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MECHANISM OF BONE HEALING Dr. Ashraf Ibrahim Department of Orthopaedic Hospital Tuanku Ampuan Najihah Kuala Pilah, Negeri Sembilan

Bone healing

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Page 1: Bone healing

MECHANISMOF

BONE HEALINGDr. Ashraf IbrahimDepartment of OrthopaedicHospital Tuanku Ampuan NajihahKuala Pilah, Negeri Sembilan

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Bone histology Component of bone Fracture Fracture healing Types of bone healing Variables influence fracture healing

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Cells Osteocytes Osteoblasts Osteoclasts

Extracellular Matrix Organic (35%)

Collagen (type I) 90% Osteocalcin, osteonectin, proteoglycans,

glycosaminoglycans, lipids (ground substance) Inorganic (65%)

Primarily hydroxyapatite Ca5(PO4)3(OH)2

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Bone Histology

Cells in Bone

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Derived from mesenchymal stem cells

Line the surface of the bone and produce osteoid

Immediate precursor is fibroblast-like preosteoblasts

Picture courtesy Gwen Childs, PhD.

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Osteoblasts surrounded by bone matrix trapped in lacunae

Function poorly understood regulating bone metabolism

in response to stress and strain

Picture courtesy Gwen Childs, PhD.

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Osteocyte lacunae are connected by canaliculi Osteocytes are interconnected by long cell processes

that project through the canaliculi Preosteoblasts also have connections via canaliculi with

the osteocytes Network probably facilitates response of bone to

mechanical and chemical factors

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Derived from hematopoietic stem cells (monocyte precursor cells)

Multinucleated cells whose function is bone resorption

Reside in bone resorption pits (Howship’s lacunae)

Parathyroid hormone stimulates receptors on osteoblasts that activate osteoclastic bone resorption

Picture courtesy Gwen Childs, PhD.

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Cortex

Periosteum

Bone marrow

Soft tissue

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Bone Histology

Thin Section of Compact Bone

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Bone Histology

Periosteum & Endosteum

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Structure & Composition

Bone consists of mesenchymal cells imbedded within abundant extra cellular matrix Bone matrix contains mineral gives tissue great strength & stiffness in compression and bending Organic component primary type I collagen great strength in tension

Nerves Lymphatics

BONE

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BONE

Two forms of bone tissue

Cortical or compact bone Cancellous or trabecular bone

Two types of bone (mechanical & biological properties)

Woven or immature bone Lamellar or mature bone

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Lamellar Bone Orderly cellular distribution

Collagen fibers arranged in parallel layers

Normal adult bone Woven Bone or immature bone (non-

lamellar) Randomly oriented collagen

fibers In adults, seen at sites of

fracture healing, tendon or ligament attachment and in pathological conditions.

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Cortical bone Comprised of osteons

(Haversian systems) runs longitudinally

Osteons communicate with medullary cavity by Volkmann’s canals that run horizontally

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Picture courtesy Gwen Childs, PhD.

osteon

Haversian canal

osteocyte

Volkmann’s canal

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Coarse with random orientation

Weaker than lamellar bone

Normally remodeled to lamellar bone

Figure from Rockwood and Green’s: Fractures in Adults, 4th ed

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More rapid rate of deposition & resorption Irregular woven pattern of matrix collagen fibril Four times the number of osteocyte per unit volume Irregular pattern of matrix mineralization

Less stiff & more easily deformed

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Potential of mesenchymal cells to deferrentiate

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Fracture is a break in the structural continuity of bone .

It may be a crack , a crumpling or a splintering of the cortex.

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ON BASIS OF ETIOLOGY - Traumatic fracture - pathologic fractures due to some

diseases - stress fracture ON BASIS OF DISPLACEMEMT - undisplaced - displaced translation ( shift ) angulation ( tilt ) rotation ( twist )

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ON BASIS OF RELATIONSHIP WITH EXTERNAL ENVIRONMENT simple / closed fracture open fracture

ON BASIS OF PATTERN Transverse Oblique Spiral Comminuted Segmental

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Adequate blood supply Adequate mechanical

stability

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FRACTURE HEALING

Sequence of fracture healing

Inflammation Repair Remodeling

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Introduction Fracture healing is a complex process that

requires the recruitment of appropriate cells (fibroblasts, macrophages, chondroblasts, osteoblasts, osteoclasts) and the subsequent expression of the appropriate genes (genes that control matrix production and organization, growth factors, transcription factors) at the right time and in the right anatomical location

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In 1975, Cruess and Dumont proposed that fracture healing may be considered to consist of three overlapping phases: an inflammatory phase, a reparative phase, and a remodeling phase

In 1989, FROST proposed the stages of fracture healing

five stages. stage of haematoma stage of granulation tissue stage of callus stage of modelling stage of remodelling

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Inflammation stage of haematoma

formation Repair stage of granulation

tissue stage of callus formation Remodelling

Stages of Fracture Healing

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The inflammatory phase peaks within 48 hours and is quite diminished by 1 week after fracture.

The reparative phase becomes activated within the first few days after fracture and persists for 2-3 months.

The remodelling phase lasts for many years

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inflammatory phase is identical to the typical inflammatory response of most tissues to traumatic injury.

Vasodilation and hyperemia, presumably mediated by histamines, prostaglandins, and various cytokines, accompany invasion of the injury site by neutrophils, basophils, and phagocytes that participate in clearing away necrotic debris.

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Disruption of blood vessels in the bone, marrow, periosteum, and surrounding tissue disruption at the time of injury results in the extravasation of blood at the fracture site and the formation of a hematoma

Local vessels thrombose causing bony necrosis at the edges of the fracture

Increased capillary permeability results in a local inflammatory milieu Osteoinductive growth factors stimulate the proliferation

and differentiation of mesenchymal stem cells

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The reparative phase, which usually begins 4 or 5 days after injury, is characterized by the invasion of pluripotential mesenchymal cells, which differentiate into fibroblasts, chondroblasts, and osteoblasts and form a soft primary fracture callus.

Proliferation of blood vessels (angiogenesis) within the periosteal tissues and marrow space helps route the appropriate cells to the fracture site and contributes to the formation of a bed of granulation tissue.

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Mesenchymal cells at the fracture site proliferate differentiate and produce the fracture callus

Two types of callus : Primary callus or Soft callus – forms in the

central region in which there is relatively low oxygen tension

The primary callus may consist of cartilage, fibrous tissue, osteoid, woven bone, and vessels.

If the primary callus is successful, healing progresses to the stage of bridging

callus or hard callus. Hard callus – formed at the periphery of the

callus by intermembranous bone formation

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Periosteal callus forms along the periphery of the fracture site Intramembranous ossification initiated

by preosteoblasts Intramedullary callus forms in the

center of the fracture site Endochondral ossification at the site

of the fracture hematoma Chemical and mechanical factors

stimulate callus formation and mineralization

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Figure from Brighton, et al, JBJS-A, 1991.

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The biochemical composition of the fracture callus matrix changes as repair progresses.

The cells replace the fibrin clot with a loose fibrous matrix containing glycosaminoglycans, proteoglycans, and types I and III collagen

In many regions they convert this tissue to more dense fibrocartilage or hyaline-like cartilage.

With formation of hyaline-like cartilage, type II collagen, cartilage-specific proteoglycan and link protein content increase.

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Woven bone is gradually converted to lamellar bone

Medullary cavity is reconstituted Stability of the fracture fragments progressively

increases . eventually clinical union occurs that is, the

fracture site becomes stable and pain-free. Radiographic union occurs when plain

radiographs show bone trabeculae or cortical bone crossing the fracture site, and often occurs later than clinical union .

Despite successful fracture healing, the bone density of the involved limb may be decreased for years

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Fracture HealingInflammation

Fracture damages the bone, blood vessels, bone matrix and surrounding soft tissue

Haematoma Inflammatory mediators

-Dilatation blood vessel- Plasma exudate- inflammatory cells- PMN lecocytes- Macrophages- Lymphocytes

Release byplatelets inj.cells

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FRACTURE HEALING

Inflammation

MacrophageDegranulating platelets release

- Cytokines (PDGF, TGF ß )- Interleukin 1 & 6- Prostaglandin E2 (PGE2)

Initiation of the repair process

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FRACTURE HEALINGINFLAMMATION

Inflammatory Necrosis Tissue and Exudate Resorbed

Fibroplasty & Chondrocytes Appears

Produce new matrix(The fracture callus)

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BONE HEALING

REPAIR

Growth factors Fibroblast Growth factor Angiogenesis Osteoclast Osteoblast Bone formation Mesenchymal cells Hard callus intramembranous bone Soft callus endochondral ossification Fracture callus matrix glycosaminoglycans, proteoglycans and collagen type I & III

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BONE HEALING

REPAIR

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BONE HEALING

Remodelling

Replacement of woven bone by lamellar bone Resorption of unneeded callus mechanical Stability

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BONE HEALINGREMODELING

Remodeling of bone trabecula

Accretion and remodeling of bone

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BONE HEALING

Fracture healing with rigid stabilization

* Healing with primary bone healing mechanism Gap healing Haversian remodeling

Osteoclast resorb fracture line deposition osteoblast

Blood vessels formation

The new bone matrix + osteocytes form new Haversian Systems or primary osteons

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Bone Healing

Direct bone formation in stabilized gap bone

Courtesy AO Risert laboratory

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Direct (primary) bone healing Indirect (secondary) bone healing

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Mechanism of bone healing seen when there is no motion at the fracture site (i.e. absolute stability)

Does not involve formation of fracture callus

Osteoblasts originate from endothelial and perivascular cells

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Contact Healing Direct contact between the fracture ends

allows healing to be with lamellar bone immediately

Gap 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)

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

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Mechanism for healing in fractures that have some motion, but not enough to disrupt the healing process.

Bridging periosteal (soft) callus and medullary (hard) callus re-establish structural continuity

Callus subsequently undergoes endochondral ossification

Process fairly rapid - weeks

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BONE HEALING

Variables Influence Fracture Healing

INJURY VARIABLES

* Open Fractures

Impeding or preventing formation # Hematoma Delaying formation repair tissue Risk of infection

* Severity of Injury

Retard fracture healing

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* Intra articular fractures

If the alignment & congruity joint surface is not restored Delayed healing or non union Joint stiffness

* Segmental fractures

* Soft tissue interposition

* Damage to the blood supply

INJURY VARIABLES

BONE HEALING

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BONE HEALING

Variables Influence Fracture Healing

Patient Variables

* Age* Nutrition

Healing process needs

- Energy- Proteins & carbohydrates

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- Corticosteroid ( )- Growth hormone- Thyroid hormone- Calcitonin- Insulin- Anabolic steroids- DM- Hypervitaminosis D- Rickets

* Systemic hormones

* Nicotine

- Inhibit fracture healing ( Vascularization?)

Rate fracture healing

Frame healing

BONE HEALING

Patient variables

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BONE HEALINGVariables Influence Fracture Healing

Tissue Variables* Cancellous or cortical bones* Bone necrosis* Bone disease

Pathologic fracture Osteoprosis Osteomalacia Primary malignant bone tumors Metastatic bone tumors Benign bone tumors Bone cysts Osteogenesis imperfecta Paget’s disease Fibrous dysplacia Hyperparathyroidism

* Infection

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BONE HEALING

Variables Influence Fracture Healing

Treatment Variables

• Apposition of fracture fragments• Loading & micromotion

Loading a fracture site stimulates bone formation Micromotion promotes fracture healing

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• Fracture stabilization

-Traction- Cast Imm- Ext.Fixation- Int.Fixation

Facilitate fracture healing byPreventing repeated disruption ofRepair tissue

Potential disadvantage of int.fixation :

Surgical exposure disrupted hematoma, blood supply Risk of infection Rigid fixation alter fracture remodeling, bone density

BONE HEALING

Treatment Variables

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BONE HEALING

Promote Fracture Healing

Bone Grafting • Autografts• Freezing & Freez drying allografts

Bone transport callus distraction Electrical fields

•Stimulate cell proliferation• Promote bone formation

Ultra Sound

Aggrecan gene expression Concentration intracellular Ca in callus chondrocyte

Demineralized bone matrix, growth factors & antologus bone narrow

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Apley’s System of Orthopaedic and Fractures, 9th edition

eMedicine, Bone remodelling www.ncbi.nlm.nih.gov/pmc/articles/

PMC3109437/