Annotation of the results obtained in 2018
This year, the model of transcatheter bioprosthesis with oval cross-section was completed using the previously developed computer model of the left heart and mitral valve. The initial design flaws were eliminated - excessive height of the racks, deficiency of the cuff cells, inadequate arrangement of the fixing elements in the ventricular zone. We also finished examinations of bioprosthesis with circular and oval cross-section in the durability stand. It was found that after 200 million cycles the functional characteristics of both valves met the required parameters regulated by GOST 31618-2012. Transprosthetic gradient across the round valve was 3.0+0.3 mm Hg, across the oval valve - 3.5+0.5 mm Hg; the maximum opening areas are not less than 60% of the area of the inner section of the stent; the volume of leakage – no more than 4 ml/cycle. Due to the positive test results, it was concluded that biological material fixation on the support frame did not require adjustment. The design of bioprostheses was verified as suitable for further in vitro and in vivo tests. Then we evaluated the consistency of the delivery system and prosthesis prototype with circular cross-section "Solertis" in vitro during implantation in mitral valve position of isolated pig heart using transapical access. The prosthesis "Solertis" is a prosthesis which has self-expanding frame made of super-elastic nitinol and leaflets and facing made of porcine pericardium. The prosthesis frame has an axisymmetric circular shape of the annular part, which is fixed in the position of mitral valve annulus due to radial extending forces. The prosthesis ventricular part is represented by two hooks, which, fixing on the posterior mitral valve leaflet, perform an “anchor” function. The delivery system prototype is a catheter with a diameter of 9 mm, consisting of a control handle, a catheter part and a working part which holds and ensures delivery of the prototype. The working part is designed in such a way that it allows to pack the bioprosthesis into the system in two versions: for transapical and transatrial implantation. The preparatory stage of the procedure consisted in prosthesis prototype crimping using cool physiological solution with a temperature of 5 oC, which allowed to reversibly plastically deform the frame and pack it into the delivery system - into the working part with fixation by the casing. Then, the delivery system with a packed prosthesis was inserted through the left ventricle apex puncture into the ventricle cavity, and then into the left atrium. After the positioning, the casing of the delivery system was shifted using the control holder to ensure controlled removal of the prosthesis. After implantation, the quality of prosthesis positioning and leaflets closing was evaluated visually from the left ventricle and left atrium views. During in vitro implantation, all elements of the system functioned predictably and complied with requirements for their work and compatibility. The delivery system allowed to insert a compressed prosthesis into its working part without leaflets deformation or their rupture. After prosthesis release from the delivery system recovery of frame diameter and full leaflets closure were achieved due to frame material (nitinol) elastic properties and its geometry. The fixing elements of the frame took the position provided by the construction and ensured the stable fixation of the transcatheter prosthesis in the position of the native mitral valve. The results of bioprosthesis and delivery system prototypes testing in vitro were evaluated as successful, because both the preparation of the system and the implantation itself were reproduced, which made it possible to proceed to the next stage of testing, the experiment on laboratory animals. Pigs were chosen as models (n = 6) for in vivo test. Before surgery, the animals underwent ultrasound examination to determine the required prosthesis size.Operations were performed in an experimental operating room under general combined anesthesia observing the asepsis and antisepsi principles. The left-sided thoracotomy was performed in the 4th intercostal space. Cardiopulmonary bypass machine was connected through the ascending aorta and the right atrium. In all cases, the prosthesis implantation was performed under direct visual control through the left atrial appendage incision using parallel cardiopulmonary bypass and heart fibrillation. A delivery system with a crimped prosthesis was inserted in the left ventricle. After positioning and orientation of the prosthesis in the projection of the mitral valve annulus, the ventricular fixators were released, then the annular and atrial parts of the prosthesis were subsequently released. Additional fixation of the prosthesis was not performed. In all animals saline test performed after implantation of the prostheses demonstrated a satisfactory valve function, a tight frame fit to the mitral valve annulus without paraprosthetic leakage. According to transesophageal echocardiography, performed after disconnection from cardiopulmonary bypass, transprosthetic regurgitation was insignificant, paraprosthetic regurgitation was not fixed, peak transprosthetic gradients did not exceed 5 mm Hg, the elements of the prosthesis and native mitral valve did not create RVOT obstruction. One animal underwent control ultrasound 4 months after implantation: the bioprosthesis had normal function, fully opened, there were no signs of trans and paraprosthetic regurgitation. There was one death 2.5 months after implantation due to pneumonia. Autopsy did not reveal signs of prosthesis dysfunction, histological examination showed the initial signs of prosthetic endocarditis. Other animals have follow-up less than 3 months. The post-implantation period is uneventful. In general, the developed delivery system and the prosthesis prototype demonstrated in vitro and in vivo experiments their viability in terms of providing a transcatheter implantation of mitral valve prosthesis using both transapical and transatrial access. The delivery system allowed to deliver and release the prosthesis in the implantation zone without frame deformation and leaflets damage. The elastic properties of the frame material provided the restoration of the prosthesis shape after release from the delivery system and the adequate valve function, which was confirmed by ultrasound data. The tests revealed the need for a number adjustments in prosthesis design to optimize the implantation procedure: processing of the frame design to the size of the delivery system, creating radial symmetry of the ventricular part (switching to a construction with three ventricular fixators), lengthening the central zone cells, reducing frame radial rigidity. The results of the 2018-year work were published in 4 papers indexing in WoS and Scopus systems, and 1 article in RSCI journal. 1 article was accepted for publication in journal indexing in Scopus. 2 oral presentation were made at the 32nd Annual Meeting of the European Association for cardio-thoracic surgeons.

 

Publications

---

Annotation of the results obtained in 2016
Studied anatomy and function of the mitral valve (MV) using methods of 3D-echocardiography and CT. By 3D-echo the critical parameters of functioning of the mitral valve in 30 patients suffering from functional mitral regurgitation (FMR) and in 15 patients of the control group of patients without dysfunction of the mitral valve. All examinations were performed on the apparatus of the Philips iE33 xMATRIX with subsequent three-dimensional quantitative analysis of the mitral valve (Mitral Valve 3D Quantification) using QLab software package. We have evaluated parameters such as the area of the mitral annulus (AMA) and contractility fibrous ring of the MV, calculated as the percentage of AMA highest to lowest, its value, and also assessed this parameter as the vertical excursion of the mitral annulus (VEMA) defined as changing the distance from the center point of the plane MV to the most remote point (long axis) to the apex of the left ventricle. We have shown that the contractile activity of the fibrous ring of MV significantly reduced in patients with ischemic mitral regurgitation compared with control group patients. In patients with FMR smallest value of AMA were in late systole of the cardiac cycle (the last third), while when functioning MV this happened in early systole (early third). In a comparative analysis with the control group, patients with FMR had a statistically significant greater maximum and minimum values of AMA (7.1 ± 1.4 compared with 3.9 ± 0.7 cm2; 8.5 ± 1.2 compared with 6.1 ± 1.3 cm2, p< 0.001 for both parameters). We have shown that the contractile activity of the fibrous ring of MV significantly reduced in patients with ischemic mitral regurgitation compared with control group patients, making (25.2 ± 6.7% compared with 41.9 ± 7.2%, p< 0.001). When conducting a correlation analysis was statistically significant positive correlation between the severity of MR (value EROA) and the minimum value of AMA (r = 0.65, p< 0.001) and contractile activity of the fibrous ring MV (r = 0.79, p< 0.001). On the other hand, it was shown that an important parameter for the functioning mitrale-ventricular complex VEMA, significantly less changed during the heart cardiac cycle when compared with the control group (5.4 ± 2.1 compared to 11.1 ± 3.1 mm, p< 0.001). Based on the 3D echocardiographic studies in patients with FMR, we have developed a principled design frameworks circular cross-section and the section follows the plane of the annulus of the native mitral valve. Developed detailed design transcatheter mitral biological prosthesis of circular cross section for reprosthesis by the method of "valve-in-valve". The mounting side of the ventricle - locking fold over the previously implanted biological prosthesis. The developed model framework was prototyping. Calculation and construction of three-dimensional models of the frame and the main drawings were implemented in the environment of the automated designing CATIA V5 (Dassault Systems, France). As the material of the frame was selected alloy of Nickel-titanium medical stamps corresponding to the ASTM standard F-2063 (Vascotube GmbH, Germany), with the effect of severalstates due to phase transition "austenite – martensite" in case of high mechanical stress. Applied design approach allowed us to unify the process of laser cutting nitinol tubing: all final dimensions of the frame, from 23 to 31 mm, which is made on the basis of a single design. The differences of the diameters of the frame obtained by thermal forming. When monitoring the viability of the design by the finite element method in engineering calculation ABAQUS (Dassault Systems, France) with a grid consisting of 19’200 cubic elements, the highest voltage value that is visualized on the plots was expected, obtained in the zones of reverse curves of the cells of the latches in the output area of the frame, but the absolute value does not exceed the threshold (1070 MPa) – 664,4 and 790,6 MPa for diameters of 23 and 31 mm, respectively. Prototypes wireframes for transcatheter biological prosthesis were manufactured by laser cutting on the A-1 Laser International (USA) with electrochemical polishing of tube outside diameter of 7.00 mm, with wall thickness of 0.50 mm. Fixing tubular shape and giving the final diameter is performed by heat treatment in the salt bath. Was developed drawings of patterns to cut out the flap of the device and facing of valves for each diameter – 23 to 31 mm. Flap apparatus cut by laser from sheets of porcine pericardium, canned diglycidyl ether of ethylene glycol and mounted on the frame. For this biological prosthesis developed the concept of the delivery system, unified for transapical and transatrial access. It was first proposed in transatrial access to use a fully thoracoscopic technology transcatheter biological reprosthesis in mitral position in two ways using a four trocar ports: 1. using operation and transatrial access; 2. when expressed adhesive process is accessed through the right atrium with a puncture of the interatrial septum in the region of the oval fossa. Developed a method of modifying biomaterial low molecular weight heparins (LMWH). To increase the number of reactive groups in the composition of the preservative was introduced in the original substance with branched structure and a large number of apachegroup – Penta-O-{1-[2-(glycidyloxy), ethoxy]-ethyl}-D-glucopyranose (pentaoxide). Methodology was developed laser smoothing (conditioning) of the fibrous xenopericardial surface. The use of pentaoxide in combination with laser exposure reduces the thickness of the biomaterial without losing the integral strength, as well as to enter additional biomaterial reactive group for binding heparin. Modification of surfaces was carried out using 4 different heparins: unfractionated heparin, dalteparin sodium, enoxaparin sodium (Klexan), bemiparin sodium (Zibor). The most pronounced improvement hemocompatible properties was achieved by using low molecular weight heparins. After 3 hours of contact with the blood xenopericardial band treated enoksaparin and bemiparin sodium, absorbed 8-10 mg/cm2 of protein (raw – 50 mg/cm2), the composition of sorbing proteins at 95% was represented by albumin. The rate of platelet aggregation when in contact with these specimens was 31%/min, which did not differ from the benchmarks (blood, not in contact with the biomaterial) – 30%/min, whereas the unmodified and modified unfractionated heparin biomaterial increased the rate of aggregation to 45 and 38%/min, respectively.

 

Publications

---

Annotation of the results obtained in 2017
The concept of bioprosthesis for transcatheter implantation in the recipient’s native mitral valve was created by the computer-aided methods. The prosthesis base on a Nitinol stent. The shape of stent's central zone and, consequently, the shape of the prosthesis is fully fittid to the anatomical proportions of the human mitral valve. The biomechanical behavior of the developed concept in the cycle of "compression to the catheter / expansion in the area of implantation" was studied using methods of mathematical modelling, as well as the durability of the bioprosthesis functioning at the loading conditions of the mitral valve position. It is shown that the functioning of the bioprosthesis does not significantly change the stress – strain state of the valve stent. Stress and strain do not exceed the maximum allowable strength limits; the main influence on the stent durability has a stress – strain state obtained at the stage of compression in a catheter. We have adjusted the design of the previously developed round-section frame of the valve for "prosthesis-in-prosthesis" implantation: one out of three ventricular fixing hooks was removed from the stent, because it caused left ventricle outflow tract obstruction. It is shown in the experiments on the porcine isolated heart that the modified design does not affect the packaging of the prosthesis into the delivery system and its opening in the implantation area; the left ventricle outflow tract is not compromised blocked after complete releasing complete. The delivery system for this bioprosthesis was developed and prototyped, unified for transapical as well as for transatrial access. The central catheter of the delivery system was designed in such a way that the cuff of the prosthesis firstly releases when transapical access, and the ventricular fixators firstly release when transatrial access. This ensures the connection of the bioprosthesis with the delivery system until final positioning, which is possible after fixing of the bioprosthesis in one of the anatomic areas: in the left atrium (at transapical access) or in the ventricle (at transatrial access). Only after that the biological prosthesis is completely released out of the delivery system. Experimental testing of the developed delivery system was accomplished using in vitro model of the pocine heart and allowed us to ascertain the adequacy of the developed design. The prototyping of round (diameter 27 mm) and oval (large 40 mm diameter) stents were performed to evaluate their functional characteristics in a puls-duplicator. It was found that the functional characteristics of the studied sizes of the both valves meet the required parameters regulated by GOST 31618-2012. Transprosthetic gradient across the round valve was 3.0+0.3 mm Hg, across the oval valve - 3.5+0.5 mm Hg; the maximum opening areas are not less than 60% of the area of the inner section of the stent; the volume of leakage – no more than 4 ml/cycle. We started testing of both valves in the durability stand (test duration is more than 6 months, valves must work at least 200 million cycles without any signs of structure damage or dysfunction). We modified technology of biomaterials treatment, which used in the manufacture of heart valves bioprostheses to increase their resistance for the most frequent long-term postoperative complication – calcification process. The screened 6 bisphosphonate compounds: four compounds out of them were wide-known drugs and two ones were the products of original synthesis of N. N. Vorozhtsov Institute of organic chemistry SB RAS. The technology of immobilization of these compounds at biomaterials (porcine aortic wall, bovine pericardium and jugular vein wall) was developed. A study of the anti-calcium effectiveness was performed using a model of accelerated calcification implanting biomaterial in the young growing rats subcutaneously. The results were evaluated by the quantitative determination of calcium in biological material by atomic absorption spectrometry, light microscopy and scanning electron microscopy with element analysis. It was found that for biomaterials having a lot of collagen (the pericardium and xenovein wall) the technology of the diepoxide preservation with pamidronic acid immobilization is effective. The basic glutaraldehyde preservation with further treatment with pamidronic acid is the most effective for the aortic wall, in which the predominant tissue components are elastin and smooth muscle cells. The results of the 2017 year work were published in 4 papers indexing in WoS and Scopus systems, and 2 articles in RSCI journals. 1 article was accepted for publication, 4 are being prepared for publication. 2 applications for invention patents were submitted, 1 patent for the invention was obtained on 2016 application. 2 oral presentation were made at the 31st Annual Meeting of the European Association for cardio-thoracic surgeons.

 

Publications

---