Fractional calculus modeling of cell viscoelasticity quantifies drug response and maturation more robustly than integer order models

Abstract

It has recently been discovered that the viscoelastic properties of cells are inherent markers reflecting the complex biological states, functions and malfunctions of the cells. Although the extraction of model parameters from the viscoelasticity data of many cell types has been done successfully using integer order mechanical and power-law viscoelastic models, there are some cell types and conditions where the goodness of fits falls behind. Thus, fractional order viscoelastic models have been proposed as more general and better suited for such modeling. In this work, we test such proposed generality using published data already fitted by integer order models. We find that cell viscoelasticity data can be fitted using fractional order viscoelastic models in more situations than integer order. For macrophages, which are among the white blood cells that function in the immune system, the fractional order Kelvin-Voigt model best captures pharmacological interventions and maturation of the cells. The steady state viscosity of macrophages decreases following depolymerization of F-actin using the drug cytochalasin D, and also decreases following myosin II breakdown using Blebbistatin. When macrophages are treated with a bacterium-derived chemoattractant, the steady state viscosity decreases. Interestingly, both the steady state viscosity and elastic modulus are progressively altered as the cells become mature and approach senescence. Taken together, these results show that fractional viscoelastic modeling, more robustly than integer order modeling, enables the further quantification of cell function and malfunction, with potential diagnostic and therapeutic applications especially in cases of cancer and immune system dysfunctions.