COMMBINI: an experimentally-informed COmputational Model of Macrophage dynamics in the Bone INjury Immunoresponse

Edoardo Borgiani*, Gabriele Nasello, Liesbeth Ory, Tim Herpelinck, Lisanne Groeneveldt, Christian H. Bucher, Katharina Schmidt-Bleek, Liesbet Geris

*Corresponding author for this work

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Abstract

Bone fracture healing is a well-orchestrated but complex process that involves numerous regulations at different scales. This complexity becomes particularly evident during the inflammatory stage, as immune cells invade the healing region and trigger a cascade of signals to promote a favorable regenerative environment. Thus, the emergence of criticalities during this stage might hinder the rest of the process. Therefore, the investigation of the many interactions that regulate the inflammation has a primary importance on the exploration of the overall healing progression. In this context, an in silico model named COMMBINI (COmputational Model of Macrophage dynamics in the Bone INjury Immunoresponse) has been developed to investigate the mechano-biological interactions during the early inflammatory stage at the tissue, cellular and molecular levels. An agent-based model is employed to simulate the behavior of immune cells, inflammatory cytokines and fracture debris as well as their reciprocal multiscale biological interactions during the development of the early inflammation (up to 5 days post-injury). The strength of the computational approach is the capacity of the in silico model to simulate the overall healing process by taking into account the numerous hidden events that contribute to its success. To calibrate the model, we present an in silico immunofluorescence method that enables a direct comparison at the cellular level between the model output and experimental immunofluorescent images. The combination of sensitivity analysis and a Genetic Algorithm allows dynamic cooperation between these techniques, enabling faster identification of the most accurate parameter values, reducing the disparity between computer simulation and histological data. The sensitivity analysis showed a higher sensibility of the computer model to the macrophage recruitment ratio during the early inflammation and to proliferation in the late stage. Furthermore, the Genetic Algorithm highlighted an underestimation of macrophage proliferation by in vitro experiments. Further experiments were conducted using another externally fixated murine model, providing an independent validation dataset. The validated COMMBINI platform serves as a novel tool to deepen the understanding of the intricacies of the early bone regeneration phases. COMMBINI aims to contribute to designing novel treatment strategies in both the biological and mechanical domains.

Original languageEnglish
Article number1231329
JournalFrontiers in Immunology
Volume14
DOIs
Publication statusPublished - 8 Nov 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 Borgiani, Nasello, Ory, Herpelinck, Groeneveldt, Bucher, Schmidt-Bleek and Geris.

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