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.
Highlights
Bone healing is a complex, well-coordinated process that starts autonomously when a bone fracture occurs
This review aims to provide the necessary information and tools to build in silico models, which can provide an additional perspective to study the critical role of the inflammatory phase in bone regeneration
ODEs often describe how spatialaverage biological entities change over time, simulating e.g. inflammatory responses (Kumar et al, 2004; Reynolds et al, 2006; Vodovotz et al, 2006; Trejo et al, 2019) or the bone healing process (Trejo et al, 2019; Lo et al, 2020) at tissue and cellular levels, and individual intracellular dynamics (Warrender et al, 2006; Peiffer et al, 2011) at subcellular level
Summary
Bone healing is a complex, well-coordinated process that starts autonomously when a bone fracture occurs. Alternative approaches to support the healing process, such as bone tissue engineering strategies, are still being tested in clinical trials or under development (Amini et al, 2012; Lammens et al, 2012; Papantoniou et al, 2021) These approaches mainly target the skeletal system and the repair phase of fracture healing, whereas recent findings have demonstrated that the skeletal and immune system are closely interacting through a carefully coordinated cross-talk between inflammatory and bone forming cells. This review aims to provide the necessary information and tools to build in silico models, which can provide an additional perspective to study the critical role of the inflammatory phase in bone regeneration
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