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Doctoral student on the road - part six - Roy's lecture

The big moment has arrived,Roey Tsezana tells about his research dealing with the creation of scaffolds for tissue engineering. After him, one of the leaders of the Blue Brain project comes on stage... No, it's not what you think - a group of researchers, with the help of the blue giant - IBM is building a computer in Switzerland that will try to imitate the actions of the human brain

The facilitators of the moshav listen toRoey Tsezana
The facilitators of the moshav listen toRoey Tsezana

The student from the Technion and ultrasound

Today is the big day, when I finally deliver my lecture. But before that there are still a few good hours, and also a lecture by the student from the Technion. I am participating as an audience to show solidarity, even though the subject is a bit problematic for me: ultrasound. Well, it's not that it's really that bad, but this whole subject involves an unpleasant amount of math and physics and I'd normally prefer to stay away from it and have it stay away from me.

The first lecture in the seminar starts well. A handsome young European doctor comes on stage. He is very reminiscent of the young doctors and models from the various TV series and even speaks reasonably, with an explanation in the first minute of how they discovered a new and strange phenomenon in their laboratory, and so far everything is fine. Then he explains how they interpret it, and suddenly everything goes wrong: equations the length of the exile run on the screen, the entire Roman, Greek and Russian alpha-byte flashes before my eyes, with one or two real numbers appearing here and there. At some point the student next to me elbows me and whispers to me that this is also what she is working on. Until now I have no idea if she meant Gamma, Sigma, Delta or Naabla (yes, there is such a letter).

The lecture of the anonymous student from the Technion goes well, when I take pictures of her with both a video camera and a regular camera, so that there will be documentation for the whole family. Really excellent lecture. I don't understand much, but she speaks loud and clear, not too fast and generally manages to create a feeling that her research is really important.

The next lecture dealt with the question of how microgravity affects the body.

My lecture: An innovative scaffold for tissue engineering

And here we are one hour before the start of my seminar. For a change, good food is served at lunch - tender and tender venison, potatoes fried to just the right amount, pasta in tomato sauce and small, fresh rolls with a crispy crust. I control myself and only taste each of the dishes. It is important not to fill your stomach too much before the lecture. It will take revenge on me towards the end of the day (that is, now, when I am writing the report on an empty stomach, because it needs to be uploaded to the website in a reasonable time), but it helped during the lecture. Oh, and in the end I didn't have a tie.

And yet, here comes the moment, to explain to the readers and to the audience at the seminar: why am I actually here in Belgium?

My research is focused on tissue engineering, and especially on the creation of scaffolds for tissue engineering. Cells by themselves will not strive to create a three-dimensional structure in the growth plate, unless we encourage them to do so and give them the right conditions. My scaffolds try to give the cells the right conditions - the cells grow around them, penetrate them and create a real tissue inside them. In today's tissue engineering, scaffolds are an inseparable part of cell growth, and there is no tissue engineering laboratory that does not work with them, or tries to develop its own scaffolds.

I create my scaffolding using a method called electro-spinning, or electric spinning in Hebrew. We take different types of polymers, dissolve them, then slowly inject the solution through a syringe, and apply a very high electric voltage to it - between 10,000 and 40,000 volts. What happens, in a quick and somewhat abstract way, is that the solution is electrified and strives to reach the surface below the syringe that is grounded to the floor. Since its viscosity is about the same as that of chewing gum, the droplet that comes out of the tip of the syringe gets longer and longer until it forms a fiber that falls to the surface. If we activate all the right parameters, we can reach fibers whose diameter will be that of a thousand hairs. And below: nano-fiber. Many such nanofibers that fall on top of each other form a scaffold into which the cells can crawl and grow.

So far so great, but there is a problem. The scaffold should be as hollow as possible, so that there is a lot of space and the cells can grow properly. Normal scaffolds created by electro-spinning do not always contain a large enough space, so the cells have difficulty penetrating and growing. This is where the method I developed with my supervisors comes in, and which we called hydro-spinning - aqueous spinning.

Instead of the fibers falling onto a solid metal surface, in hydrospinning they fall into a water bath. Because the fibers are made of a hydrophobic polymer they float on the surface and form a thin layer of nanofibers. At this point we lift them off the surface with glass, and get a very thin layer - a few micrometers thick - on the glass. We wait a few minutes for a new layer to form on the surface of the water, then lift it up with the same glass - then we have two layers, one on top of the other. We repeat this process as many times as we want - ten, a hundred, or a thousand times - and in the end we get a scaffold made up of many layers of nano-fibers, each of which is separated from the others by a fine layer of water accumulated between them.

When we put this scaffold in a vacuum environment, a miraculous thing happens. The water tries to evaporate out quickly, but the layers of nanofibers block its exit. Still, since the water exerts a lot of force and the polymer is still soft from spinning, they manage to stretch it and escape from the scaffold. This stretching of the layers causes the scaffold to swell from the inside, like a balloon, increasing its volume tenfold – which means that there are now many more empty spaces within the scaffold for the cells to sit in.

And that, in general, is the whole idea. In the experiments we did with murine muscle cells, we showed that they can penetrate a scaffold created by hydrospinning much better than they penetrate a scaffold created by electrospinning. Other experiments were conducted with human embryonic stem cells, which fail to penetrate the electrospinning scaffold at all. Our new scaffold, on the other hand, they penetrate well and also manage to create cylindrical structures inside it reminiscent of blood vessels or nerve canals. As I explained earlier, the Nobel Prize did not come out of it, but it is a technique that can advance the field in one small step.

The audience and seminar facilitators seemed to be impressed. It's hard to know for sure, but there were several people who raised their hands and asked interesting questions about the method and the logic behind it. Thank God, none of them asked the questions that could have failed me - like about the cells, for example. It is very difficult to work with human embryonic stem cells and understand what types of cells they have differentiated into, and I really did not have a clear answer to this question.

The Blue Brain Project

After my lecture, I went to a general lecture by A. Markram, Director of the Blue Brain Project in Switzerland. In the Blue Brain Project, they try to imitate the way the human brain works using a supercomputer and several tens of thousands of processors. Each processor simulates a single neuron, represented by a complex mathematical model that describes all its links in space to the other neurons. One such computer is enough to create a simulation of one cortical column, which is the basic structural unit of the human brain. Each such column contains around ten thousand neurons, and the researchers in the project are trying to understand the structural and computational principles according to which the neurons work and copy them into the supercomputer. They have already quite succeeded in this, at least in one column, and these days the plasticity of the neurons is also added to the model - the processes that allow them to make better or worse connections with other neurons, and even disconnect and connect to new neurons.

How can this technology be used? For starters, it can be used for comparison with actual studies and experiments on the brain. Every week the project team builds a new model with new biological constraints. Even without trying to make the models do anything specific, the results each time reveal new insights into the neural structure of the brain.

that's it? Definately not. Diseases related to the brain cost a trillion dollars a year (one thousand billion). Alzheimer's alone costs $100 billion a year in the United States alone. There is not even one drug today that we know exactly what it does in the brain, or how it does its action and affects the computation in the brain. Even in the case of diseases, we can understand that there is a gene that does not work or a defective protein, but we do not know how this affects the computations in the brain. Can we figure it out? According to Markram, absolutely yes. According to his predictions, by 2030 even desktop computers will be able to perform highly sophisticated brain simulations. And the future, who will align us.

It's hard for me not to feel that I'm failing to convey the feelings that fluttered in the audience during the lecture, since I'm using only words here. A significant part of the presentation was dedicated to the movies produced from the models and the supercomputer. We saw thousands of neurons connected to each other, transmitting to each other and talking to each other. And I'm sure that the same thought was going through the minds of everyone sitting in the dark auditorium: a similar thing is happening in my mind right now when I think this thought. This insight, that our brain is the only organ that thinks for itself, was exciting and uplifting and opened the way for many more thoughts - how can you influence the brain? Is it possible to speed up the pace of thought? Can we re-engineer our brain, once we understand its working principles? The answers - in the 'Blue Brain' project.

Innovations and developments in tissue engineering

Satisfied and happy, I made my way to the second tissue engineering seminar, which ended at 18:30 pm and closed the day. The only event left for today is the gala dinner of the congress, but at the price of 85 euros per diner... I gave up, thanks. At least the seminar itself was very interesting, with extraordinary studies by several young researchers.

The first to take the stage was Sarah Cheka from Ireland, who tried to describe the growth process of a tissue with a model. It all starts with stem cells migrating to the regenerated tissue, dividing, differentiating and creating the specific cells in the tissue. Cheka conducted research using finite element analysis and created a simulation of the tissue's mechanical environment. The tissue in the model is divided into a three-dimensional array of cells, each of which divides, differentiates and migrates according to a specific pattern.

The model is, of course, very rough and does not pretend to include all the parameters with the necessary degree of accuracy, but it is a start. She took into account the blood vessels adjacent to the cells and the rate and direction of their growth, the different differentiation capacity of the cells according to the shear forces applied to them and the oxygen they receive and the rate of cell maturation. She entered all this data into a model she created and used it to predict the growth of blood vessels and the various cells at the interface between bone and implant. According to the model, first of all the fibroblasts grow at the interface and improve the mechanical capabilities of the area, then the amount of chondrocytes - cartilage cells - increases, and after 22 days bone cells - osteoblasts - also begin to differentiate.

And what if weight is applied to the interface (for example, by continuously stepping on the foot)? In this case the vast majority of cells are fibroblasts, and only a very few differentiate into bone cells, cartilage cells or blood vessels. All of this is very interesting to doctors and biomedical engineers who need to understand what is happening at the interface between the implant and the bone and how it is possible to improve what is happening.

Another researcher, Stefanos Diamantoros from Germany, told us about his attempt to create a system that would understand what happens to implants after several years in the body. We know that the transplanted tissues withstand the forces exerted on them in the body for at least a few months, but it is difficult to conduct an experiment over many years that will reveal what happens to the tissues after many years in the body. Stefanos' solution was to grow the tissues in a bioreactor outside the body, and apply pulses to them that simulate the pressures they experience inside the body. He then began to increase the pulse rate, to simulate the total forces acting on the tissue over time. In other words, if for 5 years the tissue experienced a pulse rate of one beat per second, then it would be possible to simulate the same effect on a tissue that experienced a pulse rate of ten beats per second, for six months. Stefanos showed his system and explained the principles of its operation, but unfortunately there were still no final results with cells or tissues.

Melissa Mathers finished the lectures that day by describing a new rehabilitation (regenerative) medicine project designed to introduce rehabilitation medicine into industry. The project is called 'Remedy' and is intended to produce new technologies for tissue regeneration that will be available to global medicine. From a biological point of view, many materials necessary for tissue engineering are right at hand (for example, collagen), but they are not available for the industrial production of implants or tissues for transplantation. According to Mathers, two major tissue engineering companies have collapsed in recent years because sales were meager compared to investment, and the manufacturing methods for the scaffolds were inefficient.

As part of the research, Atras tested the properties of scaffolds produced from PLLA under high pressure, at room temperatures and without the use of organic solvents, and best of all - with methods that can be easily transferred to industry. Mathers tried to quantify and document the way the scaffold was created by tracking the polymer that swelled under pressure, and to create a model of the resulting scaffold.

In conclusion, the project is driven by a simple but important vision: to find effective engineering strategies that can be applied to improve the tissue production process. Engineers have an important role in tissue engineering, and not just biologists, in order to find the ways to increase the production and output of tissue engineering.

Perhaps this is also the place to tell that I found three people who seem to be interested in research collaboration. It could really advance my Ph.D. Let's hope something comes out of it.

And now, eat! There is a cow in Belgium that has my name signed on it, and I intend to leave the hotel now and track it down.

Don't miss the next episode of... "PhD student on the road!" (In which I describe the end of the conference, the planned trip to the zoo with the anonymous student and the buying of gifts for the whole family)

9 תגובות

  1. Oh, in this case, the scaffold is usually made from materials that break down on their own in the body. It can be made from polymers like PGA or PLGA that break down within weeks to months, or even polymers like PCL, that break down only after two years in the body.

  2. Roy
    Why why why didn't you tell us that your "passion" is to simply be a "doctor"..
    But if I were your mother, I would give you money for a "PhD student around the world", in the meantime you would publish some fascinating books (you have talent). In order to return "mother's" investment. Not to mention that it was simply much more interesting.. and "healthy", for a change!

  3. Roy:
    It seems to me that the cool guy's question was different and he wanted to know how - after designing the embroidery, get rid of the scaffolding.
    I know that there are scaffolds that simply remain inside the tissue forever and there are those that dissolve by themselves over time, so the question is to which of these two types do the scaffolds you build belong.

  4. Thanks everyone, I'm glad you enjoyed the articles. Tonight there will be another one (intended mainly for young researchers, with one of the most important lectures at the conference).


    I create the scaffold in layers and then inflate in a vacuum. Only then, when it is already swollen and full of cavities, do I seed it with the cells and immediately put the entire seeded scaffold into growth medium.

    Another way is to give up the vacuum inflation, and sow the cells while spinning, on each layer. So a really interesting result is obtained, in which the scaffold is full of cells from the very beginning (which is something that is very difficult to achieve with normal tissue engineering methods). We hope to show later that we can literally 'print' cells on each layer, and get a XNUMXD tissue structure with pre-designed internal structures.
    But another vision for the time being. In the meantime, even showing that we can create different layers of cells within the scaffold (similar to what happens in the skin) is not an easy task...

  5. Just a question, I hope it's not one of the failures.
    After you have created a scaffold with the cells on it, how do you blow the scaffold without damaging the cells?

  6. Roy, this is simply amazing! The method you developed sounds really fantastic, and I really liked its (relative) simplicity. There is no doubt that your method is another significant contribution to the world of science, thank you for the interesting series of articles! Really makes you want to do science!

  7. Thank you Roy for taking the trouble to upload the article, from your letter I get the impression that those who were not there missed some interesting information,

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