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.

1. FRACTURE HEALING AND
GROWTH FACTORS
DR ANITH T V

2. FRACTURE HEALING
• IT’S A 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
• DIRECT BONE HEALING
• GAP HEALING
• OSTEONAL REMODELLING
• HAVERSIAN REMODELLING
• INTRAMEMBRANEOUS OSSIFIACTION

4. SECONDARY HEALING
• ENCHONDRAL REPAIR
• INDIRECT BONE HEALING

5. PRIMARY HEALING
• THE CORTEX 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 PRIMARY BONE 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 ADVANCING OSTEOCLASTIC 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 FIXATION INHIBITS 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 SECONDARY FRACTURE 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 FRACTURES WHERE 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 TYPES OF 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 PHASE ENDS 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 :HARD CALLUS 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 IN CANCELLOUS 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 INFLUENCING FRACTURE 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 INFLUENCING FRACTURE 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 PARACRINE INFLUENCE
• TGF B
• BMPS
• FGF
• PDGF
• IGF
• CORTISONE
• ACTH
• THYROXINE
• GH
• PTH

24. TYPE OF STABILIZATION AND 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 ENHANCE FRACTURE 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 ENHANCE FRACTURE 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 (TRANSFORMING GROWTH 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 ( FIBROBLAST GROWTH 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 DERIVED GROWTH 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 MORPHOGENIC PROTEINS)
• 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 IN BMP-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 AND CELLULAR 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-LEVEL ALIF 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 ALSO KNOWN 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. THANK YOU