MECHANISM OF BONE HEALING

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

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

BONE COMPOSITION

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

Bone Histology
Cells in Bone

OSTEOBLASTS

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.

OSTEOCYTES

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.

OSTEOCYTE NETWORK

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

OSTEOCLASTS

Derived from hematopoietic stem cells (monocyte precursor cells) Multinucleated cells whose function is bone resorption Reside in bone resorption pits (Howships lacunae) Parathyroid hormone stimulates receptors on osteoblasts that activate osteoclastic bone resorption
Picture courtesy Gwen Childs, PhD.

COMPONENTS OF BONE FORMATION

Cortex Periosteum Bone marrow Soft tissue

Bone Histology
Thin Section of Compact Bone

Bone Histology
Periosteum & Endosteum

BONE
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
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

Lamellar Bone

Orderly cellular distribution

Collagen

fibers arranged in parallel layers Normal adult bone

Woven Bone or immature bone (nonlamellar)

Randomly

oriented collagen fibers In adults, seen at sites of fracture healing, tendon or ligament attachment and in pathological conditions.

LAMELLAR BONE

Cortical bone

Comprised of osteons (Haversian systems) runs longitudinally

Osteons communicate with medullary cavity by Volkmanns canals that run horizontally

HAVERSIAN SYSTEM
osteocyte osteon

Haversian canal

Picture courtesy Gwen Childs, PhD.

Volkmanns canal

WOVEN BONE
Coarse with random orientation Weaker than lamellar bone Normally remodeled to lamellar bone

Figure from Rockwood and Greens: Fractures in Adults, 4th ed

 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

Potential of mesenchymal cells to deferrentiate

FRACTURE
Fracture is a break in the structural continuity of bone . It may be a crack , a crumpling or a splintering of the cortex.

TYPES OF FRACTURES

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 )

ON BASIS OF RELATIONSHIP WITH EXTERNAL ENVIRONMENT

simple / closed fracture open fracture

Transverse Oblique Spiral Comminuted Segmental

ON BASIS OF PATTERN

PREREQUISITES FOR BONE HEALING

Adequate

blood supply Adequate mechanical stability

FRACTURE HEALING
Sequence of fracture healing

Inflammation Repair Remodeling

FRACTURE HEALING

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

HISTORY
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

FOR CONVENIENCE, WE DESCRIBE FRACTURE HEALING IN TERMS OF THE THREE PHASES RECOGNIZED BY CRUESS AND DUMONT, NOTING THAT THE REPARATIVE PHASE COMBINES SEVERAL
PROCESSES.

Stages of Fracture Healing

Inflammation stage of haematoma

formation
Repair stage of granulation tissue stage of callus formation Remodelling

DURATION

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

INFLAMMATION
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.

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

REPARATIVE PHASE
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.

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

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

REPAIR

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

REMODELING

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.

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

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

Haematoma Inflammatory mediators

-Dilatation blood vessel - Plasma exudate - inflammatory cells Release by - PMN lecocytes platelets inj.cells - Macrophages - Lymphocytes

FRACTURE HEALING

Inflammation
Macrophage Degranulating platelets release
- Cytokines (PDGF, TGF ) - Interleukin 1 & 6 - Prostaglandin E2 (PGE2)

Initiation of the repair process

FRACTURE HEALING
INFLAMMATION Inflammatory Necrosis Tissue and Exudate Resorbed

Fibroplasty & Chondrocytes Appears

Produce new matrix (The fracture callus)

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

BONE HEALING

REPAIR

BONE HEALING

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

BONE HEALING REMODELING

Remodeling of bone trabecula

Accretion and remodeling of bone

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

Bone Healing

Direct bone formation in stabilized gap bone

Courtesy AO Risert laboratory

TYPES FOR BONE HEALING

Direct

(primary) bone healing Indirect (secondary) bone healing

DIRECT BONE HEALING

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

COMPONENTS OF DIRECT BONE HEALING

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)

DIRECT BONE HEALING

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

INDIRECT BONE HEALING

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

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

BONE HEALING

INJURY VARIABLES
* 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

BONE HEALING
Variables Influence Fracture Healing

Patient Variables
* Age * Nutrition Healing process needs - Energy - Proteins & carbohydrates

BONE HEALING
Patient variables * Systemic hormones - Corticosteroid ( ) - Growth hormone - Thyroid hormone - Calcitonin - Insulin - Anabolic steroids - DM - Hypervitaminosis D - Rickets * Nicotine

Rate fracture healing

Frame healing

- Inhibit fracture healing ( Vascularization?)

BONE HEALING Variables 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 Pagets disease Fibrous dysplacia Hyperparathyroidism

* Infection

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

BONE HEALING

Treatment Variables

Fracture stabilization
-Traction - Cast Imm - Ext.Fixation - Int.Fixation
Facilitate fracture healing by Preventing repeated disruption of Repair tissue

Potential disadvantage of int.fixation : Surgical exposure disrupted hematoma, blood supply Risk of infection Rigid fixation alter fracture remodeling, bone density

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

REFERENCES
Apleys System of Orthopaedic and Fractures, 9th edition eMedicine, Bone remodelling www.ncbi.nlm.nih.gov/pmc/articles/PMC3109 437/