Towards in silico Models of the Inflammatory Response in Bone Fracture Healing

Abstract

In silico modeling is a powerful strategy to investigate the biological events occurring at tissue, cellular and subcellular level during bone fracture healing. However, most current models do not consider the impact of the inflammatory response on the later stages of bone repair. Indeed, as initiator of the healing process, this early phase can alter the regenerative outcome: if the inflammatory response is too strongly down- or upregulated, the fracture can result in a non-union. This review covers the fundamental information on fracture healing, in silico modeling and experimental validation. It starts with a description of the biology of fracture healing, paying particular attention to the inflammatory phase and its cellular and subcellular components. We then discuss the current state-of-the-art regarding in silico models of the immune response in different tissues as well as the bone regeneration process at the later stages of fracture healing. Combining the aforementioned biological and computational state-of-the-art, continuous, discrete and hybrid modeling technologies are discussed in light of their suitability to capture adequately the multiscale course of the inflammatory phase and its overall role in the healing outcome. Both in the establishment of models as in their validation step, experimental data is required. Hence, this review provides an overview of the different in vitro and in vivo set-ups that can be used to quantify cell- and tissue-scale properties and provide necessary input for model credibility assessment. In conclusion, this review aims to provide hands-on guidance for scientists interested in building in silico models as an additional tool to investigate the critical role of the inflammatory phase in bone regeneration.

Temporal dynamics of immune-stromal cell interactions in fracture healing

“…Only recently has computational modeling of fracture healing incorporated intrinsic and extrinsic effects of the immune system, to ascertain their influence on mechanical and biological properties of the callus ( 133 , 134 ). Computational models are a powerful complementary tool for guiding hypotheses when integrated with in vivo and in vitro experiments.…”

“…State-of-the-art in silico models encompass continuous, discrete, or hybrid models to interrogate the complex spatiotemporal aspects of fracture healing. No model can holistically capture these processes; however, a corpus of literature is available that aims to help researchers build their own in silico models to study the spatiotemporal effects of the immune response on fracture repair ( 133 ). Continuous models function at the tissue and cellular level; these models use partial differential equations to create a continuous overview of a given scenario to study inflammation, bone mechanics, and bone repair.…”

Strategies of Macrophages to Maintain Bone Homeostasis and Promote Bone Repair: A Narrative Review

“…Mice with defective macrophages had reduced numbers of mesenchymal progenitor cells, and the ability of these mesenchymal progenitor cells to differentiate into osteoblasts was decreased further [ 151 ]. Macrophages have been shown to be required for osteoblast mineralization of the bone matrix, and macrophage-dependent osteoblast differentiation has been shown to be dependent on BMP-2 and TGF-β signaling [ 152 , 153 ]. Macrophages also promote the synthetic effects of parathyroid hormone (PTH), a key regulatory hormone of bone homeostasis, in bone tissue [ 154 , 155 ].…”

Dual drug delivery platforms for bone tissue engineering

“… Phases of bone healing in the subcellular, cellular and tissue level (Reproduced with permission from Ref ( Lafuente-Gracia et al, 2021 ) under Creative Commons Attribution License (CC BY)). …”