Bone regulation plays a major role in several bone-related diseases (e.g. osteoporosis) and conditions (e.g. broken bone). Understanding how to improve such scenarios requires increased understanding of bone components including osteocytes, important bone cells that, when sensing force or stress, send out signals that make other cells create or destroy bone. Despite experimental evidence that osteocytes do significantly affect bone regulation, early observations revealed that the stress on the osteocyte needed to initiate bone regulating activities was much greater than the stress bones experience during daily activities. For osteocytes’ bone regulating abilities to be triggered, it appears force must somehow be amplified as it is transferred through the bone down into the microscale regions in and near the osteocytes. While various reasonable explanations for how such force amplification can arise have been suggested, a consensus has not been reached primarily because the complexity of bone has made it difficult to consider all possible factors in any single existing study. Addressing this issue, this study will develop an integrative model to combine multiple components of the osteocyte and its surrounding environment across multiple scales to better understand how everyday forces can be amplified as they travel to the osteocyte. The model will be used to identify which components of the cell are most likely responsible for sensing force. The model can also be used in future studies to consider how to improve force sensing and resulting bone regulation in individuals with osteoporosis, osteoarthritis, leukemia, broken bones, and other bone-related conditions.
The goal of this project is to better understand how osteocytes sense forces in vivo (mechanosensation) and how the osteocyte and its microenvironment amplifies stress and strain to levels detectable by osteocytes in vivo by computational modeling and laboratory experiments. This goal will be achieved by introducing a multiscale 3D computational model for the osteocyte-fluid lacuna-canaliculi system and the encasing bone matrix under mechanical loading. The integrative model comprises three parts: a cross-linked viscoelastic fiber-network based “cytosolid model†for force-bearing components in the cell; a lattice-Boltzmann-equation based “fluid model†(intracellular and extracellular) for the remaining cellular and interstitial substances; and a continuum “poroelastic model†for the bone matrix. These three submodels will be integrated through the mutual fluid-structure-interaction (FSI) using the immersed boundary (IB) framework. Model parameters will be obtained from both existing data in literature and collaborators’ in vitro experiments. The three submodels will be verified prior to assembly by separate experimental data and the integrated model will be validated using the ex-vivo experiments. Predictions of the integrated computational model on large-scale CPU-GPU computer clusters will be used to characterize the stress and strain fields, and investigate the stress and strain magnification mechanism, generate new insights into osteocyte mechanosensation and stress/strain amplification, and introduce novel experimental designs to study how disease-related changes may regulate osteocyte mechanotransduction.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
