Hydrodynamics and bioprocess considerations in designing bioreactors for cardiac tissue engineering

Abstract

One of the most attractive fields in regenerative medicine and tissue engineering is cardiac cell regeneration due to the limited capacity of the heart muscle to regenerate itself. Recent advances in the field of stem cell bioprocess technology and biomaterials have accelerated progress in creating three-dimensional (3D) cardiac engineered tissues in vitro. Control of bulk and microscopic transport efficiency, which is determined by the choice of the bioreactor design and substrate material, poses direct influence on cell viability, proliferation and differentiation in vitro. This paper provides a critical review on the hydrodynamic considerations with respect to design aspects of the bioreactor and selection of substrate material for 3D cardiac tissue engineering.

A Versatile Bioreactor for Dynamic Suspension Cell Culture. Application to the Culture of Cancer Cell Spheroids

“…Avoiding the use of impellers and/or rotational components, the presented device overcomes some major limitations of the current dynamic suspension methods. In fact, it is well established that within the stirred systems (e.g., spinner flasks, stirred tank bioreactors) (1) the interaction of cells with the moving components, and (2) the complex fluid dynamics, characterized by turbulence and/or detrimental shear stresses, could lead to cell damage and consequent low expansion efficiency and limited bioprocess reproducibility [ 4 , 9 , 28 , 30 , 32 , 33 ]. Differently, rotating bioreactors provide laminar, low-shear stress culture environments, but the complex technological solutions needed to impart rotation make them not easily scalable and unsuitable for continuous medium replacement and real-time monitoring [ 4 ].…”

“…Adopting flow rates under 20 mL/min, shear stress values lower than 1 mPa develop within the culture chamber (ultralow shear stress condition, Fig 4B ), while increasing the flow rates up to 120 mL/min, skewed right shear stress distributions are obtained, with mean values ranging from 2 to around 7 mPa (low-to-moderate shear stress condition, details in S3 Text ). The (tunable) shear stress values produced by this dynamic suspension bioreactor are (1) one order of magnitude lower than the shear stress values normally developing within a commercial spinner flask where, imposing agitation rates ranging from 15 to 50 rpm, mean shear stress values ranging from 20 to around 120 mPa are reached (with peak values of 200 mPa) [ 40 ], and (2) some orders of magnitude lower than the reference shear stress value considered critical (250 mPa) for sensitive cells like human embryonic stem cells or neonatal rat cardiomyocytes [ 33 ]. Furthermore, the simulated transport of oxygen dissolved in the medium confirms that the presence of laminar, dynamic vortex structures within the culture chamber promotes nutrients and gases mixing and transport, as well as cell transport during dynamic suspension, guaranteeing their homogeneous distribution.…”

“…Concerning stirred tank bioreactors, their performance can be affected by (1) collisions of the cells with the impeller and (2) the onset of turbulent flow, that both can induce non-physiological mechanical and hydrodynamic-shear stresses on the cells and lead to cell damage. Moreover, these unfavourable conditions can affect cell growth rate and metabolism, interfere with stem cell pluripotency, and limit efficiency and reproducibility of the culture process [ 4 , 9 , 28 , 30 , 32 , 33 ]. Rotating bioreactors generate a low-shear stress culture environment, allowing to partially overcome the limitations of stirred tank devices.…”

Hybrid amphiphilic bimodal hydrogels having mechanical and biological recognition characteristics for cardiac tissue engineering

“…The size of the cell clusters were found to be increased on the 10 th day when compared with that of 5 th day (Fig. 93 . This indicates the effective communication among the cardiomyoblast cells on both the scaffolds to get clustered and to function as a single unit.…”

Computational fluid dynamic analysis of bioprinted self‐supporting perfused tissue models

“…Similarly, MLO‐Y4s show decreasing RANKL and increasing COX‐2 as shear increases from no flow to 1 to 5 Pa (J. Li, Rose, Frances, Sun, & You, ). For cardiac tissue, shear stresses greater than 0.25 Pa have been shown to cause cellular damage and reduce cell expansion (Barash et al, ; Brown, Iyer, & Radisic, ; Lecina, Ting, Choo, Reuveny, & Oh, ; Teo, Mantalaris, & Lim, ). For bone‐marrow mesenchymal stem cells, a shear level of 0.5 Pa has been shown to inhibit proliferation and, in some cases, push the stem cells toward osteogenic differentiation.…”