Fig. 4.

Stages of bone fracture healing. After a bone fracture, an inflammatory response occurs that lasts for two weeks. This phase starts an intricate network of proinflammatory signals and growth factors. Polymorphonucleate (PMN) cells and macrophages are recruited to endocyte microdebris and micro-organisms derived from the fracture. The damage to the blood vessels results in edema. After 2–3 weeks from the fracture, endocondral bone formation occurs. During this process, the MSCs are recruited in the injured site and begin to differentiate into chondroblasts (condrogenesis), which proliferate into chondrocytes, resulting in soft calluses. Chondrocytes synthesize and secrete the cartilage matrix, containing type II collagen and proteoglycans. Between the third and sixth week, the cartilage undergoes hypertrophy and mineralization in a spatially organized way. New MSCs are recruited which differentiate into osteoblasts, leading to the formation of interwoven bone (hard callus). Mineralized bone formation is induced by the signaling of factors such as BMP, TGF-β 2 and -β 3 in the cartilaginous callus. The last phase of bone remodeling begins 8 weeks after fracture and can last up to 2 years. Communication between osteoclasts and osteoblasts, during this phase, mediates the replacement of the braided bone with lamellar bone through two key activities: removal of the bone (resorption) by the resulting osteoclasts of the hematopoietic line and formation of the bone matrix by the mesenchymal line osteoblasts