Bone fractures are common non-lethal consequences of injuries related to vehicle and sports accidents, falls or trauma and their incidence is doomed to rise with the increase in life expectancy. Long bone fractures are notorious for being slow to heal, often requiring months until the consolidation is completed [1, 2]. Fracture healing is a complex dynamic process characterized by the balance of mechanical and physiological stimuli: the biological environment is influenced by the fixation technique used to stabilize the fracture that will determine the outcome of the healing process [3]. The biological course of bone fracture healing is characterized by different steps, represented in Figure 1.

The bone fracture healing process. (A) Long bone fracture. (B) Hematoma formation around the fracture site. (C) Soft callus formation. (D) Hard callus formation. (E) Bone remodeling phase.

The first, immediate response to fracture is the formation of a hematoma, as the result of blood vessels disruption and bone marrow effusion upon the bone injury. As soon as the hematoma forms, the inflammatory cells reach the fracture site. The acute inflammatory response is the first crucial step in the fracture healing process, activating the upregulation of angiogenic factors, thus supporting the vascularization of the injured site. Just 24 hours after the injury, the pro-inflammatory response is counterbalanced by the release of anti-inflammatory cytokines involved in the recruitment of cells enrolled in the healing of the injured tissue [4]. If the acute inflammatory response remains unresolved (e.g. due to a bacterial infection at the injury site or to chronic inflammatory diseases), the healing of the fracture can be inhibited or, even worst, it may fail [5].

The second stage of the fracture healing process is characterized by the progressive evolution of the hematoma into granulation tissue, followed by the gradual replacement of the latter one in a soft callus composed of fibrous tissue and cartilage. This anabolic phase is characterized by an increase in tissue volume due to the de novo recruitment of mesenchymal progenitor cells [6]. Subsequently, these cells differentiate into osteoblasts or chondrocytes producing the extracellular matrix and cartilage, while slowly replacing the hematoma and filling the fracture gap [4]. Even if the soft callus formation confers to fractures an initial stability, the bone healing process is not completed yet.

Progressively, the soft callus is replaced through a process known as endochondral ossification, becoming more robust and mechanically rigid: the cartilaginous callus undergoes to mineralization, resorption and it is finally replaced by woven bone [7]. Once the fracture site is restored, the woven bone is then slowly substituted by lamellar bone, concluding the process with the last stage: the remodeling phase. The remodeling process is carried out by the balance of hard callus resorption by osteoclasts and lamellar bone deposition by osteoblasts [7]. This phase finally concludes the process by restoring the mechanical and biological function of the bone.


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