A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

Abstract

While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by the local oxygen tension and substrate stiffness. This was updated to include conditions for oxygen regu- lated cell death and endochondral ossification. The updated algorithm was validated by using it within a model of normal fracture healing where it predicted the experimentally observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post fracture (dpf). Furthermore, it also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment the model predicted the experimentally observed reduction in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe angiogenic impairment predicted the development of fibrous and necrotic tissue within the callus. These results provide insight into how environmental factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that endochondral ossification during fracture healing is governed by the local oxygen tension.

Stimulating Fracture Healing in Ischemic Environments: Does Oxygen Direct Stem Cell Fate during Fracture Healing?

“…Chronic hypoxia delayed healing. This has been observed previously (Heppenstall et al, 1976), and is also predicted using computer modeling approaches (OReilly et al, 2016). We did not observe a change in differentiation of osteoblasts and chondrocytes in response to altered oxygen levels.…”

“…Similarly, delivery of TSP2 decreases vascularity and decreases the ratio of bone to cartilage during fracture healing (Taylor et al, 2009; Burke et al, 2013). In silico modeling studies have also suggested that mechanical stress combined with oxygen levels act together to regulate osteoblast and chondrocyte differentiation (Carlier et al, 2015; OReilly et al, 2016). The reasons for these discrepancies are unknown, but warrant further study.…”

Multiscale Modeling of Bone Healing: Toward a Systems Biology Approach

“…Several computer models have used agent-based approaches to simulate the behavior of individual cells and to investigate their contribution to tissue patterning over the course of healing (Byrne et al, 2011; Checa et al, 2011; Carlier et al, 2012; Borgiani et al, 2015; O'Reilly et al, 2016). Using this approach, Checa et al (2011) and Borgiani et al (2015) showed that differences in the healing pattern (e.g., endosteal, periosteal, time to bringing) of different species (sheep, rat, and mice) can be explained by differences in the regulation of cellular activity by mechanical signals during the course of healing.…”

“…Several computational studies have been developed to investigate the relative role of revascularization on bone healing progression (Geris et al, 2008; Chen et al, 2009; Peiffer et al, 2011; Simon et al, 2011; Burke and Kelly, 2012; O'Reilly et al, 2016). These models have seen a clear evolution toward a multiscale approach with the aim to better reflect and understand the biology of the process.…”

“…These models have seen a clear evolution toward a multiscale approach with the aim to better reflect and understand the biology of the process. While early models simulated vascular growth as a simple diffusion process (Geris et al, 2008; Chen et al, 2009; Burke and Kelly, 2012), more recent models use a discrete approach in order to simulate the complex structure of the newly formed capillary network (Carlier et al, 2015; O'Reilly et al, 2016). …”