Fracture healing

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Fracture healing

  1. 1. FACTORS AFFECTING FRACTURE HEALING Presented by:-Dr.Sudheer kumar Moderator :-PROF.Dr.krishna reddy MS
  2. 2.  I. SYSTEMIC FACTORS OR PATIENT VARIABLES  II.LOCAL FACTORS OR TISSUE VARIABLES a.Factors independent of injury, treatment, or complications b. Factors dependent of injury or injury variables  III. Factors depending on treatment or treatment variables  IV. Factors associated with complications
  3. 3.  I. A. B. C. D. Systemic factors or patient variables Age Activity level including 1. Immobilization Nutritional status 1. Sufficient carbohydrates and protein 2. Anaemia 3. Vitamin deficiencies: C, D, K Hormonal factors 1. Growth hormone 2. Corticosteroids 3. Others (thyroid, oestrogen, androgen, calcitonin, parathyroid hormone, prostaglandins)
  4. 4.  E. Diseases: Diabetes, neuropathies, Tabesdorsalis, PVD, malignancies, immunocomprised states(hiv& aids) F. Drugs: NSAIDs, Steroids, statins,anticoagulants, Antibiotics like Fluroquinolones G. Smoking & alcohol abuse H. Hyperoxia I. Systemic growth factors J. Central nervous system trauma
  5. 5. Changes in fracture healing caused by diabetes Changes at the tissue level Reduced bone formation Reduced cartilage formation Accelerated loss of cartilage Reduced vascularity and reduced angiogenesis Changes at the molecular level Reduced expression of growth factors Reduced expression of matrix proteins Increased expression of proinflammatory genes Increased expression of pro-osteoclastogenic factors Increased expression of proapoptotic genes
  6. 6. II. Local factors A. or tissue variables Factors independent of injury, treatment, or complications 1. Type of bone cortical or cancellous 2. Abnormal bone a. Radiation necrosis b. Infection c. Tumours and other pathological conditions 3. Denervation
  7. 7. B. Factors depending on injury or injury variables 1. Degree of local damage a. Compound fracture b. Comminution of fracture c. segmental fractures d. Velocity of injury 2. 3. 4. 5. 6. 7. Extent of disruption of vascular supply to bone, its fragments (macro vascular osteonecrosis), or soft tissues; Type and location of fracture (one or two bones, e.g., tibia and fibula or tibia alone Loss of bone Soft-tissue interposition Local growth factors Intra articular fractures
  8. 8. C. 1. 2. 3. Factors depending on treatment or treatment variables Extent of surgical trauma (blood supply, heat) Implant-induced altered blood flow Degree and kind of rigidity of internal or external fixation and the influence of timing 4. Degree, duration, and direction of loadinduced deformation of bone and soft tissues 5. Apposition of fracture fragments (gap, displacement, over distraction 6. Factors stimulating posttraumatic osteogenesis (bone grafts, bone morphogenetic protein, electrical stimulation, surgical technique, intermittent venous stasis .
  9. 9.  D. Factors associated with complications 1. Infection 2. Venous stasis 3. Metal allergy
  10. 10. LOCAL REGULATION OF BONE HEALING      Growth factors Transforming growth factor Bone morphogenetic proteins Fibroblast growth factors Platelet-derived growth factors Insulin-like growth factors Cytokines Interleukin-1,-4,-6,-11, macrophage and granulocyte/macrophage (GM) colony-stimulating factors (CSFs) and Tumor Necrosis Factor Prostaglandins/ Leukotrienes Hormones Growth factor antagonists
  11. 11. SPECIFIC FACTOR STIMULATION OF OSTEOBLASTS AND OSTEOCLASTS Cytokine IL-1 TNF-α TNF-β TGF-α TGF-β PDGF IGF-1 IGF-2 FGF Bone Formation + + + -++ ++ +++ +++ +++ Bone Resorption +++ +++ +++ +++ ++ ++ 0 0 0
  12. 12. TIMING AND FUNCTION OF GROWTH FACTORS
  13. 13. TRANSFORMING GROWTH FACTOR  Super-family of growth factors (~34 members)  Acts on serine/ threonine kinase cell wall receptors  Promotes proliferation and differentiation of mesenchymal precursors for osteoblasts, osteoclasts and chondrocytes  Stimulates both enchondral and intramembranous bone formation   Induces synthesis of cartilage-specific proteoglycans and type II collagen Stimulates collagen synthesis by osteoblasts
  14. 14. BONE MORPHOGENETIC PROTEINS  These  are included in the TGF-β family Except BMP-1  Sixteen different BMP’s have been identified  BMP2-7,9 are Osteoinductive  BMP2,6, & 9 may be the most potent in osteoblastic differentiation  Involved in progenitor cell transformation to osteoblasts  Work pre- through the intracellular Smad pathway  Follow a dose/response ratio
  15. 15. BONE MORPHOGENETIC PROTEINS  Induce  cell differentiation BMP-3 (osteogenin) is an extremely potent inducer of mesenchymal tissue differentiation into bone  Promote  BMP-2 and BMP-7 induce endochondral bone formation in segmental defects  Regulate  endochondral ossification extracellular matrix production BMP-1 is an enzyme that cleaves the carboxy termini of procollagens I, II and III
  16. 16. CLINICAL USE OF BMP’S  Used at doses between 10x & 1000x native levels used in “fresh” open fractures to enhance healing and reduce need for secondary procedures after unreamed IM nailing  rhBMP-2  BMP-7 approved for use in recalcitrant nonunions in patients for whom auto grafting is not a good option (i.e. medically unstable, previous harvesting of all iliac crest sites, etc.)
  17. 17. BMP FUTURE DIRECTIONS  BMP-2  Increased fusion rate in spinal fusion  BMP-7 equally effective as ICBG in nonunions (small series: need larger studies)  Must be applied locally (insert them surgically in the fracture site) because of rapid systemic clearance.
  18. 18. BMP ANTAGONISTS  May have important role in bone formation  Noggin  Extra-cellular inhibitor  Competes with BMP-2 for receptors  BMP-13 found to limit differentiation of mesenchymal stromal cells  Inhibits osteogenic differentiation
  19. 19. FIBROBLAST GROWTH FACTORS  Both acidic (FGF-1) and basic (FGF-2) forms  Increase proliferation of chondrocytes and osteoblasts  Enhance callus formation  FGF-2 stimulates angiogenesis
  20. 20. PLATELET-DERIVED GROWTH FACTOR  A dimer of the products of two genes, PDGF-A and PDGFB  PDGF-BB and PDGF-AB are the predominant forms found in the circulation  Stimulates bone cell growth  Increases type I collagen synthesis by increasing the number of osteoblasts  PDGF-BB stimulates bone resorption by increasing the number of osteoclasts
  21. 21. INSULIN-LIKE GROWTH FACTOR  Two types: IGF-I and IGF-II  Synthesized by multiple tissues  IGF-I production in the liver is stimulated by Growth Hormone  Stimulates bone collagen and matrix synthesis  Stimulates replication of osteoblasts  Inhibits bone collagen degradation
  22. 22. CYTOKINES  Interleukin-1,-4,-6,-11, granulocyte/macrophage (GM) colony-stimulating factors (CSFs) and Tumor Necrosis Factor  Stimulate bone resorption  IL-1 is the most potent IL-1 and IL-6 synthesis is decreased by estrogen  May be mechanism for post-menopausal bone resorption Peak during 1st 24 hours of fracture healing then again during remodeling Regulate endochondral bone formation   
  23. 23. PROSTAGLANDINS / LEUKOTRIENES  Effect on bone resorption is species dependent and their overall effects in humans unknown  Prostaglandins of the E series  Stimulate osteoblastic bone formation  Inhibit activity of isolated osteoclasts  Leukotrienes  Stimulate osteoblastic bone formation  Enhance the capacity of isolated osteoclasts to form resorption pits
  24. 24. HORMONES  Estrogen  Stimulates fracture healing through receptor mediated mechanism  Modulates release of a specific inhibitor of IL-1  Thyroid hormones  Thyroxine and triiodothyronine excess stimulate osteoclastic bone resorption  Glucocorticoids  Inhibit calcium absorption from the gut causing increased PTH and therefore increased osteoclastic bone resorption
  25. 25. HORMONES (CONT.)  Parathyroid Hormone  Intermittent exposure stimulates  Osteoblasts  Increased bone formation  Growth Hormone  Mediated through IGF-1 (Somatomedin-C)  Increases callus formation and fracture strength
  26. 26. VASCULAR FACTORS  Metalloproteinases  Degrade cartilage and bones to allow invasion of vessels  Angiogenic factors  Vascular-endothelial growth factors  Mediate neo-angiogenesis & endothelial-cell specific mitogens  Angiopoietin (1&2)  Regulate formation of larger vessels and branches
  27. 27. ELECTROMAGNETIC FIELD  Electromagnetic (EM) devices are based on Wolff’s Law that bone responds to mechanical stress: In vitro bone deformation produces piezoelectric currents and streaming potentials.  Exogenous EM fields may stimulate bone growth and repair by the same mechanism  Clinical efficacy very controversial  No studies have shown PEMF to be effective in “gap healing” or pseudarthrosis
  28. 28. TYPES OF EM DEVICES Microamperes  Direct electrical current  Capacitively coupled electric fields  Pulsed electromagnetic fields (PEMF) 
  29. 29. PEMF  Approved by the FDA for the treatment of non-unions  Efficacy of bone stimulation appears to be frequency dependant Extremely low frequency (ELF) sinusoidal electric fields in the physiologic range are most effective (15 to 30 Hz range)  Specifically, PEMF signals in the 20 to 30 Hz range (postural muscle activity) appear more effective than those below 10 Hz (walking) 
  30. 30. ULTRASOUND  Low-intensity ultrasound is approved by the FDA for stimulating healing of fresh fractures  Human clinical trials show a decreased time of healing in fresh fractures treated non-operatively  Four level 1 studies show a decrease in healing time up to 38%  Has also been shown to decrease the healing time in smokers potentially reversing the ill effects of smoking
  31. 31. SUMMARY Fracture healing is influenced by many variables including mechanical stability, electrical environment, biochemical factors and blood flow  Our ability to enhance fracture healing will increase as we better understand the interaction between these variables 
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