What is fracture?Any break in continuty of bone is fractureBUTAn injury that fractures bone not only damages itscells , blood vessels and bone matrix but alsosurrounding tissues, including periosteum andmuscles.
Components of Bone Formation•Bone marrow•Cortex•Periosteum•Soft tissueNote: Periosteum has 2 layers:•an outer fibrous layer• inner more cellular and vascular cambium layerIt covers the external surface of bone and participates in healing ofmany types of fractures.The thicker more cellular periostium of infants and children has moreextensive vascular supply therefore more active in fracture healingthan adults.
Nutrient ARTERY•Normally the major blood supply for the diaphyseal cortex (80 to 85%)•Enters the long bone via a nutrient foramen•Forms medullary arteries up and down the bonePERIOSTEAL VESSELS•Arise from the capillary-rich periosteum•Supply outer 15 to 20% of cortex normally•Capable of supplying a much greater proportion of the cortex in theevent of injury to the medullary blood supply
METAPHSEAL VESSELS•Arise from periarticular vessels•Penetrate the thin cortex in the metaphyseal region andanastomose with the medullary blood supplyVascular Response in Fracture Repair •Initially decreased flow due to disrupted vessels •In several days the blood flow greatly increases, peaking at 2 weeks •Gradually returns to normal by 12 weeks
MECHANISM OF BONE FORMATION1. Cutting Cones2. Intramembranous Bone Formation3. Endochondral Bone FormationCUTTING CONESPrimarily a mechanism to remodelboneOsteoclasts at the front of the cuttingcone remove boneTrailing osteoblasts lay down newbone
Intramembranous (Periosteal) Bone FormationMechanism by which a long bone grows in widthOsteoblasts differentiate directly from preosteoblasts and lay downseams of osteoidDoes NOT involve cartilage anlageEndochondral Bone Formation 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)
Hematoma Formation (1st)Last for less than 7 daysTissue disruption results in hematoma atthe fracture siteLocal vessels thrombose causing bonynecrosis at the edges of the fractureIncreased capillary permeability results ina local inflammatory milieuOsteoinductive growth factors stimulatethe proliferation and differentiation ofmesenchymal stem cells
Cellular Formation Phase(2nd)• 2-3 weeks• Acidic environment but turning neutral• Influx of endosteal cells fromcambium layer produce a fibrouscallus (environment has highoxygen tension) then cartilage (hasa low oxygen tension environment)
Callus Formation Phase (3rd)4-12 weeksFibroblast deposit collagen in thegranulation tissueSoft Callus is formed (Unorganizednetwork of woven bone);Internal callus (grows quickly to createrigid immobilization) The hard callus lasts 3-4 months. Hard callus – a gradual connection of bone filament to the woven bone (Acts like a temporary splint) Bone is beginning to strengthen and immobilize If proper immobilization does not occur; cartilage will form instead of bone
Periosteal callus forms along theperiphery of the fracture site Intramembranous ossification initiated by preosteoblastsIntramedullary callus forms in thecenter of the fracture site Endochondral ossification at the site of the fracture hematomaChemical and mechanical factorsstimulate callus formation andmineralization
Schematic drawing of the callus healing process. Earlyintramembranous bone formation (a), growing callus volumeand diameter mainly by enchondral ossification (b), andbridging of the fragments (c).
A: Roentgenogram of a callus healing in a tibia with theosteotomy line still visible (6 weeks p.o.).B: Histological picture of a tibia osteotomy (fracture model)after bone bridging by external and intramedullary callusformation. A few areas of fibrocartilage remain at the level ofthe former fracture line (dark areas).
Callus is the first sign of union visible onx-ray after 3 weeks of #
Ossification Phase (4 th)•1- 4 Years•It will occur with adequateimmobilization•Bone ends become crossed with a newHaversian system that will eventuallylead to the laying down of primarybone Fracture is bridged and united
Remodeling Phase (5th)•Remodeling hard callus to compact bone or woven bone is graduallyconverted to lamellar bone.•May take a few years•Medullary cavity is reconstituted•Bone is restructured in response to stress and strain (Wolff’s Law)
Differences in healing between cortical and cancellousbone:Healing in cancellous bone occurs without the formation ofsignificant external callus.After the inflammatory stage bone formation is dominated byintramembranous ossificationThis is due to tremendous angiogenic potential of trabecular boneas well as fixation used for metaphyseal fractures which is oftenmore stable.
Prerequisites for Bone Healing•Adequate blood supply•Adequate mechanical stabilityMechanisms for Bone Healing•Direct (primary) bone healing•Indirect (secondary) bone healing
DIRECT BONE HEALINGMechanism of bone healing seen when there is no motion at thefracture site (i.e. rigid internal fixation)Does not involve formation of fracture callusOsteoblasts originate from endothelial and perivascular cellsA cutting cone is formed that crosses the fracture siteOsteoblasts lay down lamellar bone behind the osteoclasts forming asecondary osteonGradually the fracture is healed by the formation of numeroussecondary osteons A slow process – months to years
Components of Direct Bone HealingContact Healing Direct contact between the fracture ends allows healing to be with lamellar bone immediatelyGap 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)
INDIRECT BONE HEALING•Mechanism for healing in fracturesthat are not rigidly fixed.•Bridging periosteal (soft) callus andmedullary (hard) callus re-establishstructural continuity•Callus subsequently undergoesendochondral ossification•Process fairly rapid - weeks
Local Regulators of Bone Healing•Growth factors•Cytokines•Prostaglandins/Leukotrienes•Hormones•Growth factor antagonists
TRANSFORMING GROWTH FACTORS•Superfamily of growth factors (~34 members)•Act on serine/threonine kinase cell wall receptors•Promotes proliferation and differentiation of mesenchymalprecursors for osteoblasts, osteoclasts and chondrocytes•Stimulates both endochondral and intramembranous boneformation•Induces synthesis of cartilage-specific proteoglycans and typeII collagen•Stimulates collagen synthesis by osteoblasts
BONE MORPHOGENETIC PROTIENSOsteoinductive proteins initially isolated from demineralizedbone matrix Proven by bone formation in heterotopic muscle pouchInduce cell differentiation BMP-3 (osteogenin) is an extremely potent inducer of mesenchymal tissue differentiation into bonePromote endochondral ossification BMP-2 and BMP-7 induce endochondral bone formation in segmental defectsRegulate extracellular matrix production BMP-1 is an enzyme that cleaves the carboxy termini of procollagens I, II and III
These are included in the TGF-β family Except BMP-1BMP2-7,9 are osteoinductiveBMP2,6, & 9 may be the most potent in osteoblastic differentiationWork through the intracellular Smad pathwayFollow a dose/response ratio BMP ANTAGONISTS May have important role in bone formation Noggin Extra-cellular inhibitor Competes with BMP-2 for receptors
BMP FUTURE DIRECTIONS•BMP-2 •Increased fusion rate in spinal fusion•Must be applied locally because of rapid systemic clearance••? Effectiveness in acute fractures•? Increased wound healing in open injuries•Protein therapy vs. gene therapy
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
PLATELET DERIVED GROWTH FACTORS•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•PDGF-AB Increases type I collagen synthesis by increasing thenumber of osteoblasts•PDGF-BB stimulates bone resorption by increasing the numberof osteoclasts
INSULIN LIKE GROWTH FACTORSTwo types: IGF-I and IGF-II Synthesized by multiple tissues IGF-I production in the liver is stimulated by Growth HormoneStimulates bone collagen and matrix synthesisStimulates replication of osteoblastsInhibits bone collagen degradation
CYTOKINES•Interleukin-1,-4,-6,-11, macrophage andgranulocyte/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 resorptionPeak during 1st 24 hours then again during remodeling•Regulate endochondral bone formation
PROSTAGLANDINS/LEUKOTRIENSEffect on bone resorption is species dependent and their overalleffects in humans unknownProstaglandins of the E series •Stimulate osteoblastic bone formation •Inhibit activity of isolated osteoclastsLeukotrienes Stimulate osteoblastic bone formation Enhance the capacity of isolated osteoclasts to form resorption pits
HORMONES•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
Parathyroid Hormone Intermittent exposure stimulates •Osteoblasts •Increased bone formationGrowth Hormone •Mediated through IGF-1 (Somatomedin-C) •Increases callus formation and fracture strength•VASCULAR FACTORSMetalloproteinases Degrade cartilage and bones to allow invasion of vesselsAngiogenic factors Vascular-endothelial growth factors Mediate neo-angiogenesis & endothelial-cell specific mitogens Angiopoietin (1&2) Regulate formation of larger vessels and branches
Bone Healing under Interfragmentary MovementFracture healing under interfragmentary movement occurs bycallus formation that mechanically unites the bony fragments.•The flexural and torsional rigidity of a fracture depends on thematerial properties and the second moment of inertia (rigidity= EI) of the callus.•Particularly the increase in callus diameter has a significanteffect on the stabilization of the fracture.• Linear relation to the mechanical quality of the callus tissue(E),•The rigidity is proportional to the fourth power of thediameter (IBending = πd4/64, ITorsion = π d4/32)
The interfragmentary movement under external loadingdecreases with healing time in relation to the rigidity of thecallus. Finally, the hard callus bridges the bony fragments andreduces the interfragmentary movement to such a low level thata healing of the fracture in the cortex can take placeWhen this has happened, the callus tissue is no longer requiredand is resorbed by osteoclasts. Finally, after a remodeling process, the shape and strength ofthe normal bone are reconstituted
Healed osteotomy of a metatarsal with bony bridging ofthe cortical osteotomy gap and only small remaining callus volume.
Fracture Healing under Interfragmentary Compression•Implants and external loads Compression forcescompression and close contact ( the external traction forces =>the internal compression preload )•compression preload +friction between thefragmentsrelative movement between the fragments isavoided.•Under this absolutely stable fixation, bone healing can occurby direct osteonal bridging of the fracture line with minimallyor no callus formation .•In areas with direct contact, remodeling starts a few weeksafter fracture fixation, which leads to bridging of the fragmentsby newly formed osteons .
Haversian osteons with osteoclasts in their cutter headsresorb bone, create a tunnel that crosses the fracture line,and fill the tunnel with new bone in a process ofosteoblastic activity.In areas with a gap between the fragments, a filling of thegap by woven bone occurs as a first step before theHaversian osteons can cross the fracture area .In reality a mixture of contact and gap healing will occur.
Osteon with bone-resorbing osteoclasts (left) that drill a tunnel intothe bone and osteoblasts that lay down new bone (osteoid) and fillthe tunnel with a new bone layer (original magnification 100×) New Osteoclast Osteoblast bone
Contact healing with osteons crossing the fracture line (left). Healingof a fracture gap (right). Woven bone fills the gap before the osteonscan bridge the fracture area.
An advantage of absolute stability is that the blood vessels maycross the fracture site more easily and lead to fasterrevascularization .In contrast to callus healing, there is no increased bonediameter under direct osteonal healing.This limits the load-bearing capacity of the healing bone, whichconsequently requires a longer period of protection by theimplant.
Delayed Healing and Nonhealing under Unstable FixationWhen the interfragmentary movement is too large, the bony bridging ofthe fragments is delayed or even prevented.Large interfragmentary movements cause large tissue strains andhydrostatic pressures in the fracture that prevent the vascularization ofthe fracture zone.Without this vascularization bone cells cannot survive, bone cannot bebuilt, and only fibrocartilage can be formed . Because the resisting fibrocartilage layer in between the two bonyfragments looks like the image of a joint, the nonunion is also calledpseudarthrosis (false joint).
Variables that influence fracture healing:1. Injury variables :• Open fractures• Severity of injury : The more impact the injury has made on bone and on the tissues surrounding it, the worse the healing will become. Slight injury will only likely cause mild contusions and will thus heal so easily. However, comminuted injuries which also damaged the surrounding tissues will not heal that quickly.• Intra articular fractures : Collagenasses can break the healing process of the bone as these fractures continue to be in contact with synovial fluid. The more that collegenasses partner with synovial fluid, the slower the healing process will even become.
• Segmental fractures• Soft tissues interposition• Damage to the blood supply : Regulate blood supply well for lack of it will drag down the healing process. This is one of the factors affecting bone healing especially in parts such a scaphoid bones, talus, and femoral head. 2. Patient variables • Diseases/Disorders : Diseases which are discovered to slow down the healing of fractures are diabetes, osteoporosis, and others which result to immunocompromised state. Abnormal healing is also caused by diseases such as Ehlers-Danlos syndrome and Marfan’s syndrome.
• Age : The younger the patients and the bones are, the faster the healing process works. Young patients have bones with the ability to recover from deformities soon enough and remodel them. However, the remodeling and recovering abilities of the bones decrease as they reach maturity.• Nutrition : For healing to occur, energy is necessary in the form of protein and carbohydrates.• Systemic hormones : These hormones that affect bone healing include the growth hormone, thyroid hormone, calcitonin, and corticosteroids. The last hormone mentioned can slow down the healing process.• Nicotine and other agents
3. Tissue variables• Form of bone (cancellous or cortical) : Two types of bones – calcellous or spongy and cortical or compact bones – can be compared with the differences in the rate of their healing duration. The spongy bones have greater surface areas, more stable, and have better foods when put side by side with compact bones.• Bone necrosis• Bone disease : Any disease process that weakens the musculoskeletal tissue, like osteoporosis or osteomalacia, may impair union.• Infection : Infections cause necrosis and edema, take energy away from the healing process, and may increase the mobility of the fracture site.
4. Treatement variables• Apposition of fracture fragments : Normal apposition of fracture fragments is needed for union to occur. Inadequate reduction, excessive traction, or interposition of soft tissue will prevent healing• Loading and micromotion Inter Fragmentary Movement- Axial Movement Small interfragmentary(IFM) movements stimulate callus formation Small fracture gaps Cyclic axial movement stimulated callus volume to be advantageous
Large fracture gaps Callus formation seems to be limited and bridging of the fracture gap is delayedVery stiff fixation of a fracture can suppress the callus formationand delay healing. In such cases, an externally appliedinterfragmentary movement can be used to stimulate callus healing.However, when the fracture fixation itself allows axial movements toa sufficient extent to stimulate callus formation, an additionalexternal application of interfragmentary movements does not leadto further improvement of the healing process.
Shear MovementShear movement delays the fracture healing ? Impede vascularization and promote fibrous tissue differentiation Oblique tibial fracture (shear movements : 4 mm) -- treated with functional bracing show rapid natural healingShear movement to induce delayed unions and nonunions ? Control Shear movement Osteotomies of oblique or transverse type
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