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Bone histology, injury and repair :

Dr Ahmad shakib muhibi Bone histology, injury and repair


Definition Rigid form of connective tissue in which the extracellular matrix is impregnated with inorganic salt , mainly calcium phosphate and carbonate , providing hardness

Objectives :

Objectives Types of bone Bone membranes Bone composition Bone signaling and RANKLE Bone metabolism Bone ossification Bone growth, remolding and repair Factors affecting bone growth

Classification of bone types:

Classification of bone types Anatomy long bones flat bones Structure macroscopic appearance Cortical or compact bone Spongy or cancellous or trabecular bone microscopic appearance woven bone or immature bone lamellar bone

Morphology :

Morphology Compact Bone – cortical bone runs throughout the length of bone forming a hollow cylinder Spongy Bone –   Light, honeycomb like structure Trabeculae arranged in directions of tension & compression Present at ends of long bones Makes up most of the bone in vertebrates

Cortical bone :

80% skeleton Metabolism Structure osteon vascular canals interstitial lamellae Cortical bone

Cancellous bone or spongy bone:

Metabolism Structure Cancellous bone or spongy bone

Microscopic bone types :

Microscopic bone types Lamellar Bone Collagen fibers arranged in parallel layers Normal adult bone Woven Bone (non-lamellar) Randomly oriented collagen fibers In adults, seen at sites of fracture healing, tendon or ligament attachment and in pathological conditions

Bone membranes :

Bone membranes Two layers periosteum endosteum Functions Osteogenic Growth and repair

Bone Composition:

Bone Composition Cells Osteocytes Osteoblasts Osteoclasts Osteoprogenitor cells Extracellular Matrix Organic (35%) Collagen (type I) 90% Osteocalcin, osteonectin, proteoglycans, glycosaminoglycans, lipids (ground substance) Inorganic (65%) Primarily hydroxyapatite Ca 5 (PO 4 ) 3 (OH) 2


Osteoblasts Derived from mesenchymal stem cells Line the surface of the bone and produce osteoid Immediate precursor is fibroblast-like preosteoblasts


Osteocytes Osteoblasts surrounded by bone matrix trapped in lacunae Function poorly understood regulating bone metabolism in response to stress and strain

Osteocyte Network:

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 (Howship’s lacunae) Parathyroid hormone, osteoblasts, macrophages and lymphocyte stimulates receptors on osteoclast that activate osteoclastic bone resorption


Carbonic anhydrase Vacuolar atp ase or proton pump Low ph

Bone Signaling & RANKL :

Bone Signaling & RANKL Bone metabolism is a dynamic process that balances bone formation and bone resorption Bone resorption is done by active osteoclasts. molecules stimulating osteoclasts are RANKL PTH Interleukin 1and 6 1,25 dihydroxy vitamin D PGE2


Osteoclasts inhibiting factors Osteoprotegerin (OPG Calcitonin Estrogen transforming growth factor beta (via increase in OPG) interleukin 10 (IL-10

Normal Bone Metabolism :

Normal Bone Metabolism Regulators of bone metabolism Hormones PTH Calcitonin Sex Hormones (eg. estrogen, androgens) Growth Hormone Thyroid Hormones Steroids Vitamin D  Glucocorticosteroid

Calcitonin :

Calcitonin Origin produced by clear cells in the parafollicles of the thyroid gland (C cells) Net effect limited role in calcium homeostasis inhibit number and activity of osteoclasts  Function bone inhibits osteoclastic bone resorption by decreasing number and activity of osteoclasts osteoclast have receptor for calcitonin Inc. serum Ca > secretion of calcitonin > inhibition of osteoclasts > dec. Ca (transiently)  

Bone ossification:

Bone ossification By two methods Enchondral ossification occurs in longitudinal physeal growth embryonic long bone formation non-rigid fracture healing (secondary healing) Intramembranous ossification embryonic flat bone formation distraction osteogenesis bone formation fracture healing with rigid fixation (compression plate )

Intramembranous ossification:

Intramembranous ossification

Blood Supply:

Blood Supply Long bones have three blood supplies Nutrient artery (intramedullary) Periosteal vessels Metaphyseal vessels

Nutrient Artery:

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 bone

Periosteal Vessels:

Periosteal 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 the event of injury to the medullary blood supply

Metaphyseal Vessels:

Metaphyseal Vessels Arise from periarticular vessels Penetrate the thin cortex in the metaphyseal region and anastomose with the medullary blood supply

Vascular Response in Fracture Repair:

Vascular Response in Fracture Repair Fracture stimulates the release of growth factors that promote angiogenesis and vasodilation Blood flow is increased substantially to the fracture site this peaks at 2 weeks and normalizes at 3-5 months

Stages of Fracture Healing:

Stages of Fracture Healing Inflammation Repair Remodeling


Inflammation Tissue disruption results in hematoma at the fracture site Local vessels thrombose causing bony necrosis at the edges of the fracture Increased capillary permeability results in a local inflammatory response Osteoinductive growth factors stimulate the proliferation and differentiation of mesenchymal stem cells


Repair 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 Woven bone is gradually converted to lamellar bone Medullary cavity is reconstituted Bone is restructured in response to stress and strain (Wolff’s Law)

Remodeling :

Remodeling Wolff's Law bone remodels in response to mechanical stress Piezoelectic charges bone remodels is response to electric charges compression side is electronegative and stimulates osteoblast formation tension side is electropostive and stimulates osteoclasts Hueter-Volkmann Law theory that bone remodels in small packets of cells known as Basic Multicellular Units (BMUs) theory suggest that mechanical forces influence longitudinal growth compressive forces inhibit grow

Mechanisms for Bone Healing:

Mechanisms for Bone Healing Direct (primary) bone healing Indirect (secondary) bone healing

Direct 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 A cutting cone is formed that crosses the fracture site Osteoblasts lay down lamellar bone behind the osteoclasts forming a secondary osteon Gradually the fracture is healed by the formation of numerous secondary osteons A slow process – months to years

Components of Direct Bone Healing:

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)

Indirect Bone Healing:

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

Variables that Influence Fracture Healing:

Variables that Influence Fracture Healing Internal factors B lood supply (most important) Head Injury may increase osteogenic response Mechanical factors B. External factors low intensity pulse us bone stimulators direct current capacitively coupled electrical fields pulsed electromagnetic fields mixed

Electromagnetic Field:

Electromagnetic Field Electromagnetic (EM) devices are based on Wolff’s Law that bone responds to mechanical stress: In vitro bone deformation produces piezoelectric currents and streaming potentials. Exogenous EM fields may stimulate bone growth and repair by the same mechanism Clinical efficacy very controversial No studies have shown PEMF to be effective in “gap healing” or pseudarthrosis


Ultrasound Low-intensity ultrasound is approved by the FDA for stimulating healing of fresh fractures Modulates signal transduction, increases gene expression, increases blood flow, enhances bone remodeling and increases callus torsional strength in animal models


Ultrasound Human clinical trials show a decreased time of healing in fresh fractures treated nonoperatively Has also been shown to decrease the healing time in smokers potentially reversing the ill effects of smoking


PEMF Approved by the FDA for the treatment of non-unions Efficacy of bone stimulation appears to be frequency dependant Extremely low frequency (ELF) sinusoidal electric fields in the physiologic range are most effective (15 to 30 Hz range) Specifically, PEMF signals in the 20 to 30 Hz range (postural muscle activity) appear more effective than those below 10 Hz (walking)

Systemic Factors That Decrease Fracture Healing:

Systemic Factors That Decrease Fracture Healing Malnutrition Reduces activity and proliferation of osteochondral cells Decreased callus formation Smoking Cigarette smoke inhibits osteoblasts Nicotine causes vasoconstriction diminishing blood flow at fracture site Diabetes Mellitus Associated with collagen defects including decreased collagen content, defective cross-linking and alterations in collagen sub-type ratios HIV medications affecting healing NSAID, bisphosphonate long term, systemic corticosteroids and quinolones

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