Unique wound dressings to be marketed thanks to scientists from the University of Pardubice

28. 02. 2018

When a successful Czech biotechnology company teams up with top scientists from the University of Pardubice, we can expect great things. In the case of cooperation between Contipro and the scientists prof. Radim Hrdina and doc. Ladislav Burgert, it is the development of unique hyaluronic acid-based wound dressings. The material is currently undergoing follow-up testing at Contipro to define specific applications for the use in the pharmaceutical industry.

What were your beginnings like with Contipro, Mr. Director?

Doc. Velebný: Until 1988 I worked as a scientist at the Faculty of Medicine, Charles University, in Hradec Králové. At that time, I was trying to promote the establishment of a scientific-research centre that would transfer the results of research at the University into practice. Unfortunately, it was not that easy in the previous regime. The only possible way was through the sideline production in the nearest unified agricultural cooperative, which was in Letohrad. My goal was to establish contacts there and then start producing elastin. Unfortunately, my home faculty started to totally complicate my life before long. That's why I decided to leave it and started to focus fully on the development of the sideline production.

The cooperative system was not the ideal form for business development. The huge disadvantage was that decisions were made by a team of people there and no one was directly responsible. In addition, cow house girls were not too eager to consider the need to invest millions in instrumentation. Then it was 1989 with the Velvet Revolution. So I and my six partners decided to set up our own company and continue our business independently.

Was the transition from academia to business difficult for you? What did you have to learn?

Doc. Velebný: Absolutely everything! (laughs) The first point is that if you want to move from science to business, you have to realize that science is over for you. As the director of a company, I do not care if I do a good science. I only care about what the customer wants. For someone who likes science and does it because they want to achieve something, the impact is very hard. It was the same for me, but I had to stand it.

In the early 1990s, we set up a business strategy to help us come by money and make money for the investment in equipment we badly needed. We decided to start with something that can be easily made and sold quickly. We focused on sports nutrition, with which I had some experience - I'd been making a variety of protein supplements for my bodybuilding friends at the faculty. Later, we earned so much in this way that we could start producing hyaluronic acid and its applications for the cosmetics industry. But at that time, we were thinking ahead. We rented new laboratories and began to gradually realize my goal - the production of hyaluronic acid and related products for the pharmaceutical industry. It took us more than 10 years to reach this stage.

How did you and Associate Professor Burgert enter the story of Contipro, Professor Hrdina?

Prof. Hrdina: Hyaluronic acid is a bio-polymer that is a natural component of the skin and serves as a carrier in addition to other functions. At the beginning of our collaboration, associate professor Velebný came up with the idea of using this ability to transfer biologically active compounds to the skin or the body. However, he met with a basic problem, which is that this polysaccharide is very hydrophilic while drugs and biologically active substances are mostly hydrophobic. Thus, they do not have affinity and transmission does not work. Associate professor Velebný needed to resolve this discrepancy. And someone sent him to the Department of Organic Technology at the University of Pardubice, because we had been dealing with dyes for a long time and we had had a lot of experience with the affinity of compounds to fibres, polysaccharides and proteins.

At the very beginning, Associate Professor Velebný contacted Professor Nepraš, who was the head of the department at that time. They began to develop a process during which they captured compounds through cyanuric chloride as reactive dyes to the polysaccharide fibre of hyaluronic acid. This solution, however, later proved to be inconsistent, as it led to the creation of new unchecked molecules. Therefore, the research branch was terminated. But the collaboration with our department remained functional.

We did not participate with Associate Professor Burgert in this first project, but we wrote several in-depth reports and studies for Associate Professor Velebný on the affinity of compounds to hyaluronic acid, and so we establish a partnership. And in one of our many debates on this topic, Associate Professor Velebný sighed how great it would be if someone could spin hyaluronic acid. That's when I gave Associate Professor Burgert a formula, and he created an input hypothesis that it is a linear molecule very similar to cellulose, so it should be possible to create a fibre from it. So we started working together on a completely new hyaluronic acid spinning project. At the end of this 7-year process, we have two major outputs - endless fibre and staple microfibers of this acid.

The joint research of the University of Pardubice and Contipro was supported by two projects of the Technology Agency of the Czech Republic. What did you manage to create thanks to them?

Prof. Hrdina: We based our work on technologies that had long been known in the textile industry - wet spinning and drawing of fibres. But we developed a new technological process and ways to use them. In the resulting procedure, the hyaluronic acid polymer initially enters the wet spinning process during which it first dissolves in the water bath and then precipitates in the anti-solvent to form a fibre.

It sounds simple, but to get this done, we had to invent a bunch of additional tricks. For example, that the precipitating bath with anti-solvent is not enough, there must still be an incubating bath. Without it, we were unable to get the proper fibre structure that is absolutely essential for the downstream drawing process, during which the fibre gets the right morphology, becomes firm and flexible. It turned out that these mechanical operations played a huge role and that their definition was our main task and benefit.

How long did it take you to find the right procedure?

Prof. Hrdina: A year for sure.

Surely, you were not the only one dealing with a similar problem. Why was your solution better?

Prof. Hrdina: Everyone else tried to mix hyaluronic acid with something, add additives. We decided to try a smarter solution in the form of suitable microfiber morphology and we were the only one who managed to create it. If we had not succeeded, we would have tried admixtures. This is a standard procedure to prepare the nanofibre of hyaluronic acid, in the so called electrospinning.

This way you got to the endless microfiber of hyaluronic acid. However, you continued the research to create another output, the so-called staple microfibers. Why?

Prof. Hrdina: We decided that textiles woven from the endless microfiber would be terribly expensive. And Associate Professor Burgert thought that instead of classical textiles we could make non-woven textiles produced by pressing, just as paper is, which could be made from short staple microfibers. So he went to the cottage and in his joiner's shop he made a machine to produce them - if you could see that! Like Wichterle! He had a small plank there attached with a stocking. A rotating disk that pushed the dissolved acid through a syringe into a precipitating bath that was in motion - so the short fibres were ripped and drawn at the same time. When we then put it under the microscope, we found out that we created a very good, flexible and firm microfiber.

Associate Professor Burgert then made a mangle on which he pressed the nonwoven fabric from it, then dried it and that was it. We later found out that all of these processes must have specific conditions, otherwise it is not possible to create a good result. Fine-tuning of the technological procedures allowed us to prepare sheets of very strong and flexible hyaluron paper, weighing 5 g/m2, being thus ideal for the use in health care. When the process is performed mechanically correctly, we are able to get up to nanofibres. No additives. And there's no need for electrospinning!

The company Contipro in Dolní Dobrouč turned this original prototype into a pilot machine that has the dimensions of the office table.

How long did the phases of the research take?

Prof. Hrdina: Since the beginning, when Professor Velebny came up with the idea of spinning hyaluronic acid, to the point where we were able to prepare the fabrics of endless and staple fibre, it took seven years. For the first three years, we had the MIT project on endless fibres. When the project ended, Associate Professor Burgert began to develop staple fibres. Then we got the second TACR project on the development of staple microfibers. It took another three years.

Where do you and Associate Professor Burgert get these great ideas?

Prof. Hrdina: We meet in the evening after work with the wine and discuss what has occurred to us (laughs). We cannot do this at work; there would always be a distraction from the discussions. We cannot leave those students in the laboratories unattended. We are there primarily for them.

Mr. Director, are there any microfibers on the market yet?

Doc. Velebný: We are starting to test the material, which appears to be very promising and which was made on the basis of staple fibres. That means we are looking for suitable applications. In addition, to be able to go into the next phase of clinical testing, we must first be able to produce GMP (Good Manufacture Practice) preparations. Achieving this status with the technology that has not yet been implemented is not easy at all, which is also true for the next phase.

For example, we have now completed clinical testing of Sorelex. It is a fairly simple wound healing product, relatively easy to manufacture, the development of which has been completed within six months. But it took an infinite amount of time to pass through the approval process. Moreover, companies that do not have any GMP experience may, after all, face an audit of the State Institute for Drug Control (SÚKL), which returns everything back to the beginning.

How do you perceive the relationship between universities and industry? Is there any development?

Doc. Velebný: I think so, it's getting better. We have been trying to cooperate with universities from the very beginning in a variety of ways. Recently, we have even founded Institut Contipro, where PhD. students can apply in fields related to our activities. We, of course, have some unpleasant experiences, but we are still looking for ways to support this cooperation.

When I talk about these negative experiences, they often result from the fact that some universities do not perceive the company as a partner yet. This relationship is often defined in the style of "just give it to them, let them do what they want". And then they look surprised when we tell them that we will not deal with them in this way.

For the business, the matter of price is also absolutely crucial. We have often surprised technology transfer centres when we rejected an overpriced offer. Like other market areas, the technology transfer area is subject to the law of supply and demand.

What was the cooperation like with Professor Hrdina and Associate Professor Burgert?

Doc. Velebný: Great. We understood each other very well as people and that is the basis of any successful cooperation. They are such a bottomless well of ideas. Our company, of course, is not able to use all of them. I cannot allow fragmenting its focus. However, it is important that at the universities of the Czech Republic it is possible to create excellent results that have great social benefits and great commercial potential.

 

Mgr. Andrea Nogová
Centre for Technology and Knowledge Transfer, UPa