Oxygen as a critical determinant of bone fracture healing—A multiscale model

Abstract

Highlights The influence of oxygen was incorporated in a multiscale model of fracture healing.  The results of the oxygen model were compared with experimental observations.  An extensive sensitivity analysis of the oxygen model indicated its robustness.  Adequate spatiotemporal oxygen patterns appear to be critical for bone healing. Keywordsoxygen -angiogenesis -fracture healing -multiscale model -non-union AbstractA timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the aerobic metabolism of cells, in the activity of a myriad of enzymes as well as in the regulation of several (angiogenic) genes. In this paper, a previously developed model of bone fracture healing is further improved with a detailed description of the influence of oxygen on various cellular processes that occur during bone fracture healing. Oxygen ranges of the cell-specific oxygen-dependent processes were established based on the state-of-the art experimental knowledge through a rigorous literature study. The newly developed oxygen model is compared with previously published experimental and in silico results. An extensive sensitivity analysis was also performed on the newly introduced oxygen thresholds, indicating the robustness of the oxygen model. Finally, the oxygen model was applied to the challenging clinical case of a critical sized defect (3 mm) where it predicted the formation of a fracture non-union. Further model analyses showed that the harsh hypoxic conditions in the central region of the callus resulted in cell death and disrupted bone healing thereby indicating the importance of a timely vascularization for the successful healing of a large bone defect. In conclusion, this work demonstrates that the oxygen model 3 is a powerful tool to further unravel the complex spatiotemporal interplay of oxygen delivery, diffusion and consumption with the several healing steps, each occurring at distinct, optimal oxygen tensions during the bone repair process.

Bone fracture healing in mechanobiological modeling: A review of principles and methods

“…During endochondral ossification in particular, the cartilaginous matrix is penetrated by a vascular network before transforming into osseous tissue (Einhorn, 1998). Several studies have demonstrated that deficient angiogenesis leads to healing impairment (Carlier et al, 2015b, Kanczler and Oreffo, 2008, Saran et al, 2014, Tomlinson and Silva, 2013). Moreover, angiogenesis is a key factor for bone remodeling, because it provides the appropriate conditions for osteoblastic and osteoclastic activities (Kanczler and Oreffo, 2008, Saran et al, 2014, Claes et al, 2002).…”

“…Moreover, angiogenesis is a key factor for bone remodeling, because it provides the appropriate conditions for osteoblastic and osteoclastic activities (Kanczler and Oreffo, 2008, Saran et al, 2014, Claes et al, 2002). The endothelial cell plays a critical role in cell migration and transformation, secretion of growth factors, cell signaling, and other biological processes (Carlier et al, 2015b, Hankenson et al, 2015, Mayr-wohlfart et al, 2002). …”

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

“…Normal Fracture Healing Initially, it was assumed that vessels could only grow into the callus from the periosteum of the cortical bone (Burke and Kelly, 2012;Burke et al, 2013;Geris et al, 2008;Chen et al, 2009;Carlier et al, 2015). 3 % of the lattice points on this edge contained active vessels.…”

Unravelling the Role of Mechanical Stimuli in Regulating Cell Fate During Osteochondral Defect Repair

“…As part of this study, our previous model of angiogenesis was updated to include a feature whereby blood vessels had to form a closed loop before they were considered active 32 . The benefit of this updated algorithm was that it made the model more physiologically relevant.…”

“…If two vessels crossed the same path, anastomosis occurred and the two vessels fused together. As an extension of our previous model, and similar to the method described by Carlier et al 32 , it was assumed that blood and nutrients could only flow through vessels which had formed a closed loop. Based on this, the ECs which made up a blood vessel were considered inactive until anastomosis had occurred.…”