Orthopedic Basic Science Orthopedic Basic Science for General Surgeonfor General Surgeonfor General Surgeonfor General Surgeon

PongsakPongsak YuktanandanaYuktanandana MD., M.Sc.MD., M.Sc.

Associate professor of OrthopedicsAssociate professor of OrthopedicsAssociate professor of OrthopedicsAssociate professor of Orthopedics

Basic Science Section, RCOSTBasic Science Section, RCOST

Orthopaedic Tissues

Orthopaedics

Bone Healing

Osteoarthritis

BoneBone

�� Good blood supplyGood blood supply

�� Central Central Haversian Haversian CanalCanal for blood vessels for blood vessels and nerves and nerves and nerves and nerves

�� Concentric layersConcentric layers (rings) (rings) of matrix in lamellaof matrix in lamella

�� Osteocytes Osteocytes in spaces in spaces called called lacunalacuna

�� Connected to each Connected to each other and the Haversian other and the Haversian Canal by Canal by canniculi canniculi (little (little canals)canals)canals)canals)

�� CorticalCortical--compactcompact

�� TrabecularTrabecular--porousporous

�� Cells in remodeling: Cells in remodeling: osteoblasts (build),osteoblasts (build),

�� osteoclasts (remove)osteoclasts (remove)

Bone:Cortical(compact) and Bone:Cortical(compact) and

Trabecular (spongy)Trabecular (spongy)

Hierarchy of Structure of TendonHierarchy of Structure of Tendon

CartilageCartilage

�� Hyaline CartilageHyaline Cartilage --

TranslucentTranslucent-- has has

collagen fibers that are collagen fibers that are collagen fibers that are collagen fibers that are

not visible with light not visible with light

microscope. Nose, microscope. Nose,

ends of bonesends of bones

�� Elastic CartilageElastic Cartilage --

Visible elastic fibers, Visible elastic fibers,

very flexible. Ear pinna very flexible. Ear pinna very flexible. Ear pinna very flexible. Ear pinna

or auricleor auricle

�� Fibrous CartilageFibrous Cartilage --Bundles of collagen Bundles of collagen fibers, very obvious. fibers, very obvious. Intervertebral disksIntervertebral disks

Articular (Hyaline) CartilageArticular (Hyaline) Cartilage

�� Cartilage is smooth biphasic Cartilage is smooth biphasic

material found at the end of material found at the end of material found at the end of material found at the end of

bones within articulating bones within articulating

jointsjoints

�� Two distinct phases: Two distinct phases:

--Fluid phase: water and Fluid phase: water and

electrolyteselectrolytes

--Solid phase: chondrocytes, Solid phase: chondrocytes,

collagen fibrils, collagen fibrils,

proteoglycans and proteoglycans and

glycoproteinsglycoproteins

Functionality of Articular JointsFunctionality of Articular Joints

• Collagen: crosslinked stable network, tensile strengthstrength

• Proteoglycans: high charge density, compressive stiffness

Mow et. Al., Biomaterials, 13(2): 67-97, 1992.

Functionally graded structureOptimized lubricationLow coefficient of friction

100um

Structure and Composition of Articular Cartilage

}} Superficial Zone

• 15-22 % collagen

(wet weight)

Uncalcified Cartilage

Calcified Cartilage

}}

}Deep Zone

Middle Zone

Superficial Zone

Sagittal sections of rabbit finger joint cartilage stained by Safranin O and Fast Green (left) and under polarized light (right).

(wet weight)

• 4-7 % proteoglycan

• 60-85% water

• 3-5% cells (volume)

Subchondral Bone

100µm100µm

Cartilage Cartilage

Hierarchical Matrix ConstituentsHierarchical Matrix ConstituentsMacro (mm) Micro (µm) Nano (nm)

Proteoglycans, GlycosaminoglycansZone thickness:

PCM

H2O

Collagen

Proteoglycan

Force

Glycosaminoglycans

Femoral cartilage

Zone thickness:

10-80 µmAggrecan length: 400 nm width: 70 nm

Ultra-structure

(PCM) http://www.meddean.luc.edu/lumen/MedEd/Histo/HistoImages/hl4A-32.jpg(PG, Collagen) medinfo.ufl.edu/.../summer/handouts/connect.htm

(Zones) Mow et al. 1980

Ch

10 µm

Collagen fiber

diameter: 10 nm- 1 µm

thickness: 3 mm

Distance b/w cells: 10-200 µm

Bulk Testing

Nanoindentation

AFM

Histologic Section of Articular CartilageHistologic Section of Articular Cartilage

Structure of Articular CartilageStructure of Articular Cartilage

Superficial Zone : waterSuperficial Zone : water�� Superficial Zone : waterSuperficial Zone : water

�� Middle /Transition Zone: Middle /Transition Zone: 4040--6060%%

�� Deep Zone: PGDeep Zone: PG

�� Calcified Cartilagenous ZoneCalcified Cartilagenous Zone

H/E Blue lineH/E Blue line

Biomechanical Composition of Biomechanical Composition of

Articular CartilageArticular Cartilage

Biomechanical Composition of Biomechanical Composition of

Articular CartilageArticular Cartilage

�� ChondrocytesChondrocytes�� ChondrocytesChondrocytes

�� Extracellular MatrixExtracellular Matrix

1.1. Tissue Fluid :waterTissue Fluid :water

2.2. CollagenCollagen

3.3. ProteoglycanProteoglycan

4.4. NonNon--Collagenous Proteins Collagenous Proteins

Composition of Composition of 3 3 classes Hyaline classes Hyaline

Cartilage, Fibrocartilage , BoneCartilage, Fibrocartilage , Bone

waterwater

PG

WATERWATER

�� Friction resisitanceFriction resisitance

�� Pressure resistancePressure resistance80% �� Pressure resistancePressure resistance

�� NutritionNutrition

�� LubricationLubrication

�� Donnan osmotic pressure: PGDonnan osmotic pressure: PG

80%

60%

Collagen fiber architectureCollagen fiber architecture

TYPE 2,9,11 : Form fibrillar meshwork,PG >>Tensile stiffness,strengthTYPE6 : Attach chondrocyte to macromolecule framework

Proteoglycans AggregateProteoglycans Aggregate

Aggregan & Molecular organizationAggregan & Molecular organization

Charge to charge repulsive force-ve ion << Na, Ca <<< H20-ve ion << Na, Ca <<< H20

PGPG--Collagen NetworkCollagen Network

Chondrocyte Chondrocyte –– PG MetabolismPG Metabolism

Anaerobic pathwaySoluble mediator, matrix composition, Mechanical loaded, Hydrostatic Nutrition: synovial fluid, underlying bone

GaG linked

BIOCHEMICAL:IL-1MECHANICALPHYSICAL

Proteoglycan DegradationProteoglycan Degradation

AGING

Chondrocyte DensityChondrocyte Density

Immature, Maturing, AdultImmature, Maturing, Adult

BIOMECHANICS: BIOMECHANICS: BIPHASIC NATURE , DARCY’S LAWBIPHASIC NATURE , DARCY’S LAW

WATER IN INTERSTITIAL,DECREASE PERMEABILITY

FLOWFLOW--INDEPENDENT VISCOELASTIC SHEAR PROPERTIESINDEPENDENT VISCOELASTIC SHEAR PROPERTIES

BIPHASIC CREEP BEHAVIORBIPHASIC CREEP BEHAVIOR

ENERGY DISSIPATIONENERGY DISSIPATION

COMPRESSIVIE AND SHEAR PROPERTIESCOMPRESSIVIE AND SHEAR PROPERTIES

Mechanical Properties of Mechanical Properties of Orthopaedic TissuesOrthopaedic Tissues

��Compliant: Much softer than synthetic Compliant: Much softer than synthetic materialsmaterialsmaterialsmaterials

��Anisotropic:Properties depend on Anisotropic:Properties depend on orientationorientation

��NonNon--linear: stresslinear: stress--strainstrain

��Viscoelastic: time dependentViscoelastic: time dependent��Viscoelastic: time dependentViscoelastic: time dependent

��Poroelastic:fluid flow and permeabilityPoroelastic:fluid flow and permeability

��Remodeling:structural evolution Remodeling:structural evolution

Tendon: anatomyTendon: anatomy

�� Parallel collagen fibrils(Parallel collagen fibrils(8686% dry weight)% dry weight)

Proteoglycan matrix (Proteoglycan matrix (11--55% dry weight)% dry weight)�� Proteoglycan matrix (Proteoglycan matrix (11--55% dry weight)% dry weight)

�� CellsCells

�� fibroblastfibroblast

human flexor tendon

CollagenCollagen

�� Type IType I

8686% fat free dry weight% fat free dry weight�� 8686% fat free dry weight% fat free dry weight

�� 22//3 3 three amino acids (three amino acids (3333% glycine, % glycine, 1515% % proline, proline, 1515% hydroxyproline)% hydroxyproline)

�� Hydroxyproline and hydroxylysine are Hydroxyproline and hydroxylysine are unique to collagen and moleculeunique to collagen and moleculeunique to collagen and moleculeunique to collagen and molecule

Secondary Secondary structurestructure

�� Left Left handed handed configuraconfigurationtion

Blood supplyBlood supply

�� Vessel in perimysium, periosteal insertion Vessel in perimysium, periosteal insertion and surrounding tissue via paratenon and and surrounding tissue via paratenon and and surrounding tissue via paratenon and and surrounding tissue via paratenon and

mesotenonmesotenon

�� Nutrient from synovial diffusion pathway help Nutrient from synovial diffusion pathway help tendon healing without adhesiontendon healing without adhesion

BiomechanicsBiomechanics

�� Tensile propertiesTensile properties

TimeTime-- and historyand history--dependent behavior of dependent behavior of �� TimeTime-- and historyand history--dependent behavior of dependent behavior of tendonstendons

�� Factor affecting the mechanical properties Factor affecting the mechanical properties

of tendonsof tendons

Tensile properties: tendonTensile properties: tendon

�� Highest tensile strengthHighest tensile strength

Collagen is the strongest fibrous proteinCollagen is the strongest fibrous protein�� Collagen is the strongest fibrous proteinCollagen is the strongest fibrous protein

�� Collagen fiber arrange parallel to direction of Collagen fiber arrange parallel to direction of

tensile forcetensile force

�� Tensile properties is characterized by:Tensile properties is characterized by:

�� Mechanical(material) properties of tendon Mechanical(material) properties of tendon �� Mechanical(material) properties of tendon Mechanical(material) properties of tendon

�� bonebone--tendontendon--muscle structure propertiesmuscle structure properties

Mechanical property (stressMechanical property (stress--strain strain relationship) :relationship) :

�� Depend onDepend on

Architecture of collagenArchitecture of collagen�� Architecture of collagenArchitecture of collagen

�� Interaction of collagen with extracellular matrix and Interaction of collagen with extracellular matrix and

proteoglycanproteoglycan

�� CrossCross--sectional and elongation sectional and elongation

�� Stress: Stress:

�� load per crossload per cross--sectional areasectional area�� load per crossload per cross--sectional areasectional area

�� Strain: Strain:

�� change in length divided by gauge lengthchange in length divided by gauge length

Tendon: Stress Strain CurveTendon: Stress Strain Curve

Stress/strain CurveStress/strain CurveStress/strain CurveStress/strain CurveStress/strain CurveStress/strain CurveStress/strain CurveStress/strain Curve

Tendon PropertiesTendon Properties

StressStress--strain strain curvecurve

�� NonNon--linearity curvelinearity curve

�� Modulus(e,slope of the curve in MPa)Modulus(e,slope of the curve in MPa)

�� Tensile strength (Tensile strength (σσ,,ultimate tensile ultimate tensile strength MPa)strength MPa)

εε�� Ultimate strain (Ultimate strain (εε))

�� Strain energy density (Strain energy density (ωω in MPa)in MPa)

Structural propertiesStructural properties

�� Structural properties(loadStructural properties(load--elongation elongation relationship) of bonerelationship) of bone--tendontendon--muscle muscle relationship) of bonerelationship) of bone--tendontendon--muscle muscle

depend on material properties of:depend on material properties of:

�� Tendon substanceTendon substance

�� Bony insertion siteBony insertion site

�� Myotendinous junctionMyotendinous junctionMyotendinous junctionMyotendinous junction

Load elongation curveLoad elongation curve

�� Toe regionToe region�� Tendon stretch easilyTendon stretch easily�� Tendon stretch easilyTendon stretch easily

�� Straightening of crimped fiberStraightening of crimped fiber

�� Orienting fiber in direction of loadingOrienting fiber in direction of loading

�� Toe region is smaller in tendon than in ligamentToe region is smaller in tendon than in ligament

�� Linear region: Linear region: �� stiffness(slope N/mm)stiffness(slope N/mm)

�� Failure region:Failure region:�� Ultimate load (load at failure in N)Ultimate load (load at failure in N)

�� energy absorbed to failure (area under the curve)energy absorbed to failure (area under the curve)

TimeTime--history dependent history dependent viscoelastic properties of tendonsviscoelastic properties of tendons

�� Elongation depend on time and history of force Elongation depend on time and history of force applicationapplicationapplicationapplication

�� Up to interaction between collagen and ground Up to interaction between collagen and ground substancesubstance

�� Time dependentTime dependent�� Creep and stress relaxationCreep and stress relaxation

�� History dependentHistory dependent�� History dependentHistory dependent�� Shape of load elongation depend on previous loadingShape of load elongation depend on previous loading

Time dependent Time dependent

�� Creep is the time dependent elongation of tissue Creep is the time dependent elongation of tissue

when subjected to a constant load.when subjected to a constant load.

Time dependentTime dependent

�� StressStress--relaxation is the timerelaxation is the time--dependent decrease in dependent decrease in load when subjected to constant elongationload when subjected to constant elongation

History dependentHistory dependent

�� Shape of loadShape of load--elongation curve vary depend on elongation curve vary depend on

previous loading.previous loading.

�� Load and unloading curve follow different paths Load and unloading curve follow different paths

during single cycle, forming Hysteresis loop.during single cycle, forming Hysteresis loop.

�� Peak force decrease after many cycle.Peak force decrease after many cycle.

After many cycle load and unloading curve After many cycle load and unloading curve

History dependentHistory dependent

�� After many cycle load and unloading curve After many cycle load and unloading curve become similar to previous cycle.become similar to previous cycle.

�� In isometric contraction, tendon creep In isometric contraction, tendon creep shorten muscle and reduce fatigue stress.shorten muscle and reduce fatigue stress.

PreconditioningPreconditioning

�� First few cycles of elongation following inactivity First few cycles of elongation following inactivity reveal larger area of hysteresis(energy loss)reveal larger area of hysteresis(energy loss)reveal larger area of hysteresis(energy loss)reveal larger area of hysteresis(energy loss)

�� After conditioning(warm up), cycle become more After conditioning(warm up), cycle become more repeatablerepeatable

�� Preconditioning is important to avoid Preconditioning is important to avoid experimental errorexperimental error

�� After preconditioning, elastic strain energy is After preconditioning, elastic strain energy is 9090%%--9696% per cycle(save energy)% per cycle(save energy)After preconditioning, elastic strain energy is After preconditioning, elastic strain energy is 9090%%--9696% per cycle(save energy)% per cycle(save energy)

Factor affecting mechanical Factor affecting mechanical properties of tendonsproperties of tendons

�� Anatomical location Anatomical location

�� Exercise and immobilizationExercise and immobilization

�� AgeAge

�� Laser/heat treatmentLaser/heat treatment

LigamentLigament

�� Shorter and widerShorter and wider

Lower % of collagenLower % of collagen

�� Longer and narrowerLonger and narrower

�� Higher % of collagenHigher % of collagen

TendonTendon

�� Lower % of collagenLower % of collagen

�� Larger % of ground Larger % of ground

substancesubstance

�� Broader distribution Broader distribution of fiber direction of fiber direction

�� Higher % of collagenHigher % of collagen

�� Lower % of ground Lower % of ground

substancesubstance

�� More longitudinally More longitudinally organized fiber directionorganized fiber direction

Viscoelastic, nonlinear, inhomogeneous, anisotropic

Mechanical Properties of Cartilage

Testing GeometryTesting Geometry Equilibrium PropertyEquilibrium Property Dynamic PropertyDynamic Property

Confined CompressionConfined Compression HH =1 MPa, k=10=1 MPa, k=10--1515 mm44/Ns/Ns EE =10=10--20 MPa20 MPaConfined CompressionConfined Compression HHAA=1 MPa, k=10=1 MPa, k=10--1515 mm44/Ns/Ns EEdynCdynC=10=10--20 MPa20 MPa

IndentationIndentation EEss=0.5=0.5--1 MPa1 MPa

TensionTension E=4E=4--10 MPa10 MPa EEdynTdynT=40=40--400 MPa400 MPa

ShearShear µ=0.1µ=0.1--0.4 MPa0.4 MPa GG**=0.20=0.20--2.5 MPa2.5 MPa

OpticalOptical ν=0.15ν=0.15--0.210.21

Porous platen

Confining

chamberSolid platen

Fixation grips

Solid platen

(Properties) Mow et al. 1980, Korhonen et al. 2002, Setton et al. 1999, Mow and Hayes, 1997

Typical stressTypical stress--strain curve for a strain curve for a collagen containing materialcollagen containing material

Composition of BoneComposition of Bone

Stress strain for a cellular solid materialStress strain for a cellular solid material

Plateau region for elastrometric foam

Elastic plastic foam

Elastic bucklingElastic brittle foam

Stress strain for human compact boneStress strain for human compact bone

Fracture MechanicsFracture MechanicsFracture MechanicsFracture MechanicsFracture MechanicsFracture MechanicsFracture MechanicsFracture Mechanics

πσ=

*

2

E

aG

I

πσ=

aK πσ=

*E

ViscoelasticityViscoelasticityViscoelasticityViscoelasticityViscoelasticityViscoelasticityViscoelasticityViscoelasticity

Orthopedic implant material Orthopedic implant material propertiesproperties

Properties of BoneProperties of Bone

Biology of Bone RepairBiology of Bone RepairBiology of Bone RepairBiology of Bone Repair

Bone CompositionBone Composition

�� CellsCells�� OsteocytesOsteocytes�� OsteocytesOsteocytes

�� OsteoblastsOsteoblasts

�� OsteoclastsOsteoclasts

�� Extracellular MatrixExtracellular Matrix�� Organic (Organic (3535%)%)

•• Collagen (type I) Collagen (type I) 9090%%

•• Osteocalcin, osteonectin, proteoglycans, Osteocalcin, osteonectin, proteoglycans, glycosaminoglycans, lipids (ground substance)glycosaminoglycans, lipids (ground substance)

�� Inorganic (Inorganic (6565%)%)•• Primarily hydroxyapatite CaPrimarily hydroxyapatite Ca55(PO(PO44))33(OH)(OH)22

OsteoblastsOsteoblasts

�� Derived from Derived from �� Derived from Derived from mesenchymal stem mesenchymal stem

cellscells

�� Line the surface of the Line the surface of the bone and produce bone and produce

osteoidosteoidosteoidosteoid

�� Immediate precursor is Immediate precursor is fibroblastfibroblast--like like

preosteoblasts preosteoblasts

Picture courtesy Gwen Childs, PhD.

OsteocytesOsteocytes

�� Osteoblasts surrounded Osteoblasts surrounded by bone matrix by bone matrix by bone matrix by bone matrix

�� trapped in lacunaetrapped in lacunae

�� Function poorly Function poorly

understood understood

�� regulating bone regulating bone �� regulating bone regulating bone

metabolism in response metabolism in response to stress and strainto stress and strain

Picture courtesy Gwen Childs, PhD.

Osteocyte NetworkOsteocyte Network

�� Osteocyte lacunae are connected by Osteocyte lacunae are connected by canaliculicanaliculicanaliculicanaliculi

�� Osteocytes are interconnected by long cell Osteocytes are interconnected by long cell processes that project through the processes that project through the canaliculicanaliculi

�� Preosteoblasts also have connections via Preosteoblasts also have connections via canaliculi with the osteocytescanaliculi with the osteocytescanaliculi with the osteocytescanaliculi with the osteocytes

�� Network probably facilitates response of Network probably facilitates response of bone to mechanical and chemical factorsbone to mechanical and chemical factors

OsteoclastsOsteoclasts�� Derived from Derived from

hematopoietic stem hematopoietic stem cells (monocyte cells (monocyte precursor cells)precursor cells)precursor cells)precursor cells)

�� Multinucleated cells Multinucleated cells whose function is bone whose function is bone resorptionresorption

�� Reside in bone Reside in bone resorption pits resorption pits (Howship’s lacunae)(Howship’s lacunae)(Howship’s lacunae)(Howship’s lacunae)

�� Parathyroid hormone Parathyroid hormone stimulates stimulates receptors on receptors on osteoblastsosteoblasts that activate that activate osteoclastic bone osteoclastic bone resorptionresorption

Picture courtesy Gwen Childs, PhD.

Components of Bone FormationComponents of Bone Formation

�� CortexCortex

�� PeriosteumPeriosteum

�� Bone marrowBone marrow

�� Soft tissueSoft tissue

Prerequisites for Bone HealingPrerequisites for Bone Healing

��Adequate blood supplyAdequate blood supply��Adequate blood supplyAdequate blood supply

��Adequate mechanical stabilityAdequate mechanical stability

Mechanisms of Bone FormationMechanisms of Bone Formation

��Cutting ConesCutting Cones��Cutting ConesCutting Cones

�� Intramembranous Bone FormationIntramembranous Bone Formation

��Endochondral Bone FormationEndochondral Bone Formation

Cutting ConesCutting Cones

�� Primarily a Primarily a mechanism to mechanism to mechanism to mechanism to

remodel boneremodel bone

�� Osteoclasts at the Osteoclasts at the

front of the cutting front of the cutting cone remove bonecone remove bone

�� Trailing Trailing �� Trailing Trailing

osteoblasts lay osteoblasts lay down new bonedown new bone

Courtesy Drs. Charles Schwab and Bruce Martin

Intramembranous (Periosteal) Intramembranous (Periosteal)

Bone FormationBone Formation

�� Mechanism by which a long bone grows in Mechanism by which a long bone grows in �� Mechanism by which a long bone grows in Mechanism by which a long bone grows in widthwidth

�� Osteoblasts differentiate directly from Osteoblasts differentiate directly from

preosteoblasts and lay down seams of preosteoblasts and lay down seams of osteoid osteoid osteoid osteoid

�� Does NOT involve cartilage anlageDoes NOT involve cartilage anlage

Intramembranous Bone Intramembranous Bone

FormationFormation

Picture courtesy Gwen Childs, PhD.

Endochondral Bone FormationEndochondral Bone Formation

�� Mechanism by which a long bone grows in Mechanism by which a long bone grows in lengthlengthlengthlength

�� Osteoblasts line a cartilage precursorOsteoblasts line a cartilage precursor

�� The chondrocytes hypertrophy, The chondrocytes hypertrophy, degenerate and calcify (area of low degenerate and calcify (area of low oxygen tension)oxygen tension)

Vascular invasion of the cartilage occurs Vascular invasion of the cartilage occurs �� Vascular invasion of the cartilage occurs Vascular invasion of the cartilage occurs followed by ossification (increasing oxygen followed by ossification (increasing oxygen tension)tension)

Endochondral Bone FormationEndochondral Bone Formation

Picture courtesy Gwen Childs, PhD.

Blood SupplyBlood Supply

�� Long bones have Long bones have three blood suppliesthree blood suppliesthree blood suppliesthree blood supplies

�� Nutrient artery Nutrient artery

(intramedullary)(intramedullary)

�� Periosteal vesselsPeriosteal vessels

�� Metaphyseal vesselsMetaphyseal vessels

Periosteal

vessels

Nutrient

artery

Metaphyseal

vessels

Figure adapted from Rockwood and Green, 5th Ed

Nutrient ArteryNutrient Artery

�� Normally the major blood supply for the Normally the major blood supply for the �� Normally the major blood supply for the Normally the major blood supply for the diaphyseal cortex (diaphyseal cortex (80 80 to to 8585%)%)

�� Enters the long bone via a nutrient Enters the long bone via a nutrient

foramen foramen

�� Forms medullary arteries up and down the Forms medullary arteries up and down the �� Forms medullary arteries up and down the Forms medullary arteries up and down the bonebone

Periosteal VesselsPeriosteal Vessels

�� Arise from the capillaryArise from the capillary--rich periosteumrich periosteum

�� Supply outer Supply outer 15 15 to to 2020% of cortex normally% of cortex normally

�� Capable of supplying a much greater Capable of supplying a much greater proportion of the cortex in the event of injury proportion of the cortex in the event of injury

to the medullary blood supplyto the medullary blood supply

Metaphyseal VesselsMetaphyseal Vessels

�� Arise from periarticular vesselsArise from periarticular vessels�� Arise from periarticular vesselsArise from periarticular vessels

�� Penetrate the thin cortex in the Penetrate the thin cortex in the metaphyseal region and anastomose with metaphyseal region and anastomose with

the medullary blood supplythe medullary blood supply

Vascular Response in Fracture Vascular Response in Fracture

RepairRepair

�� Fracture stimulates the release of growth Fracture stimulates the release of growth �� Fracture stimulates the release of growth Fracture stimulates the release of growth factors that promote angiogenesis and factors that promote angiogenesis and

vasodilationvasodilation

�� Blood flow is increased substantially to the Blood flow is increased substantially to the fracture sitefracture sitefracture sitefracture site

�� Peaks at two weeks after fracturePeaks at two weeks after fracture

Mechanical StabilityMechanical Stability

�� Early stability promotes Early stability promotes revascularizationrevascularizationrevascularizationrevascularization

�� After first month, After first month, loading and loading and

interfragmentary interfragmentary motion promotes motion promotes greater callus formationgreater callus formationgreater callus formationgreater callus formation

Mechanical StabilityMechanical Stability

�� Mechanical load and small displacements Mechanical load and small displacements at the fracture site stimulate healingat the fracture site stimulate healingat the fracture site stimulate healingat the fracture site stimulate healing

�� Inadequate stabilization may result in Inadequate stabilization may result in excessive deformation at the fracture site excessive deformation at the fracture site interrupting tissue differentiation to bone interrupting tissue differentiation to bone (soft callus)(soft callus)

�� OverOver--stabilization, however, reduces stabilization, however, reduces �� OverOver--stabilization, however, reduces stabilization, however, reduces periosteal bone formation (hard callus)periosteal bone formation (hard callus)

Stages of Fracture HealingStages of Fracture Healing

InflammationInflammation��InflammationInflammation

��RepairRepair

��RemodelingRemodeling

�� Seconds → DaysSeconds → Days

�� Hematoma formationHematoma formation

�� Cytokines, mesenchymal cells Cytokines, mesenchymal cells

& leukocytes invade area& leukocytes invade area

Inflammation

Fracture Healing BiologyFracture Healing Biology

10

%

& leukocytes invade area& leukocytes invade area

�� Granular tissue formationGranular tissue formation

�� Days → WeeksDays → Weeks

�� FibroFibro--Cartilage formation Cartilage formation

�� Direct intramembranous Direct intramembranous

ossificationossification

�� Cartilage MaturationCartilage Maturation

�� Cartilage calcification Cartilage calcification

Repair

40

%

�� Cartilage calcification Cartilage calcification

(endochondral ossification)(endochondral ossification)

�� Weeks → MonthsWeeks → Months

�� Organization of woven bone Organization of woven bone

into lamellar boneinto lamellar bone

�� Recontouring of surfaceRecontouring of surface

Remodeling

http://www.netterimages.com/images/vtn/000/000/003/3462-150x150.jpg Einhorn, TA. JBJS, 77A(6), 940 (1995)

60

%

Mechanisms for Bone HealingMechanisms for Bone Healing

��Direct (primary) bone healingDirect (primary) bone healing

�� Indirect (secondary) bone healingIndirect (secondary) bone healing

Direct Bone HealingDirect Bone Healing

�� Mechanism of bone healing seen when there Mechanism of bone healing seen when there is no motion at the fracture site (i.e. rigid is no motion at the fracture site (i.e. rigid

internal fixation)internal fixation)

�� Does not involve formation of fracture callusDoes not involve formation of fracture callus

�� Osteoblasts originate from endothelial and Osteoblasts originate from endothelial and �� Osteoblasts originate from endothelial and Osteoblasts originate from endothelial and

perivascular cellsperivascular cells

Direct Bone HealingDirect Bone Healing

�� A cutting cone is formed that crosses the A cutting cone is formed that crosses the fracture site fracture site fracture site fracture site

�� Osteoblasts lay down lamellar bone Osteoblasts lay down lamellar bone

behind the osteoclasts forming a behind the osteoclasts forming a secondary osteonsecondary osteon

�� Gradually the fracture is healed by the Gradually the fracture is healed by the �� Gradually the fracture is healed by the Gradually the fracture is healed by the

formation of numerous secondary osteonsformation of numerous secondary osteons

�� A slow process A slow process –– months to yearsmonths to years

Direct Bone HealingDirect Bone Healing

Figure from http://www.vetmed.ufl.edu/sacs/notes

Indirect Bone HealingIndirect Bone Healing

�� Mechanism for healing in Mechanism for healing in fractures that are not rigidly fractures that are not rigidly fractures that are not rigidly fractures that are not rigidly fixed. fixed.

�� Bridging periosteal (soft) Bridging periosteal (soft) callus and medullary (hard) callus and medullary (hard) callus recallus re--establish structural establish structural continuitycontinuity

�� Callus subsequently Callus subsequently undergoes endochondral undergoes endochondral undergoes endochondral undergoes endochondral ossificationossification

�� Process fairly rapid Process fairly rapid -- weeksweeks

Local Regulation of Bone Local Regulation of Bone

HealingHealing

�� Growth factorsGrowth factors�� Growth factorsGrowth factors

�� CytokinesCytokines

�� Prostaglandins/LeukotrienesProstaglandins/Leukotrienes

�� HormonesHormones

�� Growth factor antagonistsGrowth factor antagonists

Growth FactorsGrowth Factors

�� Transforming growth factorTransforming growth factor

�� Bone morphogenetic proteinsBone morphogenetic proteins

�� Fibroblast growth factorsFibroblast growth factors

�� PlateletPlatelet--derived growth factorsderived growth factors

�� InsulinInsulin--like growth factorslike growth factors

Timing and Timing and

Function of Function of

Growth Growth

FactorsFactorsFactorsFactors

Table from Dimitriou, et al., Injury, 2005

BMP AntagonistsBMP Antagonists

�� May have important role in bone formationMay have important role in bone formation

NogginNoggin�� NogginNoggin

�� ExtraExtra--cellular inhibitorcellular inhibitor

�� Competes with BMPCompetes with BMP--2 2 for receptorsfor receptors

BMP Future DirectionsBMP Future Directions

�� BMPBMP--2 2

Increased fusion rate in spinal fusion Increased fusion rate in spinal fusion �� Increased fusion rate in spinal fusion Increased fusion rate in spinal fusion

�� BMPBMP--7 7 equally effective as ICBG in nonunionsequally effective as ICBG in nonunions

�� Must be applied locally because of rapid Must be applied locally because of rapid systemic clearance systemic clearance

�� ? Effectiveness in acute fractures? Effectiveness in acute fractures

�� ? Increased wound healing in open injuries? Increased wound healing in open injuries

�� Protein therapy vs. gene therapyProtein therapy vs. gene therapy

Cytokines Cytokines �� InterleukinInterleukin--11,,--44,,--66,,--1111, macrophage and , macrophage and

granulocyte/macrophage (GM) colonygranulocyte/macrophage (GM) colony--stimulating factors (CSFs) and Tumor stimulating factors (CSFs) and Tumor stimulating factors (CSFs) and Tumor stimulating factors (CSFs) and Tumor Necrosis FactorNecrosis Factor

�� Stimulate bone resorptionStimulate bone resorption�� ILIL--1 1 is the most potentis the most potent

�� ILIL--1 1 and ILand IL--6 6 synthesis is decreased by synthesis is decreased by estrogenestrogenestrogenestrogen�� May be mechanism for postMay be mechanism for post--menopausal bone menopausal bone

resorptionresorption

�� Peak during Peak during 11stst 24 24 hours then again during hours then again during remodelingremodeling

�� Regulate endochondral bone formationRegulate endochondral bone formation

Specific Factor Stimulation of Specific Factor Stimulation of

Osteoblasts and OsteoclastsOsteoblasts and Osteoclasts

CytokineCytokine Bone FormationBone Formation Bone ResorptionBone ResorptionCytokineCytokine Bone FormationBone Formation Bone ResorptionBone Resorption

ILIL--11 ++ ++++++

TNFTNF--αα ++ ++++++

TNFTNF--ββ ++ ++++++

TGFTGF--αα ---- ++++++

TGFTGF--ββ ++++ ++++

PDGFPDGF ++++ ++++PDGFPDGF ++++ ++++

IGFIGF--11 ++++++ 00

IGFIGF--22 ++++++ 00

FGFFGF ++++++ 00

Prostaglandins / LeukotrienesProstaglandins / Leukotrienes

�� Effect on bone resorption is species dependent Effect on bone resorption is species dependent and their overall effects in humans unknownand their overall effects in humans unknownand their overall effects in humans unknownand their overall effects in humans unknown

�� Prostaglandins of the E seriesProstaglandins of the E series�� Stimulate osteoblastic bone formationStimulate osteoblastic bone formation

�� Inhibit activity of isolated osteoclastsInhibit activity of isolated osteoclasts

�� LeukotrienesLeukotrienes�� Stimulate osteoblastic bone formationStimulate osteoblastic bone formation

�� Enhance the capacity of isolated osteoclasts to form Enhance the capacity of isolated osteoclasts to form resorption pitsresorption pits

HormonesHormones

�� EstrogenEstrogen�� Stimulates fracture healing through receptor mediated Stimulates fracture healing through receptor mediated �� Stimulates fracture healing through receptor mediated Stimulates fracture healing through receptor mediated

mechanismmechanism

�� Modulates release of a specific inhibitor of ILModulates release of a specific inhibitor of IL--11

�� Thyroid hormonesThyroid hormones�� Thyroxine and triiodothyronine stimulate osteoclastic Thyroxine and triiodothyronine stimulate osteoclastic

bone resorptionbone resorption

�� GlucocorticoidsGlucocorticoids�� GlucocorticoidsGlucocorticoids�� Inhibit calcium absorption from the gut causing Inhibit calcium absorption from the gut causing

increased PTH and therefore increased osteoclastic increased PTH and therefore increased osteoclastic bone resorptionbone resorption

Hormones (cont.)Hormones (cont.)

�� Parathyroid HormoneParathyroid Hormone

Intermittent exposure stimulatesIntermittent exposure stimulates�� Intermittent exposure stimulatesIntermittent exposure stimulates

•• OsteoblastsOsteoblasts

•• Increased bone formationIncreased bone formation

�� Growth HormoneGrowth Hormone

�� Mediated through IGFMediated through IGF--1 1 (Somatomedin(Somatomedin--C)C)�� Mediated through IGFMediated through IGF--1 1 (Somatomedin(Somatomedin--C)C)

�� Increases callus formation and fracture Increases callus formation and fracture

strengthstrength

Vascular FactorsVascular Factors

�� MetalloproteinasesMetalloproteinasesDegrade cartilage and bones to allow invasion Degrade cartilage and bones to allow invasion �� Degrade cartilage and bones to allow invasion Degrade cartilage and bones to allow invasion of vesselsof vessels

�� Angiogenic factorsAngiogenic factors�� VascularVascular--endothelial growth factorsendothelial growth factors

•• Mediate neoMediate neo--angiogenesis & endothelialangiogenesis & endothelial--cell cell specific mitogensspecific mitogensspecific mitogensspecific mitogens

�� Angiopoietin (Angiopoietin (11&&22))•• Regulate formation of larger vessels and branches Regulate formation of larger vessels and branches

Local Anatomic Factors That Local Anatomic Factors That

Influence Fracture HealingInfluence Fracture Healing�� Soft tissue injurySoft tissue injury

�� Interruption of local Interruption of local �� Interruption of local Interruption of local

blood supplyblood supply

�� Interposition of soft Interposition of soft tissue at fracture sitetissue at fracture site

�� Bone death caused Bone death caused

by radiation, thermal by radiation, thermal by radiation, thermal by radiation, thermal or chemical burns or or chemical burns or

infectioninfection

Systemic Factors That Systemic Factors That

Decrease Fracture HealingDecrease Fracture Healing�� MalnutritionMalnutrition

�� Causes reduced activity and proliferation of Causes reduced activity and proliferation of �� Causes reduced activity and proliferation of Causes reduced activity and proliferation of osteochondral cellsosteochondral cells

�� Decreased callus formationDecreased callus formation

�� SmokingSmoking�� Cigarette smoke inhibits osteoblastsCigarette smoke inhibits osteoblasts

�� Nicotine causes vasoconstriction diminishing blood Nicotine causes vasoconstriction diminishing blood flow at fracture siteflow at fracture siteflow at fracture siteflow at fracture site

�� Diabetes MellitusDiabetes Mellitus�� Associated with collagen defects including decreased Associated with collagen defects including decreased

collagen content, defective crosscollagen content, defective cross--linking and linking and alterations in collagen subalterations in collagen sub--type ratiostype ratios

Electromagnetic FieldElectromagnetic Field

�� In vitro bone deformation produces piezoelectric In vitro bone deformation produces piezoelectric currents and streaming potentialscurrents and streaming potentialscurrents and streaming potentialscurrents and streaming potentials

�� Electromagnetic (EM) devices are based on Electromagnetic (EM) devices are based on Wolff’s Law that bone responds to mechanical Wolff’s Law that bone responds to mechanical

stress: Exogenous EM fields may simulate stress: Exogenous EM fields may simulate mechanical loading and stimulate bone growth mechanical loading and stimulate bone growth and repairand repairand repairand repair

�� Clinical efficacy very controversialClinical efficacy very controversial

Types of EM DevicesTypes of EM Devices

MicroamperesMicroamperes�� MicroamperesMicroamperes

�� Direct electrical currentDirect electrical current

�� Capacitively coupled electric fieldsCapacitively coupled electric fields

�� Pulsed electromagnetic fields (PEMF)Pulsed electromagnetic fields (PEMF)

PEMFPEMF

�� Approved by the FDA for the treatment of nonApproved by the FDA for the treatment of non--unionsunionsunionsunions

�� Efficacy of bone stimulation appears to be Efficacy of bone stimulation appears to be frequency dependantfrequency dependant�� Extremely low frequency (ELF) sinusoidal electric Extremely low frequency (ELF) sinusoidal electric

fields in the physiologic range are most effective (fields in the physiologic range are most effective (15 15 to to 30 30 Hz range)Hz range)

�� Specifically, PEMF signals in the Specifically, PEMF signals in the 20 20 to to 30 30 Hz range Hz range �� Specifically, PEMF signals in the Specifically, PEMF signals in the 20 20 to to 30 30 Hz range Hz range (postural muscle activity) appear more effective than (postural muscle activity) appear more effective than those below those below 10 10 Hz (walking)Hz (walking)

UltrasoundUltrasound

�� LowLow--intensity ultrasound is approved by intensity ultrasound is approved by the FDA for stimulating healing of fresh the FDA for stimulating healing of fresh the FDA for stimulating healing of fresh the FDA for stimulating healing of fresh

fracturesfractures

�� Modulates signal transduction, increases Modulates signal transduction, increases gene expression, increases blood flow, gene expression, increases blood flow,

enhances bone remodeling and increases enhances bone remodeling and increases enhances bone remodeling and increases enhances bone remodeling and increases callus torsional strength in animal modelscallus torsional strength in animal models

UltrasoundUltrasound

�� Human clinical trials show a decreased Human clinical trials show a decreased �� Human clinical trials show a decreased Human clinical trials show a decreased time of healing in fresh fracturestime of healing in fresh fractures

�� Has also been shown to decrease the Has also been shown to decrease the

healing time in smokers potentially healing time in smokers potentially reversing the ill effects of smokingreversing the ill effects of smokingreversing the ill effects of smokingreversing the ill effects of smoking

Fracture Healing SummaryFracture Healing Summary

�� Fracture healing is influenced by many Fracture healing is influenced by many �� Fracture healing is influenced by many Fracture healing is influenced by many variables including mechanical stability, variables including mechanical stability,

electrical environment, biochemical electrical environment, biochemical factors and blood flowfactors and blood flow

�� Our ability to enhance fracture healing Our ability to enhance fracture healing

will increase as we better understand will increase as we better understand will increase as we better understand will increase as we better understand the interaction between these variables the interaction between these variables