Abstract
Integration of biophysical stimulation in test systems is established in diverse branches of biomedical sciences including toxicology. This is largely motivated by the need to create novel experimental setups capable of reproducing more closely in vivo physiological conditions. Indeed, we face the need to increase predictive power and experimental output, albeit reducing the use of animals in toxicity testing. In vivo, mechanical stimulation is essential for cellular homeostasis. In vitro, diverse strategies can be used to model this crucial component. The compliance of the extracellular matrix can be tuned by modifying the stiffness or through the deformation of substrates hosting the cells via static or dynamic strain. Moreover, cells can be cultivated under shear stress deriving from the movement of the extracellular fluids. In turn, introduction of physical cues in the cell culture environment modulates differentiation, functional properties, and metabolic competence, thus influencing cellular capability to cope with toxic insults. This review summarizes the state of the art of integration of biophysical stimuli in model systems for toxicity testing, discusses future challenges, and provides perspectives for the further advancement of in vitro cytotoxicity studies.
Highlights
The ongoing development of experimental setups for in vitro toxicity testing, in particular the advent of organ-on-a-chip models [1,2,3,4,5,6,7,8,9,10,11,12,13], opened new dimensions in deciphering cytotoxicity processes.With the introduction of biophysical stimulation, for instance in microfluidics systems or 3D structures, an additional degree of complexity is added to the biochemical reactions triggered by the compounds of interest
This review summarizes the state of the art of integration of biophysical stimuli in model systems for toxicity testing, discusses future challenges, and provides perspectives for the further advancement of in vitro cytotoxicity studies
As well as in an artificial cell culture environment, cells can be classified as suspension cells—growing and proliferating without the need to attach to a substrate—and as adherent cells
Summary
The ongoing development of experimental setups for in vitro toxicity testing, in particular the advent of organ-on-a-chip models [1,2,3,4,5,6,7,8,9,10,11,12,13], opened new dimensions in deciphering cytotoxicity processes. The combination of α and β integrin heterodimers bridges the connection between the intracellular environment and different components of the ECM like laminin or collagen [42,43,44] It was recently highlighted how the physiological role of integrins could be extended toward the binding of viruses, bacteria, and parasites as well as being a target for several poisons [45]. Data published in the last 25 years were considered and key words included “shear stress and cytotoxicity/toxicity,” “stretching and cytotoxicity/toxicity” “biomechanical stimulation and cytotoxicity/toxicity,” “mechanical strain and toxicity,” “matrix/substrate/ECM stiffness and toxicity/cytotoxicity” This approach allowed us to summarize observational and mechanistic studies and to identify the strength and the limitations of the integration of biophysics in cytotoxicity testing
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