An innovative domestically developed device for extracorporeal blood purification has been registered in Russia: appropriate permit for clinical administration was issued by the Russian Federal Service for Surveillance in Healthcare (Roszdravnadzor) This medical product has a potential to save thousands of lives of patients suffering from septicemia and toxic shock syndrome. It has been developed and produced by Efferon, the resident of Skolkovo Biomed Cluster.
According to Ivan Bessonov, the Efferon’s founder and CTO, their products have already been used in a couple of dozen clinics in Moscow, Saint Petersburg and other cities across the Russian Federation. In his interview for Sk.ru Ivan Bessonov, who is a graduate from the Department of Chemistry of Lomonosov Moscow State University, told us about his unconventional project.
Efferon’s founder and CTO Ivan Bessonov Photo: Efferon.
It took just 3 years for a team composed of young scientists to develop an adsorbing agent capable of filtering the blood which circulates within the extracorporeal loop, from the dangerous toxins. According to Skolkovo experts, this device is the most effective and safe for patients among similar products available in the Russian market; and it is many times cheaper that similar imported products
What makes this project distinctive from others is the fact that Svetlana Romashina, one of the most recognized Russian sportswomen, a five-time Olympic champion, 18-time world champion in water ballet, stood at the origins of the project.
As Svetlana said, she had been contemplating on how to contribute to making our world a better place to live in. “The first idea that it could be something to do with health care came up to my mind long ago, when my team-mates and I witnessed early death of our friend. But I was so young at that time,” Svetlana recalled. By the time when her desire to do something important for other people was supported with broader financial capabilities resulting from her successful career in sport, she got acquainted with a team of MSU graduates, who were young like her.
The idea of this project appeared very important for Svetlana, and she decided to invest in it. “Of course, it would be too tough for me to open a car show room, like some football players do, but I found myself quite capable of supporting a startup company at an early roll-out stage.”
Svetlana Romashina “Of course, it would be too tough for me to open a car show room, like some football players do, but I found myself quite capable of supporting a startup company at an early roll-out stage.” Photo from a private album.
As Ivan Bessonov recalled, he started targeted fund raising when the development process came to the point when it became quite obvious that they had invented a worthy thing. “Moscow is a small world. I have a habit to do things like this using my peers, my contacts, my friends and friends of my friends. At some point, Svetlana joined this chain. As far as I know, she had never made any investments like this before. It was the first experience for her.”
After a year Efferon became the Skolkovo resident. With the financial support provided by the Skolkovo Foundation, it took 2 years for Efferon project to finalize the prototype and register a medical product. At the same time some private investors were attracted, Ivan Bessonov called them ‘the market players with many-years of expertise’.
“The project is supported by private investments, and it has a comprehensive and attractive business model, which I’m quite proud of,” the founder says. “The fact that private investors decided to invest their money to participate in our project proves that the product we’re working on is a good thing.”
Tough path from idea to success
The same way as the Olympic champion Svetlana Romashina was looking for an opportunity to invest in something capable of saving human lives, Ivan Bessonov with his diploma in organic chemistry was looking for, as he described it, a kind of ‘bridge’ between chemistry, biology and medicine, which he was much interested in for all his life. The most obvious trajectory is to find and create new medication, and this path is cost-intensive and long, as “it takes many years to have the idea turned into some practical achievements.”
Still there is another, very interesting domain directly associated with the profession of a scientist - polymers and biomaterials, which allows developing medical products. Regulatory issues are not so complicated in this domain, and it takes less time and money to have the product reach the consumer market, and this was the way the Efferon’s project team had chosen.
A trap for LPS Photo: Efferon.
Before proceeding with sorbents capable to save patients from septicemia, Ivan Bessonov and his former classmate Alexei Morozov together with their colleagues were working on a different task. They were attempting to develop bactericidal polymers to produce sterile bactericidal coatings. Such coatings can protect orthopedic implants from proliferating microflora and prevent infection-caused complications after their installation.
“All bacteria are covered with external membranes,” Ivan Bessonov explains. “If this membrane is destroyed, for example, by contacting a substance seeking to stick to this membrane - so much so that it even attempts to get inside - the integrity of the membrane will be lost, and the internal contents of the bacteria will leak out through the hole. This is the way the renowned antibacterial preparations - octenisept or chlorhexidine work. We learnt how to make biocompatible polymer materials with similar properties.
We achieved certain success in this field and even published an article in a recognized science magazine Materials Science and Engineering. In terms of practical achievements we received the results which we managed to use further on, when the project changed its initial trajectory.
We started thinking of any other applications for the molecules capable of ‘sticking’ to bacterial membranes. The first idea was to make water filtration systems with antibacterial filters. We also conducted a series of experiments in this area. As we found out, among our polymer materials there were some specific materials with the surface which was particularly very much ‘adhesive’ for bacteria. However, even being stuck onto the surface of polymer molecules, those bacteria were not going to die, they felt well enough for further reproduction.
Does that mean failure? It would be so frustrating to consider such unconventional outcome as a failure. We continued our investigation: which task could be solved using the unconventional properties of ‘adhesive’ molecules? The doctors I knew told me about some approaches to septicemia treatment by using blood purification technologies. Among all the specialists we had discussions with, there was one person showing the most profound interest towards our work, he had immense practical experience in this field - I’m taking about Professor Sergey Khoroshilov, the Head of the Department of Burdenko Main Military Hospital. He told us a lot about pros and cons of current solutions they were using. This was the task, the challenge we started our project with, three years ago, by establishing a legal entity, Efferon.”
A ‘fishing rod’ with a ‘jig’ for LPS capturing
The problem has global nature - this is septicemia, or blood poisoning: among 100,000 patients about 200 morbid events are recorded, and due to the growing number of surgical operations the number of such morbid events is also growing; this is one of the major causes for deaths in hospitals, the death rate may reach 60%.
Septicemia is generally caused by deadliest toxin, lypopolysaccharide (LPS). This is a component of bacteria’s external membrane which provokes the extraordinary response from the human immune system. This explains why today there are no medications for efficient septicemia treatment available. “Use of antibiotic solves the problem of the infection itself, but has no impact on the body’s reaction to toxic LPS molecules,” our source says.
Neither did we succeed in inventing efficient and safe medications targeting LPS.
In recent years, various solutions both in theory and in clinical applications emerged - different types of cartridges with filter elements, sorbents, membranes, which are intended to remove LPS from blood. Efferon project team proposed their own original method.
“Imagine that you have put a fishing rod with a jig into the blood, and try to capture certain molecules,” Ivan Bessonov gives illustrated description of the technology. “If we are talking about LPS-selective hemosorption, i.e. selective removal of LPS molecules from blood, then you should know the structure of the materials capable of solving this task. There is some inertial matrix, some indissoluble layer, substrate. There is some molecule cultivated on the surface of those polymer materials, which engages LPS. In fact, this works the same way as the active substance of some medication. But at this point this substance does not penetrate the human body, it is neither metabolized nor distributed in tissues. This feature significantly mitigates the risk of side effects to occur.”
Efferon’s team managed to create new molecules able to link toxin molecules, but this was only 50% of success.
Photo: Efferon.
“We realized that we have a true ‘LPS trap’ in our hands, but we don’t have any suitable matrix to put this trap on,” Ivan Bessonov continues. “And we were lucky to meet an outstanding chemist, the Head of the Laboratory at the Institute of organoelement compounds named after A.N. Nesmeyanov, professor Vadim Davankov. He is the author of a number of pioneering publications in the field of porous polymers, a ‘father’ of so-called ‘super-stitched polystyrene’. He suggested that we should use matrices on the basis of this material. So we merged our LPS traps and his matrix made of super-stitched polystyrene, and we did something, which nobody had done before. This matrix has very good biological properties, this is safe polymer material; blood is very sensitive to external impact - it can coagulate, plasma proteins can be removed from it, red blood cells can be destroyed – and these are only three of the many scenarios which can happen to blood when it is in contact with foreign materials. All those problems can be successfully solved using Professor Davankov’s matrix.
There are only few manufacturers able to offer solutions like these. None of them offers equivalent products, copying the competing solutions, so there are no 100% equivalents: all the manufacturers use different ligands and different substrates. There are some products from US, they are also based on the input by Professor Davankov, featuring a similar polymer-based matrix, but they are non-selective sorbents, which means they don’t include any ligand to link LPS molecules, so these products are not suitable for septicemia treatment. That’s why I said that we made something which had never been done before: we took one of the best blood-friendly matrices and supplemented it with the most efficient anti-LPS weapon.”
Ivan Taskin from Skolkovo Biomed agrees: “Efferon’s solution exceeds all the current equivalents in terms of effectiveness, which is possible due to its higher adsorbing capacity, and it is much cheaper that the competing products. This solution will make it possible to use an efficient method of extracorporeal detoxication and save lives of thousands of patients suffering from septicemia.”
Time factor
Effectiveness mentioned by the Foundation’s expert stands for the amount of LPS which can be absorbed by the particular adsorbing capacity. One more thing to consider is how safe it is for the blood to contact with this material.
And there is also the factor of time which means how long the procedure is lasting. And it will play a critical role.
“All procedures of extracorporeal blood purification are supported by anticoagulant therapy,” Ivan Bessonov says. “The patient receives a heparin injection to prevent the blood from coagulation. Too much heparin is also bad, as it increases the risk of internal bleeding. Under some health conditions it is prohibited to make heparine injections. A doctor has to ‘walk’ a very thin line. On the one hand, it would be good to have a longer purification procedure to remove more LPS; on the other hand, it means longer heparin exposure, which also poses some risk. Finally, the adsorbing capacity of the product is of critical importance: suppose, we found the best dose of heparin allowing for 12 hours of purification procedure, but it has no sense, as after just one hour of purification all ‘seats’ will be occupied by LPS!
In other words, the best combination of safety and effectiveness stands for the longest possible duration of useful purification. A perfect device, perfect absorber would make it possible to have the patient connected thereto for 24 hours or even longer - we are talking about patients in critical condition. In real life this is impossible because of two obstacles: first, risks of internal bleeding resulted from the anticoagulant therapy, and, secondly, adsorbing capacity which can be exhausted. For those products which are currently used in the market this capacity gets exhausted very soon. This is about the functionality, but there are also some commercial parameters of the product. Products offered today in the domestic market cost incredibly much - if we compare our solution with, for example, a Japanese equivalent, the latter is many times more expensive.”
Broad range of application
Efferon has two venues in Moscow - in MSU’s Scientific Center and in Skolkovo. The first venue accommodates the laboratories where the sorbent is produced, and further development and quality assurance are carried out.
“In medicine, safety is the top priority,” Ivan Bessonov emphasizes. “The application is very critical, so pay special attention to the quality assurance. Those procedures are even more resource- and labor-intensive than the production process. Each and every sorbent is subject to check-up, every consignment of the sorbent we produce, no tolerances are possible here.”
The solution developed by Efferon potentially has a broad range of application Photo: Efferon.
In Skolkovo Technopark the team is using clean rooms facilities Class 7 ISO with “Module 42” Shared Use Center It is a place where assembly and packaging of medical products happen. Packaged absorbers are sterilized by gamma-rays.
In the long-term perspective the company is planning to conduct a series of extended clinical research for various types of septicemia and sub-populations of patients.
“The area of primary infection localization makes the course of the disease very different,” Sergey Khoroshilov, a clinical scientific consultant of the project says. “It can be located, for example, in the lower pelvis. There is a type of septicemia associated with pneumonia, ventilator-associated pneumonia is particularly dangerous. There is burn-associated septicemia. There is obstetric septicemia. Septicemia with oncological patients is the whole separately standing challenge. It is necessary to find various criteria for beginning the blood purification procedure, its conditions and duration. It is important to demonstrate the effectiveness of the method for various types of septicemia.
“LPS-selective hemosorption is a relatively new method, and no perfect application algorithms are available yet. In the context of multi-center studies we are now focusing on the patients with abdominal septicemia complicated with toxic shock syndrome, and at the early stages of the process,” Ivan Bessonov says. “According to the current vision, using our method for this category of patients is particularly good. They are patients in critical condition, with adverse forecast, but the science says we can help here.”
In the future the company would like to extend the range of possible applications for their solution. There are some types of patient’s condition, when ‘septicemia’ diagnosis is not reasonable, but molecular mechanisms of this condition are very close to septicemia, and researchers hope that selective hemosorption will be able to help those patients. For example, we can talk about what is called “post-resuscitation disease”; this is especially common as complications after heart surgery. Now there are several clinical studies in the world, when during surgical operations the absorber is included in the artificial blood circulation circuit to avoid complications instead of combating them afterwards. This approach is reported to significantly mitigate the risks of post-surgery complications. It sounds like some science fiction, but in Germany these services are already part of individual health insurance program.
What we want is to make this solution affordable in Russia as well”