Doing tissues

Doing tissues

How our biologists have learned how to grow bones, and former lawyer – how to cash on it.

When in 2008 Alexey Shershnev was transferring from “Pravex-Bank” to Kyiv city Health Department, he even did not dream of growing human bones in five years. As of today former bank manager owns and manages private clinic ilaya – the first in Ukraine and, probably, in the world, which restores bones from patients’ cells. Which returned freedom of movement to almost a hundred of Ukrainians and already to several foreigners. And it will move beyond.

Imagine that a person after the accident has his bone crushed to pulp to that extent that iе cannot grow together any more. And due to the lack of bone fragment, body part is inactive, for example, arm or leg. In such cases, the injured person usually becomes physically handicapped: loses the limb or it is amputated at all. Ukrainian scientists offer an alternative. They take stem cells from bone marrow of injured person and “plant” them to special frame in the shape of required bone fragment. Soon after the grown bio-detail is put in place of the missing part. That’s where cells continue to divide until the bone grows together – in such a manner the wounded person regains his/her ability to move.

Biologists knew long ago that multipotent mesenchymal stromal cells (MMSC – one of the types of stem cells) may become the bone tissue cells. Scientists even have learned how to induce them to turn into bone cells. But such methods make no provision for MMSC to be divided to the extent required for the coalescence of bone. Ukrainian experts have met the challenge in a different way. They use other types of cells: endosteal and periosteal. When growing together with them, MMSC have time to be formed into fully-fledged bone.

Medicine industry secrets of capital city

Leonid Chernovetskyi became Kyiv city mayor in 2006 and offered to many employees of his “Pravex-Bank” to be the part of his team. Newly elected mayor proposed to lawyer Alexey Shershnev to puzzle out how the finances of capital’s health care were organized: how much and why Kyivites pay for sort of free medicine. In such a manner Alexey became the Deputy Head of Kyiv city Health Department and started to study the new sphere for himself.

Director General of ilaya Alexey Shershnev

Director General of ilaya Alexey Shershnev

“As of that time it was the most closed structure, shielded by some so-called super expert appraisal, in which no one has any clue, and therefore does not interfere. In fact, there is stronghold of corruption and theft in it, hidden behind specific knowledge, for example, how to cut out an appendix,” – he recalled.

At that time the capital city allocated UAH 2.7 bln for the medicine support. But when Shershnev calculated the turnover of only the 20 largest hospitals, it amounted to UAH 7 bln. The amount for the rest 172 municipal health institutions shall be several times higher. This evidenced only one: medical workers leave income for themselves and lay expenses upon the municipal budget. What is more, Kyivites pay twice for the medicine: through taxes and under the counter. Moreover, the special fund of the budget, to which patients transfer official charitable contributions, received UAH 80 bln only. Alexey stared to find the way how this number may be increased, basically – through the inspections and discussions with Chief Medical Officers. According to him in 2010 the special fund managed to collect UAH 240 bln.

“I have looked enough at how one shall not do and I decided to establish my own company,” Alexey said, “I saw that that there is nothing to be afraid in this field, except for ordinary business.”

Not by reproduction alone

By that time, he made friends with with Roman Vasiliev and Dmitriy Zubov – biologists, who previously worked at Donetsk city Institute of Urgent and Reconstructive Surgery named after Gusak. “They showed what things they do with cellular technologies and I was amazed. We discussed what is needed to have this direction developed and decided to create separate subdivision.” businessman said. He did not start studying materiel and placed confidence in scientists in this regard. He was focused on the economic dimension.

There are no competitors in Ukraine in tissues growing, but this field requires key investments with no quick return on investments

In this fashion the former public servant started to prepare clinic including three directions: reproduction, related clinical services and regeneration. The first one – relatively simple business and about fifty clinics help to become parents. There are no competitors in Ukraine in tissues growing, but his field requires key investments with no quick return on investments.

Creation of medical center cost about $5 mln, of which major investments were spent on the laboratory. It is equipped with the latest technology – its square meter costs almost €5 thous. Another 1.5 mln were spent on equipment, inclusive of for air control. It is needed for the cells to be grown at the same level of oxygen, as the human tissues have. As a consequence of this, cells, that are being grown, have better adaptability to human body.

Shershnev contributed one part of the money by himself, for the second – he found financial partner Alexey Kotkovsky, for the third – he agreed upon a loan with “Ukreximbank”. Thus in 2012 clinic called ilaya was established.

Freedom to cellular technologies

It was easy to collect investments. To get license for the work with stem cells – a lot more complicated. Clinic introduced the strictest work standards, laboratory corresponds to the official pharmaceutical GMP standard. But it was not convincing for the Ministry of Health.

“We were in the road of one company that did not want anyone else to get a license. It had a great influence on the decision of medical public servants at that time. Its representatives even promised me that we would not get a license. It was their way to monopolize the market – stand for the licensing of everything possible and do not give licenses to anyone,” Alexey said. “We fought as hard we could: we were lobbying, proving, explaining.”

In 2013 clinic got license – it took a year and a half. And in two years the field was into luck. Then the Verkhovna Rada cancelled a great number of licenses, and for the remaining licenses it placed the ministers under obligation to reconsider terms and conditions. The Ministry of Health left licenses only for medical practice and activity of cord blood banks and banks of other tissues. To a large extent this liberalization became available thanks to efforts of ilaya, Shershnev added.

“As of today it is no longer a problem to get a license in Ukraine – we helped to break this barrier and gave birth to competitors for ourselves.” businessman proudly said. “Too bad that due to the fact that we could not get a license, about hundred people have lost their legs, but we could save them.”

Alexey does not say the name of company, which raise difficulties for the receipt of license for a long time. But he argues that he does not consider it as a competitor, since ilaya works with another type of cells. “I used to tell them: while we are wasting our efforts for monopoly position retention and for the fight with it, powerful Western companies will come here and will drive us out.” – Head of ilaya recalled.

Bioengineering rehabilitation for wounded

In 2013 clinic was already able to grow cells, but it could not use it without experienced orthopaedist-traumatologist. And in September 2014 orthopaedist-traumatologist Vladimir Oksimets, who was previously working at the Institute of Urgent and Reconstructive Surgery named after Gusak. He was the one, who brought the news: regeneration experts will soon have a lot of work, given that there was act of war on the east, which means – there will be a lot of broken bones and burns.

The first client of the clinic in “Regeneration” direction was 46 year old Natalya from Kramatorsk city. In the early hours of August 1 the shell exploded near her house and shell fragments wounded her arm and leg. The wounded person received surgical operation without delay, but the bone of the shoulder was badly damaged – distance between its parts was too large and therefore it simply did not grow together. Woman could lose a limb. The only option to save it was “growing” of the required section of the bone of upper arm, in other words, ilaya’s help was needed.

But such a surgical operation is rather expensive – high prime cost of materials and procedures. Even at a discount of the clinic UAH 103 thous. was needed – it was $8 thous. at that time.

Charitable Fund “Abundant Life”, which previously cooperated with the clinic, helped out. This organization found the sum of money required for the treatment of Natalya. In November the inhabitant of Kramatorsk city received surgical operation: biologists of ilaya succeeded in growing of cell-tissue material from cells of Natalia, and this material was implanted by Vladimir Oksimets to the place of missing part of the bone. And in the body the implant finally turned into the bone.

“I would simply lose my arm,” Natalya told four months after surgical operation. “X-ray images show the increase of coalescence. Sensibility is starting to emerge in my hand, fingers move more, thumb did not move at all, and now millimeter by millimeter it is working more and more.”

But the majority of help in treatment of persons, wounded in the east, is received from “People’s Project”, owned by businessman from Mykolaiv city and friend of Shershnev – David Arakhamia, who as early as in March 2014 founded the volunteer center, collecting funds to help the Ukrainian soldiers, suffered from combat actions.

It was “People’s Project”, which raised money for the treatment in ilaya of the first soldier of anti-terrorist operation (ATO) – Yurii Saveliev, whose shoulder was shattered by bullet. The soldier was likely to become physically handicapped, but the experts of the clinic made the arm properly functioning again. Soon medical works of ilaya conducted several surgical operations a month – new wounded persons were admitted from Donbass region, and volunteer center of Arakhamia did not stop seeking for money for their treatment. The clinic itself earns nothing on the treatment, surgical operations are performed at cost price, Shershnev assures.

In total, ilaya admitted for treatment over 70 wounded persons, 40 of them already finished their treatment, i.e. saved their bones

In total, within joint project called “Bioengineering Rehabilitation for Wounded” with “People’s Project” ilaya admitted for treatment over 70 wounded persons, 40 of them already finished their treatment, i.e. saved their bones. “If the bone failed to grow together from the first time, we will perform the repeated surgical operation. There was not a single case when the bone failed to grow together eventually. But for us to get to know on healing, we shall keep track of patients. We had one runaway patient, we are unaware: whether his bone grew together or not. Another one is in the war and we cannot get him back. Our understanding is that, if he went to war, this means that his collarbone grew together in a proper way.” CEO of ilaya told on the success of medical workers.

If Ukrainians only knew

The clinic made no money on wounded persons, but gained important experience. Moreover, other patients started to be aware of the possibility to save arm or leg using the stem cells. As of today surgical operations on bone restoration are performed by clinic at the price of $15-20 thous., of which earnings are about a third of the amount. There are dozens of such “commercial” customers, Shershnev told. Moreover, patients from abroad have already started to come – for this purpose clinic opened representative office in Valencia.

We might have more patients if Ukrainians only knew on the bone regeneration possibilities. But domestic doctors, either out of ignorance or not willing to help to the competitor, offer traditional solution in the event of injury: amputation. Shershnev holds up as an example the female motorcyclist, who was admitted to clinic after severe traffic accident. “She was told in the Institute of Traumatology: “It is economically reasonable for you to amputate your leg.” he argued.

And what is more, our medical market is weak and unstructured, continues CEO of ilaya: “After all, it is the insurance company, which shall come to us, and it pays money, let’s say, for endoprosthesis replacement of hip joint, and which will ask us whether we will be able to restore the joint and thereby to cut costs for general insurance compensations?

We may show the effectiveness with the aid of statistics, but it is missing, no one is in a hurry to do it. On the contrary, our direct competitors from the Institute of Traumatology conceal how many similar surgical operations they have already performed, and what was their result. But there will be transparency, then we will be able to prove that $10 thous. for the grown bone will create economic and moral effect, which is more by a factor of hundreds, than amputations and prostheses.”

To familiarize people with the alternative, ilaya is actively informing on the possibilities of stem cells, achievements of clinic and “Bioengineering Rehabilitation for Wounded” project. Clinic publishes the colorful brochures, posts video, Alexey himself is able to meet frequently and to speak long hours with journalists. Every year at the end of May, team participates in annual charitable “Chestnut Run” and run 5 km accompanied by ATO soldiers, healed by ilaya technology, – as the evidence that its technique is working.

“We build marketing in a greater degree on information and explanation from the start. Currently we just visiting conferences, demonstrate with the example of social project. And only then, maybe, thanks to this, new customers of biotechnologies will emerge.” Shershnev told.

Throughout the body

Scientists of ilaya went extra mile. Vasiliev and Zubov have learned to grow cells from the precious little volume of material – at present we need 5 ml of bone marrow and one month only. As a comparison, French colleagues need 50 ml and two months for this. Scientists of ilaya managed to grow yet another type of cells – forming vascular system of bone and required to remedy large bone defect. And for the guy, who got into road traffic accident, medical workers of ilaya even managed to grow skull fragment – these bones differ from the bones of the limbs.

Unlike Western inventions, Kyiv city analogue of skin is created not from animal cells, but from own cells of the patient or from donated cells

Furthermore, clinic participates in “Skin Bank. Burns Treatment” project. As a part of this project clinic grows biomaterial, which allows for the quick healing of wounds and prevents formation of scars. Unlike Western inventions, Kyiv city analogue of skin is created not from animal cells, but from own cells of the patient or from donated cells. However, this material in most cases saves patients with trophic ulcers.

“ilaya.Regeneration” is developing new medical directions too. For instance, through the use of stem cells clinic turns to treatment of spinal disc herniation and multiple sclerosis. Or offers to those who wish to create and store a stock of their own cells, which may sooner or later assist in treatment of diseases or staying young.

To prepare for the future, clinic established separate R&D division. Ant it plans to create a lot of new things: biochemical laboratory, which will provide means for deep-level explanation of cellular therapy effect, 3D printing for orthopedics. Soon, clinic will begin to explore how the cellular therapy is helping to treat diabetes and to find solutions for problems in disorder of cornea or eye retina. R&D prospects – to support scientists, who have some work and hypotheses. “We will give pointers how to make vision a reality, how together, on a contractual basis, to put development into practice” Volodymyr Melnyk, Head of R&D-direction of ilaya promised.

Advantages of misunderstood

At this point other businessmen in Ukraine are not interested in cellular technologies, Shershnev said. At least, none of the entrepreneurs asked him to share his experience. “Businessmen have poor knowledge to realize that this is not new biologically active supplement or exotic folk medicine. There shall be understanding that that cellular technologies – are the reality, are the high-tech” Alexey explained.

He advises other businessmen to invest in something, which is currently little-known. “It is better to deal in the field, in which nothing is clear yet. But then to make sense of it – then you will be able to capture the full benefits.” Alexey told and held up as an example the Silicon Valley, where investors expressly invest in the most preposterous directions, but which will result in important expert appraisal. And Ukraine is very favorable place for such R&D-activity. “We have relatively soft legislation, there are no super-restrictions, like the West does.”  Shershnev said, “For many Ukrainians clinical trials – are the last chance to recover their health.” CEO of ilaya also recommends to go to the West and to do a bit of studying how to organize the innovative business.

Where else would he invest, if there is a possibility? In genetics. “Interesting things are presently happening there. For instance, CRISPR technology allowing for the replacement of pathologic section of genetic code by the new one – there will be many useful inventions based on it.” he told. What would Shershnev advise himself when creating ilaya? “To give more attention to financial part and to select team in a more scrupulous way.” biotech-businessman told.

Scientists started to try stem cells for treatment away back in 1950s, and successful results were delivered in 1960s

It was starting from burns

In 1981, professor of Massachusetts Institute of Technology Eugene Bell, Eugene Bell, published his article, in which he described how skin tissue was grown from patient’s cells in a laboratory environment to heal wounds. This work became foundation for many studies of how in a similar way other tissues may be restored. The article inspired many scientists in post-Soviet states too. In 1999 director of Donetsk city Institute of Urgent and Reconstructive Surgery, Volodymyr Gusak, decided to create the special laboratory, which studied the possibility to cultivate cells and tissues. Through their use scientist was going to treat burns, which were of frequent occurrence in mining injuries. In 2002 laboratory was launched, and grown tissues saved many wounded persons from fire. And considering that many injuries were accompanied by severe fractures, experts of Donetsk R&D Institute of Traumatology and Orthopedics also tried to grow bone tissue. They also succeeded in this.

Biologist of ilaya clinic Roman Vasiliev

Biologist of ilaya clinic Roman Vasiliev

Initially, the state supported cellular technologies development and even created the regulatory authority – Coordination Center for Transplantation of Organs, Tissues and Cells, and then – Institute of Genetic and Regenerative Medicine. But there were not so many real work, possibilities to explore the opportunities of cells growing in state institutions, Roman Vasiliev complained, who worked in Donetsk city Institute of Urgent and Reconstructive Surgery. “I was disappointed in the tendencies, which prevailed in Ukrainian medicine of that time, and I departed to Kyiv city for my colleague Zubov”, biologist said. Here the scientists met with Alexey Shershnev and decided to create the laboratory with him to explore the cellular regeneration. This is how the “Regeneration” direction appeared in ilaya.

In a private clinic the things were going faster. “We performed several preclinical trials and submitted the animal tests results to regulatory authority. We were the first in Ukraine to perform trials in compliance with world’s canons of clinical trial.” Vasiliev told. Ilaya submitted documents to regulatory authority for clinical trials of cellular bone restoration technique, but it didn’t yield any result. “Ministry of Health blames us for experimenting on soldiers, but this is a charitable project for them.” biologist argued.

ATO soldier expressed thanks to ilaya in his Facebook

ATO soldier expressed thanks to ilaya in his Facebook

This does not prevent scientists of ilaya from participating in international scientific life. They take part in conferences, share their experiences. In 2013 they published the article on cellular regeneration of bone tissue in leading specialized publication Regenerative Medicine. In this very publication the similar method was described by experts of American National Military Medical Center – this is the world’s second description of technique. The truth is that Americans restore bones not from patient’s cells, but from donated cells – this is another technique. Is there anyone else in the world, who may do the same? “We cannot say for sure,” Shershnev told, “but we have not yet seen any specialized publications about the same technique.”

Currently ilaya is waiting for the acquisition of patent for its technology. According to Shershnev, this is a long-term procedure. But when clinic acquires the patent, performs clinical trials, then its methodology will get the official recognition. And then you we will be able to share it with our colleagues, receive royalties, actively attract customers from abroad. And thus, we will be able to learn about the possibilities of stem cells and with their help – to heal people even more.