Inflammation plays important roles in the early steps of fracture healing including, the recruitment, expansion, growth and differentiation of mesenchymal stem cells (MSCs), the coordinated interplay of many other cell types, growth factors, and extracellular matrix (ECM) components, as well as the production of cartilage and bone matrix in a temporally controlled manner. There are three stages of fracture healing: the reactive stage, the reparative stage, and the remodelling stage. After a bone fracture, the reparative process initiates from a hematoma and inflammatory reaction at the fracture site. In the inflammatory phase, the shortage of peripheral vasculature causes an anoxic environment that leads to the formation of a cartilaginous template, which initiates the differentiation process that restores endochondral (EC) ossification.
The proliferation and differentiation of bone marrow stem cells (BMSCs) into chondrocytes and osteoblasts is a critical component of this phase of fracture healing. In the reparative phase, chondrocytes facilitate ECM deposition at the fracture site, which forms a transient soft callus. During the initial stage of remodelling, the callus of the femoral head is transformed into vascularized and mineralized tissue, allowing the initial stages of osteoclast resorption to commence. Later, during bone remodelling, skeletal elements heal into the appropriate shapes. The importance of invading vascular EC during bone formation has been established, and defective bone vasculature was reported in osteoporosis and rickets patients. Therefore, vascular endothelial growth factor (VEGF) expression in bone repair and neovascularization is driven with the support of nutrition, oxygen transport and tissue oxygenation, which are required for the differentiation of osteoblasts