24 June 2015: Animal Studies
Injectable Tissue-Engineered Pulmonary Heart Valve Implantation Into the Pig Model: A Feasibility Study
Franziska Schlegel ABDEF , Aida Salameh ABCD , Katja Oelmann AB , Michelle Halling B , Stefan Dhein BCD , Friedrich W. Mohr A , Pascal M. Dohmen ABCDEFG
DOI: 10.12659/MSMBR.894838
Med Sci Monit Basic Res 2015; 21:135-140
Abstract
BACKGROUND: Transcatheter pulmonary valve replacement is currently performed in clinical trials, but is limited by the use of glutaraldehyde-treated bioprostheses. This feasibility study was performed to evaluate delivery-related tissue distortion during implantation of tissue-engineered (TE) heart valves.
MATERIAL AND METHODS: The injectable TE heart valve was mounted on a self-expanding nitinol stent (n=7) and delivered into the pulmonary position in 7 pigs, (weight 26 to 31 kg), performing a sternotomy or limited lateral thoracotomy. Prior to implantation, the injectable TE heart valves were crimped and inserted into an applicator. Positioning of the implants was guided by fluoroscopy, and after careful deployment, angiographic examination was performed to evaluate the correct delivered position. Hemodynamic measurements were performed by epicardial echocardiography. Finally, the animals were sacrificed and the injectable TE heart valves were inspected by gross examination and histological examination.
RESULTS: Orthotopic deliveries of the injectable TE heart valves were all successful performed, expect in 1 where the valve migrated due to a discrepancy between pulmonary valve annulus size and injectable TE valve size. Angiographic evaluation (n=6) showed normal valve function, supported by epicardial echocardiography in which no increased flow velocity was measured, neither trans- nor paravalvular regurgitation. Histological evaluation demonstrated absence of tissue damage from the delivery process.
CONCLUSIONS: Transcatheter implantation of an injectable TE heart valve seems to be possible without tissue distortion due to the delivery system.
Keywords: Alloys, Feasibility Studies, Fluoroscopy, Heart Valve Diseases - surgery, Heart Valve Prosthesis Implantation - methods, Hemodynamics, Stents, Swine, Tissue Engineering - methods
Background
The incidence of complex congenital heart disease is approximately 8.21/1000 live births in Canada, with involvement of the right ventricular outflow tract (RVOT) of approximately 10% [1]. Generally, initial RVOT reconstruction is performed by patch, but due to the absence of a sufficient functioning pulmonary valve, the right ventricle will be volume-overloaded and dilate over time. The volume overload of the right ventricle is usually well tolerated, but over time it might lead to decreased exercise tolerance, dyspnea, arrhythmia, symptoms of heart failure, and, eventually, sudden death [2,3]. At the time of ventricle dilatation, a valve conduit is chosen to reconstruct the RVOT, since today’s available valve conduits degenerate over time in absence of regeneration or growth potential [4–6].
The ideal would be a living autologous valve with regeneration, remodelling, and growth potential, implanted with minimal invasiveness, without tissue distortion or compromising valve function. Tissue engineering techniques allows us to construct valves with remodelling, regeneration, and growth potential, but these valves have only limited availability for clinical use and are conventionally implanted [7,8].
In 2000 Bonhoeffer et al. [9] began using glutaraldehyde-fixed bovine jugular veins mounted on balloon-expandable stainless stents to be percutaneously implanted. These valves were initially implanted in patients with pulmonary valve stenosis, but nowadays pulmonary valve regurgitations can also be treated with these valves if the current annulus size is still suitable and not over-dilated [10]. General disadvantages of the current clinically available transcatheter valves are availability for selected cases, high rate of stent fractures [11], and increased risk of endocarditis during follow-up [12]. Glutaraldehyde treatment is not an optimal option in congenital heart disease treatment because there is lack of growth potential as well as increased risk for early deterioration [13,14]. The aim of the present study was to evaluate the implantation of a newly designed injectable TE pulmonary heart valve with a self-expandable nitinol stent to reconstruct the RVOT.
Material and Methods
VALVE DESIGN:
Details on decellularization of porcine pulmonary heart valves were previously reported [15]. In brief, fresh porcine pulmonary heart valves were obtained from the slaughterhouse. After preparation and carefully trimming the muscle tissue to a minimum, the valves were placed in antibiotic solutions until decellularization with deoxycholic acid (Sigma Chemical Co, St. Louis, MO) was started. Extensive rinsing and ethanol treatment was performed before final sterilization. The decellularized pulmonary valves were sutured into a self-expendable nitinol stent (PFM Medical AG, Koeln, Germany) with a diameter of 16 mm (Figure 1A, 1B). This size was chosen because the diameter of the pulmonary valve annulus was preoperatively measured, adding 10% to ensure optimal fitting of the injectable TE heart valve into the pulmonary valve annulus.
IMPLANTATION PROCEDURE:
Seven healthy pigs between 6 and 9 months of age with a median weight of 28 kg (range 26–31 kg) were included in this study. All animals were pre-medicated and, after general anesthesia was induced, mechanical ventilation was started. A median sternotomy or limited lateral thoracotomy was performed to implant the injectable TE pulmonary heart valve. A bolus of 5.000 IU heparin intravenously was administered and the pericardium was opened. One purse-string suture was placed at the level of the right ventricular outflow tract. After crimping the valve for at least 30 min, an introducer was used to implant the injectable TE pulmonary heart valve (Figure 2). The release procedure was guided by fluoroscopy and performed under rapid pacing. The implanted valve was studied by epicardial echocardiographic examination (Vivid; GE Healthcare, Munich Germany), invasive pressure, and angiographic measurements. Finally, 4–6 h after implantation, the animals were sacrificed and the injectable TE heart valves were explanted, rinsed, and subjected to gross examination and histopathological analysis.
Results
The injectable TE heart valve was guided by fluoroscopy (Figure 3) and successfully delivered in all animals, except in 1 were the valve migrated due to the discrepancy between the implanted valve and the native pulmonary valve annulus. Angiography and epicardial echocardiography proved that all injectable TE heart valves were competent, and no trans- or paravalvular leakage was seen in any of the 6 successful implantations (Figure 4). Invasive pressure measurement showed a median maximum pressure gradient of 4 mm Hg (range 3–5 mm Hg) and median maximum pressure gradient of 8 mm Hg (range 6–12 mm Hg), confirmed by epicardial echocardiographic examination. During follow-up, none of the valves migrated and hemodynamic behavior of the implanted valves was stable.
Gross examination of the injectable TE heart valve showed pliable leaflets without tears or bleeding. The leaflets were all intact and showed no thrombus formation (Figure 5A, 5B).
Histopathological examination showed a preserved extracellular matrix with absence of any tissue damage due to the delivery system or implantation process (Figure 6A–6D).
Discussion
LIMITATIONS OF THE STUDY:
This feasibility study was performed to evaluate the influence of delivery procedure on an injectable TE heart valve. However, due to the limitation of the acute setting of these experiments, long-term implantation studies will be needed to evaluate the injectable TE heart valve behavior under permanent burden.
Conclusions
Transcatheter implantation of an injectable TE heart valve seems to be feasible, without tissue distortion due to the delivery procedure.
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