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Fracture healing and growth factors
The document discusses fracture healing and the role of growth factors. It describes the two types of fracture healing as primary and secondary healing. Primary healing involves direct bone healing without callus formation, while secondary healing involves endochondral bone formation and callus. The stages of secondary fracture healing are described as the inflammatory phase, soft callus formation, hard callus formation, and bone remodeling. Several local and systemic factors that can influence fracture healing are provided. Finally, the roles and mechanisms of several important bone growth factors, such as TGF-β, IGF-1, IGF-2, FGF, PDGF, and BMPs in fracture healing are summarized.
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Fracture healing and growth factors
- 1. FRACTURE HEALING AND GROWTHFACTORS DR ANITH T V
- 2. FRACTURE HEALING • IT’SA COMPLEX SYSTEMIC AND ORGANISED CASCADE OF REGENERATIVE TISSUE FORMATAION WITH INFLUENCES FROM LOCAL AND SYSTEMIC FACTORS. • IT’S A REGENERATIVE PROCESSES RATHER THAN HEALING • 2 TYPES • PRIMARY AND SECONDARY
- 3. PRIMARY HEALING • DIRECTBONE HEALING • GAP HEALING • OSTEONAL REMODELLING • HAVERSIAN REMODELLING • INTRAMEMBRANEOUS OSSIFIACTION
- 4. SECONDARY HEALING • ENCHONDRALREPAIR • INDIRECT BONE HEALING
- 5. PRIMARY HEALING • THECORTEX ATTEMPTS TO REESTABLISH ITSELF WITHOUT THE FORMATION OF CALLUS. • OCCURS WHEN FRACTURE IS ANATOMICALLY REDUCED, BLOOD SUPPLY PRESERVED, RIGIDLY STABILISED WITH INTERNAL FIXATION PHYSIOLOGICAL COMPRESSION • THE GAP MUST BE <400 µ m. • STRAIN < 2%
- 6. STAGES IN PRIMARYBONE HEALING 1. RESORPTION OF BONE ENDS : COMPRESSION AND DAMAGE TO BLOOD SUPPLY AT THE FRACTURE SITE CAUSES PARTIAL RESORPTION AT BONE ENDS. 2. FIBROUS TISSUE FORMATION : COLLAGEN RICH GRANULATION TISSUE FROM FRACTURE HEMATOMA. AS THERE IS ABSOLUTE STABILITY, THE BONE ASSUMES AS THERE IS NO FRACTURE AT ALL AND FURTHER 3. MATURATION TO LAMELLAR BONE : AS THERE IS CLOSE APPOSITION OF FRACTURE ENDS THE NORMAL PROCESSES OF HAVERSIAN REMODELLING OCCURS.
- 7. • THE ADVANCINGOSTEOCLASTIC MIGRATION FRONT IN THE FORM OF CUTTING CONES CROSS THE FRACTURE SITE, • FURTHER FIBROUS TISSUE FORMATION • FOLLOWED BY OSTEOBLASTIC OSSIFICATION. • THIN CAPILLARY VESSELS THEN SEAL THE GAP.
- 8. SECONDARY BONE HEALING •INVOLVES CALLUS FORMATION AND INVOLVES PARTICIPATION OF PERIOSTEUM AND EXTERNAL SOFT TISSUES. • CALLUS SERVES AS SPLINT, ALLOWING MOTION ENSURING MECHANICAL STRENGTH AS IT HEALS. • AS BONE IS ABLE TO WITHSTAND MORE STRESS THE CALLUS INCREASES THE STRENGTH.
- 9. • RIGID FIXATIONINHIBITS SECONDARY BONE HEALING AND IS ENHANCES BY MICRO MOTIONS. • HEAD INJURY ENHANCES OSTEOGENIC RESPONSE TO FRACTURE HEALING • NICOTINE INCREASE THE RISK OF NON UNION. • STRAIN BETWEEN 2 TO 10%
- 10. STAGES IN SECONDARYFRACTURE HEALING • STAGE 1 : INFLAMMATORY PHASE • STAGE 2 : STAGE OF SOFT CALLUS FORMATION • STAGE 3 : STAGE OF HARD CALLUS FORMATION • STAGE 4 : BONE REMODELLING
- 12. STAGE 1 :INFLAMMATORY PHASE (0 TO 7 DAYS) • 1.A HEMATOMA FORMATION AND INDUCED INFLAMMATION • CHARACTERISED BY AN ACCUMULATION OF MESENCHYMAL CELLS AROUND THE FRACTURE SITE. • THE FORMED HEMATOMA IS A SOURCE OF GROWTH FACTORS. • PDGF & TGF B ARE RELEASED FROM PLATLETS • PDGF, IL 1 & 6 RECRUITS INFLAMMATORY CELLS TO THE FRACTURE SITES. • OSTEOBLAST PROGENITORS ARE RECRUITED FROM THE BONE MARROW
- 13. • IN FRACTURESWHERE PERIOSTEUM IS INTACT MESENCHYMAL CELLS COMES FROM CAMBIUM LAYER. • IN FRACTURES WHERE PERIOSTEUM GETS STRIPPED THE CELLS ARE DERIVED FROM PERICYTES FOUND AROUND CAPILLARIES, ARTERIOLES AND VENULES. • FIBROBLAST AND MESENCHYMAL CELLS MIGRATE TO FRACTURE SITE AND GRANULATION TISSUE STARTS TO FORM AROUND THE FRACTURE SITE ENDS. • BMPS INDUCE METAPLASIA OF MESENCHYMAL CELLS INTO OSTEOBLASTS. • TGF B INDUCE MESENCHYMAL CELLS AND OSTEOBLASTS TO PRODUCE TYPE 2 COLLAGEN AND PROTEOGLYCANS.
- 14. STAGE 1 :INFLAMMATORY PHASE (0 TO 7 DAYS) • 1.B GRANULATION TISSUE FORMATION • THE HEMATOMA IS INFILTRATED BY DEVELOPING VESSELS FROM SURROUNDING HEALING TISSUE UNDER THE INFLUENCE OF VEGF. • THE PROLIFERATING FIBROBLAST ALONG WITH THE INGROWING VESSELS EVOLVE INTO FIBROVASCULAR GRANULATION TISSUE RICH IN TYPE 2 COLLAGEN.
- 15. STAGE 2 :SOFT CALLUS FORMATION(7–21 DAYS) • AT AROUND 2 WEEKS THE PERIOSTEAL DERIVED CELLS FEW MILLIMETERS PROXIMAL FROM FRACTURE DEVELOPS INTO CHONDROBLASTS/ OSTEOBLASTS. • LOW OXYGEN TENSION, LOW PH AND MOVEMENTS FAVOR CHONDROCYTE FORMATION TO DEPOSIT HYALINE CARTILAGE. • HIGH OXYGEN TENSION, HIGH PH, AND STABILITY PREDISPOSE TO OSTEOBLAST RECRUITMENT AND THEN DEPOSITING THE ORGANIC MATRIX AND WOVEN BONE • THUS A CHONDROID – OSTEOID IS FORMED. • SUBSEQUENT MINERALISATION OF THIS CONDROID OSTEOID OCCURS. • THE FRACTURE DURING THIS STAGE BECOMES STICKY, IE DEFORMABLE BUT NOT DISPLACEABLE BY PHYSIOLOGICAL LOADS.
- 16. • 3 TYPESOF CALLUS FORMATION 1. PERIOSTEAL BRIDGING CALLUS – NO RELATION WITH SIZE OF HEMATOMA, BUT REFLECTS THE NEED FOR STABILISATION IF BLOOD SUPPLY IS ADEQUATE AND IS IVERSELY RELATED. 2. INTRAMEDULLARY CALLUS – DOUBLE CONCAVE SHAPE, LAID DOWN FROM INSIDE OF BONE SUPPLIED BY INTRA MED. SYSTEM, IT’S THE PREDOMINANT RESPONSE DURING GAP REPAIR. 3. INTERCORTICAL UNITING CALLUS – FORMS IN B/W THE OPPOSED CORTICES OF FRACTURED ENDS, SIZE TOTALLY DEPENDS ON REDUCTION AND APPOSITION OF BONE ENDS.
- 17. THUS THIS PHASEENDS WITH THE FRACTURE SITE WHICH IS ENVELOPED WITH POLYMORPHOUS MASS OF MINERALISED TISSUES CONSISTING OF CALCIFIED CARTILAGE, WOVEN BONE MADE FROM CARTILAGE AND WOVEN BONE FORMED DIRECTLY.
- 18. STAGE 3 :HARDCALLUS FORMATION(3WKS– 3MONTHS) THE WOVEN MINERALISED BONE IS REPLACED BY PRIMARY LAMELLAR BONE
- 19. STAGE 4 :BONE REMODELLING(MONTHS TO YEARS) • THE PROCESSES OF SLOW RESTORATION OF NORMAL BONE STRUCTURE. • THE INITALLY DEPOSITED TYPE 2 COLLAGEN IS REPLACED BY TYPE 1 COLLAGEN ON WHICH THERE IS RAPID MINERALISATION • THE PROCESSES OF FORMATION OF LAMELLAR BONE IN HYALINE CARTILAGE IS CALLED ENCHONDRAL OSSIFICATION & FROM WOVEN BONE IS CALLED BONY SUBSTITUTION. • PRIMARY LAMELLAR BONE (MULTIDIRECTIONAL OSTEONS) THEN IS TRANSFORMED TO SECONDARY LAMELLAR BONE (LONGITUDINAL OSTEONS).
- 20. FRACTURE HEALING INCANCELLOUS BONE • CREEPING SUSTITUTION COINED BY PHEMISTER • ITS SEEN IN INTRA ARTICULAR AND PERI ARTICULAER FRACTURES STABILISED BY RIGID FIXATION ANATOMICALLY. • ALSO SEEN ON APPLICATION OF CANCELLOUS BONE GRAFT. • 1 ST GRANULATION TISSUE INVADES THE AREAS OF RESORPTION, THE PLEURIPOTENT MESENCHYMAL CELLS DIFFERENTIATE TO OSTEOBLAST LAYS DOWN NEW OSTEOID ALONG THE DEAD TRABACULAE FORMING AN OSTEOID TUBE. • THE NECROTIC TISSUE IS REMOVED BY MACROPHAGES, CONVERTING THEM INTO HOLLOW TUBE, LATER INVADED BY GRANULATION TISSUE AND FORM NEW BONE INSIDE.
- 21. LOCAL FACTORS INFLUENCINGFRACTURE REPAIR • TYPE OF BONE • TYPE OF FRACTURE (OPEN VS CLOSED, COMMINUTION AND BONE LOSS) • INTRA ARTICULAR FRACTURE • SOFT TISSUE INJURY • SINGLE OR BOTH BONE FRACTURE • INFECTION ( MISDIRECTION OF ENERGY AND INF CELLS) • TYPE OF TREATMENT AND FIXATION
- 22. SYSTEMIC FACTORS INFLUENCINGFRACTURE REPAIR • AGE • ACTIVITY LEVEL • NUTRITIONAL STATUS • VITAMIN AND MINERAL DEFICIENCIES • DM, ANAEMIA, NEUROPATHIES • DRUGS – NSAIDS, CHEMOTHERAPY, PHENYTOIN, Ca CHANNEL BLOCKERS, STEROID, TETRACYCLINES) • HIV - SUPRESSES TNF A • ALCOHOL ABUSE • SMOKING
- 23. ENDOCRINE AND PARACRINEINFLUENCE • TGF B • BMPS • FGF • PDGF • IGF • CORTISONE • ACTH • THYROXINE • GH • PTH
- 24. TYPE OF STABILIZATIONAND PREDOMINANT FRACTURE HEALING • POP CAST – SECONDARY UNION • DCP – PRIMARY UNION • LOCKED PLATE WITH COMPRESSION- PRIMARY UNION • LOCKED PLATE WITHOUT COMPRESSION- SECONDARY PREDOMINATES • MIPPO – SECONDARY UNION • INTRAMEDULLARY NAILING – SECONDARY UNION • TBW – PRIMARY UNION • EXFIX – ELASTIC – SECONDARY, RIGID – PRIMARY UNION • BUTRESS PLATING – PRIMARY UNION • INTRAARTICUALR FRACTURE PLATING – PRIMARY CORTICAL UNION + CREEPING SUBSTITUTION AT CANCELLOUS SURFACE.
- 25. METHODS TO ENHANCEFRACTURE REPAIR BIOPHYSICAL STIMULATION (MECHANICAL AND ELECTRICAL STIMULATION) A. ULTRASOUND B. ELECTRICAL STIMULATION C. ELECTROCORPOREAL SHOCK WAVE THERAPY D. DISTRACTION HISTIOGENESIS/ OSTEOGENESIS E. CONTROLLED AXIAL MICROMOTION F. INTERMITTENT PNEUMATIC SOFT TISSUE COMPRESSION G. FUNCTIONAL CAST BRACING.
- 26. METHODS TO ENHANCEFRACTURE REPAIR BIOLOGICAL METHODS OSTEOCONDUCTIVE – BONE GRAFT SUBSTITUTES OSTEOINDUCTIVE – BMPS, PRP, CONDITIONED PLASMA OSTEOGENIC – BG, BM INFILTRATION SYSTEMIC AGENTS – PG, FIBRONECTIN
- 27. BONE GROWTH FACTORS •TGF B • BMP • IGF 1 • IGF 2 • PDGF • FGF
- 28. TGF B (TRANSFORMINGGROWTH FACTOR ) • MECHANISM • SECRETED IN A PARACRINE FASHION • BOTH OSTEOBLAST AND OSTEOCLASTS SYNTHESIZE AND RESPOND TO TGF-B • FOUND IN FRACTURE HEMATOMAS AND BELIEVED TO REGULATE CARTILAGE AND BONE FORMATION IN FRACTURE CALLUS • STIMULATES PRODUCTION OF TYPE II COLLAGEN AND PROTEOGLYCANS BY MESENCHYMAL CELLS. • INDUCES OSTEOBLASTS TO SYNTHESIZE COLLAGEN • SIGNAL PATHWAY SIGNAL MECHANISM INVOLVES TRANSMEMBRANE SERINE/THREONINE KINASE RECEPTORS • CLINICAL APPLICATIONS • TGF-B IS USED TO COAT POROUS COATED IMPLANTS TO PROMOTE BONE INGROWTH
- 29. IGF -1 • OVERVIEW •IGF-1, FORMERLY KNOWN AS SOMATOMEDIN-C, POSSIBLY ACTS BY BOTH PARACRINE AND ENDOCRINE HORMONE PATHWAYS • MOST ABUNDANT GROWTH FACTOR IN BONE • MECHANISM • THE PRODUCTS OF THE GH-IGF-1 SYSTEM INDUCE PROLIFERATION WITHOUT MATURATION OF THE GROWTH PLATE AND THUS INDUCE LINEAR SKELETAL GROWTH. • IGF-1 HAVE A ROLE IN ENHANCING BONE FORMATION IN DEFECTS THAT HEAL VIA INTRAMEMBRANOUS OSSIFICATION • SIGNAL PATHWAY SIGNAL MECHANISM INVOLVES TYROSINE KINASE RECEPTORS
- 30. IGF -2 • OVERVIEW •MORE POTENT THAN IGF-1 • MECHANISM • STIMULATES TYPE I COLLAGEN PRODUCTION • STIMULATES CARTILAGE MATRIX SYNTHESIS • STIMULATES CELLULAR PROLIFERATION • STIMULATES BONE FORMATION • SIGNAL PATHWAY • SIGNAL MECHANISM INVOLVES TYROSINE KINASE RECEPTORS
- 31. FGF ( FIBROBLASTGROWTH FACTOR ) • OVERVIEW • FGF-1 AND FGF-2 ARE MOST ABUNDANT • PROMOTE GROWTH AND DIFFERENTIATION OF A VARIETY OF CELLS • EPITHELIAL CELLS • MYOCYTES • OSTEOBLASTS • CHONDROCYTES • MECHANISM • BINDS TO MEMBRANE SPANNING TYROSINE KINASE • ASSOCIATED WITH ANGIOGENESIS AND CHONDROCYTE AND OSTEOBLAST ACTIVATION • INVOLVED IN EARLY STAGES OF FRACTURE HEALING
- 32. PDGF (PLATELET DERIVEDGROWTH FACTOR) • MECHANISM • RELEASED FROM PLATELETS AND SIGNALS INFLAMMATORY CELLS TO MIGRATE TO FRACTURE SITE • ROLE IN FRACTURE HEALING AND BONE REPAIR HAS NOT BEEN CLEARLY DEFINED • SIGNAL PATHWAY & CELLULAR TARGETS • SIGNAL MECHANISM INVOLVES TYROSINE KINASE RECEPTORS
- 33. BMPS (BONE MORPHOGENICPROTEINS) • BMPS BELONGS TO SUPERFAMILY OF GROWTH FACTORS CALLED TGF-B SUPERFAMILY EXCEPT BMP 1 • BMP 1 IS A PROTINEASE INVOLVED IN COLLAGEN SYNTHESIS. • BMP DESIGNATED AS BMP-1 TO BMP-16. • BMP 2,4,6, AND 7 EXHIBIT OSTEOINDUCTIVE ACTIVITY • BMP 3 DOES NOT EXHIBIT OSTEOINDUCTIVE ACTIVITY
- 34. • MUTATIONS INBMP-4 ARE ASSOCIATED WITH FIBRODYSPLASIA OSSIFICANS PROGRESSIVA. • LOCAL CONCENTRATION OF BMPS ARE IMPORTANT THAN TOTAL DOSE OF BMPS • SO VARIOUS CARRIERS SUCH AS DEMINERALISED COLLAGEN BONE MATRIX, COLLAGEN PRODUCTS, RESORBABLE POLYMERS CALCIUM PHOSPHATE CERAMICS ARE BEING USED FOR INCREASING ITS LOCAL CONCENTRATION. • COLLAGEN BASED CARRIERS ARE THE BEST AMONG ALL.
- 35. • MECHANISM -OSTEOINDUCTIVE -LEADS TO BONE FORMATION -ACTIVATES MESENCHYMAL CELLS TO TRANSFORM INTO OSTEOBLASTS AND PRODUCE BONE -HAS BEEN FOUND TO INCREASE CHONDROGENIC PHENOTYPE AND MATRIX SYNTHESIS IN INTERVERTEBRAL DISCS • BMP 2,6,9 ACT ON EARLY PHASE OF CONVERSION OF UNDIFFERENTIATED MESENCHYMAL CELLS TO PRE OSTEOBLASTS. • MOST OTHER BMPS ACT ON TERMINAL DIFFERENTIATION OF PRE OSTEOBLASTS TO OSTEOBLASTS
- 36. SIGNALING PATHWAYS ANDCELLULAR TARGETS - BMP TARGETS UNDIFFERENTIATED PERIVASCULAR MESENCHYMAL CELLS - ACTIVATES A TRANSMEMBRANE SERINE/THREONINE KINASE RECEPTOR THAT LEADS TO THE ACTIVATION OF INTRACELLULAR SIGNALING MOLECULES CALLED SMADS
- 37. FDAAPPROVED USES rhBMP-2 • SINGLE-LEVELALIF FROM L2 TO S1 LEVELS IN DEGENERATIVE DISC DISEASE TOGETHER WITH THE LUMBAR TAPERED FUSION DEVICE. • OPEN TIBIAL SHAFT FRACTURES STABILIZED WITH AN IM NAIL AND TREATED WITHIN 14 DAYS OF THE INITIAL INJURY. • TIBIA NON UNIONS.
- 38. rhBMP-7 • ITS ALSOKNOWN ASOSTEOGENIC PROTEIN 1 (OP-1) • AS AN ALTERNATIVE TO AUTOGRAFT IN RECALCITRANT LONG BONE NONUNIONS WHERE USE OF AUTOGRAFT IS UNFEASIBLE AND ALTERNATIVE TREATMENTS HAVE FAILED • AS AN ALTERNATIVE TO AUTOGRAFT IN COMPROMISED PATIENTS (WITH OSTEOPOROSIS, SMOKING OR DIABETES) REQUIRING REVISION • POSTEROLATERAL/INTERTRANSVERSE LUMBAR FUSION FOR WHOM AUTOLOGOUS BONE AND BONE MARROW HARVEST ARE NOT FEASIBLE OR ARE NOT EXPECTED TO PROMOTE FUSION
- 39. CONTRAINDICATIONS - BMPS •PREGNANCY • ALLERGY TO BOVINE TYPE I COLLAGEN OR RECOMBINANT HUMAN RHBMP-2 • INFECTION • TUMOR • SKELETAL IMMATURITY
- 40.