2.2. Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity during Fracture Healing

Smoking causes delayed union and/or nonunion of bone fractures. Unfortunately, orthopedic surgeons rarely delay surgery in patients who smoke nor do they suggest methods for patients to quit smoking. It is important to recommend smoking cessation methods such as transdermal patches, chewing gum, lozenges, inhalers, sprays, bupropion, and varenicline during the perioperative period. Smoking cessation in the perioperative period appears to be effective in reducing delayed union and nonunion rates of bone fractures, even if performed up to 4 weeks prior to the surgery [73].

Hao et al. published a study in which they exposed three murine strains (C57BL/6J, 129 × 1/SvJ, and BALB/cJ) to cigarette smoke for 3 months before performing a midshaft transverse femoral osteotomy. Using radiography, microcomputed tomography, and biomechanical tests, the authors evaluated fracture healing 4 weeks after the osteotomy. The radiographic study showed a significant decrease in the fracture healing capacity of 129 × 1/SvJ smoke-exposed mice. The microcomputed tomography results showed a delay in the remodeling of the fracture calluses in all three strains after exposure to cigarette smoke. The biomechanical tests showed a more significant deterioration of functional properties in the 129 × 1/SvJ mice than in the C57BL/6J and BALB/cJ mice after exposure to cigarette smoke. In other words, the 129 × 1/SvJ strain was the most suitable for simulating the smoke-induced deterioration of fracture healing. In the 129 × 1/SvJ mice, the authors investigated the molecular and cellular disorders of fracture healing caused by cigarette smoke using histology, flow cytometry, and multiplex cytokine/chemokine analysis. The histological analysis showed abnormal chondrogenesis due to cigarette smoke exposure. In addition, significant populations of repair cells, including skeletal stem cells and their subsequent progenitors, showed a decrease in post-injury expansion as a result of cigarette smoke exposure. Furthermore, the authors observed a significant increase in pro-inflammatory mediators and immune cell recruitment in fracture hematomas in the mice exposed to smoke. These results show the important cellular and molecular disorders that occur during fracture healing due to smoking, such as abnormal chondrogenesis, aberrant activity of skeletal stem and progenitor cells, and an intense initial inflammatory response [74]. Table 3 shows the main factors that induce and delay bone healing according to recent publications on the molecular mechanisms of bone healing.