Pathophysiology of fracture healing


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bone healing and factors affecting it

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Pathophysiology of fracture healing

  1. 1. Speaker-Raghavendra MS Moderator-Dr Marulasiddappa G
  2. 2.  Fracture is a break in the continuity of bone or periosteum  The healing of fracture is in many ways similar to soft tissue healing except that the end result is mineralized mesenchymal tissue i.e BONE  Fracture healing starts as soon as bone breaks and continues for many months
  3. 3.  In 17th century Albrecht Haller, observed invading capillary buds in fracture callus and thought that blood vessels are responsible for callus formation  John Hunter, a pupil of Haller, described the morphologic sequence of fracture healing.  In 1873, Kolliker observed the role of multinucleated giant cells, osteoclast to be responsible for bone resorption.  In1939, Gluksman suggested pressure and shearing stresses are possible stimuli for fracture healing.  In 1961, Tonna and Cronkie demonstrated the role of local mesenchymal cells in fracture repair.
  4. 4.  Bone marrow  Periosteum  Cortex  Soft tissue
  5. 5. Is a membrane that lines the outer surface of all bones except at the joints of long bones. Is made up of :  Outer FIBROUS layer : made up of white connective and elastic tissue.  Inner CAMBIUM layer : which has a looser composition, is more vascular and contains cells with osteogenic potency.
  6. 6. 1. Anchors tendons and ligaments to bone. 2. Acts as a limiting membrane. 3. Participates in growth (appositional) and repair through the activities of the osteoprogenitor cells . 4. Periosteum helps in fracture healing by forming periosteal callus. 5. It also lessen the displacement of the # and helps in reduction. 6. Allows passage of blood vessels, lymphatics and nerves into and out of the bone.
  7. 7.  Are basophilic, cuboidal to pyramidal in shape , associated with bone formation, these cells are located where new bone is forming, eg: in the periosteum.  Osteoblasts often appear stratified as in an epithelium.  The nucleus is large with a single prominent nucleolus.  Osteoblasts contain the enzyme alkaline phosphatase used to calcify the osseous matrix.  They synthesize type 1 collagen, osteocalcin (bone Gla protein) and osteonectin
  8. 8.  Giant, multinuclear cells which vary greatly in shape.  They are found on the surfaces of osseous tissue usually in shallow depressions called Howship’s lacunae.  The cytoplasm is slightly basophilic and contains lysosomal vacuoles.  Under E.M. the cell surface facing the osseous matrix shows numerous cytoplasmic projections and microvilli described as a ruffled border.
  10. 10.  Basically, an osteoblast that has been enclosed within the bony matrix in a space called the lacuna.  The cytoplasm of the osteocyte is faintly basophilic containing fat droplets and granules of glycogen with single dark stained nucleus.  In developing bone, the cytoplasmic processes from one osteocyte make contact with the processes (i.e.: cannaliculi) from adjoining osteocytes. In mature bone, the processes are withdrawn almost completely.  In mature bone the empty canaliculi remain as passage ways for the diffusion of nutrients and wastes between bone and blood. 12
  11. 11. 13
  12. 12.  Are flattened epithelium in adult skeleton found on resting surfaces.  Plays active role in differentiation of progenitor cells  Controls osteoclasts, mineral hemostasis and may secrete collagenase.  Lines – endosteal surface of marrow cavity - periosteal surface - vascular channels within osteons. 14
  13. 13.  Endoochondral  Intramembranous ossification  Oppositional new bone formation  Osteonal migration (creeping substitution)
  14. 14.  Mechanism by which a long bone grows in width.  Osteoblasts differentiate directly from pre osteoblasts and lay down seams of osteoid.  Does NOT involve cartilage anlage. 16
  15. 15. 17
  16. 16.  Mechanism by which a long bone grows in length.  Osteoblasts line a cartilage precursor.  The chondrocytes hypertrophy, degenerate and calcify (area of low oxygen tension).  Vascular invasion of the cartilage occurs followed by ossification (increasing oxygen tension). 18
  17. 17. Picture courtesy Gwen Childs, PhD.
  18. 18.  The process of bone remodelling by osteoclastic resorption and creation of new vascular channals with osteoblastic bone formation resulting in new haversian systems  Seen in bone healing after bone grafting
  19. 19.  Primarily a mechanism to remodel bone.  Osteoclasts at the front of the cutting cone remove bone.  Trailing osteoblasts lay down new bone. 21
  20. 20. 22
  21. 21. • Stage of hematoma formation • Stage of inflammation and cellular proliferation Reactive phase • Stage of callus formation • stage of consolidation Reparative phase • Stage of remodeling Remodeling phase 1975, Cruess and Dumont 1989, FROST
  22. 22.  Torn vessels will bleed and form hematoma  A mass of clotted blood(hematoma) formed around the fracture site
  23. 23.  Hematoma is invaded inflammatory cells & they degrade necrotic tissue  Release of TGF- β,PDGF by macrophages  Procuring osteoprogenitor cells
  24. 24.  new capillaries organize fracture hematoma into granulation tissue – procallus  Fibroblasts and osteogenic cells invade procallus.  Make collagen fibers which connect ends together  Chondroblasts begin to produce fibrocatilage  This is called soft callus(7days-6wks)
  25. 25.  Osteoblasts lay more boney trabacule  Fibrocartilagenous frame work is calcified to form boney callus(6-12wks)  Now fracture is painless and allows weight bearing
  26. 26.  Globular callus is slowly remodeled over years  More trabacule are layed in the line of stress and non stressed area is resorbed  Hence bone will take original shape
  27. 27.  A bone will adapt to mechanical stress and strain by changing size, shape and structure
  28. 28.  Direct (primary) bone healing  Indirect (secondary) bone healing
  29. 29.  Mechanism of bone healing seen when there is no motion at the fracture site (i.e. absolute stability)  Does not involve formation of fracture callus  Osteoblasts originate from endothelial and perivascular cells
  30. 30.  Contact Healing  Direct contact between the fracture ends allows healing to be with lamellar bone immediately  Gap Healing  Gaps less than 200-500 microns are primarily filled with woven bone that is subsequently remodeled into lamellar bone  Larger gaps are healed by indirect bone healing (partially filled with fibrous tissue that undergoes secondary ossification)
  31. 31.  Mechanism for healing in fractures that have some motion, but not enough to disrupt the healing process.  Bridging periosteal (soft) callus and medullary (hard) callus re-establish structural continuity  Callus subsequently undergoes endochondral ossification  Process fairly rapid - weeks
  32. 32.  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
  33. 33.  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
  34. 34.  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 pre- osteoblasts  Work through the intracellular Smad pathway  Follow a dose/response ratio
  35. 35.  Osteoinductive proteins initially isolated from demineralized bone matrix  Induce cell differentiation  BMP-3 (osteogenin) is an extremely potent inducer of mesenchymal tissue differentiation into bone  Promote endochondral ossification  BMP-2 and BMP-7 induce endochondral bone formation in segmental defects  Regulate extracellular matrix production  BMP-1 is an enzyme that cleaves the carboxy termini of procollagens I, II and III
  36. 36. Table from Dimitriou, et al., Injury, 2005
  37. 37.  Used at doses between 10x & 1000x native levels  Negligible risk of excessive bone formation  rhBMP-2 used in “fresh” open fractures to enhance healing and reduce need for secondary procedures after unreamed IM nailing  It is found that application of rhBMP-2 decreases infection rate in Type IIIA & B open fractures.  BMP-7 approved for use in recalcitrant nonunions in patients for whom autografting is not a good option (i.e. medically unstable, previous harvesting of all iliac crest sites, etc.)
  38. 38.  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 because of rapid systemic clearance
  39. 39.  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
  40. 40.  Both acidic (FGF-1) and basic (FGF-2) forms  Increase proliferation of chondrocytes and osteoblasts  Enhance callus formation  FGF-2 stimulates angiogenesis
  41. 41.  A dimer of the products of two genes, PDGF-A and PDGF-B  PDGF-BB and PDGF-AB are the predominant forms found in the circulation  Stimulates bone cell growth  Mitogen for cells of mesenchymal origin  Increases type I collagen synthesis by increasing the number of osteoblasts  PDGF-BB stimulates bone resorption by increasing the number of osteoclasts
  42. 42.  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
  43. 43.  Interleukin-1,-4,-6,-11, macrophage and 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 then again during remodeling  Regulate endochondral bone formation
  44. 44. Cytokine Bone Formation Bone Resorption IL-1 + +++ TNF-α + +++ TNF-β + +++ TGF-α -- +++ TGF-β ++ ++ PDGF ++ ++ IGF-1 +++ 0 IGF-2 +++ 0 FGF +++ 0
  45. 45.  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
  46. 46.  Estrogen  Stimulates fracture healing through receptor mediated mechanism  Modulates release of a specific inhibitor of IL-1  Thyroid hormones  Thyroxine and triiodothyronine stimulate osteoclastic bone resorption  Glucocorticoids  Inhibit calcium absorption from the gut causing increased PTH and therefore increased osteoclastic bone resorption
  47. 47.  Parathyroid Hormone  Intermittent exposure stimulates  Osteoblasts  Increased bone formation  Growth Hormone  Mediated through IGF-1 (Somatomedin-C)  Increases callus formation and fracture strength
  48. 48.  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
  49. 49. Systemic Factors  A. Age  B. Activity level including  1. General immobilization  2. Space flight  C. Nutritional status  D. Hormonal factors  1. Growth hormone  2. Corticosteroids (microvascular osteonecrosis)  3. Others (thyroid, estrogen, androgen, calcitonin,  parathyroid hormone, prostaglandins)  E. Diseases: diabetes, anemia, neuropathies, tabes  F. Vitamin deficiencies, A, C, D, K  G. Drugs: nonsteroidal antiinflammatory drugs (NSAIDs),  anticoagulants, factor XIII, calcium channel blockers  (verapamil), cytotoxins, diphosphonates, phenytoin,  sodium fluoride, tetracycline  H. Other substances (nicotine, alcohol)  I. Hyperoxia  J. Systemic growth factors  K. Environmental temperature  L. Central nervous system trauma
  50. 50.  Local Factors A. Factors independent of injury, treatment, or  complications  1. Type of bone  2. Abnormal bone  a. Radiation necrosis  b. Infection  c. Tumors and other pathological conditions  3. Denervation B. Factors depending on injury  1. Degree of local damage  a. Compound fracture  b. Comminution of fracture  c. Velocity of injury  d. Low circulatory levels of vitamin K1  2. Extent of disruption of vascular supply to bone, its  fragments (macrovascular osteonecrosis), or soft  tissues; severity of injury  3. Type and location of fracture (one or two bones,  e.g., tibia and fibula or tibia alone)  4. Loss of bone  5. Soft tissue interposition  6. Local growth factors
  51. 51.  C. Factors depending on treatment  1. Extent of surgical trauma (blood supply, heat)  2. Implant-induced altered blood flow  3. Degree and kind of rigidity of internal or external  fixation and the influence of timing  4. Degree, duration, and direction of load-induced  deformation of bone and soft tissues  5. Extent of contact between fragments (gap, displacement,  overdistraction)  6. Factors stimulating posttraumatic osteogenesis  (bone grafts, bone morphogenetic protein, electrical  stimulation, surgical technique, intermittent  venous stasis [Bier])  D. Factors associated with complications  1. Infection  2. Venous stasis  3. Metal allergy
  52. 52.  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
  53. 53.  Microamperes  Direct electrical current  Capacitively coupled electric fields  Pulsed electromagnetic fields (PEMF)
  54. 54.  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)
  55. 55.  Low-intensity ultrasound is approved by the FDA for stimulating healing of fresh fractures  Modulates signal transduction, increases gene expression, increases blood flow, enhances bone remodeling and increases callus torsional strength in animal models
  56. 56.  Human clinical trials show a decreased time of healing in fresh fractures treated nonoperatively  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