Bone Healing & Bone Grafting Yin-Chih Fu Associate Professor Orthopedic Department Kaohsiung...

Bone Healing & Bone Bone Healing & Bone GraftingGrafting

Yin-Chih FuYin-Chih FuAssociate ProfessorAssociate ProfessorOrthopedic DepartmentOrthopedic DepartmentKaohsiung Municipal Hsiao-Kang HospitalKaohsiung Municipal Hsiao-Kang HospitalKaohsiung Medical University HospitalKaohsiung Medical University Hospital

2014.08.162014.08.16

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Healing in Bone

• 1D - Hematoma formation (fibrin mesh)

• 3D - Inflammation – PDGF, IL, TGF• 1W - Soft callus – granulation, matrix.• 3-6W - Callus – ossification, woven

bone• 8+W - Re-modeling – absorb/deposit,

strength, lamellate.

Fracture

1 Day Hematoma formation (fibrin mesh)

3 DayInflammation – PDGF, IL, TGF

黃金 72小時

inflammatory cellsRelease PDGF, IL, TGF

3 DayInflammation – PDGF, IL, TGF

Macrophage, PMN

清理戰場

1 WeekSoft callus – BMP-2, VEGF, Angiopoietin-1, 2

ChondrocytesRelease VEGF

1 WeekSoft callus – granulation, matrix.

VEGF, Angiopoietin-1, 2

3-6 WeekCallus – ossification, woven bone

Stages of wound healing

Time after injury

Hemostasis

Inflammation

Proliferation

Resolution/ Remodeling

PMNs, Macrophages, Lymphocytes

Reepithelialization, Angiogenesis, Fibrogenesis,

Vessel regression, Collagen remodeling

Fibrin clot, platelet deposition

1D 3D 1wk 6wk 8wk

Healing in Bone

Fracture Healing

• Indirect healing (Secondary, Callus)

• Direct healing (Primary)

Fracture Healing

Indirect healing (Secondary, Callus)Formation of bone via tissues which undergo change in material structure until skeletal continuity is restored

Direct healing (Primary)

Indirect Fracture Healing

Impact Hematoma

Hemopoetic cells secrete growth factors

Fibroblasts, osteoprogenitor cells, mesenchymal cells


Impact Hematoma Inflammation

Granulation tissue 100% strain at failure


Impact Hematoma Inflammation Soft Callus

2 weeks 10% strain at failure


Impact Hematoma Inflammation Soft Callus Hard Callus

2% strain at failure


•Impact

•Haematoma

•Inflammation

•Soft Callus

•Hard Callus

•Remodeling– Years– Wolff’s law

VOL. 84-B, No. 8, NOVEMBER 2002

Indirect Healing - Movement• Movement is desirable• Provided the movement does

not disrupt the healing cells

10m 5m5m40m 10m

Comminuted fragment

Direct Fracture Healing

• Fracture stable– No movement under physiological load

• Bone ends compressed– Can occur in cortical and cancellous bone

Direct Fracture Healing

• No callus• Cutting cones cross

fracture site• Lay down new

osteones directly

Direct Healing

• Movement

– Undesirable

– Even small amounts likely to disrupt healing

Absolute stability

Augmentation of fracture healing

• Bone Grafts• Bone Graft Substitutes• Osteo-inductive agents• Mechanical methods• Ultrasound• Electromagnetic fields

Bone substitutes

• An agent for the prevention of treatment of nonunoins

• As a “void filler” to maintain joint of metaphyseal alignment

Bone Graft Properties• Osteoconduction

– 3D scaffold• Osteo-induction

– Biological stimulus• Mesenchymal cells

Osteoprogenitor cells

• Osteogenic– Contains living cells that

can differentiate to from bone

• Structural

AutograftAutograftAdvantagesAdvantages

Osteoinductivity and osteoconductivityOsteoinductivity and osteoconductivity

OsteogenesisOsteogenesis

Cortical and cancellous formsCortical and cancellous forms

Structural supportStructural support

BiocompatibilityBiocompatibility

Host site incorporationHost site incorporation

Remodeling into normal boneRemodeling into normal bone36

AutograftAutograft

DisadvantagesDisadvantages

Limited supplyLimited supply

Variable qualityVariable quality

Difficulty of harvestingDifficulty of harvesting

Increases in surgical time, hospital stay, and costIncreases in surgical time, hospital stay, and cost

Postoperative pain, risk of infection, risk of Postoperative pain, risk of infection, risk of fracturefracture

Potential nidus for infection (avascular bone)Potential nidus for infection (avascular bone)

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AllograftAllograft

Herrera and investigator report on distal radial Herrera and investigator report on distal radial fractures treated with external fixation and fractures treated with external fixation and internal fixation together with cancellous bone internal fixation together with cancellous bone grafts and concluded that grafts and concluded that allograft was a allograft was a useful adjunct for treatment of unstable distal useful adjunct for treatment of unstable distal radial fracturesradial fractures

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AllograftAllograft

No Level I evidence supports corticocancellous No Level I evidence supports corticocancellous allografts in reconstructive trauma surgery, but allografts in reconstructive trauma surgery, but Level II and IV evidence does exist, as noted Level II and IV evidence does exist, as noted earlier.earlier.

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Osteo-inductive agents

• Transforming growth factor Superfamily– BMPs

– GDFs (growth differentiation factors)

– Possibly TGF-β 1, 2, and 3.

Demineralized bone matrix

•Acid extraction of allograft

– type-1 collagen– non-

collagenous proteins

– osteoinductive growth factors: BMP, GDFs, TGF1,2 + 3

Different companies , processing differentALLOGRAFT, no reported infection transmission

Demineralized Bone Demineralized Bone MatrixMatrix

One prospective, controlled study showed One prospective, controlled study showed equivalent rates of spinal fusion between sides equivalent rates of spinal fusion between sides in patients who had been treated with in patients who had been treated with autograft on one side and a 2:1 ratio autograft on one side and a 2:1 ratio composite of Grafton DBM gel and autograft on composite of Grafton DBM gel and autograft on the other, suggesting the the other, suggesting the potential use of potential use of Grafton DBM as a bone graft extender in spine Grafton DBM as a bone graft extender in spine fusionsfusions

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Concentrated bone marrow aspirate

• Non union – 75-95% success• Aseptic non-unions

– Only works if adequate cell concentration

– Hernigou Pet al Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am. 2005;87:1430 -7

• Concentrated BM aspirate– Ongoing multicentre RCT in

France– Open tibial fractures

Clinical Application of Clinical Application of Autologous Bone MarrowAutologous Bone Marrow

No level I or II evidence documents the No level I or II evidence documents the effectiveness of bone marrow for the effectiveness of bone marrow for the enhancement of bone healing.enhancement of bone healing.

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Osteoconductive

Osteoinductive

BMP 7 (OP-1)

• Tibial non-unions– RCT OP1 v autogenous graft– No difference in union rate– Less infections – Friedlaender et al J Bone Joint Surg Am. 2001;83 Suppl

1(Pt 2):S151-8.

• Open Tibia– OP1 v control– Less secondary interventions– McKee et al Proceedings of the 18th Annual

Meeting of the Orthopaedic Trauma Association; 2002 Oct 11-13

BMP 2

• Open tibial fractures– Control v 6mg v 12mg– Higher dose

• Fewer secondary procedures• accelerated time to union• improved wound-healing• Reduced infection rateGovender et al Recombinant human bone morphogenetic protein-2

for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84:2123-34.

Human Bone Morphogenetic Human Bone Morphogenetic Protein (hBMP)Protein (hBMP)

No Level I evidence that rhBMP in combination No Level I evidence that rhBMP in combination with the usual internal fixation will reduce the with the usual internal fixation will reduce the nonunion rate in these patientsnonunion rate in these patients

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Human Bone Morphogenetic Human Bone Morphogenetic Protein (hBMP)Protein (hBMP)

Only Level II evidence that BMPs can be useful Only Level II evidence that BMPs can be useful in areas other than spine fusionin areas other than spine fusion

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Osteoconductive

Making the break. Karin Hing's fellowship has brought independence to pursue her work on bone graft substitutes.

Osteoconductive Osteoconductive materials Vs autograft encouraging.– Calcium sulfate

• Predictable resorption• Resorbs a little too fast

– Calcium phosphates • Tricalcium phosphate TCP• Hydroxyapatite• TCP is more rapidly absorbed than hydroxyapatite, TCP

inadequate when structural support is desired– Injectable osteoconductive cements

• Several variations

Graft substitutesGraft substitutes

There is no absolute indication for using graft There is no absolute indication for using graft in the fracture setting, but it may be a useful in the fracture setting, but it may be a useful adjunctadjunct

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The use of graft substitutes can be The use of graft substitutes can be considered for a comminuted distal considered for a comminuted distal radius fracture with a substantial radius fracture with a substantial metaphyseal voidmetaphyseal void

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Calcium Phosphate Calcium Phosphate Synthetic SubstitutesSynthetic Substitutes

The calcium phosphate synthetic substitutes The calcium phosphate synthetic substitutes have been investigated as devices by the FDA have been investigated as devices by the FDA and by industry over the last 8 yearsand by industry over the last 8 years

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• Dynagraft®(GenSci): 採用 PF-127(Pluronic®) 為載體製成

黏土狀

• Osteofil® SoloCervical Allograft(Regeneration

Technologies): 則是以膠原蛋白 (collagen) 為載體

• Grafton® (Osteotech): 則採用丙三醇 (glycerol) 為載體 , 以增

加黏稠度之方式賦予產品良好之可塑性

可塑性之凝膠 (gel) 或黏土 (putty) 狀之骨填補材

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• 使用磷酸鈣鹽類粉體與磷酸溶液混合後 , 在 37°C 時

可因水合作用產生自我硬化 (self-setting) 之磷酸鈣骨水

泥 (calcium phosphate cement, CPC)

• BoneSource® (Stryker Leibinger)

• α-BSM®(Etex)

• Norian® SRS®(Skeletal Repair System)

(Synthes)

具有可注射性 (injectable)

Higher compressive strength of calcium phosphate bone substitute in a biomechanical study of tibial plateau fractures

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Level I evidence supports the use of bioabsorbable calcium phosphate material,

such as α-BSM, as the treatment of choice for subarticular defects in tibial plateau fractures.

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Zimmermann and colleagues found significantly better DASH scores in distal radius fractures for the calcium phosphate group.

Six of the studies also reported loss-of-reduction outcome, and calcium phosphate significantly reduced the incidence of loss of fracture reduction compared with controls

Loss of fracture alignment was 48% less likely when calcium phosphate was used. For every 17 patients treated with calcium phosphate, one loss of fracture reduction could be prevented

DASH scores in distal radius DASH scores in distal radius fracturesfractures

Calcium SulfateCalcium Sulfate Synthetic Synthetic Substitutes OsteoSet (Wright Substitutes OsteoSet (Wright

Medical Technology, Arlington, TN)Medical Technology, Arlington, TN)

There is no Level I or II There is no Level I or II evidence that the healing is evidence that the healing is enhanced, and indeed, healing enhanced, and indeed, healing may be worse in periarticular may be worse in periarticular injuries or nonunions with the injuries or nonunions with the addition of calcium sulfateaddition of calcium sulfate

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Calcium sulfate Calcium sulfate complicationscomplications

Some cases of severe inflammatory response Some cases of severe inflammatory response particularly in tumor cases. particularly in tumor cases.

It has been hypothesized that the rapid It has been hypothesized that the rapid absorption of the calcium sulfate pellets into a absorption of the calcium sulfate pellets into a calcium-rich fluid stimulates inflammationcalcium-rich fluid stimulates inflammation

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Recommendations for Fixation of Recommendations for Fixation of the Wrist Using Bone Graft the Wrist Using Bone Graft

SubstitutesSubstitutes

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Fracture and/or other Fracture and/or other defectdefect

Recommended Recommended TreatmentTreatment

Simple distal radius fracture with Simple distal radius fracture with significant metaphyseal defectsignificant metaphyseal defect Calcium phosphateCalcium phosphate cement + pins cement + pins

significant cortical and metaphyseal significant cortical and metaphyseal defectdefect

Calcium phosphateCalcium phosphate cement + plate cement + plate and screws in osteoporotic bone or and screws in osteoporotic bone or

tricalcium phosphate in good-quality tricalcium phosphate in good-quality bonebone

Distal radius malunion (metaphyseal)Distal radius malunion (metaphyseal)Plate and screws + Plate and screws + calcium calcium

phosphatephosphate cement or iliac crest bone cement or iliac crest bone graftgraft

Radius, ulna, humerus nonunion Radius, ulna, humerus nonunion (metaphyseal or diaphyseal)(metaphyseal or diaphyseal)

Iliac crest bone graft or tricalcium Iliac crest bone graft or tricalcium phosphate+ bone marrow aspirate phosphate+ bone marrow aspirate

+/- BMP+electrical stimulation+/- BMP+electrical stimulation

Tricalcium phosphateTricalcium phosphate vs vs

Calcium phosphateCalcium phosphate

Tricalcium phosphateTricalcium phosphate

Porous, looks like crumbly chalkPorous, looks like crumbly chalk

Poor strength: require cortical integrity Poor strength: require cortical integrity

Prefer to fill a diaphyseal defectPrefer to fill a diaphyseal defect


Like grout rather than glueLike grout rather than glue

Minimal exothermic,and lack the tensile Minimal exothermic,and lack the tensile propertiesproperties

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Tricalcium phosphateTricalcium phosphate

Can be used if sufficient cortical integrity exists Can be used if sufficient cortical integrity exists

Simple fracture or defectSimple fracture or defect

Cortical strength is reestablished with plates, Cortical strength is reestablished with plates, pins, or an external fixatorpins, or an external fixator

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The defect is The defect is larger than 1 cmlarger than 1 cm and the primary and the primary purpose of reconstituting the metaphysis is to purpose of reconstituting the metaphysis is to resist resist compressive forcescompressive forces

Can be used Can be used in a comminuted intra-articular in a comminuted intra-articular fracture that alignment can be restored with fracture that alignment can be restored with no gap no gap

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ContraindicationsContraindications

Should not be used for a comminuted intra-Should not be used for a comminuted intra-articular fracture of the radiusarticular fracture of the radius

Local shear stresses that exceed the Local shear stresses that exceed the compressive strength capabilitiescompressive strength capabilities

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MIIG® X3 High Strength Injectable

Graft For Compression Fractures

（ an injectable calcium sulfate）

•InjectsInjects

•ResorbsResorbs

•Remodels into boneRemodels into bone

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PRO-DENSE® Bone Graft SubstitutePRO-DENSE® Bone Graft Substitute

75% CaSO475% CaSO4

Primary osteoconductive Primary osteoconductive fillerfiller

Resorbs first primarily Resorbs first primarily through simple dissolution through simple dissolution to allow early vascular to allow early vascular infiltrationinfiltration

25% CaPO425% CaPO4(brushite and granular (brushite and granular TCP)TCP)

Osteoclastic resorptionOsteoclastic resorption

Secondary porous scaffold Secondary porous scaffold that is resorbed after that is resorbed after primary fillerprimary filler

TCP granules are resorbed TCP granules are resorbed in the third and final in the third and final phasephase

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Composited of osteoinductive and Composited of osteoinductive and osteoconductive materials may be osteoconductive materials may be useful for both periarticular useful for both periarticular metaphyseal defects and metaphyseal defects and diaphyseal defectsdiaphyseal defects

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Thank You

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Bone Healing & Bone Grafting Yin-Chih Fu Associate Professor Orthopedic Department Kaohsiung...

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