Culture Models of Cardiac Tissue Engineered Constructs

Early models of engineered cardiac tissue constructs relied on static conditions for in-vitro culture prior to in-vivo implantation. In static culture, with no fluid mixing, large diffusive gradients are formed between the outside and the inside of the constructs. Therefore, the cells in the center of the constructs lack sufficient nutrient supply, the toxic metabolites are poorly removed, and many - if not most - ofthe cells die [108]. Oxygen and carbon dioxide diffusion into the cardiac scaffold is the main limiting factor for gas exchange under static culture conditions [109]. A simple approach that may increase the diffusion of nutrients and gases and also enhance waste removal is to grow cells on a 3D polymer scaffolds that is placed in a dynamic environment, such as that provided by a perfused bioreactor [110].

Bioreactors have been utilized for a variety of diverse applications for cardiac tissue engineering, such as: (1) cell expansion; (2) production of 3D tissues from

Fig. 1.5 Dynamic culture of cells or tissue constructs in rotating wall vessel bioreactors; (A) a high-aspect ratio vessel (HARV), (B) a hydrodynamic focusing bioreactor (HFB).

isolated cells in vitro; (3) production of 3D tissue constructs with cells on the scaffolds in vitro; and (4) directly as organ support devices [108, 111-114]. Amongst the dynamic bioreactors, different types of rotating wall vessel (RWV) bioreactors, such as the STLV (slow-turning lateral vessel), the HARV (high aspect ratio vessel; Fig. 1.5A) and the HFB (hydro-dynamic focusing bioreactor; Fig. 1.5B), have been used for cardiac tissue engineering.

These venues provide improved mass transport [113], leading to enhanced metabolic activity [110] and electrophysiological and molecular properties [115] of the constructs. It has been shown that the pO2, pH and pCO2 were better and more consistently maintained in these bioreactors than under static conditions, and facilitated aerobic respiration for constructs with higher cell densities [109, 116].

Recent studies have indicated that applied shear stress has a beneficial effect on the quality and quantity of the generated cardiac tissues [117]. Furthermore, a new generation of RWV bioreactors has been designed to impose mechanical stretch [56] on engineered heart constructs. The development of engineered cardiac tissue is modulated by mechanical signals [118]. The organization, composition, and function of the engineered cardiac tissue can be achieved by application of physiological regimens of cyclic strain [119]. Previously, Vandenburgh et al. [120] demonstrated that physical stimuli improved the proliferation and distribution of the seeded human heart cells throughout the scaffold structure, and further stimulated the formation and organization of ECM, which was responsible for improvements in the mechanical strength of the cardiac graft and population with cells. Future bioreactors for cardiac tissue engineering should combine both perfusion and mechanical stimuli, for example by allowing for adjustable pulsatile flow and varying levels of pressure [103, 110].

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