Introduction Fracture healing involves a complex and sequential set of events to restore injured bone to pre-fracture condition stem cells are crucial to the fracture repair process periosteum and endosteum are the two major sources Fracture stability dictates the type of healing that will occur mechanical stability governs the mechanical strain when the strain is below 2%, primary bone healing will occur when the strain is between 2% and 10%, secondary bone healing will occur Modes of bone healing primary bone healing (strain is < 2%) intramembranous healing login to view 1 more bullet occurs with absolute stability constructs secondary bone healing (strain is between 2%-10%) involves responses in the periosteum and external soft tissues. login to view 2 more bullets bone healing may occur as a combination of the above two process depending on the stability throughout the construct Type of Fracture Healing with Treatment Technique Cast treatment Secondary: endochondral ossification External fixation Secondary: endochondral ossification IM nailing Secondary: endochondral ossification Compression plate Primary: Haversian remodeling Secondary Bone Healing Stages of Fracture Healing Inflammation Hematoma forms and provides a source of hematopoietic cells capable of secreting growth factors. Macrophages, neutrophils, and platelets release several cytokines this includes PDGF, TNF-Alpha, TGF-Beta, IL-1,6, 10,12 they may be detected as early as 24 hours post-injury lack of TNF-Alpha (ie. HIV) results in delay of both endochondral/ intramembranous ossification BMPs, fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around fracture ends During fracture healing granulation tissue tolerates the greatest strain before failure Osteoblasts and fibroblasts proliferate Inhibition of COX-2 (ie NSAIDs) causes repression of runx-2/osterix, which are critical for differentiation of osteoblastic cells Repair Primary callus forms within two weeks. If the bone ends are not touching, then bridging soft callus forms. The mechanical environment drives differentiation of either osteoblastic (stable enviroment) or chondryocytic (unstable environment) lineages of cells Endochondral ossification converts soft callus to hard callus (woven bone). Medullary callus also supplements the bridging soft callus Cytokines drive chondocytic differentiation. Cartilage production provides provisional stabilization Type II collagen (cartilage) is produced early in fracture healing and then followed by type I collagen (bone) expression Amount of callus is inversely proportional to extent of immobilization Primary cortical healing occurs with rigid immobilization (ie. compression plating) Endochondral healing with periosteal bridging occurs with closed treatment Remodeling Begins in middle of repair phase and continues long after clinical union Chondrocytes undergo terminal differentiation Complex interplay of signaling pathways including, indian hedgehog (Ihh), parathyroid hormone-related peptide (PTHrP), FGF and BMP These molecules are also involved in terminal differentiation of the appendicular skeleton Type X collagen types is expressed by hypertrophic chondrocytes as the extraarticular matrix undergoes calcification Proteases degrade the extracellular matrix Cartilaginous calcification takes place at the junction between the maturing chondrocytes and newly forming bone Multiple factors are expressed as bone is formed including TGF-Betas, IGFs, osteocalcin, collagen I, V and XI Subsequently, chondrocytes become apoptotic and VEGF production leads to new vessel invasion Newly formed bone (woven bone) is remodeling via organized osteoblastic/osteoclastic activity Shaped through Wolff's law: bone remodels in response to mechanical stress Piezoelectric charges: bone remodels is response to electric charges: compression side is electronegative and stimulates osteoblast formation, tension side is electropostive and simulates osteoclasts Variables that Influence Fracture Healing Internal variables blood supply (most important) initially the blood flow decreases with vascular disruption after few hours to days, the blood flow increases login to view 1 more bullet un-reamed nails maintain the endosteal blood supply login to view 2 more bullets head injury may increase osteogenic response mechanical factors bony soft tissue attachments mechanical stability/strain location of injury degree of bone loss pattern (segmental or fractures with butterfly fragments) login to view 1 more bullet External variables Low Intensity Pulsed Ultrasound (LIPUS) exact mechanism for enhancement of fracture healing is not clear login to view 3 more bullets accelerates fracture healing and increases mechanical strength of callus (including torque and stiffness) login to view 1 more bullet healing rates for delayed unions/nonunions has been reported to be close to 80% bone stimulators four main delivery modes of electrical stimulation login to view 7 more bullets they lead to elevated concentrations of TGF-Beta and BMP COX-2 promotes fracture healing by causing mesenchymal stem cells to differentiate into osteoblasts radiation (high dose) long term changes within the remodeling systems cellularity is diminished Patient factors diet nutritional deficiencies login to view 3 more bullets in a rat fracture model login to view 2 more bullets gastric bypass patients login to view 4 more bullets diabetes mellitus affects the repair and remodeling of bone login to view 3 more bullets fracture healing takes 1.6 times longer in diabetic patients versus non-diabetic patients nicotine decreases rate of fracture healing inhibits growth of new blood vessels as bone is remodeled increase risk of nonunion (increases risk of pseudoarthrosis in spine fusion by 500%) decreased strength of fracture callus smokers can take ~70% longer to heal open tibial shaft fractures versus non-smokers HIV higher prevalence of fragility fractures with associated delayed healing contributing factors login to view 4 more bullets medications affecting healing bisphosphonates are recognized as a cause of osteoporotic fractures with long term usage login to view 2 more bullets systemic corticosteroids login to view 1 more bullet NSAIDs login to view 1 more bullet quinolones login to view 1 more bullet