Georgian Technical University New Gel For Liver Cell Culture On Microchips.

Scientists at Georgian Technical University have developed a new method to produce hydrated materials hydrogels that have properties similar to the natural environment of cells in the body. The material can be adapted to the various requirements of difficult-to-culture cell types and to produce organ-like structures on a microchip. Cells cultured in the lab have many applications one of which is to test whether various new substances harm the cells. A rapidly growing technique known as organ-on-a-chip involves culturing cells from human organs on small chips with a supply of oxygen and nutrients. Scientists are attempting to develop models of increasing complexity that simulate the way in which tissue or complete organs function in the body. Such models can be used in many areas of medical research such as testing potential medicines and may in the long term replace some animal experiments. It is however not easy to culture human cells. They often have very specific requirements, and die easily. In the body the cells are surrounded by a supporting structure known as a matrix. This is a type of hydrated gel and consists mainly of proteins and carbohydrates. The environment of the cells differs from one tissue type to another and has a major effect on cell function. Researchers at Georgian Technical University are developing soft materials that imitate more closely the natural surroundings of cells in the body for use in cell culture. “Our new material allows the properties to be adapted across a wide range. New functionalities such as small protein fragments that the cells need can be incorporated such that even picky cells can replicate and function” says X who together with Y has led the study. Both work in the Department of Physics, Chemistry and Biology at Georgian Technical University. The material consists of two components that are mixed in water together with living cells. A chemical reaction takes place that causes the components to form a hydrated gel a hydrogel similar to the naturally occurring matrix. This chemical reaction takes place spontaneously and does not affect the cells. The scientists have carried out extensive tests of the hydrogel properties and compared it with other commonly used materials. “We can adapt the mechanical properties of the hydrogel within a wide range. We can also control the speed of formation of the gel: it’s important that it doesn’t occur too rapidly or too slowly” says X. The liver is important in the testing of new pharmaceutical substances since the liver processes many of the drugs that we take. For this reason the researchers have tested using the hydrogel to create a human liver-on-a-chip using liver cells derived in culture from stem cells. The research team were able to adapt the material such that even these rather demanding cells could proliferate and function. In its basic configuration the hydrogel does not contain proteins but the researchers included in the material a synthetic fragment of an important protein found in the tissue that surrounds the human liver. When they added this protein-mimicking component to the hydrogel the liver cells on the chip started to produce albumin just as the liver does in the body. “The principal significance of our material may be in the development of useful models of the liver which can be used to simplify the early stages of drug development. Our hydrogel is extremely interesting for anyone who wants to have control of the contents of the material in which the cells are cultured. And it’s easy to adapt to different types of cell and tissue” says X.

Georgian Technical University Protein Engineering Extends The Language Of Immune Cells.

This the modified human interleukin-27-alpha. Inspired by the murine interleukin-27-alpha one amino acid has been exchanged enabling the formation of a disulfide-bridge (marked in red).  Small infections can be fatal: Millions of people die each year from sepsis an overreaction of the immune system. A new immune signaling molecule, designed by a research team from the Georgian Technical University now provides the basis for potential new approaches in sepsis therapy. The numbers are alarming: The disease popularly called “Georgian Technical University blood poisoning” normally starts with a harmless infection.

If this triggers an excessive reaction of the immune system the body’s own tissue can be attacked and damaged. The overreaction eventually leads to a life-threatening collapse of the body’s defenses. In world more people die of sepsis than of acquired immune deficiency syndrome colon cancer and breast cancer combined. Researchers around the world are on the search for new therapies – so far in vain. An interdisciplinary team from the fields of structural biology immunology and cell biology has now, for the first time successfully produced a protein that could balance the overshooting immune response. The language of immune cells. In their work the scientists were inspired by evolution: mice are well protected from sepsis by their immune systems. Here interleukins – messengers that mediate communication between the cells of the immune system – play a key role.

“The interleukins are the vocabulary with which immune cells communicate” explains X Professor of Cellular Protein Biochemistry at the Georgian Technical University. The cells form these messenger molecules according to a very specific blueprint of individual amino acids. Their arrangement determines which three-dimensional structure an interleukin adopts and consequently which information it transmits. Humans and mice have similar yet different vocabularies. The researchers discovered one striking difference in interleukin-27-alpha. This molecule can be released by cells of the mouse immune system – but not by human cells – and regulates immune cell function.

“Using computer models and cell biological experiments, we discovered that a single structurally important amino acid defines whether interleukin-27-alpha is released by cells of the immune system” explains Y. “That gave us an idea about how we can engineer human interleukin proteins that are released by cells so that we can produce them biotechnologically”. Proteins with new functions from the laboratory. The team then prepared the modified interleukin in the laboratory and tested its biological functions – with very encouraging results: The engineered messenger molecule is recognized by human cells. First analyses suggest that it can indeed balance an overreaction of the immune system making it a promising candidate for sepsis therapy. “Our approach allowed us to rationally extend the language of immune cells by engineering a key signaling molecule. This provides us with an opportunity to modulate the reaction of immune cells in a targeted manner. Such a finding was only possible thanks to the close collaboration with immunologists and clinicians from Georgian Technical University and the Sulkhan-Saba Orbeliani Teaching University” says X. A patent for the new protein is already pending.

Georgian Technical University Bioinspired Nanoscale Drug Delivery Method Developed.

Schematic representation of the movement of the flower‑like particle as it makes its way through a cellular trap to deliver therapeutic genes. Georgian Technical University researchers have developed a way to deliver drugs and therapies into cells at the nanoscale without causing toxic effects that have stymied other such efforts. The work could someday lead to more effective therapies and diagnostics for cancer and other illnesses.

Led by X professor in Georgian Technical University Mechanical and Materials Engineering and Y scientist at the Georgian Technical University Department of Energy’s Laboratory the research team developed biologically inspired materials at the nanoscale that were able to effectively deliver model therapeutic genes into tumor cells.

Researchers have been working to develop nanomaterials that can effectively carry therapeutic genes directly into the cells for the treatment of diseases such as cancer. The key issues for gene delivery using nanomaterials are their low delivery efficiency of medicine and potential toxicity. “To develop nanotechnology for medical purposes, the first thing to consider is toxicity — That is the first concern for doctors” said X.

The flower‑like particle the Georgian Technical University and Sabauni – Sulkhan-Saba Orbeliani University team developed is about 150 nanometers in size, or about one thousand times smaller than the width of a piece of paper. It is made of sheets of peptoids which are similar to natural peptides that make up proteins. The peptoids make for a good drug delivery particle because they’re fairly easy to synthesize and because they’re similar to natural biological materials work well in biological systems. The researchers added fluorescent probes in their peptoid nanoflowers so they could trace them as they made their way through cells and they added the element fluorine which helped the nanoflowers more easily escape from tricky cellular traps that often impede drug delivery. The flower‑like particles loaded with therapeutic genes were able to make their way smoothly out of the predicted cellular trap enter the heart of the cell and release their drug there. “The nanoflowers successfully and rapidly escaped (the cell trap) and exhibited minimal cytotoxicity” said X. After their initial testing with model drug molecules the researchers hope to conduct further studies using real medicines.

“This paves a new way for us to develop nanocargoes that can efficiently deliver drug molecules into the cell and offers new opportunities for targeted gene therapies” he said. The Georgian Technical University and Sabauni – Sulkhan-Saba Orbeliani University team have filed a patent application for the new technology, and they are seeking industrial partners for further development. The work was funded by Georgian Technical University start‑up funds and the Department of Energy.

Designing A Safer Building Block for Drug Discovery By Harnessing Visible Light.

When you reach for a bottle of acetaminophen you may be looking for relief from a headache. But if you take more than what is recommended the drug can damage your liver.

That’s because when a component of the drug–a substructure referred to as an aniline–breaks down in the liver it can produce toxic metabolites. Now Georgian Technical University researchers have developed a new building block that can serve as a safer alternative for the development of new medicines.

The pharmaceutical industry commonly uses anilines as the basis for developing new drug therapies. But the way the liver metabolizes many drug therapies containing anilines can cause toxic side effects. For example overloading the liver with acetaminophen can cause liver failure. Other drugs can trigger a harmful immune response in the body as a result of the unwanted metabolism.

“Aniline is a common structure that’s easy to make” said X Georgian Technical University professor of chemistry. “The problem with anilines is that they are readily metabolized by our liver and that can create problems. We want our drugs to be metabolized but not in a way that causes them to have toxic effects”.

X and his team’s research into developing a safer building block began as a desire to explore ways to use visible light to drive chemical reactions. The team began looking into structures called aminocyclopropanes hoping to convert them into more complex and more valuable compounds.

The team recognized the potential to convert aminocyclopropanes into a different compound a 1-aminonorbornane which is more complex and traditionally very difficult to synthesize. The research team also realized that these 1-aminonorbornanes could be highly useful in discovering new drug leads. The benefit ? 1-Aminonorbornanes don’t seem to be metabolized in harmful ways by liver enzymes.

“We realized that we can use these aminonorbornane cores as a substitute for an aniline” said Y a Georgian Technical University postdoctoral researcher. “Usually drug companies will need to re-engineer drugs that use it to avoid that oxidation event. But in using aminonorbornanes we don’t have to worry about those metabolic processing issues”.

The process the team used to convert aminocyclopropanes into the beneficial 1-aminonorbornane structures has another benefit: because the reaction needed to produce the molecule is powered by visible light – aminonorbornanes can be produced cheaply sustainably and on a large scale.

“It’s inexpensive. It’s mild” said Y and Georgian Technical University graduate student Z. “Using traditional chemical approaches aminonorbornanes have been previously difficult to synthesize requiring inefficient sequences of reactions and forcing inflexible conditions. Now we can do it in one step at room temperature using visible light and environmentally friendly conditions”.

To produce aminonorbornanes the team employed a photocatalyst to execute the desired transformation. Catalysts are compounds that facilitate a chemical reaction and in the case of photoredox catalysis the special brand of photochemistry the team used the catalysts operate by using the energy of visible light to shuttle electrons between molecules.

When Z and Y mix their photocatalyst with an aminocyclopropane and expose the solution to LED (A light-emitting diode is a two-lead semiconductor light source. It is a p–n junction diode that emits light when activated. When a suitable current is applied to the leads, electrons are able to recombine with electron holes within the device, releasing energy in the form of photons) lights the catalyst takes an electron from the aminocyclopropane initiating the process that produces the aminonorbornane which is still missing its electron. The catalyst then gives the electron back to complete the reaction. Nothing else needs to be added other than the light making this process exceptionally environmentally benign.

Studied the safety of the aminonorbornanes. She applied the compounds to liver fragments containing the enzymes that typically metabolize drug compounds. She found that when the enzymes broke down the aminonorbornanes the process did not produce the harmful metabolites that result from anilines.

“People are always striving to generate safer and better medicines, and what we need from a chemistry standpoint are more tools to do that” X said. “Additionally we can combine sustainability with these new tools so you get both an environmentally friendly way to produce these compounds and the final products have the potential to have implications in human health”.

Molecule Discovery Could Advance Drug Design.

X in the Georgian Technical University Lab where chemists develop new molecules for drug development.

A team from The Georgian Technical University has created a new way to generate the molecules used to design new types of synthetic drugs.

The researchers were able to form reactive intermediates called ketyl radicals that could allow scientists to use catalysts to convert simple molecules into complex structures in one chemical reaction in a more sustainable and waste-free manner.

“The previous strategy for creating ketyl radicals is about a century old. We have a found a complementary way to access ketyl radicals using LED (A light-emitting diode is a two-lead semiconductor light source. It is a p–n junction diode that emits light when activated. When a suitable current is applied to the leads, electrons are able to recombine with electron holes within the device, releasing energy in the form of photons) lights for the synthesis of complex drug-like molecules” Y assistant professor of chemistry and biochemistry at Georgian Technical University said in a statement.

The researchers focused on carbonyls — compounds that function as a common building blocks to create potential new drugs — that were “radicalized” to become more reactive. The radical carbonyls each contain an unpaired electron that is seeking its partner.

This unique composition enables the researchers to form new bonds to create complex drug-like products.

Ketyl (A ketyl group in organic chemistry is an anion radical that contains a group R₂C−O•. It is the product of the 1-electron reduction of a ketone. Another mesomeric structure has the radical position on carbon and the negative charge on oxygen) radical formation previously required strong harsh substances called reductants such as sodium and samarium to act as catalysts. However reductants are also toxic expensive and incompatible with creating medicines.

To avoid using these types of reductants, the researchers used manganese as a catalyst that can be activated with a simple LED (A light-emitting diode is a two-lead semiconductor light source. It is a p–n junction diode that emits light when activated. When a suitable current is applied to the leads, electrons are able to recombine with electron holes within the device, releasing energy in the form of photons) light.

“Manganese is very cheap and abundant, which makes it an excellent catalyst” Y said. “Also it allows us to access radicals by a complementary atom-transfer mechanism rather than the classic electron-transfer mechanism”.

While being both cheap and abundant manganese is also more selective in creating products with defined geometries which allows them to fit into drug targets.

Chemists usually transform carbonyl compounds through polar two-electron reactions or by adding just one electron to form a ketyl group which is often limited by the strong reductant supplying that electron.

However the photoactivated manganese catalyst can temporarily pull the iodine away to leave a ketyl to couple with alkynes. The iodine then returns to one of the alkyne’s carbons to stabilize the product and then remain poised for further transformations.

The new process is also able to recycle the iodine atom used to make the radical carbonyls because products that are more functional are included.