In silico mechano-chemical model of bone healing for the regeneration of critical defects: The effect of BMP-2

The healing of bone defects is a challenge for both tissue engineering and modern ortho- paedics. This problem has been addressed through the study of scaffold constructs com- bined with mechanoregulatory theories, disregarding the influence of chemical factors and their respective delivery devices. Of the chemical factors involved in the bone healing pro- cess, bone morphogenetic protein-2 (BMP-2) has been identified as one of the most power- ful osteoinductive proteins. The aim of this work is to develop and validate a mechano- chemical regulatory model to study the effect of BMP-2 on the healing of large bone defects in silico. We first collected a range of quantitative experimental data from the literature con- cerning the effects of BMP-2 on cellular activity, specifically proliferation, migration, differen- tiation, maturation and extracellular matrix production. These data were then used to define a model governed by mechano-chemical stimuli to simulate the healing of large bone de- fects under the following conditions: natural healing, an empty hydrogel implanted in the de- fect and a hydrogel soaked with BMP-2 implanted in the defect. For the latter condition, successful defect healing was predicted, in agreement with previous in vivo experiments. Further in vivo comparisons showed the potential of the model, which accurately predicted bone tissue formation during healing, bone tissue distribution across the defect and the quantity of bone inside the defect. The proposed mechano-chemical model also estimated the effect of BMP-2 on cells and the evolution of healing in large bone defects. This novel in silico tool provides valuable insight for bone tissue regeneration strategies

Computational model of mesenchymal migration in 3D under chemotaxis

Cell chemotaxis is an important characteristic of cellular migration, which takes part in crucial aspects of life and development. In this work, we propose a novel in silico model of mesenchymal 3D migration with competing protrusions under a chemotactic gradient. Based on recent experimental observations, we identify three main stages that can regulate mesenchymal chemotaxis: chemosensing, dendritic protrusion dynamics and cell–matrix interactions. Therefore, each of these features is considered as a different module of the main regulatory computational algorithm. The numerical model was particularized for the case of fibroblast chemotaxis under a PDGF-bb gradient. Fibroblasts migration was simulated embedded in two different 3D matrices – collagen and fibrin – and under several PDGF-bb concentrations. Validation of the model results was provided through qualitative and quantitative comparison with in vitro studies. Our numerical predictions of cell trajectories and speeds were within the measured in vitro ranges in both collagen and fibrin matrices. Although in fibrin, the migration speed of fibroblasts is very low, because fibrin is a stiffer and more entangling matrix. Testing PDGF-bb concentrations, we noticed that an increment of this factor produces a speed increment. At 1 ng mL-1 a speed peak is reached after which the migration speed diminishes again. Moreover, we observed that fibrin exerts a dampening behavior on migration, significantly affecting the migration efficiency