Abstract
Secondary bone fracture healing is a physiological process that leads to functional tissue regeneration via endochondral bone formation. In vivo studies have demonstrated that early mobilization and the application of mechanical loads enhances the process of fracture healing. However, the influence of specific mechanical stimuli and particular effects during specific phases of fracture healing remain to be elucidated. In this work, we have developed and provided proof-of-concept of an in vitro human organotypic model of physiological loading of a cartilage callus, based on a novel perfused compression bioreactor (PCB) system. We then used the fracture callus model to investigate the regulatory role of dynamic mechanical loading. Our findings provide a proof-of-principle that dynamic mechanical loading applied by the PCB can enhance the maturation process of mesenchymal stromal cells toward late hypertrophic chondrocytes and the mineralization of the deposited extracellular matrix. The PCB provides a promising tool to study fracture healing and for the in vitro assessment of alternative fracture treatments based on engineered tissue grafts or pharmaceutical compounds, allowing for the reduction of animal experiments.
Highlights
Bone fracture healing is a natural, physiological process leading to functional tissue regeneration through a highly orchestrated sequence (Gerstenfeld et al, 2003; Behonick et al, 2007; Marsell and Einhorn, 2011)
Our findings provide a proof-of-principle that dynamic mechanical loading applied by the perfused compression bioreactor (PCB) can enhance the maturation process of mesenchymal stromal cells toward late hypertrophic chondrocytes and the mineralization of the deposited extracellular matrix
A process recapitulating the process of endochondral bone formation, is divided into four main phases: hemorrhage and inflammation, soft callus formation, hard callus formation, and callus remodeling (Sfeir et al, 2005; Schindeler et al, 2008)
Summary
Bone fracture healing is a natural, physiological process leading to functional tissue regeneration through a highly orchestrated sequence (Gerstenfeld et al, 2003; Behonick et al, 2007; Marsell and Einhorn, 2011). A process recapitulating the process of endochondral bone formation, is divided into four main phases: hemorrhage and inflammation, soft callus formation, hard callus formation, and callus remodeling (Sfeir et al, 2005; Schindeler et al, 2008). Following initial hemorrhage and inflammation, a key step during secondary fracture healing is the formation of a soft fracture callus, consisting of cartilaginous extracellular matrix, chondrocytes, and fibroblasts. During the subsequent phase of hard callus formation, a mineralized cartilaginous template is gradually replaced with unordered woven bone matrix. The woven bone is fully remodeled toward cortical and/or trabecular bone in a spatially and temporally choreographed manner (Sfeir et al, 2005; Schindeler et al, 2008)
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