The Ukrainian startup xPand is developing a prosthetic aortic valve. It has no domestic counterparts, and the foreign ones are practically inaccessible to patients in Ukraine, which deprives them of their last chance to survive. The Innovation House met with the startup team, had a look at their creation and found out why Ukrainian patients may never get inexpensive aortic valve prostheses.
There are four valves in the human heart. They are necessary to make our “pump” move blood only “forward”. And now imagine that one of these valves was damaged and does not work properly. For example, the aortic valve, through which the left ventricle forces oxygen-saturated blood to the aorta, does not open in a proper way. This happens, as a rule, with the age due to calcification of the valve leaflets. And this leads to a disease called aortic stenosis. Worldwide, over 300,000 people suffer from severe aortic stenosis, which often threatens their lives.
The best thing that medicine came up with in this case is to replace the damaged valve with an artificial one, that is, with the prosthesis. In order to do this, the doctors cut the person’s chest, stop the heart, connect the body to the system of artificial blood circulation and place an artificial valve instead of a spoiled native one. There are people who live with such a valve for 40 years. This operation is successfully carried out in Ukraine, but the patient will have to pay for it from 80,000 to 300,000 UAH.
The problem is that such replacement of the aortic valve is often required for elderly people suffering from complex concomitant diseases, and their body just cannot survive such an operation. 20 years ago, such patients were simply doomed. But at the end of the last century and the beginning of this century, a new technology was developed that made it possible to implant an artificial valve without cutting the chest and stopping the heart.
A delicate matter
In such operations, a prosthesis of a special construction is used. In the compressed form, it is compact enough to go through the vessels to the heart and thus get to the place where it needs to be installed. In the right place, it expands to the working size and begins to perform those functions that could no longer be properly performed by the native valve. The technology is called TAVI (transcatheter aortic valve implantation). The first operation using such technology was carried out in 2002 by the French cardiologist Alain Cribier.
Today, there is also another way of delivering aortic valves. A small — up to 4 cm — incision is made between the patient’s ribs, and through this cut the surgeon gets to the heart, punctures it in a certain place and inserts a prosthetic valve through the formed opening. It is important that both methods are suitable for cases where open heart surgery is impossible or too risky.
Today, such technologies are widespread in Europe and North America. In Ukraine, TAVI was successfully applied for the first time in 2012. At that time, four patients at the Amosov Institute got CoreValve artificial valves from Medtronic. But these are only isolated cases, while according to theoretical calculations up to 14,000 people may require such operations in Ukraine.
One of the main obstacles is the cost of a prosthesis, which is about €20,000, depending on the manufacturer and model. And the total cost of the whole procedure, from the moment of hospitalization to the discharge, is about €38,000 in Germany (information for 2016).
In practice, the only possible way of getting TAVI for a Ukrainian patient is finding a few thousand euros and going abroad for treatment.
The price of success
The Ukrainian startup xPand has set itself the goal of making an analogue of the transcatheter prosthesis of the aortic valve, as well as its implantation system, costing up to $5,000 together with all the manipulations.
The history of this development began in Germany, namely at the Munich Heart Center, where the team of researchers decided to create an inexpensive prosthesis for the aortic valve, oriented to the markets of developing countries. In 2014, the first drawings of the future valve appeared. But it turned out that the cost of developing and testing such a product in Europe would be unbearable.
Meanwhile, a group of entrepreneurs from Ukraine became interested in the project and invested more than €1.5 million in it.
As a result, xPand contacted the Brazilian company Labcor Laboratorios Ltda, which specializes in producing biological prostheses, and ordered prototypes of their valve, and then a few completed products for clinical trials. In December 2016 they were installed to the two patients at the clinic for adults of the Center for Pediatric Cardiology and Cardiac Surgery of the Ministry of Health of Ukraine. At that time, one woman was 77 and the other one was 79 years old and both suffered from severe aortic stenosis.
“One and a half years after the procedure, patients feel well and motivate the xPand team to continue their work on the project,” says Oleksandr Talalayev, head of the startup. Now xPand faces the task of organizing the production of such valves in Ukraine, testing them and getting all the necessary permits to enter the market.
At first, the team of the project, including, in addition to Oleksandr, three other participants, was located in a rented premises belonging to the veterinary clinic on the outskirts of Kyiv, in Pushcha-Vodytsia. But recently they moved to their own newly constructed building nearby.
The prosthesis of the aortic valve that the Ukrainian startup is working on, consists of two parts — a metal stent and leaflets made of a calf pericardium.
The stent looks like a tube of 4 cm in length, rolled up of wire mesh. It is made of nitinol — an alloy consisting of 55% nickel and 45% titanium. This alloy has a very important property — shape memory. It means that, under certain conditions, if the nitinol piece is cooled below 0°C and deformed, then after heating to a certain positive temperature, it will return to its original shape. Such stents of prosthetic heart valves are manufactured in Germany.
Inside this “tube” the three valve leafs made of a calf pericardium are fixed (pericardium is something like a membrane that surrounds the heart of the animal). The startup team has a seamstress Natalia, who literally sews such valves by hand with a special surgical thread.
It is with this pericardium, that the startup has difficulties. The point is that any medical product must undergo a procedure for assessment of compliance with the specifications. But the document regulating such a procedure for products containing animal tissues simply does not exist in our country.
Therefore, the developers found themselves in a dead end — without the permission from the conformity assessment bodies, they cannot even begin to test the valve on animals, not to mention clinical trials in humans. The authors of the project turned to the Ministry of Health, but, in their words, they did not hear a clear answer, which would bring them closer to the solution of the problem.
Pulse: 900 beats per minute
Meanwhile, the valves are tested on a special stand. Distilled water is pumped through them — it forces the valves to open and close in the same way as they should do in the heart. But if the heart makes about 70 beats per minute on the average, in such an experiment the valve makes 900 beats per minute (that is, it “beats” almost 13 times faster).
After every 50 million cycles, it is checked whether the valve is not damaged and can perform its function normally. If everything is fine, testing continues. Today, there are already the valves that have completed 450 million cycles — if converted to the duration of human life, it will be almost 12 years.
The Innovation House asked a full member of the European Association for Cardio-Thoracic Surgery, Doctor of Medical Sciences, Oleksandr Bablyak, who is not directly involved in the project, to comment on the prospects of xPand.
— Transcatheter valve technology has been developing in the world for more than 15 years. During this time, the risk of such operations decreased from 20% to 5%, but it still remains considerably higher compared to open heart procedures. Therefore, according to recent international recommendations, transcatheter valves are not an alternative to “open” surgery, but are complementary to it. For example, they allow valve implantation with less trauma in patients over the age of 80 or in patients with past cardiac surgery.
The above-described creation of domestic authors in collaboration with German colleagues is definitely interesting from the clinical point of view. The expectation of cardiologists and cardiac surgeons in Ukraine is that the xPand valve will not concede to foreign counterparts by the efficiency and safety and at the same time will be affordable for Ukrainian citizens. Will it meet these expectations or not, we will know only after the completion of all the tests of valve readiness for widespread clinical use.
The project promises to be successful. But it should be understood that the introduction of new technologies takes a lot of time and effort. Checking the valve for safety and efficacy necessarily includes preclinical (implantation in animals) and clinical (operations in humans upon their consent) tests. These are international standards, and we must comply with them.