A novel customizable modular bioreactor system for whole-heart cultivation under controlled 3D biomechanical stimulation

Abstract

In the last decade, cardiovascular tissue engineering has made great progress developing new strategies for regenerative medicine applications. However, while tissue engineered heart valves are already entering the clinical routine, tissue engineered myocardial substitutes are still restrained to experimental approaches. In contrast to the heart valves, tissue engineered myocardium cannot be repopulated in vivo because of its biological complexity, requiring elaborate cultivation conditions ex vivo. Although new promising approaches-like the whole-heart decellularization concept-have entered the myocardial tissue engineering field, bioreactor technology needed for the generation of functional myocardial tissue still lags behind in the sense of user-friendly, flexible and low cost systems. Here, we present a novel customizable modular bioreactor system that can be used for whole-heart cultivation. Out of a commercially obtainable original equipment manufacturer platform we constructed a modular bioreactor system specifically aimed at the cultivation of decellularized whole-hearts through perfusion and controlled 3D biomechanical stimulation with a simple but highly flexible operation platform based on LabVIEW. The modular setup not only allows a wide range of variance regarding medium conditioning under controlled 3D myocardial stretching but can also easily be upgraded for e.g. electrophysiological monitoring or stimulation, allowing for a tailor-made low-cost myocardial bioreactor system.

Electrical and mechanical stimulation of cardiac cells and tissue constructs

“…Another system developed to enable perfusion and electrical stimulation in 3D is the use of a re-cellularized decellularized heart [370–372]. For example, in a decellularized rat heart re-cellularized with isolated CMs, perfusion of the heart (in at the left atrium and out through the aortic valve) was used to inflate and deflate the ventricles providing mechanical stimulation via both flow and mechanical stretch [370].…”

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

“…Nevertheless, the native endothelial cell layer was reseeded by HUVECs, albeit with partial interruption. Although reseeding has been previously reported in rats [7]–[9], this is the first time that this technology has been scaled to whole hearts of human size and complexity. Porcine hearts, however, pose unique challenges.…”

“…Ott et al published their seminal work on perfusion-decellularization with cell-seeding in rat hearts [8], with subsequent progress by others [7], [9]. Whereas these experiments have undeniably been harbingers of progress in cardiac tissue engineering, murine hearts are much smaller in size and complexity than human hearts.…”

“…Whereas considerable progress has been made with rat hearts [7]–[9], experiments with human-sized porcine hearts lag much behind [10], [11]. We present the first experimental prototype of a tissue-engineered porcine whole-heart, with perfused organ culture in a bioreactor and formation of myocardium that generates intrinsic electrical activity.…”

Decellularized scaffolds as a platform for bioengineered organs

“…The application of 3D left ventricular stretch with an inflatable latex balloon inserted into decellularized rodent hearts results in improved cellular 3D spatial orientation and alignment [30]. …”