Bioartificial Heart: A Human-Sized Porcine Model – The Way Ahead

Abstract

BackgroundA bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Native hearts decellularized with preserved architecture and vasculature may provide an acellular tissue platform for organ regeneration. We sought to develop a tissue-engineered whole-heart neoscaffold in human-sized porcine hearts.MethodsWe decellularized porcine hearts (n = 10) by coronary perfusion with ionic detergents in a modified Langendorff circuit. We confirmed decellularization by histology, transmission electron microscopy and fluorescence microscopy, quantified residual DNA by spectrophotometry, and evaluated biomechanical stability with ex-vivo left-ventricular pressure/volume studies, all compared to controls. We then mounted the decellularized porcine hearts in a bioreactor and reseeded them with murine neonatal cardiac cells and human umbilical cord derived endothelial cells (HUVEC) under simulated physiological conditions.ResultsDecellularized hearts lacked intracellular components but retained specific collagen fibers, proteoglycan, elastin and mechanical integrity; quantitative DNA analysis demonstrated a significant reduction of DNA compared to controls (82.6±3.2 ng DNA/mg tissue vs. 473.2±13.4 ng DNA/mg tissue, p<0.05). Recellularized porcine whole-heart neoscaffolds demonstrated re-endothelialization of coronary vasculature and measurable intrinsic myocardial electrical activity at 10 days, with perfused organ culture maintained for up to 3 weeks.ConclusionsHuman-sized decellularized porcine hearts provide a promising tissue-engineering platform that may lead to future clinical strategies in the treatment of heart failure.

Bioengineering for Organ Transplantation: Progress and Challenges

“…Direct injection attempts have resulted in dense cellularity at the injection site with poor distribution throughout the remainder. 9,25 The first evidence of the potential of a scaled-up model was recently reported using porcine heart scaffolds. 25 Successfully decellularized porcine hearts were reseeded with murine cardiomyocytes and human umbilical vein endothelial cells (HUVECs) resulting in a construct that exhibited intrinsic electrical activity.…”

“…9,25 The first evidence of the potential of a scaled-up model was recently reported using porcine heart scaffolds. 25 Successfully decellularized porcine hearts were reseeded with murine cardiomyocytes and human umbilical vein endothelial cells (HUVECs) resulting in a construct that exhibited intrinsic electrical activity. 25 Further work is still required to achieve a fully functional bioartificial heart of appropriate clinical scale with focus on suitability of cardiac cell sources (including the use of conspecific cells), enhancing reseeding techniques to promote sufficient dispersion, and optimization of in vitro organ culture.…”

“…25 Successfully decellularized porcine hearts were reseeded with murine cardiomyocytes and human umbilical vein endothelial cells (HUVECs) resulting in a construct that exhibited intrinsic electrical activity. 25 Further work is still required to achieve a fully functional bioartificial heart of appropriate clinical scale with focus on suitability of cardiac cell sources (including the use of conspecific cells), enhancing reseeding techniques to promote sufficient dispersion, and optimization of in vitro organ culture. 25 Lung Challenges in developing a biocompatible lung scaffold initially revolved around the production of a highly elastic matrix to facilitate reproduction of the complex lung architecture required to support gas exchange.…”

“…25 Further work is still required to achieve a fully functional bioartificial heart of appropriate clinical scale with focus on suitability of cardiac cell sources (including the use of conspecific cells), enhancing reseeding techniques to promote sufficient dispersion, and optimization of in vitro organ culture. 25 Lung Challenges in developing a biocompatible lung scaffold initially revolved around the production of a highly elastic matrix to facilitate reproduction of the complex lung architecture required to support gas exchange. 26 The development of a suitable scaffold followed by successful reseeding with endothelial cells and epithelial cells, was reported in 2 initial small animal studies.…”

Acellular porcine heart matrices: whole organ decellularization with 3D-Bioscaffold & vascular preservation

“…At a larger scale using porcine hearts via retrograde aortic perfusion, successive perfusates of 0.02% trypsin/0.05% EDTA, 3% Triton X-100, and 4% deoxycholate with PBS rinses between reagents also resulted in successful decellularization [25]. Other porcine heart decellularization protocols implemented similar methods [25,26], with a few additional detergents such as CHAPS (3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate) [27] used in heart valves and other organs [28,29]. All detergents have the potential to inflict damage on the ECM and disrupt the ultrastructure, by damaging the collagen and glycosaminoglycans for example [29].…”