Experiment Study Of Transcatheter Polymeric Prosthetic Heart Valve Based On Ultramicroporous Expanded Polytetrafluoroethylene

Part IA novel large animal model for in vivoassessment of polymeric materials for use inprosthetic heart valvesObjective: To develop and implement a novel large animal model without extracorporealcirculation for in vivo assessment of polymeric materials for use in prosthetic heart valves.In this model, the researchers can achieve to implant polymeric materials simultaneouslyinto both of the systemic circulation and pulmonary circulation. Methods: Five male sheep,weighing(22.4±1.8)kg, were used. The posterior-lateral incision of left chest wasperformed. The ultramicropore expanded polytetrafluoroethylene (ePTFE) membrane wasmade into two monocusp valves, which were implanted into the proximal descending aortaand the left pulmonary artery, respectively. Low-dose aspirin was given daily for1monthafter surgery. After20weeks follow-up, the sheep were euthanized, and the ePTFEmembranes were explanted and assessed. Results: All5sheep were successfully operatedon. There were no obvious post-operative complications except of overmuch of thoracicdrainage in one sheep. All5sheep survived20weeks after surgery. By autopsy, only oneePTFE membrane in the left pulmonary artery was found totally adherent to the vascularwall, while the others kept mobile. None of the ePTFE membranes were found thrombus,calcification, or degradation by macroscopy and microscopy. The surface of ePTFEmembranes in the left pulmonary artery were covered with obvious neointima, leading tothickening and stiffness of the membranes. While, the ePTFE membranes in thedescending aorta had no neointima, and kept smooth and flexible. Conclusion: This novellarge animal model provides an effective, convenient and reliable way for in vivoassessment of polymeric materials used in prosthetic heart valves. Besides, by this model,the researchers can reduce the required number of animals, and assess the polymericmaterials by contrast between in the systemic circulation and in the pulmonary circulation.Considering ePTFE in pulmonary circulation showed significant neointimal hyperplasia,ePTFE should be surface modified in order to further improve its biocompatibility and to be more suitable for the study of ePTFE transcatheter pulmonary valve. While, theultramicropore ePTFE in systemic circulation showed satisfactory results, so it can bedirectly applied to the study of ePTFE transcatheter aortic valve. Part IIPhosphorylcholine coating enhancesbiocompatibility of ePTFE used in polymericprosthetic heart valvesObjective: Ultramicropore expanded polytetrafluoroethylene(ePTFE) is one of theresearch focuses in polymeric prosthetic heart valves. This study aimed to assess thebiocompatibility after phosphorylcholine(PC) coating of ePTFE. Methods: PC derivativewas synthetised using2-methacryloxyethyl phosphorylcholine(MPC) and N-butyl methacrylate (BMA). ePTFE was coated of PC derivative by plasmasurface activation. Then the PC-coated ePTFE and uncoated ePTFE(as control) wereanalysed by scanning electron microscope(SEM), tensile stress-strain test, water contactangle test, in vitro hemolytic test, bovine serum protein absorption test, platelet count, andplatelet activation test by P selectin. Results: PC-coating did not influence ePTFE inbiomechanical properties and hemolytic test.SEM showed the mean micropore diameter ofePTFE was significantly decreased after PC-coating. The contact angle, protein absorptionamount, and platelet activation rate in PC-coated ePTFE were all significantly lower thanthose in uncoated ePTFE. The platelet count test demonstrated PC-coating improvedantiplatelet adhesion ability of ePTFE. Conclusion: PC-coating can improve anti-thrombusfunction, suppress protein adsorption,and enhance biocompatibility of ePTFE. PC-coatedePTFE become more appropriate for use in polymeric heart valves. Part IIITranscatheter pulmonary valve implantationin sheep:3-month evaluation of a novelballoon-expandable ePTFE valved stent.Objective: To evaluate the short-and medium-term effects after transcatheter pulmonaryvalve implantation in sheep using a novel transcatheter polymeric prosthetic pulmonaryvalve(PPHV).Methods:①In this study, we designed and manufactured a novel transcatheter polymerictrileaflet prosthetic pulmonary valve with a balloon-expandable stent, which was made ofcobalt-chromium alloy. The valve leaflet was made of0.1-mm ultramicropore expandedpolytetrafluoroethylene (ePTFE) coated with phosphorylcholine(PC). The stents were invitro tested by compression resistance test and elastic resilience test. PPHVs were in vitrotested by pulsating flow test and accelerated fatigue test.②PPHVs were in vivo tested in pulmonary valve position of sheep.We chose bovinepericardium valve as control. PPHVs were implanted in situ by right ventricular apicalapproach in12healthy sheep (10for PPHV and2for bovine pericardium valve) weighingan average of (22.1±2.3) kg. Oral warfarin was given for4weeks after implantation.Angiography and cardiac catheter examination were performed after implantation to assessimmediate valvular function. Color Doppler echocardiography,64-row computedtomography, angiography and cardiac catheter examination were used to assess valvularfunction4weeks and12weeks after implantation. One randomly selected sheep withPPHV was euthanized4weeks after implantation, and the other sheep were euthanized12weeks after implantation. The explanted valved stents were analyzed macroscopically andmicroscopically, and assessed for calcification.Results:①The results of the compression resistance test and elastic resilience test of thestents were good. The stent could recover to initial shape even if compressed by one thirdof its diameter. PPHVs were in vitro tested by pulsating flow test and accelerated fatiguetest, the results of which met the national criterion. The PPHVs could reach to200millioncircles in accelerated fatigue test. ②Two PPHVs failed to be implanted in situ of pulmonary valve position in sheep.Implantation was successful in the other10sheep. One sheep died of pneumonia15daysafter surgery. The other9sheep survived at the end of follow-up.Echocardiography4weeks after implantation showed all the prosthetic valves exhibitednormal functionality and no significant insufficiency or stenosis. Echocardiography12weeks after implantation showed no insufficiency of all six PPHVs, however, mildstenosis(the most peak-peak transvalvular pressure gradient (PG) was38mmHg) wasfound in five PPHVs and no significant stenosis was found in the other one. While,echocardiography12weeks after bovine pericardium valve implantation showed nosignificant insufficiency or stenosis in one sheep and mild stenosis and mild insufficiencyin the other one. Cardiac catheter examination showed PG of the PPHVs were（3.8±1.2）mmHg before implantation,（5.5±1.0）mmHg right after implantation,（12.3±5.4）mmHg4weeks after implantation, and （27.3±8.1）mmHg12weeks after implantation，while PG of two bovine pericardium valves12weeks after implantation were14and25mmHg. Angiography of all the sheep right after implantation,4weeks after implantation,and12weeks after implantation demonstrated orthotopic position and exhibited normaloperation. CT of all the sheep4weeks and12weeks after implantation demonstratedorthotopic position and no deformation of the valved stents. Pathological examination ofthe PPHV explanted from the pulmonary valve position of sheep4weeks after surgeryshowed the valve leaflets were smooth without significant tissue deposits, thrombus orcalcification and slight fibrous overgrowth at the bottom of the valve leaflets, in thecommissural areas and on the sealing cuff. Pathological examination of the explantedPPHVs12weeks after implantation showed no degradation or damage of the ePTFEleaflets and most of the leaflets were thin and pliable, without significant thrombus orcalcification, while visible pannus overgrowth was found at the bottom of the valve leaflets,in the commissural areas and on the sealing cuff. The pathological findings of the twobovine pericardium valves12weeks after implantation were similar to PPHVs. Mildpannus overgrowth was found at the bottom of the valve leaflets, in the commissural areasand on the sealing cuff. However, significant fragmentation and disruption of collagen andelastic fibers were found in the bovine pericardium valve leaflets, and the calcium contentof the bovine pericardium valves was significant higher than PPHVs.Conclusion: The success rate of transcatheter pulmonary valve implantation by hybridprocedure and right ventricular apical approach is satisfactory. The short-and medium-term effects of the novel PC-coated ePTFE pulmonary valve after transcatheterpulmonary valve implantation in sheep is good. The novel PPHV exhibits goodanti-adhesion,anti-degradation, anti-thrombus, anti-calcification performance and goodbiomechanical property. The hemodynamic parameter of PPHV is comparable to bovinepericardium valve. Optimizing the valve design that increases the flow of the commissuralareas and the bottom of the valve might eventually eliminate the problem about pannusovergrowth. Part IVDevelopment of a novel polymerictranscatheter aortic valve: a preliminary studyin sheepObjective: To evaluate the feasibility of transcatheter aortic valve implantation in sheepusing a novel polymeric prosthetic valve, and to assess the immediate valvularfunctionality of the polymeric prosthetic valves after in situ implantation in sheep.Methods: In this study, we designed a novel polymeric trileaflet transcatheter aortic valvewith a balloon-expandable stent, and the valve leaflet was made of0.1-mm expandedpolytetrafluoroethylene (ePTFE). Polymeric aortic valves were implanted in situ by leftventricular apical approach in8healthy sheep, weighing (21.5±1.7)kg. Angiography,color doppler echocardiography, and64-row computed tomography were performed afterimplantation to assess immediate valvular function. All sheep were chosed to be sacrificed2h after valve implantation for macroscopic examination. Results: One sheep died ofsevere aortic valve regurgitation because the stented valve was implanted below the normalposition. One sheep died of ventricular fibrillation because the stented valve was higherthan the normal position and influenced the blood-supply of coronary arteries. Implantationwas successful in the other6sheep.Angiography showed all the prosthetic valvesdemonstrated orthotopic position and exhibited normal open and close functionality and noinfluence of blood-supply of coronary arteries. Echocardiography showed good functionality for all prosthetic valves, none or trace valve regurgitation in four sheep, andmild valve regurgitation in the other two sheep. The peak-peak transvalvular pressuregradient of the prosthetic valves was (14.2±7.1)mmHg. CT demonstrated orthotopicposition and no deformation of the valved stents and no influence of blood-supply ofcoronary arteries. Autopsy showed the prosthetic valve fully replaced the native valve anddid not influence coronary arteries and mitral valve. Conclusion: Placement of the novelePTFE transcatheter aortic valve in sheep is feasible and effective. Part VTranscatheter pulmonary valve implantationin sheep:1-month evaluation of a novelself-expanding ePTFE valved stent.Objective: To design an more convenient and effective polymeric transcatheter heart valveand delivery system, and to evaluate early valvular functionality after transcatheterpulmonary valve implantation in sheep using a novel self-expanding expandedpolytetrafluoroethylene (ePTFE) pulmonary valve. Methods: In this study, we designed anovel polymeric trileaflet transcatheter pulmonary valve with a self-expanding nitinol stent,and the valve leaflet was made of0.1-mm phosphorylcholine coated ultramicroporousePTFE. Pulmonary valve stents were implanted in situ by right ventricular apical approachin7healthy sheep weighing an average of (27.1±1.1) kg. Angiography and hemodynamicmeasurement were performed after implantation to assess immediate valvular function.Color Doppler echocardiography and hemodynamic measurement were used to assessvalvular function4weeks after implantation. Results: Implantation was successful in7sheep. Mean X-ray exposure time was significantly shorter than that when implantation ofthe balloon-expandable valved stents.Angiography at implantation showed all theprosthetic valves demonstrated orthotopic position and exhibited normal open and closefunctionality and no stenosis or insufficiency. One sheep died16days after implantationdue to infective endocarditis. All other sheep survived among the1-month study time.Echocardiography4weeks after implantation showed all the prosthetic valvesexhibited orthotopic position, normal functionality and no significant valve excrescent.Echocardiography demonstrated none valve regurgitation in four sheep, and trace valveregurgitation in the other two sheep. Hemodynamic measurement revealed that thepeak-peak transvalvular pressure gradient of the polymeric valves was (6.0±2.2)mmHginitially, and(9.5±2.7) mmHg at follow-up. Conclusion: The novel transcatheter heartvalve and delivery system is convenient, safe, and effective. After4weeks of implantation,the novel transcatheter memory nitinol self-expanding ePTFE pulmonary valved stentsdemonstrated good function in sheep.