Mechanical interaction of cell with extracellular environment affects its function. The mechanisms by which mechanical stimuli are sensed and transduced into biochemical responses are still not well understood. Considering this, two finite element (FE) bendo-tensegrity models of a cell in different states are proposed with the aim to characterize cell deformation under different mechanical loading conditions: a suspended cell model elucidating the global response of cell in tensile test simulation and an adherent cell model explicating its local response in atomic force microscopy (AFM) indentation simulation. The force-elongation curve obtained from tensile test simulation lies within the range of experimentally obtained characteristics of smooth muscle cells (SMCs) and illustrates a nonlinear increase in reaction force with cell stretching. The force-indentation curves obtained from indentation simulations lie within the range of experimentally obtained curves of embryonic stem cells (ESCs) and exhibit the influence of indentation site on the overall reaction force of cell. Simulation results have demonstrated that actin filaments (AFs) and microtubules (MTs) play a crucial role in the cell stiffness during stretching, whereas actin cortex (AC) along with actin bundles (ABs) and MTs are essential for the cell rigidity during indentation. The proposed models quantify the mechanical contribution of individual cytoskeletal components to cell mechanics and the deformation of nucleus under different mechanical loading conditions. These results can aid in better understanding of structure-function relationships in living cells.

Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. Notably, in silico models are regarded as powerful tools to further understand the signaling pathways that regulate this intricate spatial cellular interplay. To this end, we have established a 3D multiscale micro-multiphysics agent-based (micro-MPA) in silico model of trabecular bone remodeling using longitudinal in vivo data from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A) mice, a mouse model of premature aging. Our in silico model includes a variety of cells as single agents and receptor-ligand kinetics, mechanomics, diffusion and decay of cytokines which regulate the cells’ behavior. We highlighted its capabilities by simulating trabecular bone remodeling in the CV6 of five mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. Based on the progression of the average trabecular bone volume fraction (BV/TV), we identified a configuration of the model parameters to simulate homeostatic trabecular bone remodeling, here named basal. Crucially, we also produced anabolic, anti-anabolic, catabolic and anti-catabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. Our results showed that changes in the levels of OPG and RANKL were positively and negatively correlated with the BV/TV values after 4 weeks in comparison to basal levels, respectively. Conversely, changes in Scl levels produced small fluctuations in BV/TV in comparison to the basal state. From these results, Scl was deemed to be the main driver of equilibrium while RANKL and OPG were shown to be involved in changes in bone volume fraction with potential relevance for age-related bone features. Ultimately, this micro-MPA model provides valuable insights into how cells respond to their local mechanical environment and can help to identify critical pathways affected by degenerative conditions and ageing.

Presently, total joint replacement (TJR) is a standard procedure in orthopedic surgery. Adequate osseointegration of the implant components still remains a clinical issue. However, active stimulation of bone tissue to enhance bone ongrowth at the implant surfaces has not been widely investigated so far. For the last several years, invasive electromagnetically induced osseotherapy has been employed in clinical practice, e.g., for the treatment of avascular necrosis, femoral neck fractures, and pseudarthrosis. In the present study, the approach of exploiting the electric stimulation effect was transferred to the field of TJR. Therefore, a commercially available total hip stem was instrumented with an electrode on its surface in order to generate an electric field supporting the regeneration of the surrounding bone tissue. The objective was to conduct numerical simulations validated by experimental investigations as a proof of concept for an instrumented electro-stimulative total hip stem. The results revealed that the calculated electric field around a total hip stem fulfills the requirements to stimulate adjacent bone tissue when using clinically applied electric voltages. The derived numerical and experimental data of electric potentials and corresponding electric fields are encouraging for the implementation of active electrical stimulation in uncemented total hip stems to enhance their osseointegration.

Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. In silico models have been of help to further understand the signaling pathways that regulate the spatial cellular interplay. We have established a 3D multiscale micro-multiphysics agent-based (micro-MPA)in silicomodel of trabecular bone remodeling using longitudinalin vivodata from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A)mice, a mouse model of premature aging. Our model includes a variety of cells as single agents and receptor-ligand kinetics, mechanotransduction, diffusion and decay of cytokines which regulate the cells' behavior. The micro-MPA model was applied for simulating trabecular bone remodeling in the CV6 of 5 mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. We identified a configuration of the model parameters to simulate a homeostatic trabecular bone remodeling. Additionally, our simulations showed different anabolic, anti-anabolic, catabolic and anticatabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. From these results, we concluded that OPG inhibits osteoclastic bone resorption by reducing the osteoclast recruitment, RANKL promotes bone resorption by enhancing the osteoclast recruitment and Scl blocks bone formation by inhibiting osteoblast differentiation. The variations in trabecular bone volume fraction and thickness (BV/TV and Tb.Th) were relatively higher with variations of one standard deviation in the levels of RANKL compared to OPG and Scl. This micro-MPA model will help us to better understand how cells respond to the mechanical signal by changing their activity in response to their local mechanical environment.