1. GOOD MORNING 1

2. DEPARTMENT OF ORTHOPAEDICS J.J.M MEDICAL COLLEGE , DAVANGERE SEMINAR ON ANATOMY OF FRACTURE HEALING MODERATORS: PRESENTED BY: DR G C BASAVARAJADR ROHIT KUMAR PROFFESOR & UNIT HEAD PG IN ORTHOPAEDICS DR SHAKEEL KHAN DATED:19.01.11 ASSOCIATE PROFESSOR

3. Fracture is defined as a break in the continuity of bone. Fracture results in loss of its mechanical stability and also partial destruction of blood supply. Healing means to make whole or sound again, to cure, leaving a scar behind. But following fracture a scar is not formed, instead a bone has formed a new at the original fracture site. So rather than bone healing the appropriate nomenclature would be BONE REGENERATION 3 INTRODUCTION

4. History of fracture and its knowledge dates back to Egyptian mummies of 2700 B.C 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. 4 HISTORY

5. 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. 5 Contd…..

6. Bone is essentially a highly vascular, living, constantly changing mineralized connective tissue which makes up body’s skeleton. Other functions are: - Bone provides protection for the vital organs of the body( eg: heart and brain) - The hematopoietic bone marrow is protected by the surrounding bony tissue. - Storage of calcium and phosphate. 6 WHAT IS BONE ?

7. Living bone is white, with either dense texture like ivory or honeycombed by large cavites. Spongy bone (cancellous) : is composed of a lattice or network of branching bone spicules or trabeculae. The spaces between the bone spicules contain bone marrow. Compact bone (cortical / outer): appears as a mass of bony tissue lacking spaces visible to the unaided eye. 7 MACROSCOPY

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9. Woven (Immature bone):Characterized by random arrangement of cells and collagen ,associated with periods of rapid bone formation, such as in initial stage of fracture healing. Lamellar bone (Mature bone) : Characterized by an orderly cellular distribution and properly oriented collagen fibres . This constitutes organised bone both cortical and cancellous 9 MICROSCOPY

10. Comprises of osteons (Haversian systems) Osteons communicate with medullary cavity by Volkmann’s canals 10 CORTICAL BONE .

11. HAVERSIAN CANAL 11 osteon osteocyte Haversian canal Cells, nerves & vessels Volkmann’s canal Connects osteons Haversian canal Volkmann’s canal

12. WOVEN BONE Coarse with random orientation Weaker than lamellar bone Normally remodeled to lamellar bone 12

13. 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 osteogenicpotency. 13 PERIOSTEUM

14. Anchors tendons and ligaments to bone. Acts as a limiting membrane. Participates in growth (appositional) and repair through the activities of the osteoprogenitor cells . Periosteumhelps in fracture healing by forming periosteal callus. It also lessen the displacement of the # and helps in reduction. Allows passage of blood vessels, lymphatics and nerves into and out of the bone. 14 FUNCTIONS OF PERIOSTEUM:

15. 15 BLOOD SUPPLY OF BONE Long bones have three blood supplies -Nutrient artery (intramedullary) 80-85% -Periosteal vessels -Metaphyseal vessels have hair pin arrangement.

16. In miniature long bones, the nutrient artery breaks up into a plexus immediately upon reaching the medullary cavity. In contrast in cancellous bone the blood supply reaches its destinations more directly without significant branching . Therefore the healing where vascular re estabilishment is necessary happens rapidly. The nerve supply to a bone comes along with the blood supply. Nerve supply includes sensory nerve supply, vasomotor nerve supply and sympathetic nerve supply. 16

17. Accompanying the blood vessels there are usually fine medullated /non medullated nerve fibres which extend into the haversian system and in large numbers to the periosteum. These nerves are mainly concern with innervation of blood vessels, although periosteum and bone have been described in being sensitive to pain and vibration. It is not clear whether bone has a direct neural input .. 17

18. Fracture stimulates the release of growth factors that promote angiogenesis and vasodilation. Blood flow is increased substantially to the fracture site. Peaks at two weeks after fracture 18 VASCULAR RESPONE IS FRACTURE REPAIR

19. 19 BONE COMPOSITION CELLS OSTEO PROGENITOR CELLS OSTEOBLASTS OSTEOCLASTS OSTEOCYTES BONE LINING CELLS EXTRACELLULAR MATRIX 1. ORGANIC & WATER 35% Type Ι Collagen 90% Osteocalcin, Osteonectin, Proteoglycans, Glycosaminoglycans, Lipids (ground substance) 2. INORGANIC 65% Primarily hydroxyapatite Ca10(PO4)6(OH)2

20. 1.OSTEO PROGENITOR CELLS 20

21. Are basophilic, cuboidal to pyrimidal 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. 21 2.OSTEOBLASTS

22. 22 The synthesis type 1 collagen, osteocalcin (bone Glaprotein) and osteonectin

23. 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. 23 3.OSTEOCLASTS

24. RUFFLED BORDER OSTEOCLASTS MICROSCOPIC PICTURE ELECTRON MICROSCOPY 24

25. 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 nucleous. In developing bone, the cytoplasmic processes from one osteocyte make contact with the processes (ie: 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. 25 4.OSTEOCYTES

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27. 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. 27 5.BONE LINING CELLS

28. 28 HEALING AFTER FRACTURE FIXATION DIRECT/PRIMARY: Mechanism of bone healing seen when there is no motion at the fracture site (i.e. rigid internal fixation). Does not involve formation of fracture callus. Osteoblasts originate from endothelial and perivascular cells.

29. 29 CONTD: INDIRECT/SECONDARY: Mechanism for healing in fractures that are not rigidly fixed. Bridging periosteal (soft) callus and medullary (hard) callus re-establish structural continuity. Callus subsequently undergoes endochondral ossification.

30. 30 TYPES OF BONE HEALING PRIMARY CONTACT HEALING: When there is direct contact between the cortical bone ends, lamellar bone forms directly across the fracture line , parallel to long axis of the bone, by direct extension of osteons. GAP HEALING:Osteoblasts differentiate and start depositing osteoidson the exposed surfaces of fragment ends, mostly without a preceding osteoclasticresorption which is later converted into the lamellar bone .

31. 31 CONTD: SECONDARY: It is usual type consisting of formation of callus either of cartilaginous or fibrous. This callus is later replaced by lamellar bone. It is comparable to healing of soft tissue by filling of gaps with vascular granulation tissue.

32. 32 OSTEO INDUCTION CONDUCTION INTEGRATION OSTEOINDUCTION: This term mean that primitive, undifferentiated and pleuripotent cells are somehow stimulated to develop into the bone forming cell lineage.one proposed definition is process by which osteogenesis is induced. OSTEOCONDUCTION:A scaffold of collagenous network has developed, upon which the reparative cells produce callus and bone

33. It facilitates bone deposition in an orderly fashion and helps the callus to bridge the gap between the fragments. OSTEOINTEGRATION:The direct structural and functional connection between living bone and the surface of a load-bearing implant. 33

34. Cutting Cones Intramembranous Bone Formation Endochondral Bone Formation 34 MECHANISM OF BONE FORMATION

35. Primarily a mechanism to remodel bone. Osteoclasts at the front of the cutting cone remove bone. Trailing osteoblasts lay down new bone. 35 CUTTING CONES

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37. 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. 37 INTRAMEMBRANOUS BONE FORMATION(PERIOSTEAL)

38. INTRAMEMBRANOUS BONE FORMATION 38

39. 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). 39 ENDOCHONDRAL BONE FORMATION

40. There are 3 major phases with sub divisions: A. Reactive Phase: i. Fracture and inflammatory phase. ii. Stage of hematoma formation. iii. Granulation tissue formation. B. Reparative Phase: iv. Cartilage Callus formation. v. Lamellar bone deposition. C. Remodeling Phase: vi. Remodeling to original bone contour. 40 STAGES OF FRACTURE HEALING

41. 41 A.REACTIVE PHASE I .Fracture & inflammatory phase : After fracture the first change seen by light and electron microscopy is the presence of blood cells within the tissues which are adjacent to the injury site. Soon after fracture, the blood vessels constrict, stopping any further bleeding.

42. 42 ii. Stage of Hematoma formation: Within a few hours after fracture, the extravascular blood cells form a blood clot, known as a hematoma. All of the cells within the blood clot degenerate and die. The fracture hematoma immobilizes &splints the fracture. The fracture haematoma provides a fibrin scaffold that facilitates migration of repair cells.

43. 43 iii. Granulation Tissue Formation: Within this same area, the fibroblasts survive and replicate. They form a loose aggregate of cells, interspersed with small blood vessels, known as granulation tissuewhich grows forward, outside and inside the bone to bridge the fracture. They are stimulated by vasoactive mediators like serotonin and histamine.

44. 44 B. REPARATIVE PHASE iv. Cartilage Callus formation : Days after the # the periosteal cells proximal to the fracture gap and fibroblasts develop into chondroblasts which form hyaline cartilage. The periosteal cells distal to the fracture gap develop into osteoblasts which form woven bone. These 2 tissues unite with their counterparts and culminate into new mass of heterogenous tissue called Fracture Callusrestoring some of its original strength.

45. 45 v. Lamellar bone deposition: Or consolidation ..where hyaline cartilage and woven bone is replaced by lamellar bone. This process is called Endochondral ossification. At this point, the mineralized matrix is penetrated by channels, each containing a microvessel and numerous osteoblasts. This new lamellar bone is in the form of trabecular bonewhich restores bone’s original strength.

46. 46 C. REMODELLING PHASE vi. Remodelling to original bone contour: The remodeling process substitutes the trabecular bone with compact bone. The trabecular bone is first resorbed by osteoclasts, creating a shallow resorption pit known as a "Howship's lacuna". Then osteoblasts deposit compact bone within the resorption pit. Eventually, the fracture callus is remodelled.

47. STAGE 1- A healing bone subjected to torsion fails through original # site with a low stiffness pattern. STAGE 2- The bone still fails through the # site , but the characteristic indicate high stiffness pattern(hard tissue pattern) STAGE 3 – The bone fails partly through the original # site and partly through the previously intact bone with a high stiffness pattern . STAGE 4 –Failure does not occur through the # site duplicates the mechanical properties of uninjured tissue. 47 STAGES BASED ON REACTION TO TORSIONAL TESTING

48. 48 # HEALING IN CANCELLOUS BONE 1.Cancellous bone heals by - “CREEPING SUBSTITUTION” New blood vessels can invade the trabecular of cancellous bone and bone opposition may take place directly on to the surface of trabeculum.

49. 49 2.Heals at the point of direct contact: Cancellousbone certainly can unite very rapidly, but it unites rapidly only at the points of direct contact. 3.No bridging callus : Cancellous bone unites only by contact, not by throwing out callus even when it is cut of due to dense attachment of the periosteum.

50. 50 4.No death of osteocytes: Takes place in the cut edges of divided trabeculaein cancellous bone. This must be because of the blood supply is good and large surface area of the trabecular spaces combined with relatively thin trabeculae, keep the osteocytes nourished. 5.Has tendency for late collapse : This lack of callus production by cancellous bone explains the tendency to late collapse which have been distracted. Eg: after reduction of colle’s fracture a hallow cavity is left in the cancellous end of the radius.

51. FRACTURE HEALING IN CHILDREN Compared with the relatively static mature bone of adult, the changing structure and function both physiological and biomechanical of immature bones make them susceptible to different patterns of fracture. Fracture in children are more common and are more likely to occur after seemingly insignificant trauma. Damage involving specific growth regions such as the physis or epiphyseal ossification center may lead to acute and chronic growth disturbances.

52. Higher collagen to bone ratio- this lowers the modulus of elasticity and tensile strength of bone. Higher cellular and porus bone –reduces tendency of # to propagate explains why children dont have communited #’s. Bone fails in both tension and compression- explains why buckle #’s happen in children. Bone transitions- between metaphysis and dyphysis has discontinuity, leading to certain types of #’s… 52 PEDIATRIC BONE ??

53. 53 FEATURES OF PEDIATRIC BONE AND THEIR MANAGEMENT EFFECTS FEATURE: Thick cartilage Thick periosteum More collagen More cancellous bone Growth plate Stronger ligaments MANAGEMENT EFFECT: Not imaged by x rays. Healing rapid. Fractures easily. Simple # patterns. Remodels deformity. Bone fails first.

54. 54 Growth plate: The most obvious difference The relative strength of plate with the bone changes with age .eg: physis in children is stronger than adjacent bone so diaphyseal #’s are more common. HELPS # MANAGEMENT: by remodeling.. INJURED GROWTH PLATE CAUSES DEFORMITY due to asymmetry.

55. PHYSIS/GROWTH PLATE: Physis or growth plates primary function is rapid integrated longitudinal and latitudinal growth. Ischemia of physis due to fracture can lead to growth disturbances. zones within the physis : The resting cartilage zone The proliferating cartilage zone The zone of hypertrophy and The zone of calcification.

56. Accounts for ¼ of childhood fractures . Physeal injuries can occur from infection,ischemia,tumors. They are more common in boys and in upper limb. These are of great importance as they determine growth and remodelling potential. Fractures generally occur in zone of provisional calcification ,sparing the germinal zone. Most sensitive to injury is proximal tibial epiphysis. 56 PHYSEAL INJURIES

57. 57 PLASTIC BOWING OF ULNA BUCKLE OR TORUS # GENU RECURVATUM DUE TO PHYSEAL GROWTH ARREST AVULSION # OF TIBIAL SPINE … BONE FAILS BEFORE ACL GREENSTICK #

58. FRACTUREREPAIR IN CHILDREN Fracture healing in children follow same pattern of adults but with some peculiarities : PERIOSTEUM: In the contrast to adults the periosteum strips away easily from the underlying bone in children. Allowing fracture haematoma to dissect along the diaphysis and metaphysis and this is evident in the subsequent amount of new bone formation along the shaft. Dense attachment of the periosteum into the zone of ranvier limit subperiosteal hematoma formation to the metaphysic and diaphysis.

59. 59 REMODELLING IN CHILDREN The remodelling phase is the longest phase and in children may continue until skeletal maturation. Remodelling is better in children compared to adult, This is in response to constantly changing stress Patterns in children during skeletal growth and development.

60. LOCAL FACTORS. CHEMICAL FACTORS. VASCULAR FACTORS. SYSTEMIC FACTORS. ELECTROMAGNETIC FACTORS. TREATMENT FACTORS. 60 FACTORS INFLUENCING BONE HEALING

61. A.Typeof bone: Calcellous(spongy) bone V/S cortical bone. B. Degree of Trauma: Extensive soft tissue injury and comminuted #‘s V/S Mild contusions C.VascularInjury: Inadequate blood supply impairs healing. Especially vulnerable areas are the femoral head, talus, and scaphoid bones. D. Degree of Immobilization: Immobilized for vascular ingrowth and bone healing to occur. 61 1.LOCAL FACTORS

62. Repeated disruptions of repair tissue, especially to areas with marginal blood supply or heavy soft tissue damage, will impair healing. E.Type of Fractures: Intraarticularfractures communicate with synovial fluid, which contains collagenases that retard bone healingV/S Open fractures result in infections V/S Segmental fractures have disrupted blood supply. F.SoftTissue Interposition: G.others:Bone death caused by radiation, thermal or chemical burns or infection. 62 CONTD..

63. 1.MESSENGER 2.GROWTH 3.PERMEABILITY SUBSTANCES FACTORS FACTORS -Serotonin -Transforming GF -Proteases -Prostaglandins -Fibroblast GF -Polypeptides -Histamines -Platelet derived GF -Amines -Thromboxane -Insulin like GF -Bone morphogenic proteins(BMP) 63 2.CHEMICAL FACTORS

64. 1.MESSENGER SUBSTANCE: A.CYTOKINES- IL-1,4,6,11, macrophage and granulocyte/macrophage (GM) (CSFs) & (TNF) stimulate bone resorption. IL-1 ,6 synthesis is decreased by estrogen -May be mechanism for post-menopausal bone resorption & it regulates endochondral bone formation. B.PROSTAGLANDINS of the E series- -Stimulate osteoblastic bone formation and inhibit activity of isolated osteoclasts. C.LEUKOTRINES- Stimulate osteoblastic bone formation and enhance the capacity of isolated osteoclasts to form resorptionpits. 64

65. 2.GROWTH FACTORS: A.Transforming growth factor(TGF): Superfamily of growth factors (~34 members) Act on serine/threonine kinase cell wall receptors Promotes proliferation and differentiation of osteoblasts, osteoclasts and chondrocytes Stimulates both endochondral and intramembranous bone formation and collagen type 2 synthesis. B.Fibroblast growth factors(FGF): Both acidic (FGF-1) and basic (FGF-2) forms Increase proliferation of chondrocytes and osteoblasts Enhance callus formation & stimulates angiogenesis. 65

66. C.Platelet derived growth factor(PDGF): A dimer, genes PDGF-A and PDGF-B Stimulates bone cell growth Increases type I collagen synthesis by increasing the number of osteoblasts. PDGF-B stimulates bone resorption. D.Insulin like growth factor(ILGF): Two types IGF1 &IGF2 out of which IGF1 is produced in liver and stimulated by growth hormone. Stimulates bone collagen & matrix synthesis and replicates osteoblasts . It also inhibits collagen degradation. 66

67. E.BoneMorphogenic Proteins (BMP): BMP was discovered by Marshall Uristin 1965. They areOsteoinductive proteins initially isolated from demineralized bone matrix. FUNCTIONS: 1. Induce cell differentiation : BMP 3(osteogenin). 2. Promote endochondralossification: BMP 2 & 7. 3. Regulate extracellular matrix production :BMP1. 4.Increase fusion rates in Spinal fusions (anterior lumbar interbodyfusion): BMP 2 5.Non unions: BMP 7 as good as bone grafting . These are included in the TGF-βfamily except BMP 1. Must be applied locally because of rapid systemic clearance . 67

68. 3.PERMEABILITY FACTORS: -Protease – Plasmin , Kalikrein, Globulin permeability factor. -Polypeptides –leucotaxime, Bradykinin, Kallidin -Amines – Adrenalin, nor-adrenalin, Histamine. These factors work in ways that : Increase capillary permeability Alteration in diffusion mechanism in intracellular matrix Cellular migration Proliferation & differentiation New blood vessel formation Matrix synthesis Growth & development. 68

69. 69 3.VASCULAR FACTORS A. Metalloproteinases: Degrade cartilage and bones to allow invasion of vessels B. Angiogenic factors: Vascular-endothelial growth factors mediate neo-angiogenesis & endothelial-cell specific mitogens. C. Angiopoietin (І & ІІ) Regulate formation of larger vessels and branches.

70. A.Age: Young patients heal rapidly and have a remarkable ability to remodel V/S old . B.Nutrition: An adequate metabolic stage with sufficient carbohydrates and protein is necessary. C.SystemicDiseases: and those causing an immunocompromised state will likely delay healing. Illnesses like Marfan’s syndrome and Ehlers-Danlos syndrome cause abnormal musculoskeletal healing. 70 4.SYSTEMIC FACTORS

71. D.HORMONES: Estrogen Stimulates fracture healing through receptor mediated mechanism. 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. Parathyroid Hormone Growth Hormone Mediated through IGF-1 (Somatomedin-C) Increases callus formation and fracture strength 71

72. In vitro bone deformation produces piezoelectric currents and streaming potentials. Electromagnetic (EM) devices are based on Wolff’s Law that bone responds to mechanical stress: Exogenous EM fields may simulate mechanical loading and stimulate bone growth and repair TYPES ARE : Ultrasound. Direct electrical current. Pulsed electromagnetic fields (PEMF). 72 5.ELECTROMAGNETIC FACTORS

73. 73 A.Ultrasound therapy: Low-intensity ultrasound is approved by the FDA for stimulating healing of fresh fractures. Modulates signal transduction, increases gene expression (aggrecan ), increases blood flow, enhances bone remodeling and increases callus torsional strength in animal models.

74. 74 B.Direct Electrical current: Electric stimulation of bone has been taught to be an effective and non invasive method for fracture healing and treating fracture non union. Studies shows that electric field generated helps in proliferation of bone cells.

75. 75 A/K CAST WITH CATHODES ELECTEOMAGNETIC FIELD

76. 76 C.Pulsed electromagnetic fields (PEMF). Approved by the FDA for the treatment of non-unions Efficacy of bone stimulation appears to be frequency dependant are most effective (15 to 30 Hz range)

78. LOADING AND MICROMOTION .

79. FRACTURE STABILIZATION.

80. RIGID FIXATION.

81. BONE GRAFTING. 77 6.TREATMENT FACTORS

82. 78 OTHER RECENT ADVANCES: GROWTH FACTOR THERAPY Due to their ability to stimulate proliferation and differentiation of mesenchymal and osteoprogenitor cells they have shown great promise for their ability to promote fracture repair . APPLICATION OF PLATELET RICH PLASMA Injecting platelet rich plasma at fracture site helps in fracture healing . TISSUE ENGINEERING, STEM CEELS AND GENE THERAPIES In past decade tissue culture and stem cells have been implicated in enhancing fracture healing and articular cartilage regeneration.

83. Fracture healing is influenced by many variables including mechanical stability, electrical environment, biochemical factors and blood flow etc… Our ability to enhance fracture healing will increase as we better understand the interaction between these variables. 79 SUMMARY

84. CAMPBELL TEXTBOOK OF ORTHOPAEDICS 11TH EDITION.. TUREK ORTHOPAEDICS 4TH EDITION. WHEELES TEXT BOOK OF ORTHOPAEDICS. INTERNET. FUNDAMENTAL OF PEDIATRIC ORTHOPAEDICS By Lynn T. Stahel 80 BIBLIOGRAPHY

85. 81