Abstract
Three-dimensional (3D) cell culture is often mentioned in the context of regenerative medicine, for example, for the replacement of ischemic myocardium with tissue-engineered muscle constructs. Additionally, 3D cell culture is used, although less commonly, in basic research, toxicology, and drug development. These applications have recently benefited from innovations in stem cell technologies allowing the mass-production of hiPSC-derived cardiomyocytes or other cardiovascular cells, and from new culturing methods including organ-on-chip and bioprinting technologies. On the analysis side, improved sensors, computer-assisted image analysis, and data collection techniques have lowered the bar for switching to 3D cell culture models. Nevertheless, 3D cell culture is not as widespread or standardized as traditional cell culture methods using monolayers of cells on flat surfaces. The many possibilities of 3D cell culture, but also its limitations, drawbacks and methodological pitfalls, are less well-known. This article reviews currently used cardiovascular 3D cell culture production methods and analysis techniques for the investigation of cardiotoxicity, in drug development and for disease modeling.
Highlights
Specialty section: This article was submitted to Cardiovascular Biologics and Regenerative Medicine, a section of the journal Frontiers in Cardiovascular Medicine
Current 3D cell culture model systems that are in use for drug testing and toxicology applications mostly fall into two main categories: They contain A. a scaffold matrix, typically a hydrogel, which is mixed with and populated by cells and forms a strip or hourglass-shaped contracting MT between attachment sites, called an engineered heart tissue (EHT) (Figure 1) [5], or B. smaller cellular aggregates forming by self-assembly without scaffold proteins in hanging drops or in multi-well plates with non-adhesive surfaces (Figure 2)
An increasing number of studies making use of cardiac scaffold-free spheroids for drug testing and toxicology has been published in the last couple of years [6, 7] and frequently, a mix or co-culture of several cell types is used, such as rodent or human primaryor human induced pluripotent stem cell-derived cardiomyocytes, fibroblasts, stem cells, and endothelial cells [19,20,21,22,23]
Summary
A number of different types of 3D culture models and production methods have been developed in the cardiovascular field (Table 1). The most basic form of 3D culture is the multicellular aggregate as it occurs by self-assembly of floating cells on lowattachment surfaces ( called liquid-overlay method). Such a suspension culture can be made in inexpensive ways, for example by using a sterile dish with a thin film of agarose. Additional concepts have been published that are making use of combined techniques, such as cell layers with pre-formed vascular trees obtained from animals, bioprinted and microcontact models as components of micro-physiological platforms and larger tissues for surgical applications [51, 66, 67]
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