The hungrier they are, the more likely they will tolerate bitter taste to obtain more calories.”

But the real answer to how flies make these decisions is a little more complex, according to the study published July 5 in the journal Nature Communications.

According to the research team, led by Preeti Sareen, associate research scientist at Yale, flies relay sensory information to a portion of their brain called the fan-shaped body, where signals are integrated, triggering what amounts to the insect version of an executive decision. The researchers found that patterns of neuronal activity in the fan-shaped body change adaptively when novel food choices are introduced, which dictates the fly’s decision over what food to eat.

But researchers went a step further. And things got even stranger. They found they could change a fly’s choice by manipulating neurons in areas of the brain that feed into the fan-shaped body. For example, when they caused a decrease in activity in the neurons involved in metabolism, the found that it made hungry flies choose the lower calorie food.

“It is one big feedback loop, not just top-down decision making,” Nitabach said.

And this is where there are connections to food choices of humans, he said. Neural activity in both a fly’s brain and a human’s brain are regulated by the secretion of neuropeptides and the neurotransmitter dopamine, which in humans helps regulate sensations of reward. Changes in this network may alter how the brain responds to different types of food. In other words, neurochemistry may sometimes dictate food choices we think we are making consciously.

“The study provides a template to understand how it is that things like hunger and internal emotional states influence our behavior,” Nitabach said.

Sareen and Li Yan McCurdy, a graduate student at Yale School of Medicine, are co-authors of the paper.

Reference: Sareen, P.F., McCurdy, L.Y. & Nitabach, M.N. A neuronal ensemble encoding adaptive choice during sensory conflict in Drosophila. Nat Commun 12, 4131 (2021).

Provided by Yale University

Structures Discovered In Brain Cancer Patients Can Help Fight Tumors (Medicine)

Researchers at Uppsala University have discovered lymph node-like structures close to the tumour in brain cancer patients, where immune cells can be activated to attack the tumour. They also found that immunotherapy enhanced the formation of these structures in a mouse model. This discovery suggests new opportunities to regulate the anti-tumour response of the immune system.

Glioma is a deadly brain tumour with a dismal prognosis. One reason why brain tumours are very hard to treat is that our immune system, which is designed to detect and destroy foreign cells including cancer cells, cannot easily reach the tumour site due to the barriers that surround the brain.

To fight a developing tumour, killer immune cells such as T lymphocytes must be activated and primed in our lymph nodes, before travelling to the tumour site to effectively kill the cancer cells. Because of the barriers around the brain, it is a challenging process for T lymphocytes to reach the tumour.

In the study now published in the journal Nature Communications, the researchers describe their discovery of structures similar to lymph nodes in the brain where T lymphocytes could be activated.

“It was extremely exciting to discover for the first time the presence of lymph node-like structures in glioma patients. These structures are known as tertiary lymphoid structures (TLS) and they are not found in healthy individuals. They have all the components needed to support lymphocyte activation on-site which means that they could have a positive effect on the anti-tumour immune response,” says Alessandra Vaccaro, PhD student at the Department of Immunology, Genetics and Pathology and shared first author of the study.

The researchers also showed that the formation of TLS in the brain can be induced by a type of immunotherapy in glioma-bearing mice. Indeed, when they treated the mice with immunostimulatory antibodies called αCD40, the formation of TLS was enhanced and always occurred in proximity to tumours.

“Learning that immunotherapies can modulate the formation of tertiary lymphoid structures in the brain offers exciting opportunities to find new ways of regulating the anti-tumour immune response in glioma,” says Anna Dimberg who has led the study.

αCD40 is currently being tested to treat brain tumours in a number of clinical trials. In the study now published, the researchers found that while αCD40 boosted TLS formation, it also counterproductively inhibited the tumour-killing ability of the T lymphocytes. The study has therefore provided important insights into the multifaceted effects of αCD40 therapy.

Reference: van Hooren, L., Vaccaro, A., Ramachandran, M. et al. Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat Commun 12, 4127 (2021).

Provided by Uppsala University