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  •  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
      • the periosteum and endosteum are the two major sources
  • Fracture stability dictates the type of healing that will occur
    • the 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
        • occurs via Haversian remodeling
      • occurs with absolute stability constructs
    • secondary bone healing (strain is between 2%-10%)
      • involves responses in the periosteum and external soft tissues. 
        • enchondral healing
          • occurs with non-rigid fixation, as fracture braces, external fixation, bridge plating, intramedullary nailing, etc. 
    • 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: enchondral ossification
External fixation Secondary: enchondral ossification
IM nailing Secondary: enchondral ossification
Compression plate Primary: Haversian remodeling
Secondary Bone Healing

Stages of Fracture Healing
  • Hematoma forms and provides source of hemopoieitic 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 enchondral/intramembranous ossification
  • 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
  • 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
  • Enchondral 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)
    • enchondral healing with periosteal bridging occurs with closed treatment
  • 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 BMPs, 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
    • piezoelectic 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 
        • this peaks at 2 weeks and normalizes at 3-5 months
      • un-reamed nails maintain the endosteal blood supply
        • reaming compromises of the inner 50-80% of the cortex
        • looser fitting nails allow more quick reperfusion of the endosteal blood supply versus canal filling nails 
    • 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)
        • increased risk of nonunion likely secondary to compromise of the blood supply to the intercalary segement
  • External variables
    • Low Intensity Pulsed Ultrasound (LIPUS)
      • exact mechanism for enhancement of fracture healing is not clear
        • alteration of protein expression
        • elevation of vascularity
        • development of mechanical strain gradient
      • accelerates fracture healing and increases mechanical strength of callus (including torque and stiffness) 
        • the beneficial ultrasound signal is 30 mW/cm2 pulsed-wave   
      • healing rates for delayed unions/nonunions has been reported to be close to 80%
    • bone stimulators
      • four main delivery modes of electrical stimulation
        • direct current
          • decrease osteoclast activity and increase osteoblast activity by reducing oxygen concentration and increasing local tissue pH 
        • capacitively coupled electrical fields (alternating current, AC)
          • affect synthesis of cAMP, collagen and calcification of carilage
        • pulsed electromagnetic fields
          • cause calcification of fibrocartilage
        • combined magnetic fields
      • 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
        • vitamin D and calcium
        • as high as 84% of patients with nonunion were found to have metabolic issues
          • greater than 66% of these patients had vitamin D deficiencies
      • in a rat fracture model 
        • protein malnourishment decreases fracture callus strength
        • amino acid supplementation increases muscle protein content and fracture callus mineralization
      • gastric bypass patients
        • calcium absorption is affected because of duodenal bypass with Roux-en-Y procedure
          • leads to decreased Ca/Vit D levels, hyperparathyroidism (secondary) & increased Ca resportion from bone
        • treat these patients with Ca/Vit D supplementation 
        • gastric banding does not lead to these abnormalities because the duodenum is not bypassed
    • diabetes mellitus
      • affects the repair and remodeling of bone
        • decreased cellularity of the fracture callus
        • delayed enchondral ossification 
        • diminished strength of the fracture callus
      • 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
        • anti-retroviral medication
        • poor intraosseous circulation
        • TNF-Alpha deficiency
        • poor nutritional intake
    • medications affecting healing
      • bisphosphonates are recognized as a cause of osteoporotic fractures with long term usage
        • recent studies demonstrated longer healing times for surgically treated wrist fractures in patients on bisphosphonates
        • long term usage may be associated with atypical subtrochanteric/femoral shaft fractures
      • systemic corticosteroids 
        • studies have shown a 6.5% higher rate of intertrochanteric fracture non unions 
      • NSAIDs
        • prolonged healing time becaue of COX enzyme inhbition
      • quinolones
        • toxic to chondrocytes and diminishes fracture repair

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