Live Pacemakers
Cellular motor
Diana Khomyakova, "Science in Siberia"
Researchers from the E.N. Meshalkin National Medical Research Center, the FIT Institute of Cytology and Genetics SB RAS and the Moscow Institute of Physics and Technology are developing a biological pacemaker to restore heart rhythm. It will consist of the cells of the patient's own body and will be able to replace the artificial device.
"Our heart is four–chambered, and inside it there are two small "batteries" - sinus and atrioventricular nodes. The impulse arises in the first, excites the second and spreads to other parts of the heart. Normally, the biological variation of the heart rate ranges from 60 to 90 beats per minute. However, for some people, these "batteries" wear out. Someone with age, someone - because of autoimmune reactions, someone had an infectious process and affected the structures of the heart. There are many reasons, but the consequence is one – the sinus and atrioventricular nodes are affected, which is why the heart begins to beat very slowly, at a rate of up to 20-30 beats per minute, which directly threatens life," says Artem Grigoryevich Strelnikov, head of the Department of development, coordination and implementation of scientific activities of the E.N. Meshalkin NMIC.
In order to restore the heart rhythm, today a pacemaker is implanted in the patient – a special artificial battery that is inserted into the chest. Electrodes are screwed into the vein, atrium and ventricle, and the device begins to regularly supply an electric pulse and impose a rhythm of 60-90 beats per minute on the heart.
Thus, the problem is solved, but the patient remains dependent on batteries and electrodes for life. A metal object is constantly in the chest, it can become infected, cause bedsores and even get out. In addition, this device does not have a very long service life. Every four to five years, you have to cut the soft tissues of the breast and change the battery. The electrodes also wear out – then they are worn out, then they break. They have to be cut out, replaced, and they can also bring an infection into the heart. There are no alternatives for such patients yet.
"The idea of creating a biological pacemaker has been floating in the world for a long time. We have set ourselves the task: to move one step forward and develop a system that would make it possible to make an alternative to artificial electric pacemakers. The idea is to introduce biological cells into the heart that will generate electrical impulses," says Artem Strelnikov.
Such cells are called pacemaker cells. Normally, they are present in the heart and are responsible for generating the rhythm of heart contractions, but due to various pathologies they are affected and cease to perform their functions.
"The concept of our project is to make an analogue of these cells or to develop a technology for obtaining them in a test tube and then implant them back into the patient's body," says David Sergeevich Sergeevich, PhD, head of the Laboratory of Experimental Surgery and Morphology at the E.N. Meshalkin NMIC.
To obtain pacemakers, pluripotent cell technology is used, which is being developed in the Laboratory of Epigenetics of Development of the FIT Institute of Cytology and Genetics SB RAS under the supervision of Doctor of Biological Sciences Suren Minasovich Zakiyan.
"We are engaged in the cellular part, we get pacemaker cells from induced pluripotent stem cells, as well as from simple stem cells. As a result of our manipulations, contractile cardiomyocytes are mainly isolated – roughly speaking, those cells that make up the myocardial muscles, they are not all pacemakers. Now we are faced with the task: to get rhythm drivers from the general population of cardiomyocytes, to increase their share in the protocol," says Sofia Viktorovna Pavlova, a researcher at the Laboratory of Epigenetics of FITZ ICiG SB RAS, Candidate of Biological Sciences.
Characterization of cardiomyocytes (day 25 of differentiation) by enzyme immunoassay staining to the marker of cardiomyocytes TnT (red) progenitor cells (Nkx2.5), dividing cells (Ki67), ventricular (MLS2) and pacemakers (HCN4).
However, creating pacemaker cells is not enough. The fact is that if they are simply placed in the body, they will not take root – since they do not form connections with each other, do not interact with neighboring cells, they have no supports. The staff of the Laboratory of Excitable Systems of the Moscow Institute of Physics and Technology, led by Professor Konstantin Igorevich Agladze, helps to overcome this barrier.
"We check the electrophysiological characteristics of the obtained cells and select substrates for them that would be most suitable for insertion into a biological object and correspond to the real extracellular matrix. They can be both biodegradable and represent a matrix that can take root in the body. Now we are at the stage of selection," says laboratory engineer Valeria Aleksandrovna Tsvelaya.
The E.N. Meshalkin NMIC has technologies that allow implanting pacemaker cells with substrates without incision of the chest. A long tube of an electrode is passed through a puncture in the thigh to the heart, at the tip of which there is a needle. With the help of this device, the doctor inserts cells into the target areas, like a syringe. All actions performed inside the body are controlled through a digital 3D navigation system. In addition, there are ways to accurately monitor how effectively the new cells work.
"Now transplantation is carried out at the organ level: the liver and heart are transplanted, but they have not yet learned how to replace thinner, cellular structures. Heart transplantation has its own problems: extremely low survival rate, a large percentage of rejection, the transplanted organ is eventually affected anyway. Here you can also "repair" the patient's own heart. We are just coming up with technologies that will allow us to do this," says Artem Strelnikov. – We have three groups working in parallel, a single working team regularly contacts each other. The stages are carried out simultaneously: in vitro, on large vertebrates and on small vertebrates. We are working out surgical methods of pacemaker cell transplantation, we are developing the cells themselves (we are looking at how long they will generate a signal, how controlled they are) and we are developing ways to grow these cells better so that they are suitable for our surgical manipulations."
To date, the main methods of surgical transplantation have already been created, primary cells with electrical activity have been obtained, substrates have been formed – it has been proven that the necessary cells grow there, interact with each other and generate electrical impulses. The next stage is the primary implantation of pacemaker cells in laboratory pigs. It is necessary to see how long they will function in a large organism and how this technology is applicable to medicine.
"Experimental experience on animals is very important, because when translating theoretical research into real conditions, big problems can arise," says David Sergeevich. – Now our task is to see how our biopacemakers, who work in vitro, will behave when integrated into the conduction system of the heart. It is constantly shrinking, and we need to develop such an implantation technology so that we can get to the right zone as accurately as possible without disturbing the normal physiology of the heart rhythm. And it's actually very difficult. In our experimental operating room, we have installed equipment similar to what is in real operating rooms. Literally in the next few weeks we plan to do this implantation and see what we are getting, what other issues need to be resolved."
"We are bringing this technology to make it as suitable as possible for further practical application, we are implementing the so-called translational chain. The main problem in the current fundamental research is that many of them are unsuitable for further practical application. For example, it is possible to develop some cells that will have good electrical activity, but will be alien to the body or will begin to lead to oncological neoplasms. Today, we are already at the stage of fundamental research forming the basis for an applied one that would have the potential to be introduced into clinical practice," says Artem Strelnikov.
If the experiment is successful, it will open the way to preclinical and clinical trials. Scientists expect to switch to the latter in the next five years, although they do not promise that they will meet these deadlines.
The work is carried out with the financial support of the RNF grant No. 17-75-30009.
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