After Bone Fracture

After bone fracture, many chemical and biological processes are triggered in the bone. After fracture, a cascade of signaling biomolecules and cellular changes induces bone healing simultaneously and sequentially. Generally, the bone healing process comprises four consecutive steps, that is, inflammation (reactive phase), fibrocartilage callus formation (reparative phase), bony callus formation (reparative phase), and remodeling phase [31]. In the inflammatory phase, damage of vasculature results in the recruitment of inflammatory cells (e.g., monocytes, lymphocytes, platelets, macrophages, neutrophils). Prostaglandin mediation then induces fibroblast infiltration and, finally, many bioactive molecules are synthesized at the defect site. These
At this stage, TGF-β, FGF-I, II, BMP-2, BMP-4, BMP-7, PDGF, IL-1, IL-6, angiopontin I, II, VEGF, osteonectin, fibronectin and collagens (II, III, IV, V, VI, IX, X) play a major role. Vascular ingrowth occurs simultaneously with collagen matrix formation, and consequently osteoid secretion and mineralization occur. These processes result in new soft callus formation around the defect site (bony callus formation stage) [31-33]. In addition to the aforementioned biomolecules at the late stage, RANKL and macrophage colony-stimulating factor (M-CSF) are two other important factors that are involved at this stage. Eventually, at the last stage, the replacement of woven bone and cartilage of the fracture callus with trabecular bone leads to restoration of the original strength of the bone. Remodeling of the initial bone callus formed during primary bone formation is followed by secondary bone formation and resorption, in order to re-establish the anatomical shape and mechanical support. At this stage, IL-1, IL-6, RANK1, and M-CSF are the key factors for bone remodeling [32,
Physical entrapment of bioactive molecules in biomaterials is the most commonly used strategy. To date, different delivery vehicles, including polymeric microparticles, liposomes, hydrogels, foams, and bone cements, have been used for physically entrapping bone growth factors [35]. In the physical entrapment strategy, diffusion and scaffold degradation are the two possible mechanisms for fast release of GFs. Otherwise, the affinity of biomolecules to biomaterials could induce sustained release of bioactive molecules [7]. Dispersion of biomolecules in different biomaterials has also been used for coating the surfaces of implants [35]. For instance, titanium implants have been coated with poly(D,L-lactide), in order to control the release rate of embedded TGF-β1 and IGF-1 [36]. Besides physical entrapment, adsorption and physisorption are the other mechanisms of protein delivery. For instance, the common method for fabricating a BMP delivery vehicle is impregnation of absorbable collagen sponge with BMP solution [37]. Alternatively, the bioactive molecule could be localized in the scaffold using covalent binding. Moreover, a delivery system that is regulated by an internal stimulus can be designed to control the release rate of biomolecules. Commonly, an appropriate delivery system in tissue engineering applications should