Marrow Stromal Cell based Stem Cell Based Transcatheter Aortic Valve Implantation: First Experiences in a Preclinical Model

Abstract

Objectives: We investigate the combination of transcatheter aortic-valve implantation (TAVI) and a novel concept of stem cell-based, tissue-engineered heart-valves (TEHV) comprising minimally-invasive techniques for both, cell-harvest and valve-delivery. Background: TAVI represents an emerging technology for the treatment of aorticvalve disease. The utilized bioprostheses are inherently prone to calcific-degeneration and recent evidence suggests even accelerated degeneration resulting from structuraldamage due to the crimping-procedures. Autologous, living heart-valve prosthesis with regeneration and repair capacities would overcome such limitations. Methods: Within a one-step intervention, tri-leaflet TEHV, generated from biodegradable synthetic-scaffolds, were integrated into self-expanding nitinol-stents, seeded with autologous bone-marrow mononuclear cells, crimped and transapically delivered into adult sheep (n=12). The animals were followed up for up to 2weeks. TEHV-functionality was assessed by fluoroscopy, echocardiography and computedtomography. Post-mortem analysis was performed using histology, extracellular-matrix analysis and electron-microscopy. Results: Transapical aortic implantation of TEHV was successful in all animals (n=12) and the entire procedure-time from cell-harvest to TEHV-delivery was 109±14min. Fluoroscopy and echocardiography displayed TEHV-functionality demonstrating an adequate leaflet-mobility and co-aptation. Explanted TEHV showed intact leafletstructures with well defined cusps without signs of thrombus-formation or structuraldamage. Histology and ECM analysis displayed a high cellularity indicative for an early cellular-remodelling and in-growth after 2weeks. Conclusion: For the first time, we demonstrate the principal feasibility of a transcatheter, stem cell-based TEHV implantation into the aortic-valve position within a one-step intervention. Its long term functionality proven, a stem cell-based TEHV 3 approach may represent a next generation heart-valve concept extending the clinical indication of transcatheter valves beyond elderly high-risk patients.

Living-Engineered Valves for Transcatheter Venous Valve Repair

“…constructs. 9 In particular in the field of heart valve regeneration, several recent preclinical large animal trials involving sheep 14,15,17 and non-human primate models 16 showed promising initial results and underline the potential of this technology for future therapeutic concepts. Given the major complications when using xeno-or homogenic venous valve transplants, Teebken et al 37 investigated for the first time TEVVs based on a homologous decellularized matrix in the ovine model.…”

“…[40][41][42] Also the group of Pavcnik et al reported a minimally invasive transcatheter approach based on a xenogenic bioprosthetic venous valve system with initial promising results. [43][44][45] Therefore, besides the use of an autologous low-invasive cell source (such as BMMSCs), a clinically relevant TEVV concept requires a combination of the tissue engineering technology with minimally invasive delivery methods, which has already been successfully demonstrated for heart valve tissue engineering in the ovine model for the low- 14 as well as the high-pressure system 17 up to 2 months in vivo. Recently, stented TEHVs could also be minimally invasively delivered into the orthotopic pulmonary position of a clinically relevant non-human primate model that shows promising results in vivo with confluent endothelialization and interstitial valve remodeling.…”

“…This study was followed by a similar approach using bone marrow mononuclear cells in a clinically relevant large animal model 16 as well as in the high-pressure environment. 17 The fabrication of autologous cell-based tissue-engineered venous valves (TEVVs) raises significant challenges in the light of the miniaturized dimensions of native venous valves.…”

Bioprinting a cardiac valve

“…However, it is difficult to a fabricate artificial scaffold with exact native leaflet shape, structure and flexibility -so there is the possibility of regurgitation in artificial valve construct due to lack of proper coaptation. Compared to 3D porous structures and hydrogels, nanofibrous mesh is more equivalent to leaflet structurally and morphologically (Emmert et al , 2012, Zund et al , 1998.…”

Evolution of Transcatheter Aortic Valve Replacement

“…During the last years, attempts were made to develop an autologous tissue engineering aortic valve prosthesis that could be implanted percutaneously. 126,127 This device is anticipated to grow and remodel following the changes that occur in the human body, adopt the cellular phenotypes and structural organization of the native valve, and have a physiological function and increased durability. The first results in animals are encouraging; however, additional technological advances are needed to improve the design of the valve, and research is required to confirm the safety and long-term efficacy of the device before having application in the clinical arena.…”