Agent-based modelling of late-stage mechanical loading of femur defects in prematurely ageing PolgA mice
- 1Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
Abstract
Mechanical loading applied to a bone defect after bridging relies on mechanosensitive osteocytes to orchestrate the structural adaptation of the callus. The load-adaptive capacity is typically compromised in the aged skeleton due to cellular senescence. However, bridged osteotomies in aged mice exhibit a robust remodelling response to mechanical stimulation, pointing towards a regaining of mechanosensitivity. We hypothesised that the regaining of mechanosensitivity in the remodelling phase is driven either by mechanical compensation via a reduced callus volume or by the functional rejuvenation of the embedded osteocyte (OCY) population. To test this hypothesis, we developed a micro-Multiphysics Agent-based (micro-MPA) model of the remodelling phase during bone regeneration. We employed a hierarchical grid-search to calibrate the model based on bone volume fraction using weekly time-lapsed micro-computed tomography (micro-CT) data from femoral osteotomies in prematurely ageing female PolgA mice. A 15-week-old (young) group was used to identify the mechanical boundary conditions for habitual (control) and for additional late-stage cyclic mechanical loading (loading). These boundary conditions were then applied to 38-week-old (aged) PolgA mice where the callus was seeded either with osteocytes exhibiting age-associated functional decline (degenerated) or rejuvenated osteocytes. The simulation outcomes were compared to the in vivo reference data (at 42 weeks of age) via root mean square error (RMSE). The degenerated OCY simulation resulted in a moderate fit for the aged loading group (RMSE = 13.5%), whereas the rejuvenated OCY simulation yielded higher predictive accuracy (RMSE = 5.9%). These results suggest that while native bone in the aged mice displayed attenuated adaptive responses, callus tissue with rejuvenated osteocyte populations maintained robust remodelling comparable to the young mice. These in silico results suggest that the regenerative potential of new tissue is modulated by the functional age of its embedded osteocytes rather than the systemic environment, thereby contributing to a better understanding of the regenerative capacity of the aged skeleton.
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BibTeX
@article{kendall2026agentbased,
title = {{Agent-based modelling of late-stage mechanical loading of femur defects in prematurely ageing PolgA mice}},
author = {Jack J. Kendall and Charles Ledoux and Francisco C. Marques and Gisela A. Kuhn and Friederike A. Schulte and Ralph Müller},
journal = {Frontiers in Bioengineering and Biotechnology},
year = {2026},
month = oct,
doi = {10.3389/fbioe.2026.1879777},
url = {https://doi.org/10.3389/fbioe.2026.1879777},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Agent-based modelling of late-stage mechanical loading of femur defects in prematurely ageing PolgA mice
AU - Jack J. Kendall
AU - Charles Ledoux
AU - Francisco C. Marques
AU - Gisela A. Kuhn
AU - Friederike A. Schulte
AU - Ralph Müller
PY - 2026
DA - 2026/10/21
JO - Frontiers in Bioengineering and Biotechnology
DO - 10.3389/fbioe.2026.1879777
UR - https://doi.org/10.3389/fbioe.2026.1879777
AB - Mechanical loading applied to a bone defect after bridging relies on mechanosensitive osteocytes to orchestrate the structural adaptation of the callus. The load-adaptive capacity is typically compromised in the aged skeleton due to cellular senescence. However, bridged osteotomies in aged mice exhibit a robust remodelling response to mechanical stimulation, pointing towards a regaining of mechanosensitivity. We hypothesised that the regaining of mechanosensitivity in the remodelling phase is driven either by mechanical compensation via a reduced callus volume or by the functional rejuvenation of the embedded osteocyte (OCY) population. To test this hypothesis, we developed a micro-Multiphysics Agent-based (micro-MPA) model of the remodelling phase during bone regeneration. We employed a hierarchical grid-search to calibrate the model based on bone volume fraction using weekly time-lapsed micro-computed tomography (micro-CT) data from femoral osteotomies in prematurely ageing female PolgA mice. A 15-week-old (young) group was used to identify the mechanical boundary conditions for habitual (control) and for additional late-stage cyclic mechanical loading (loading). These boundary conditions were then applied to 38-week-old (aged) PolgA mice where the callus was seeded either with osteocytes exhibiting age-associated functional decline (degenerated) or rejuvenated osteocytes. The simulation outcomes were compared to the in vivo reference data (at 42 weeks of age) via root mean square error (RMSE). The degenerated OCY simulation resulted in a moderate fit for the aged loading group (RMSE = 13.5%), whereas the rejuvenated OCY simulation yielded higher predictive accuracy (RMSE = 5.9%). These results suggest that while native bone in the aged mice displayed attenuated adaptive responses, callus tissue with rejuvenated osteocyte populations maintained robust remodelling comparable to the young mice. These in silico results suggest that the regenerative potential of new tissue is modulated by the functional age of its embedded osteocytes rather than the systemic environment, thereby contributing to a better understanding of the regenerative capacity of the aged skeleton.
SN - 2296-4185
ER -