Reza Omid MD

Orthopaedic Basic Science 1) Science of Bones Bone Histology

Lamellar Bone: normal bone, stress oriented o Less osteocytes and turnover than woven bone o 2 subtypes of lamellar bone:

Cortical: aka compact bone makes up 80% of skeleton mainly diaphyseal composed of tightly packed osteons or haversian

systems connected by haversian (or volkman) canals slow turnover high Youngs module (E)

Cancellous: aka spongy bone or trabecular bone mainly metaphyseal/epiphyseal, vertebral body,

calcaneus less dense and more remodeling according to lines of

stress high turnover more elastic and smaller Youngs module (E)

*Cement lines are found in cortical bone indicating where bone resorption has stopped and new bone formation has begun. Cement lines define the outer border of an osteon Woven Bone: immature/pathologic bone, NOT stress oriented

o More osteocytes and turnover than lamellar bone o Weaker and more flexible than lamellar bone o Immature bone found in embryonic skeleton & fracture callus o Pathologic bone found in osteogenic sarcoma and fibrous dysplasia

Cell Types Found in Bone

1. Osteoblasts: form bone a. Derived from undifferentiated mesenchymal cells (osteoprogenitor

cells) found in periosteum, endosteum and haversian canals b. Produce bone so produce:

i. alkaline phosphatase ii. type 1 collagen iii. osteocalcin

c. more Golgi, ER and mitochondria than other cells d. 2 subtypes:

i. more differentiated, activated cells that line bone surfaces

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Reza Omid MD

ii. less active resting cells which maintain the ionic mileu of bone. Disruption of the lining cell layer activated these cells

e. Respond to several factors: i. PTH (releases RANKL to stimulate osteoclastic activity) ii. Vitamin D (stimulates matrix and alkaline phosphatase

synthesis and production of bone-specific proteins such as osteocalcin which then upregulates osteoblasts)

iii. Glucocorticoids (decreases bone production) iv. Prostaglandins (increase cAMP to cause increased

resorption) v. Estrogen (anabolic and anticatabolic to increase bone

production) vi. PDGF

vii. Cbf-1:RUNX2 is the main activator of osteoblasts. Cbf-1:RUNX2 is also critical during the process of chondrocyte hypertrophy and terminal differentiation and mice without Cbf-1:RUNX2 have an absence of hypertrophic chondrocytes in some growth plates

1. Mutations of Cbf-1:RUNX2 result in cleidocranial dysplasia (abnormal/absent clavicles with face)

f. Certain antiseptic agents are toxic to cultured osteoblasts including: i. Hydrogen peroxide ii. Betadine iii. Bacitracin is less toxic

2. Osteoclasts: resorb bone a. Multinucleated irregularly shaped giant cells from hematopoetic

tissues (monocyte progenitors form giant cells by fusion) b. Possess ruffled brush borders (which are plasma membrane

enfoldings that increase surface area and are important for bone resorption) and surrounding clear zone

c. RANK ligand (from osteoblasts) binds to osteoclasts on RANK to increase bone resorption. This mechanism is inhibited by osteoprotegerin binding to RANK-L and preventing interaction with osteoclasts and induces apoptosis.

d. Synthesize TRAP (tartrate-resistant acid phosphate) e. Bind to bone via integrin (vitronectin) and produce H+ ions (via

carbonic anhydrase) to decrease the pH and increase solubility of hydroxyapatite crystals [Ca10(PO4)6(OH)2] and organic matrix is removed by digestion.

f. Have calcitonin receptors but NOT PTH receptors g. Responsible for bone resorption in metastasis and multiple

myeloma and total joint osteolysis.

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Reza Omid MD

h. IL-1 is a potent stimulator of osteoclastic bone resportion and has been found in the membranes surrounding loose total joint implants.

i. IL-10 suppresses osteoclast formation j. Bisphosphonates inhibit osteoclast resportion by preventing ruffed

borders from forming and inducing apoptosis 3. Osteocytes: maintain bone

a. 90% of cells found in mature bone b. are former osteoblasts trapped in newly formed matrix (which they

help preserve) c. high nucleus to cytoplasm ration with long interconnecting

cytoplasmic processes d. important for control of extracellular calcium and phosphate

concentration e. directly stimulated by calcitonin f. inhibited by PTH

4. Osteoprogenitor cells: become osteoblasts Line Haversian canals, endosteum and periosteum Await stimulus to differentiate into osteoblasts

5. Lining cells: narrow flattened cells that form an envelope around bone Wnt- catenin Pathway -Wnt (mammalian homologue of wingless in drosophila) is very similar to BMP (essential for osteogenesis) but uses a different signaling pathway -Wnt binds to receptors frizzled and LDLR5 and LDLR6 and activates catenin which go to the nucleus to regulate gene expression -Sclerostin and Dickkopf (DKK-1) are antagonists of Wnt -BMP uses smad to cause gene expression Bone Matrix -Composed of organic (40%) and inorganic component (60%) -Organic component is composed of:

1. primarily type I collagen 2. proteoglycans (provides compressive strength) 3. non-collagenous matrix proteins (osteocalcin, osteonectin, osteopontin) 4. growth factors and cytokines

-Inorganic component is composed of: 1. calcium hydroxyapatite (provides main compressive strength) 2. osteocalcium phosphate (brushite)

-Collagen is layed down in an arrangement that forms hole zones (which are gaps between two consecutive fibrils and pores which are gaps between two side to side fibrils. Mineral deposition (calcification) occurs within the hole zones and pores. Cross linking decreases collagen solubility and increases its tensile strength.

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Reza Omid MD

-Osteocalcin is the most abundant non-collagenous matrix protein. It is inhibited by PTH and stimulated by vitamin D. Osteocalcin levels can be measured in the serum or urine as a marker of bone turnover. Increased levels of osteocalcin can be seen in Pagets disesase, Renal osteodystrophy, Hyper-PTH -Osteonectin (aka SPARC) is secreted by platelets and osteoblasts and regulates calcium and organizing the mineral in bone matrix -Osteopontin is a cell binding protein (similar role to integrins) Bone Physiology -Wolffs Law: bone remodels in response to mechanical stress. Increased stress causes increased bone gain and less stress results in loss of bone (disuse osteopenia). Bone loss seen with paraplegia/quadriplegia occurs throughout the skeleton (except the skull) for about 16 months and then levels off at 2/3 of the original bone mass. -Bone remodels in response to electrical changes. Compressive side is electronegative and stimulates osteoblasts. Tension side is electropositive and stimulates osteoclasts. -Hueter-Volkmann Law: bone remodeling occurs in small packets of cells known as basic multicellular units (BMU), modulated by systemic hormones and local cytokines. Mechanical factors can influence longitudinal growth, bone remodeling and fracture repair. Compressive forces inhibit growth and tensile forces stimulate growth. This law is seen in the progression of scoliosis and Blounts disease. Bone Remodeling -Cortical bone remodeling occurs by osteoclastic tunneling (cutting cones), followed by layering of osteoblasts and successive deposition of layers of lamellae (after the cement line has been laid down) until the tunnel size has narrowed to the diameter of the osteonal central canal. The head of the cutting cone is made up of osteoclasts, which bore holes through hard cortical bone. Behind osteoclasts are capillaries, followed by osteoblasts that lay down osteoid to fill the resorption cavity. -Cancellous bone remodeling occurs by osteoclastic resorption, followed by osteoblasts laying down new bone. Bone Blood Supply -Bone receives 5-10% of cardiac output. -Long bones receive blood from 3 sources:

1. Nutrient artery: gives rise to the medullary blood supply and supplies the inner 2/3. This supply is disrupted by fracture and reaming

a. High pressure system 2. Metaphyseal-Epiphyseal system: arises from periarticular

vascular plexus (ex: genicular arteries)

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Reza Omid MD

3. Periosteal system: supplies the outer 1/3 a. Low pressure system

-Blood flow is normally centrifugal (inside to outside) in adults due to high pressure of the nutrient artery and low pressure of the periosteal system. In a completely displaced fracture with disruption of the endosteal (nutrient) system, the periosteum predominates and flow becomes centripetal (outside to inside). Blood flow in immature bones is centripetal due to the very well developed periosteum. -Venous flow in mature bones is centripetal (outside to inside) from sinusoids to emissary veins -Hypoxia, hypercapnia, and sympathectomy increases blood flow to the bone -Regional acceleratory phenomenon is the response of blood flow to a fracture and is initially decreased due to vascular disruption at the fracture site and within hours to days, blood flow increases and peaks at 2 weeks and returns to normal between 3-5 months. Enchondral Ossification -Bone replaces a cartilage model (but cartilage is NOT converted to bone)

1. Undifferentiated cells secrete a cartilaginous matrix and differentiates into chondrocytes

2. Matrix mineralizes and is invades by vascular buds that bring osteoprogenitor cells into the matrix

3. Osteoclasts resorb calcified cartilage and the osteoblasts form bone -Examples of enchondral ossification:

Embronic long bones Longitudinal growth (physis) Fracture callus (relative stability) Bone formed via use of BDM

-Achondroplasia is a disease of abnormal enchondral ossification Intramembranous Ossification -Bone formation without a cartilage model

1. Undifferentiated mesenchymal cells aggregate into layers (or membranes) 2. These cells differentiate into osteoblasts and deposite organic matrix that

mineralizes to form bone -Examples of intramembranous ossification:

Embryonic flat bone formation (pelvis, clavicle, vault of skull) Bone formation during distraction osteogenesis Blastema bone (occurs in young children with amputations) Bone formed with absolute stability

-Cleidocranial dystosis is a disease of abnormal intramembranous ossification Appositional Ossification -Osteoblasts align themselves on existing bone surface and lay down new bone

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Reza Omid MD

-Examples of appositional ossification: Periosteal bone enlargement (width) Bone formation phase of bone remodeling

-Diseases of abnormal appositional ossification: Melorheostosis Pagets disease Caffeys disease (infantile hyperostosis)

Physeal Zones 1. Epiphysis 2. Reserve zone: cells store lipids, glycogen and PG aggregates for later

growth and matrix production -Decreased oxygen tension

o Affected by lysosomal storage diseases (Gaucher), Pseudoachondroplasia, Kneist syndrome, Gaucher disease, Diastrophic dysplasia (Reserve Place Kicker has Good Distance)

3. Proliferation zone: longitudinal growth occurs with stacking of chodrocytes (top cell is the dividing mother cell) -Increased oxygen tension -Increased PG in surrounding matrix inhibiting calcification -Cellular proliferation and matrix production occurs in this zone

o Affected by Gigantism and Achondroplasia (GPA) 4. Hypertrophic zone: chondrocytes increase 5 times in size and accumulate

calcium in their mitochondria and then die to release calcium. -Decreased oxygen tension -rate of chondrocyted maturation is regulated by systemic hormones and local growth factors. PTHrP inhibits chondrocyte maturation. Indian hedgehog is produced by growth plate chondrovytes and regulates expression of PTHrP -Composed of 3 sub-zones:

Maturation zone Degenerative zone Zone of provisional calcification

-This zone widens in Rickets -Encondromas originate here

o Affected by Rickets, SCFE, Mucopolysaccaridoses, Osteomalacia, Rickets, Encondroma, SCFE, Physeal fractures (MORE Sex Please)

5. Metaphysis: Primary spongiosa Secondary spongiosa

o Affected by SCFE with endocrinopathy

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Reza Omid MD

6. Diaphysis Bone Injury -Fracture healing is a continuum proceeding from inflammation through repair (soft callus followed by hard callus) and ending in remodeling -Most important factor in bone healing is blood supply -Head injury can increase the osteogenic response to fracture (HO) -Nicotine increases time to fracture healing and increases the risk of non-union (tibia) and decreases strength of the facture callus. Also it increases the risk of pseudoarthrosis after a lumbar fusion by up to 500% -NSAIDs also adversely affect fracture repair and lumbar spine fusions -Inflammation phase starts with bleeding from the fracture site and surrounding soft tissue creating a hematoma which provides a source of hematopoietic cells capable of secreting growth factors. Fibroblasts, mesenchymal cells and osteoprogenitor cells are present at the fracture site. Granulation tissue forms at the fracture ends -Repair phase is when the primary (soft) callus forms at about 2 weeks and at this stage shortening does not occur but angular deformity can still occur. During callus formation, type 2 collagen is expressed early followed by type 1 collagen. -Remodeling phase begins during the middle of the repair phase and continues long after the fracture has clinically healed (up to 7 years). Fracture healing is complete when there is repopulation of the marrow space. -Cortisone decreases callus proliferation -Thyroid and PTH increase bone remodeling -Growth hormone increases callus volume -Low-intensity pulsed ultrasound accelerates fracture healing and increases the mechanical strength of callus, including torque and stiffness. The proposed mechanism is that cells responsible for fracture healing respond favorably to the mechanical energy transmitted by the ultrasound signal. Allograft -Fresh allograft is most immunogenic and most osteoinductive -Fresh-Frozen is less immunogenic but still preserves BMP -Freeze-Dried allograft is least immunogenic but looses structural integrity and depletes BMP. Purely osteoconductive (crutons) Distraction Osteogenesis -Use of distraction to stimulate formation of bone. Under optimal stable conditions, bone forms via intramembranous ossification (unstable conditions form enchondral ossification or even pseudoarthrosis). -Histologic phases:

1. Latency phase: 5-7 days

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Reza Omid MD

2. Distraction phase: 1mm/day (divided into 0.25mm per 6 hours) or 1 inch per month.

3. Consolidation phase: twice as long as the distraction phase -Uses for distaction osteogenesis:

o Limb lengthening o Hypertrophic non-union o Deformity correction via differential lengthening (Taylor spatial

frame for Blounts disease) o Segmental bone loss via bone transport

-Conditions that promote optimal bone formation during distraction osteogenesis:

o Low energy corticotomy/osteotomy (corticotomy is better because leaves medullary canal intact)

o Minimal soft tissue stripping at corticotomy site o Stable ex-fix construct o Latency period of 5-7 days (no lengthening done during this time) o Distraction done at 0.25mm/6 hours o Neutral fixation interval (no distraction done during consolidation phase) o Normal physiologic use of the extremity including weight bearing

Bone Metabolism -Bone serves as a reservoir for >99% of the bodys calcium. Plasma calcium (

Reza Omid MD

phosphate filtration. Decreased calcium levels in the extracellular fluid stimulates 2 cells to release PTH. PTH acts on the intestines, kidney and bone and causes bone resportion to increase serum calcium levels. -Vitamin D is a naturally occurring steroid activated by UV sunlight and from dietary intake. Vitamin D helps actively absorb calcium from the duodenum and also at the kidney. Phenytoin (as well as most other anticonvulsant meds) causes impaired metabolism of vitamin D. Primary function of vitamin D is to increase the calcium and phosphate absorption by the intestines. Daily intake of vitamin D should be 800 mg/d. -Vitamin D metabolism is shown below:

-Calcitonin is a peptide produced by clear cells of the thyroid gland. Increased serum calcium levels cause secretion of calcitonin (controlled by 2 receptors). Calcitonin decreases osteoclast number and activity and leads to a decrease in serum calcium. -Markers of bone resorption:

1. Urinary hydroxyproline 2. Pyridoline cross-links

-Serum alkaline phosphatase is a marker of bone formation

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Reza Omid MD

Osteomalacia

Description o Failure of mineralization of bone due to multiple etiologies (see

table below). o Rickets is osteomalacia in children o Lack of vitamin D is the underlying factor

Poor nutritional intake Lack of sunlight Renal or Liver disease

History & Physical o Most common symptom is pain, sometimes localized, more often

bilateral and symmetrical; often initially vague but gradually becomes severe.

o May be proximal muscle weakness Etiology

-Seen commonly in chronic alcoholics

Pathophysiology o The total amount of bone is normal (unlike osteoporosis) but there

is a lack of mineralization o Serum calcium is low normal, phosphate is very low and alkaline

phosphatase is very high

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Reza Omid MD

o Serum vitamin 25-OH-D is markedly depressed, while 1,25(OH) levels may be initially normal, although they too eventually fall.

o PTH levels tend to rise considerably, resulting in relative preservation of the serum calcium (at the expense of the bones)

Imaging o Radiographs reveal generalized osteopenia

Classically multiple bilateral and symmetrical cortical lucent areas in the ribs, scapula, pelvis and femoral neck. These lucent areas represent stress fractures and typically lie perpendicular to the long axis of the bone (sometimes referred to as Loosers zones or Milkmans lines)

The axial skeleton is more often affected clinically than the peripheral skeleton

Pathology o Microscopic examination (transiliac bone biopsy) is required for

diagnosis and must reveal at least 10% of total bone volume constituted by non-mineralized matrix (osteoid) and widened osteoid seams are seen.

Treatment o Large doses of vitamin D

Primary Hyperparathyroidism -Overproduction of PTH from an hypertrophy/adenoma/carcinoma which leads to increased serum calcium and decreased serum phosphate. -Leads to osteopenia, osteitis fibrosa cystica (fibrous replacement of marrow), brown tumors (giant cells, RBC and hemosiderin) and chondrocalcinosis -Radiographic findings include deformed osteopenic bones, fractures, areas of radiolucency (at tufts of phalanges, distal clavicle, vertebral end plates), soft tissue calcifications Albright Hereditary Osteodystrophy -Form of pseudohypoparathryroidism (lack of effect of PTH at target cells, PTH levels normal to high) associated with:

1. Short 1st/4th/5th metacarpals and metatarsals 2. Brachydactyly 3. Exostosis 4. Obesity 5. Diminished intelligence

-Pseudo- pseudohypoparathryroidism is a normocalcemic disorder which is phenotypically similar to pseudohypoparathryroidism however there is a normal response to PTH.

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Renal Osteodystrophy (Secondary Hyperparathyroidism) -Abnormal bone metabolism in patients with chronic renal disease. -Glomerular damage causes phosphate retention and hyperphosphatemia, inhibits vitamin D production and decreased GI absorption of calcium and also increased phosphate which leads to ectopic calcification (basal ganglia) -Tubular damage causes loss of -hydroxylase activity so decreased vitamin D production which decreases GI absorption of calcium leading to hypocalcemia and secondary hyperparathyroidism. Phosphate retention also occurs which causes a rise in PTH as well. The elevated PTH then causes osteitis fibrosa, ectopic calcifications and osteomalacia (osteopenia & fragility fractures). -Traditionally, patients on dialysis were also having worsening of their osteomalacia due to the high aluminum levels in the dialysis fluid. The aluminum competed with other ions to prevent proper formation of the hydroxyapatitie crystals. Now days the dialysis fluid is not made with aluminum so this is not so much of a problem. -Treatment of renal osteodystrophy is to give phosphate binders as well as high levels of vitamin D Rickets -In children the equivalent to osteomalacia in adults -Failure of mineralization leading to changes in the physis in the zone of provisional calcification (increased width and disorientation of the physis) -Cortical thinning and bowing -Several subtypes of Rickets:

1. Nutritional Rickets a. Vitamin D deficiency: rare except for in Asians, premature

babies and patients with sprue (malabsorption). Low calcium and phosphate, increased PTH, low vitamin D levels.

i. Rachitic rosary ii. Bowing of the knees iii. Codfish vertebrae iv. Coxa vara v. Milkmans fracture (Loosers lines) vi. Growth retardation vii. Muscle hypotonia

-Treatment is 5000 IUD Vitamin D b. Calcium deficiency c. Phosphate deficiency

2. Hereditary Vitamin D-dependent Rickets -Similar to vitamin D deficiency rickets but worse -Patients may have total baldness

a. Type I: defect in renal 25-OH Vitamin D 1-hydroxylase enzyme

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Reza Omid MD

b. Type II: defect in intracellular receptor for 1,25 (OH)2 vitamin D 3. Familial Hypophosphatemic Rickets

-aka phosphate diabetes -X-linked dominant -Due to impaired renal tubular reabsorption of phosphate -Vitamin D resistant rickets (impaired vitamin D response) -Normal GFR -Treatment is phosphate replacement and high dose vitamin D

Osteoporosis -Quantitative (not qualitative) defect of bone -2.5 SD below the peak bone mass of a 25 year old -Vertebral body fracture is the most common -Lab values are normal, need DEXA scan -Z-scores give results for age controlled -T-scores gives results for young normal adults -Must rule out hyperthyroidism, hype-PTH, Cushings and malignancy -Risk Factors: sedentary, thin Caucasian women of norther European descent, smokers, heavy drinkers, dilantin use, poor diet, breast feeders, family history, premature menopause. -History of 2 osteoporotic vertebral fractures is the strongest predictor of subsequent vertebral fractures in post-menopausal women. -3 major types of osteoporosis:

1. Senile (age-related): affects trabecular bone and cortical bone a. Related to poor calcium absorption b. Hip fractures and Pelvis fractures

2. Post-menopausal (high turnover): affects trabecular bone primarily a. Vertebral body and distal radius fractures b. Distal radius fractures

3. Glucocorticoid induced (low turnover): -Treatment for Osteoporosis:

1. Diet and adequate calcium and vitamin D 2. Weight bearing exercise 3. Estrogen therapy evaluation (works best when started within 6 years of

menopause) 4. Bisphosphonates (Fosamax): bind farnesyl disphosphate synthase and

cause apoptosis in osteoclasts.. Can also be used for OI, Padgets, Osteopetrosis and metastasis

5. Calcitonin 6. Tamoxifen 7. SERMs

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Reza Omid MD

8. Anabolic: PTH (Forteo) is PTH given intermittently to stimulate osteoblasts but can only give for 2 years, may cause osteosarcoma

Idiopathic Transient Osteoporosis of the Hip -Uncommon disorder of exclusion -Most commonly seen in 3rd trimester of pregnancy but also occurs in men (middle age) -Present with groin pain, limited ROM and localized osteopenia (without history of trauma) -MRI is highly sensitive but not specific and must rule out infection, osteonecrosis and neoplasm. -Self-limited disease and resolves within 6-8 months with restricted WB and pain control. Osteochondroses -Osteochondrosis is a disease causing degenerative changes in the ossification centers of the epiphysis of bones, particularly during periods of rapid growth in children. The process can continue to AVN. AKA traction apophysitis. May or may not be associated with trauma, inflammation of joint capsule, or vascular insult/secondary thrombosis. -Examples of osteochondroses:

1. Van Necks Disease: ischiopubic synchrondosis 2. Legg-Calve-Perthese Disease: femoral head 3. Osgood-Schlatter Disease: tibial tuberosity 4. Sinding-Larsen-Johansson Syndrome: inferior patella 5. Blouts Disease: proximal tibial epiphysis 6. Severs Disease: calcaneus 7. Kohlers Disease: navicular 8. Friedbergs Infraction: 2nd metatarsal head 9. Scheuermanns Disease: discovertebral junction 10. Panners Disease: capitellum 11. Thiemanns Disease: phalanges of the hand 12. Kienbocks Disease: lunate 13. Iselins Disease: 5th metatarsal base 14. Preisers Disease: scaphoid

2) Science of Joints Articular Cartilage -Articular cartilage is a resilient load bearing tissue that forms the articulating surface of joints. It provides a surfaces with low friction and absorbs mechanical shock and spreads the load onto subchondral bone. -Contains no nerves, blood vessels or lymphatics

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Reza Omid MD

-Collagen of articular cartilage provides tensile strength -Proteoglycans of articular cartilage provides compressive strength -Thickest cartilage is under the patella -4 Zones of Articular Cartilage:

1. Superficial zone: resists shear force, 10-20% a. Lamina splendens (unique superficial layer that consists of fibrils

and little or no PG and no cells b. Ellipsoidal chondrocyte layer

-High water content -Low PG content -Acts as a barrier against movement of molecules between the synovium and the articular cartilage -Damage to this zone may contribute to development of OA. Also damage to this zone could release molecules into the synovial fluid and stimulate a immune response.

2. Middle (Intermediate) zone: resists compressive forces, 40-60% -Rounded chondrocytes spread out -Most metabolically active -Randomly arranged collagen fibers

3. Deep zone: resists compressive forces, 30% -Chondrocytes in columns -Low water content -High PG content -Largest collagen fibers, fibers arranged vertical (perpendicular to surface)

*Tidemark separates the deep zone from the calcified zone. It resists shear forces.

The number of tidemarks increases with age as the tissue is remodeled. 4. Calcified zone:

-seperates the articular cartilage from the subchondral bone -anchors the cartilage to the bone (equivalent of Sharpys fibers with ligaments)

-Articular Cartilage Composition:

1. Water: 65-80% of total weight a. Resists compression

2. Type II collagen: 10-20% of total weight (50% of dry weight) a. Provides tensile properties and acts as a framework to immobilize

ECM & PG 3. Proteoglycan Aggragate: 5-10% of total weight

a. GAGs contain carboxyl & sulfate groups (keratin and chondroitin sulfate). GAGs are negatively charged and bind water (act like a sponge) and the negative charges repel each other maximizing volume.

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4. Chondrocytes: 2% of total weight a. Produce all the ECM macromolecules and degradative enzymes. b. Chondrocytes are responsible for formation of all ECM

macromolecules and maintenance of articular cartilage. They are derived from mesenchymal cells and are metabolically active (anaerobic). There numbers decrease with age. Chondrocytes respond to environmental stimuli. Exposure of IL-1 may lead to degredation of ECM.

-Articular cartilage nutrition is via diffusion and requires joint mobilization to allow for movement of the synovial fluid over the articular surface. Collagen -At least 15 types of collagen, all triple helix structures composed of 3 -chain polypeptides with large quantities of glycine and praline. Also contain hydroxyproline, hydroxylysine and glycosylated hydroxylysine. -Hydroxylation of collagen requires vitamin C

1. Type 1 Collagen: most common type of collagen a. Found in bone, tendon, ligament, meniscus, annulus fibrosus of

discs, skin, pubic symphysis, articular discs (AC/SC joints) b. Any site where fibrocartilage is found (microfracture)

2. Type 2 Collagen: a. Found in articular (hyaline) cartilage, nucleus pulposus of discs. b. Early fracture callus

3. Type 3 Collagen: Found in skin and blood vessels 4. Type 4 Collagen: Found in basement membranes 5. Type 6 Collagen:

a. Minor component of normal articular cartilage b. Increases significantly in early OA

6. Type 9 Collagen: Adhesive cartilages which link together with Type 11 collagen and other type 2

7. Type 10 Collagen: a. Found only near calcified cartilage (calcified zone of articular

cartilage and hypertrophic zone of growth plate) b. Produced by hypertrophic chondrocytes during enchondral

ossification seen in: i. Fracture callus ii. Growth plate iii. HO formation iv. Calcifying cartilaginous tumors

c. Genetic defect of type 10 collagen seen in Schmidss metaphyseal chondroplasia

8. Type 11 Collagen: More adhesive than type 9 9. Type 12 Collagen: Found in tendons

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-Proteoglycans (PG) are complex macromolecules that consist of a protein core with covalently bound GAG chains aka proteoglycan aggregate. Half life of PG are 3 months. PG produce cartilages porous structure and trap and hold water (regulate and retain water in the matrix) -95% of proteoglycans are chondroitin and keratin sulfate. The sulfate molecules are the negative charge that attracts positive cations (Na+& K+) and increase osmotic pressure to inflate the elastic meshwork with water for compression properties. Proteoglycan aggregate are made up of a hyaluronic acid with several aggregan molecules bond to it. Each aggrecan molecule has several regions: chondroitin rich region and keratin rich region. Aggregate size decreases with age. -Glycosaminoglycans are long chain disaccharide units that make up PG once bound to hyaluronic acid. Types of GAG:

1. Chondroitin Sulfate (most prevalent, found in articular cartilage, concentrated at ends of aggrecan molecules)

a. 4-isomer decreases with age b. 4-isomer increases with OA c. 6-isomer remains constant with age d. total chondroitin decreases with age

2. Keratin Sulfate (articular cartilage, concentrated in middle of aggrecan molecules)

a. Increases with age b. Decreases with OA

3. Dermatan Sulfate 4. Hyaluronate (HA)

a. HA is unique because it is not sulfated like the other GAG and not covalently bound to a protein core so not part of a PG

-Glucosamine and Chondroitin Sulfate supplements are over the counter chondroprotective agents. Glucosamine stimulates chodrocytes and synoviocyte activites. Chondroitin sulfate inhibits degredative enzymes and prevent sfibrin thrombus formation in periarticular tissue. These supplements improve pain, joint line tenderness, ROM and walking speed but no studies show that they affect mechanical properties or biomechanical consistency of articular cartilage. -Cartilage Oligometric Protein (COMP) is a protein concentrated primarily in the chondrocyte territorial matrix. COMP appears to be present mainly in articular cartilage and binds to chondrocytes and serves as a serum marker for cartilage turnover and of progression of cartilage degeneration in patients OA/RA or any inflammatory arthritis. COMP can also be used for monitoring efficiency of treatment. -Creep is a time-dependent deformation of a viscoelastic tissue (articular cartilage) due to a constant load). Rate of creep is governed by the rate at which fluid may be forced out from the tissue, which in turn, is governed by the permeability and stiffness of the matrix. The tissue will creep until an equilibrium value is reached.

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-Mechanosignal transduction occurs via integrins in chodrocytes as pressure or deformation is transmitted to the cell to increase mRNA expression. Synovium -Composed of 2 distinct layers:

1. Intimal lining: in direct contact with IA cavity and responsible for production of hyaluronic acid

a. Loosely organized and avascular layer 1-2 cells layers thick 2. Sublining: lies beneath the intimal lining and is acellular and contains

scattered blood vessels, fat cells and fibroblasts. -Cell types present in the synovium:

1. Type A cells: macrophage like (phagocytosis) 2. Type B cells: fibroblast like (produce synovial fluid)

-Synovial fluid consists of HA, lubricin, proteinase, collagenase and PG. It is an ultrafiltrate of plasma and contains no RBC, clotting factors or hemoglobin Meniscus -Deepens the articular surface of synovial joints and found in the:

1. AC joint 2. SC joint 3. Glenohumeral joint 4. Hip joint 5. Knee joint

-The meniscus broadens the contact area and distributes the load. More elastic and less permeable than cartilage. -Composed of type 1 collagen (fibrocartilage) -Medial meniscus of the knee is semicircular (C-shaped) -Lateral meniscus of the knee is circular -2 meniscofemoral ligaments run from the posterior horn of the lateral meniscus to the medial femoral condyle. Anterior to the PCL is the ligament of Humphrey and posterior to the PCL is the ligament of Wrisberg. -2 cell types found within meniscus:

1. Fusiform cells in the superficial zone 2. Fibrochondrocytes (ovoid/polygonal cells) found in the remainder of the

tissue. These cells are responsible for meniscal healing in the peripheral zone. Meniscal tears with a rim width

Reza Omid MD

-Meniscus motion (excursion is AP displacement) occurs with knee range of motion of 0-120:

o Medial meniscus excursion is 5.1 0.96 o Lateral meniscus excursion is 11.2 3.27

-Limited peripheral blood supply to the meniscus originates from the lateral and medial genicular arteries (both inferior and superior). It penetrates 10-30% of the medial meniscus and 10-25% of the lateral meniscus. The medial inner 2/3 of the meniscus derives nutrition from the synovial fluid via mechanical pumping. -Anterior and posterior horns of the menisci are most richly innervated (particularly the posterior horn). During extremes of flexion/extension, the horns of the menisci become taut and this increases tension then activates the mechanoreceptors. 3 types of mechanoreceptors found:

1. Ruffini endings 2. Golgi tendon organs 3. Pacinian corpuscles

-Following ACL transaction, the meniscus undergoes alterations in ECM, including increased water content and decreased GAG concentration. With age, meniscus undergo discoloration and increased deposition of calcium pyrophosphate dehydrate crystals, but water content does not change with age (unlike articular cartilage). However there is an increased chondroitin 6 to chondroitin 4 ratio with age (similar to articular cartilage). Synovial Fluid -Synovial fluid id an acellular plasma ultrafiltrate that lubricates the joint. Its high viscosity gives it important mechanical properties and is related to large amounts of polymerized hyaluronic acid. -Should be sent for gram stain, culture, WBC with differential, and crystal analysis -Dye should be injected only after fluid is obtained from the joint because the bactericidal effect of iodinated contrast material can cause a false negative culture result. -Non-inflammatory synovial fluid contains 200 WBC, 25% PMN, glucose and protein values equal to serum values and volume 3.5 cc. Inflammation decreases viscosity of synovial fluid so it decreases the string sign length. -Infectious synovial fluid contains >50,000-80,000 WBC, 75% PMN, glucose levels significantly decreased and protein levels increased. Inflammation decreases viscosity of synovial fluid so it decreases the string sign length. Non-Inflammatory Arthritis

1. Osteoarthritis: a. Most common form of arthritis (most common in knee) b. Increased water content (age causes decreased water content)

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c. Increased chondroitin 4 sulfate d. Decreased keratin sulfate e. Increased cathepsins B&D f. Increased metalloproteinases (collagenase, gelatinase) g. IL-1 increases synthesis of these enzymes h. Post-menopausal arthritis of the medial clavicle seen on the

dominant extremity i. OA may be primary (intrinsic defect) or secondary (trauma,

infection, congenital) j. Pathologic changes of OA include:

i. subchondral cysts (arise secondary to microfracture and may contain an amorphous gelatinous material)

ii. osteophytes (as a compensation to abnormal joint forces) iii. joint space narrowing iv. eburnation of joint surface v. chondral cloning (>1 chondrocyte per lacunae) vi. replication and breakdown of tidemark vii. sclerotic bone formation

k. Radiographic changes of OA include: i. Osteophytes ii. Joint space narrowing iii. Subchondral sclerosis iv. Subchondral cyst v. Hand (DIP/PIP/CMC) vi. Knee (asymmetric involvement vii. Hip (superolateral involvement)

2. Neuropathic Arthritis (Charcot Joint Disease): a. Extreme form of OA caused by disrupted sensory innervation

(neuropathy) b. Present with swelling, warmth, erythema, minimal pain, variable

WBC & ESR (very similar to osteomyelitis and both are common in DM)

c. Charcot joint is usually a contraindication for a total joint arthroplasty

d. Causes of Charcot joint: i. Diabetes Mellitus ii. Syphilis iii. B-12 deficiency iv. Leprosy (2nd most common cause for UE involvement) v. Syringomyelia (most common cause for UE involvement) vi. Myelomenigocele/Spinal cord injury

e. Radiographic evaluation of Charcot joint: i. Severe destruction of both sides of the joint

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ii. Scattered chunks of bone embedded in fibrous tissue, fragmentation of bone, heterotopic ossification

iii. Very difficult to distinguish between osteomyelitis and Charcot on x-ray, MRI and labs

iv. Technitium bone scan may look similar (hot) for both osteomyelitis and Charcot.

v. Indium leukocyte scan may be hot or positive for osteomyelitis and cold or negative for Charcot

f. Eichenholtz Classification: i. Development phase: fragmentation of bone ii. Coalescense phase: absorption of small bone fragments and

fusion of joints iii. Remodeling phase: healing and new bone formation

g. Treatment of Charcot Arthropathy: i. Initial treatment is to off load the foot with a total contact

cast, usually for 3-6 months ii. Involvement side skin temperature similar to the uninvolved

side is the best indicator for D/C of the cast. Acute phase (fragmentation and collapse) of Charcot is characterized by an increase of 3-4F between involved (hot) and uninvolved side.

iii. If total contact casting fails, reconstructive fusion and finally amputation may be needed.

3. Acute Rheumatic Fever: a. Arthritis and arthralgias following untreated group A -hemolytic

strep infection (pharyngitis not cellulitis) b. Acute onset of red, tender, extremely painful joint effusions c. Carditis, erythema marginatum (painless macules), subcutaneous

nodules (extensor surface of UE) and chorea d. Arthritis is migratory and involves multiple large joints e. Diagnosis by Jones criteria (2 major or 1 major and 2 minor) f. Antistreptolysin O titers elevated in 80% of patients g. Treatment is PCN and ASA

4. Ochronosis: a. Degenerative arthritis secondary to alkaptonuria b. Error of homogentisic acid oxidase enzyme system (tyrosine and

phenylalanine catabolism) c. Excess homogentisic acid deposited in joints and then polymerize

(turn black) d. Black urine e. Onchronotic spondylitis (calcification and narrowing of the

intervertebral discs) in 4th decade of life. Inflammatory Arthritis

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1. Rheumatoid arthritis: a. Required diagnostic criteria: morning stiffness, swelling, nodules,

positive lab values and radiographic findings. b. Cell mediated (T-cell) response against soft tissue, then cartilage

and bone c. Mononuclear cells are primary cellular mediator of tissue

destruction in RA d. Associated with HLA-DR4 and HLA-DW4 e. Elevated ESR, CRP and RF (IgM or IgG against the Fc portion of

IgG), decreased complement levels f. Subcutaneous nodules (are strongly associated with + RF) are seen

in 20% of patients with RA g. Hands with ulnar deviation of MCP, Hallus valgus, claw toes h. Common in knee, elbow, shoulder, ankle and c-spine. i. Systemic manifestations include: rheumatoid vasculitis, pericarditis,

pulmonary disease (pleuritis, nodules, fibrosis), c-spine destabilization

j. Radiographic finding of RA: 1. periacetabular erosions 2. symmetric joint involvement 3. osteopenia 4. protrusion acetabuli

k. Feltys syndrome: RA + splenomegaly + leucopenia l. Stills disease: acute onset arthritis + fever + rash +

splenomegaly m. Rheumatoid factor is positive for:

1. RA 2. Sjorgrens syndrome 3. Sarcoidosis 4. SLE

n. Rheumatoid factor is negative for: 1. Ankylosing spondylitis 2. Gout 3. Psoriatic arthritis 4. Reiters syndrome

o. Antinuclear antibodies are found in: 1. SLE 2. Sjogrens syndrome 3. Scleroderma

p. Synovectomy decreases pain and swelling associated with the synovitis but does not prevent radiographic progression or the future need for total knee arthroplasty nor does it improve joint ROM. After synovectomy, the synovium initially regenerates normally but degenerates to rheumatoid synovial tissue over time.

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2. Sjogrens Syndrome: a. Autoimmune exocrinopathy b. Similar presentation as RA c. Decreased salivation d. Decreased lacrimal gland secretion (keratoconjunctivitis) sicca

complex e. Lymphoid proliferation

3. Systemic lupus erythematosus (SLE): a. African american women b. Fever butterfly malar rash, pancytopenia, nephritis, pericarditis and

polyarthritis. c. Joint involvement is most common feature (75%), acute red tender

swelling of PIPs, MCPs, carpus, knee and other joints. d. Not as destructive as RA e. Mortality related to renal disease f. Positive ANA g. Polymyalgia Rheumatica: aching and stiffness of shoulder and

pelvic girdle, malaise, HA and anorexia. Markedly elevated ESR, anemia and increased alkaline phosphatase. May be associated with temporal arteritis (which requires biopsy for definitive diagnosis). Treat symptomatically or with steroids if refractory. Temporal arteritis needs urgent steroids to prevent blindness.

4. Relapsing polychondritis: a. Episodic inflammation b. Diffuse self-limited arthritis c. Progressive cartilage destruction systemic vasculitis d. Primarily involves the ears (thickening) e. Also seen are inflammatory eye disorders, tracheal involvement,

hearing disorders and sometimes cardiac involvement. f. Autoimmune disease involving type 2 collagen g. Supportive treatment, consider dapsone

5. Juvenile rheumatoid arthritis: a. 3 major types of JRA:

1. systemic (20%) 2. pauciarticular (30%): 4 joints involved 3. polyarticular (50%): 5 joints involved

b. early onset is before teens, late onset is as teen or later c. Seronegative polyarticular JRA seen in girls d. Seropositive polyarticular JRA seen in girls and frequently

develops into adult RA e. Early onset pauciarticular JRA seen in girls and associated with

iridiocyclitis in 50% f. Late onset pauciarticular JRA seen in boys

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g. Treatment of JRA is high dose ASA with frequent ophthalmologic examinations. Only occasionally is gold or remittive drugs used.

6. Spondyloarthropathies -HLA-B27 is positive for all these conditions -aka enthesopathies (occur at ligament insertion onto bone) -RF negative

a. Ankylosing Spondylitis: 1. bilateral sacroiliitis acute uveitis 2. HLA-B27 is diagnostic 3. insidious onset of back pain and hip pain during 3rd-4th

decade 4. progressive spinal kyphosis (chin to chest deformity) 5. squaring of vertebrae 6. vertical syndesmophytes 7. obliteration of SI joints 8. whiskering of enthesis 9. difficult c-spine fractures associated with epidural

hemorrhage 10. associated with protrusion acetabuli 11. often associated with heart disease and pulmonary fibrosis 12. extraarticular manifestations include: amyloidosis,

arachnoiditis, aortitis, iritis, colitis, sarcoidosis 13. DISH is very similar to AS except the radiographic findings

are non-marginal syndesmophytes (AS has marginal syndesmophytes) and appears as melting wax. It is predominantly on the right side in the thoracic spine.

b. Reiters Syndrome: 1. classic triad: conjunctivitis, urethritis, oligoarticular arthritis

(cant see, cant pee, cant climb a tree) 2. painless oral ulcers, penile ulcers and pustular lesions on

extremities, palms, soles (aka keratoderma blennorrlagium)

3. plantar heel pain is common (fluffy periosteal calcifications near calcaneal spur.

4. metatarsal head erosion and calcaneal periostitis is common with reoccurrence

5. HLA-B27 positive 6. sacroilitis is 60% 7. Treatment is NSAIDs, PT, sulfa drugs

c. Psoriatic Arthropathy: 1. 5-10% of patients with psoriasis 2. HLA-B27 seen in 50% 3. oligoarticular involvement which affects small joints of the

hands and feet.

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4. nail pitting, fragmentation and discoloration 5. sausage digits 6. pencil in a cup deformity with DIP involvement

d. Enteropathic Arthritis: 1. 10-20% of patients with crohns disease and ulcerative

colitis 2. 5% or more experience axial disease 3. common in large weight bearing joints 4. presents as acute monoarticular synovitis that precedes

bowel symptoms 5. HLA-B27 in 50%

7. Crystal deposition disease a. Gout:

1. disorder of nucleic acid metabolism causing hyperuricemia which leads to monosodium urate crystal deposition in joints.

2. crystals activate inflammatory mediators, activate platelets, IL-1 and complement.

3. inflammatory mediators inhibited by colchicines 4. phagocytosis is inhibited by indomethacin and

phenylbutazone 5. great toe involvement (podagra) 6. tophi deposition (ear, eyelid, olecranon, Achilles) 7. renal disease/stones in 2% 8. kidneys are 2nd most commonly affected organ 9. x-ray: punched out periarticular erosions with sclerotic

overhanging borders 10. needle shaped crystals 11. negative bifringent crystals (yellow): means the long axis

of the crystal is parallel to the compensator and the crystal is yellow (if the gout crystal was perpendicular it would appear blue)

b. Pseudogout: 1. aka calcium pyrophosphate deposition disease (CPPD) 2. a disorder of pyrophosphate metabolism 3. acute attacks (like gout) but especially prevalent in the

knee 4. short blunt rhomboid-shaped crystals 5. weakly positively bifringent (blue): means the long axis of

crystal is parallel to compensator and crystal is blue (if the CPPD crystal was perpendicular it would appear yellow)

6. chondrocalcinosis is common -Chondrocalcinosis: calcification of the cartilage and meniscus. Seen commonly in:

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1. pseudogout (CPPD) 2. ochronosis 3. hyperparathyroidism 4. hypothyroidism 5. hemachromatosis 6. old trauma

c. Calcium Hydroxyapatite Crystal Deposition 1. destructive arthropathy due to IA deposition of calcium

hydroxyapatite crystals which releases enzymes (collagenase and neutral proteases)

2. commonly seen in knee and shoulder 3. in the shoulder results in cuff tear arthropathy (aka

Milwaukee shoulder) Infectious Arthritis

1. Pyogenic: a. From hematogenous spread or extension of osteomyelitis b. At risk patients include:

i. IVDA ii. Sexually active (GC is most common: intracellular

diplococcus) iii. DM iv. RA v. Trauma (open facture or CFI) vi. Surgery

c. Destruction of cartilage occurs via 2 mechanisma: i. Direct (proteolytic enzyme degredation) ii. Indirect (increased pressure and lack of nutrition)

d. Treatment is I&D with 2-3 weeks IV antibiotics 2. Tuberculous:

a. Chronic granulomatous infection (mycobacterium tuberculosus) b. Via hematogenous spread c. Most common in spine and LE d. 80% monoarticular e. positive PPD and acid fast bacilli on synovial gram stain f. granulomas with langerhan giant cells on histology g. radiographic changes seen:

i. subchondral osteoporosis ii. cystic changes iii. notch-like bony destruction at joint edges iv. osteolytic changes on both sides of the joint

h. treatment is I&D with R.I.P.E. antibiotics 3. Lyme disease:

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a. acute self-limited joint effusions, especially in the shoulder and knee

b. recur frequently c. borrelia burgdorferi (spirochete) d. transmitted by Ioxodes tick bite e. stages of disease:

i. Rash (erythema chronicum migrans) and arthralgia ii. Myocarditis, Bells palsy, meningitis and heart block iii. Arthritis and chronic CNS changes

f. immune complexes and cryoglobulins accumulate in the synovial fluid

g. diagnosis is via ELISA because gram stain is negative h. treatment in doxycycline in stage 1 and ceftriaxone in stage 2 or 3.

4. Fungal: a. more common in neonates, AIDs patients and IVDA b. candida albicans c. KOH prep of synovial fluid d. treat with 5-flucytosine e. blastomycosis, coccidiomycosis and histo often require

amphotericin and sometimes given IA to limit systemic effects Hemorrhagic Arthritis

1. Hemophilic Arthropathy: a. X-linked recessive b. Factor 8 deficiency (hemophilia A) or factor 9 (hemophilia B) c. Repeat hemarthrosis due to minor trauma, leading to synovitis,

cartilage destruction and joint deformity d. Disease severity:

i. mild is 5-25% levels ii. moderate is 1-5% levels iii. severe is 0-1% levels

e. Knee is most commonly involved followed by elbow > ankle> shoulder>spine

f. Radiographic findings: i. Squared off patella = Jordans sign (also seen in JRA) ii. Widening of intercondylar notch iii. Enlarged femoral condyles that appear to fall off the tibia

g. Iliacus hematoma can cause femoral nerve palsy h. Management is to replace the factor levels, splint, compression,

steroids, synovectomy and arthroplasty i. Synovectomy reduces the incidence of recurrent hemarthrosis (less

pain and swelling)

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j. Synoviorthesis (destruction of synovium with IA injection of radioactive P32 chromic phosphate) for treatment of chronic hemophilic synovitis that is resistant to conventional treatment

k. Factor levels should be maintained @100% during the first post-op week and 50-75% during the 2nd week. Presnec of inhibitor that represents an IgG to the clotting factor proteins (causes the patient to have no response to factor replacement therapy) is a relative contraindication to any elective procedure. This inhibitor is seen in 5-25% of patients.

l. New monoclonal factor 8 is prone to induce inhibitors 2. Sickle Cell Disease:

a. Leads to local infarction due to capillary stasis b. Bone infarcts and ischemic necrosis may occur in multiple bones in

sickle cell disease c. Thalassemia does not produce infarcts or necrosis d. Dactilitis with metacarpal/metatarsal periosteal new bone formation

may also be seen. e. Osteomyelitis is uncommon (staph aureus is most common but

salmonella is most characteristic). Salmonella spread can come from gallbladder infection

f. AVN of the femoral head is common requiring THA g. Results of TJA are poor with sickle cell due to ongoing negative

bone remodeling 3. PVNS

3) Growth and Development of the Skeleton Limb Development -The appendicular skeleton forms between the 4th and 8th weeks of gestation. The limb bud begins as an out-pouching from the lateral body wall and initially consists of both ectodermal and mesodermal layers. -This initial outgrowth appears to be under the control of the FGF family because FGF-1, FGF-2 and FGF-4 all are able to induce the formation of ectopic limb buds. -The progressive enlargement of the limb bud results from biomechanical signaling between the layer of ectodermal cells at the distal layer, apical ectodermal ridge (AER), and the rapidly proliferating mesodermal cells, progress zone, adjacent tot his ectodermal layer. -The apical ectodermal ridge (AER) is to promote the outgrowth of the limb bud in the proximal distal direction by maintaining the mesodermal cells in an undifferentiated state.

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-The role of the progress zone is to secrete a factor that maintains the AER. If the AER is experimentally removed, the cells immediately subjacent to the AER undergo massivce cell death, and the limb formation is truncated at a variable proximal-distal level, depending on the timing of the AER removal. The severe transverse phocomelic birth defects caused by thalidomide exposure during the 1st trimester of pregnancy have been postulated to involve damage to the progress zone. -Surgical replacement of the AER or implantation of a bead loaded with FGF-4 prevents this cell death and restores the normal proximal-distal axis of limb formation. The proximal-distal axis of limb formation is therefore under control of the FGF family. -As the limb bud enlarges, its constituent cells acquire a positional identity with respect to each of the three axes (proximal-distal, anterior-posterior, dorsal-ventral) that ultimately specifies cell fate and sculpts the mesenchymal condensations that form the precursors of the skeletal elements of the limb. This positional identity is acquired as cells pass through the progress zone beneath the AER. -Cells located in the zone of polarizing activity (ZPA) in the posterior aspect of the limb bud direct both the number and type of digits formed. This organizing activity of the ZPA has been traced to the product of the Sonic hedgehog (Shh) gene. Shh controls the formation of digits by activating the expression of homeobox (HOX) genes. -Limb formation along the dorsal-ventral axis of the limb bud is under the control of a member of the Wnt gene family, Wnt-7a. This regulatory molecule is expressed in a restricted area on the dorsal aspect of the limb bud and specifies dorsal-ventral patterning. Misexpression of Wnt-7a on the ventral aspect of the limb bud in mice results in digits that flex in the dorsal direction and extend in the ventral direction. -During the 6th week of development, mesenchymal condensations within the limb bud, which serve as models for skeletal development, undergo chondrogenesis as the cells begin the synthesize a cartilage extracellular matrix. This transformation into cartilage tissue is regulated by the activity of members of the SOX gene family, specifically SOX5, SOX6 and SOX9. -Mutations of SOX9 have been linked to camptomelic dysplasia (). -Three dimentional regulatory axis of limb bud pattern formation:

1. Proximal-Distal: FGF 2. Dorsal-Ventral: Wnt-7a 3. Anterior-Posterior: Shh

4) Science of Muscluar Tissue -Myotendon junction is the weakest link in the muscle. It is often the site of tears, especially with eccentric contractions (muscle lengthens while contracting)

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-Sarcomere is composed of thick (myosin) and thin (actin) filaments intricately arranged to allow the fibers to slide past each other. The sarcomere is arranged into bands and lines:

o H-band: contains myosin only o I-band: contains actin only o A-band: contains actin and myosin o M-line: interconnecting site of myosin o Z-line: anchors the thin (actin) filaments

-Neuromuscular junction: stimulus for a muscle contraction comes from the brain and travels down the spine to the muscle. The motor endplate (specialized synapse formed between the nerve and muscle) releases ACh from presynaptic vesicles. The Ach then binds to a postsynaptic receptors to cause depolarization of the SR which then releases calcium into the muscle cytoplasm. Calcium binds to troponin (on thin filaments) causing them to change the position of topomyosin (also on the thin filaments) and expose the actin filaments. Actin-myosin cross bridging forms and with ATP breakdown of ATP the thick and thin filaments slide past one another causing contraction of the muscle. -Botunlinum A toxin blocks ACh release presynaptically -Non-depolarizing drugs (curare, pancuronium and vecuronium) competitively bind to ACh recepts to block impulse transmission (long term paralytic) -Depolarizing drugs (succinylcholine) binds to ACh receptors to cause temporary depolarization of muscle membrane (short term paralytic) -Anticholinesterases (neostigmine, edrophonium) act at the autonomic ganglia, prevents breakdown of ACh to enhance its effects. These meds are reversal agents for non-depolarizing drugs. These meds have muscarinic effects (bronchospasm, bradycardia, bronchorrhea) 3 Types of Muscle Contraction:

1. Isotonic Contraction: -muscle tension is constant throughout the ROM. -measure of dynamic strength -free weight exercise is an example -has several phases:

i. Concentric contraction: the muscle shortens during contraction

ii. Eccentric contraction: the muscle lengthens during contraction

2. Isometric Contraction: -muscle tension is generated but length remains unchanged. -a measure of static (not dynamic) strength -increases strength at a specific joint angle at which the training is being affected

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-benefits seem to occur during the early stages of training or rehab -optimal effects occur at maximal contraction and long enough duration to recruit as many fibers as possible and best when done several times per day -example is wall sits

3. Isokinetic Contraction: -muscle tension is generated as the muscle maximally contracts at a constant velocity over a full ROM -best for maximizing strength and are a measure of dynamic strength -effective at slow speeds (60/sec) -cybex machines (exerts a force that equals that exerted by the person)

i. Concentric contraction phase ii. Eccentric contraction phase

-Eccentric contraction is a phase of muscle contraction, not a type of muscle contraction. The muscle lengthens during the contraction (internal force is less than the external force). Eccentric contractions have the greatest potential for high muscle tension and muscle injury. Example is a negative. It is questionable if it is more effective than other forms of training, some say no. -Concentric contraction is a phase of muscle contraction, not a type of muscle contraction. The muscle shortens during the contraction (internal force exceeds the external force). -Plyometrics are a special type of exercise. It is implosion training in which the muscles are loaded suddenly and forcefully stretched before they can contract. It is very effective at power generation. Like eccentric loading, it has been shown to increase muscle soreness and have an increased risk of injury. Examples are catching and throwing a medicine ball, jumping down from a box and jumping back up. The stretch stores elastic energy which increases the force of the concentric contraction. -Closed-chain exercises include loading an extremity with the most distal segment stabilized or not moving (on the ground). This allows muscular co-contraction around a joint, which minimizes joint shear (places less stress on the ACL). Stationary bike is an open chain exercise and is harmful to an ACL reconstruction. -Type 1 Muscle Fibers:

o Slow twitch o Oxidative (red) fibers (slow red ox) o Aerobic therefore more mitochondria and high capillary density o Good for endurance sports o First muscles lost without rehabilitation o Low anaerobic capacity

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-Type IIA Muscle Fibers: o Fast twitch o Glycolytic (white) and oxidative fibers (FOG fast oxidative

glycolytic) o Not as prevalent in humans (seen in humbingbirds) o Good for strength

-Type IIB Muscle Fibers: o Fast twitch o Glycolytic (white) only (unlike IIA) o Anaerobic o Quick contractions with larger and stronger motor units o Good for sprinters and strength atheletes o Strength training causes hypertrophy of these fibers

ATP-CP System -aka Phosphogen system -meets the metabolic requirement for intense muscle activity that lasts up to 20 sec, such as sprinting a 100-200 meter dash. -converts stored carbohydrates from within the muscle fiber itself to energy -does not use oxygen -does not produce lactate -energy is derived from the high energy phosphate bonds of ATP -creatine supplements can increase the amount of work that is produced in 1st few max-effort anaerobic trials but does not increase peak force production Lactic Anaerobic System -meets the metabolic requirement for intense muscle activity that lasts 20-120 sec, such as a 400 meter dash. -involves hydrolysis of on glucose molecule to ultimately produce lactic acid plus energy converting 2 molecules of ADP to 2 molecules of ATP Aerobic System -when oxygen is available, the aerobic system replenishes ATP through oxidative phosphorylation and the Krebs cycle. It uses glucose or fatty acids to produce ATP. Meets the metabolic requirements for episodes of longer duration and lower-intensity muscle activities. -Aerobic exercise in a healthy adult is recommended for 3-5 days per week for 20-60 min per session. Training should be at 60-90% of max heart rate. Max heart rate is approximately 220 bpm age. Aerobic conditioning has proved effective in lowering the incidence of back injury in workers and in helping elderly remain ambulatory. A significant decline in aerobic fitness occurs after just 2 weeks of no training (detraining) Basic Science of Sports Medicine

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Reza Omid MD

-Unhealthy weigth loss due to fluid and food restriction (seen in wrestlers, fighters and jockeys) is associated with:

1. reduced cardiac output 2. increased heart rate 3. smaller stroke volume 4. lower oxygen consumption 5. decreased renal blood flow 6. electrolyte loss (hypokalemia)

-Fluid replacement regimen for a competitive athlete is to replace enough water to maintain pre-practive weight and maintain a normal diet. Fluid carbohydrate and electrolyte replacement is most effective when the osmolarity of the replacement fluid is

Reza Omid MD

system recruitment. Electrical stimulation (US therapy) can help offset these effects.

4) Science of Nervous Tissue CNS Injuries -Patients may continue to improve up to 6 months after a stroke and up to 18 months after traumatic brain injury. Most common mechanism of spinal cord injury in adults is MVA. If

Reza Omid MD

o Vibration Peripheral Nerve Morphology -Axon coated with a fibrous tissue called endoneurium, group into nerve bundles called fascicles, which are covered with a connective tissue called perineurium. Peripheral nerves are composed of one (mono), a few (oligo) or several (poly) fascicles and surrounding areolar connective tissue (epineurium) enclosed within an epineurial sheath. Perineurium which surrounds the bundles of fascicles within a peripheral nerve is the primary structure responsible for tensile strength. Epineurium is thicker but has less tensile strength and may function more to resist compressive forces. -Blood supply to nerves is from an extrinsic blood supply from vessels that run in loose connective tissue surrounding the nerve trunk. Intrinsic blood supply is from vascular plexus in the epineurium, perineurium and endoneurium (with interconnections between these three plexus) -Peripheral nerve injury leads to death of the distal axons and Wallerian degeneration (of myelin) which extends distal to the somatosensory receptor. Proximal axonal budding occurs (after 1 month delay) and leads to regeneration at rate of about 1mm/day (possibly 3-5mm/day in children). Pain is the first modality to return -Nerve regeneration is influenced by:

1. Contact guidance: attraction to basal lamina of the Schwann cell 2. Neurotrophism: factors enhancing growth 3. Neurotropism: preferential attraction towards nerves rather than other

tissues -Upper Motor Neuron Signs (brain or spinal cord):

o Decreased strength o Increased tone o Hyperreflexia o Babinski o Hoffman o Clonus

-Lower Motor Neuron Signs (nerve injuries): o Decreased strength o Loss of tone o Loss of reflexes o Fasciculations o Atrophy of muscles

-Types of Nerve Injuries: o Neuropraxia: reversible coduction block characterized by local

ischemia and selective demyelination of axon sheath Most common Best prognosis

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Reza Omid MD

o Axonotmesis: more severe injury with disruption of the axon and myelin sheath but leaving the epineurium intact

o Neurotmesis: complete nerve division with disruption of the endoneurium

Worst prognosis -Football stingers or burners are neuropraxia from a brachial plexus stretch injury. Nerve stretching can affect function as 8% elongation can diminish a nerves microcirculation and 15% elongation disrupts axons. A + histamine response implies that there is an intact reflex arc indicating that the lesion is proximal to the ganglion (pre-ganglionic) -It is crucial to properly align nevre ends during surgical repair in order to maximize potential for functional recovery. Types of nerve repair include:

1. Direct muscular neurontization: insert nerve stump into the muscle belly

2. Epineural repair: primary repair of outer connective tissue a. Used for smaller nerves (digital nerves) b. Remember kissing but no sex

3. Grouped fascicular repair: reapproximation of individual fascicles under a microscope.

a. No significant improvement in results over epineural repair has been documented

b. Used for larger nerves.

5) Science of Connective Tissue -Tendons insert into bone via four transitional tissues (for force dissipation):

1. Tendon 2. Fibrocartilage 3. Mineralized fibrocartilage (Sharpys fibers) 4. Bone

-Consists of fibroblasts arranged in parallel rows in fascicles of type 1 collagen (85%) with surrounding loose areolar tissue called the peritenon. Tendons attach muscle to bone (via Sharpeys fibers). Immobilization leads to increased tendon strength at the expense of ROM but decreases tendon strength at the tendon-bone interface. Tendon repairs are weakest at 7-10 days and regain maximum strength at 6 months. Two types of tendons are found in the body:

1. Paratenon-covered tendons 2. Sheathed tendons

-Paratenon tendons are vascularized tendons. They have many vessels supplying a rich capillary system. They heal better than sheathed tendons. Examples include the patellar tendon and Achilles tendon -Sheathed tendons have a mesotenon (vincula) which carries a vessel that supplies only one tendon segment. Avascular areas receive nutrition via

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diffusion from vascularized segments. Examples include flexor tendons of the hand. -Ligaments stabilize joints (connect bone to bone) and are composed of type 1 collagen (70%). Fibers are more variable than tendons and have higher elastin content. They have uniform microvascularity (unlike tendons) and receives its supply at the insertion site. They also possess mechanoreceptors and free nerve endings. They insert onto bone via direct or indirect insertion. Early healing is via type 3 collagen which is converted to type 1 collagen. Mobilization increases strength of the ligaments. -Ligament sprains include 3 grades:

1. Grade 1 Sprain: ligament is stretched but remains intact and results in no instability

2. Grade 2 Sprain: partial tears that lead to mild instability 3. Grade 3 Sprain: complete tears that result in significant joint instability

-Rupture of sequential series of collagen fiber bundles distributed throughout the body of the ligament (as opposed to localized to one specific area) is most common mechanism of ligament failure. Ligaments doe not plastically deform. Midsubstance tears are common in adults. Avulsion injuries (with small piece of bone) are more common in children. Ligament avulsion typically occurs between the unmineralized and mineralized fibrocartilage layers. Local injections of corticosteroids at a site of injured ligament is detrimental to the healing process. -Fibrillin is a component of elastic fiber system. Fibrillin metabolism defect has been demonstrated in some patients with adolescent idiopathic scoliosis as well as Marfans. -Magic angle of MRI occurs when a tendon or ligament is oriented near 55 to the magnetic field, T1 images may appear to have increased signal and create false appearance of pathology. Most commonly seen in the shoulder, knee and ankle -Intervertebral discs of the spine contains various neuropepties including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide (VIP) and c-flanking peptide of neuropeptide (CPON). They are composed of 2 components:

1. Central Nucleus Pulposus: hydrated gel with compressibility i. High GAG and low collagen ii. Type 2 collagen

2. Annulus Fibrosis: increased tensile strength i. High collagen and low GAG ii. Type 1 collagen iii. Superficial layer contains nerve fibers

6) Science of Perioperative Problems Blood Gas Evaluation

1) pO2 = 7(FiO2)-pCO2

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o pO2 is the anticipated or normal pO2 in a normal person given FiO2. pCO2 is from the ABG value obtained

2) Once pO2 (anticipated) is calculated, you subtract this from the pO2 given from the ABG to determine the Aa-gradient

o Aa-gradiant = Anticipated pO2 Observed pO2 3) Calculate the percentage physiologic shunt from the Aa-gradient as:

o Percentage physiologic shunt = Aa-gradient/20 Thromboembolism Risk Factors

o History of thromboembolism o Obesity o Malignancy o Age o CHF o Birth control pills o Varicose veins o Smoking o General anesthesia o Increased blood viscosity (factor V leiden) o Immobilization o Paralysis o Pregnancy

Virchows Triad

1) Venous stasis 2) Hypercoagulability 3) Intimal injury

Deep Vein Thrombosis -Pain, swelling and + Homans sign -Venography is the gold standard (97% accurate) -I125 labeled fibrinogen (op-site has false positive) -Duplex US (B-mode) is 90% accurate -Doppler is good for bedside study -DVT is uncommon after elective spine surgery so only mechanical prophylaxis is recommended. -Treatment is indicated for all thigh DVTs but below the popliteal fossa is controversial -Pre-op identification of DVT in a patient with lower extremity or pelvic trauma is an indication for placement of a vena cava filter -Coumadin inhibits hepatic enzymes (vitamin-k dependent epoxide and reductase) to decrease carboxylation of the vitamin k-dependednt proteins:

1) Factor 2 (prothrombin) 2) Factor 7

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Reza Omid MD

3) Factor 9 4) Factor 10

-Effects of coumadin can be reversed with vitamin K or more rapidly with fresh frozen plasma. Rifampin and phenobarbital are antagonistic to coumadin. Erythromycin is contraindicated with coumadin use. COumadin is most effective for DVT prophylaxis/treatment but takes 3-5 days for full effect and the initial few days there is a hypercoagulable state so recommended to bridge with lovenox. Treatment for DVT is for 3 months with INR at 2-3. Coumadin is monitored with PT/INR -Heparin is antithrombin III inhibitor and can be monitored via PTT -Lovenox inhibits clotting factors by forming complexes with antithrombin III and factors IIa and Xa but you cannot monitor and must use with caution in patients with renal disease. Bleeding/oozing is a concern with lovenox. -Indomethacin is a very potent NSAID and acts at lipooxygenase side of arachadonic acid metabolism (as opposed to COX), which results in inhibition of leukotriene inflammatory mediators. Pulmonary Embolism -Acute onset of pleuritic chest pain, tachypnea, tachycardia. -Work up includes:

1) EKG (RBBB, RAD, ST depression or T-wave inversion in lead III) 2) CXR (hyperlucency) 3) ABG (respiratory alkylosis due to low CO2, but normal ABG does not

exclude this diagnosis) 4) V/Q scan 5) Pulmonary angiogram (gold standard) 6) CTPA (CT pulmonary angiogram) but not as good as pulmonary

angiogram -Treatment is with heparin or therapeutic lovenox (1mg/kg/BID) for 7-10 days followed by 3 months of coumadin -Thrombolytic agents indicated if patient is unstable -IVC filters in select cases Coagulation -A cascade of enzymatic reactions ending with fibrin clot formation via 2 interconnected pathways:

1) Intrinsic pathway: monitored by PTT a. Activated when factor 12 contacts collagen of damaged vessels

2) Extrinsic pathway: monitored by PT a. Activated by thromboplastin released into circulation after cellular

injury (surgery or trauma) -Bleeding time measures platelet function

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-Fibrinolytic system is responsible for dissolving clots. Plasminogen is converted to plasmin (with help of tissue activators, factor 12a and thrombin) and plasmin dissolves fibrin clots. Adult Respiratory Distress Syndrome -Acute respiratory failure secondary to pulmonary edema after trauma, shock or infection. -Causes of ARDS include:

1) Pulmonary infection 2) Sepsis 3) Fat embolism (from multiple long bone fractures) 4) Microembolism 5) Aspiration 6) Fluid overload 7) Atelectasis 8) O2 toxicity 9) Pulmonary contusion 10) Head injury

-Complement activation leads to further progression -Tachypnea, dyspnea, hypoxemia and decreased lung compliance -Clinical diagnosis of ARDS after long bone fractures is best made with ABGs -50% mortality associated with ARDS -Treatment is ventilation with PEEP or high frequency percussive ventilation -Steroids are not useful -Stabilization of long bones decreases risk but must contemplate damage control versus early definitive stabilization. Fat Embolism Syndrome -Usually occurs at 24-72 hours after trauma (before the time frame for PE) -Clinical findings include:

o Hypoxemia (PO2

Reza Omid MD

-Malnutrition is present in 50% of surgical ward patients. -Work up includes:

o Anergy panel o Albumin (2-3 weeks life) >3-3.5g/dl o Pre-albumin (2 days life) >20mg/dl o Transferrin (1 week life) ~0.16-0.36g/dl o Fibronectin (1 day life)

-Arm muscle circumference measurement is the best indicator of mutritional status -Wound dehiscence, infection, pneumonia and sepsis can result from poor nutrition. -Lack of enteral feeding can lead to atrophy of the intestinal mucosae, leading in turn to bacterial translocation -Enteral protein supplements have proven effective in patients at risk of developing multiple organ system failure. Provide patients with:

1) Boost with meals TID 2) MVI Qday 3) Vitamin C 500mg Qday or BID 4) Zinc Sulfate 220mg Qday 5) Iron Sulfate 325mg BID or TID

-Wound healing measurements:

1) TcPO2 > 30mmHg 2) ABI > 0.45 3) Toe pressure > 40mmHg 4) Albumin > 3.0g/dl 5) Total lymphocyte count >1500 cells/mm3 6) Total protein >6.2 g/dl 7) Hemoglobin >10g/dl

-Frostbite: treat with general rewarming of entire body plus rapid rewarming of hands and feet in a warm bath (104F or 40C for 15-30min). Also splint, give tetanus, antibiotics and provide analgesics. Severe swelling may occur upon rewarming so monitor for compartment syndrome -Kneeling frame for spine surgery causes:

o Decreased intraabdominal pressure o Decreased pressure on the IVC o Decreased pressure on vertebral venous system o Decreased blood loss

Malignant Hyperthermia -Autosomal dominant hypermetabolic disorder of skeletal muscle, has impaired sarcoplasmic reticulum and calcium homeostasis -Masseter muscle spasm, increased temperature, rigidity and acidosis

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-Most accurate method of diagnosis is muscle biopsy -Occurs with halothane and succinylcholine -Patients at risk are:

1) Duchennes muscular dystrophy 2) Arthrogryposis 3) Osteogenesis imperfecta

-Treat with dandrolene, correct electrolytes and increase uring output as well as cooling measures. Surgical Tourniquet -Can injure nerves and muscles (EMG abnormalities may occur in 70% of patients using the tourniquet. -Careful application, wide cuffs, lower pressures (200mmHg for the UE and 250mmHg in the LE or 100-150mmHg above systolic pressure for LE) -Double cuffs are useful to prevent pain at the tourniquet site. 1st inflate the proximal cuff and infuse with lidocaine, then inflate the distal cuff (now anesthetized) and deflate the proximal cuff. -Equilibrium can be re-estabilished within 5 min after 90 minutes of use but requires 15 minutes after use for 3 hours. Do not exceed 2 hours of use at a time. -Esmark bandage and elevation (for 5 min) can be used to prevent a venous tourniquet. Only 2 layers of webril are required when using a tourniquet, as more will decrease the pressure.

7) Science of Biomaterial & Biomechanics Biomaterials -Loads: forces that act on a body (compression, tension, shear and torsion) -Deformations: temporary (elastic) or permanent (plastic) change in the shape of a body. Changes in load produce changes in deformation -Stress = force/area (N/m2) in pascals -Normal stresses (compressive or tensile) are perpendicular to the surface on which they act. -Shear stresses are parallel to the surface on which they act -Strain=change in length/original length -Strain is a relative measure of the deformation -Hookes Law: stress is proportional to the strain up to a limit (proportional limit) -Youngs Modulus (E): measure of the stiffness of a material or its ability to resist deformation. -E=stress/strain (slope of the curve) -The larger the E the more stress shielding seen -Comparison of different materials/tissues (from highest E to lowest):

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Reza Omid MD

1) Ceramic (Al2O3) 2) Co-Cr-Mo (Alloy) 3) Stainless steel (iron, chromium and nickel) 4) Titanium 5) Cortical bone 6) PMMA 7) Polyethylene 8) Cancellous bone 9) Tendon/Ligament 10) Cartilage

-Yield point (proportional limit) on a stress strain curve is the transition point from the elastic to the plastic range. -Ultimate strength: maximum strength obtained by the material -Breaking point: point where the material fractures -Plastic deformation: change in length after removing the load (before the breaking point) in the plastic range. -Strain energy: the capacity of a material (such as bone) to absorb energy. On a stress strain curve it is illustrated as the area under the curve. Total strain energy is recoverable energy (resilience) + dissipated strain energy. A measure of the toughness (ability to absorb energy before failure) of a material -Materials/Structures:

1. Brittle materials: exhibit a linear stress strain curve up to the point of failure (PMMA). Undergo only fully recoverable (elastic) deformation before failure and have little or no capacity to undergo permanent (plastic) deformation before failure

2. Ductile materials: undergo a large amount of plastic deformation prior to failure (metal). Ductility is a measure of post-yield deformation.

3. Viscoelastic materials: exhibit stress-strain behavior that is time-rate dependent (bone and ligament); the materials deformation depends on the load and the rate at which the load is applied. The modulus of a viscoelastic material increases as the strain rate increases. Viscoelastic behavior is a function of the internal friction of a material.

4. Isotropic materials: possess the same mechanical properties in all directions (golf ball)

5. Anisotropic materials: have mechanical properties that vary with the direction of the applied load (bone)

6. Homogeneous materials: have a uniform structure or composition throughout

-Fatigue failure: occurs with repetitive loading cycles at stress below the ultimate tensile strength. Fatigue failure depends on the magnitude of the stress and the number of cycles. If the stress is less than a predetermined amount of stress, called the endurance limit (the max stress under which the material will not fail regardless of how many loading cycles are applied), the material may be loaded an infinite number of times without breaking.

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-Creep (aka Cold Flow): progressive deformation of metals (or other materials such as PE) in response to a constant force applied over an extended period. If sudden stress, followed by constant loading, causes a material to continue to deform, it demonstrates creep. Creep can produce a permanent deformity and may affect mechanical function (such as in a TJA) -Corrosion: chemical dissolving of metals as may occur in the high-saline environment of the body.

316L stainless steel is the most likely metal to undergo pitting and crevice corrosion

The risk of galvanic corrosion is highest between 316L stainless steel and cobalt-chromium (Co-Cr) alloy.

Modular components of THA have direct contact between either similar or dissimilar metals (at the modular junction) and thereby have corrosion products (metal oxides, metal chlorides, etc).

-Galvanic corrosion can be decreased by using similar metals (plates and screws with similar metals), with proper design of implants and with passivation (a thin layer that effectively separates the metal from the solution (stainless steel coated by chromium oxide)

8) Orthopaedic Infectious Disease -Microorganisms gain access to muscluloskeletal system via 3 mechanisms:

1) Hematogenous 2) Spread from a contiguous source (adjacent osetomyelitis) 3) Direct inoculation (trauma/surgery)

-Virulence is the ability of an organism to overcome the host defenses and cause infection. -Defense mechanisms of Staphlococcus aureus include:

1) Excretion of protein A: inactivates host IgG 2) Production of capsular polysaccarides: inhibits opsonization and

phagocytosis 3) Formation of a biofilm

-Host factors that facilitate infection: 1) Reduced vascularity (arterial disease, venous stasis, irradiation,

scarring, smoking) 2) Neuropathy 3) Presence of implants 4) Trauma (predisposes by compromising the soft tissue, by creating a

dead space with hematoma) 5) Renal or liver disease 6) Malignancy 7) Rheumatologic disease 8) Alcoholism 9) Immunocompromised state (HIV/AIDS)

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Reza Omid MD

10) IVDA Inflammatory Markers -Become elevated with infections, fractures and chronic inflammatory diseases

1) ESR (erythrocyte sedimentation rate): Unreliable in neonates, patients with sickle cell disese and patients

taking steroids. Unreliable in patients with short period of symptoms (

Reza Omid MD

c. Cellulitis will show up during 1st two phases but not 3rd phase as opposed to osteomyelitis

d. Bone marrow scan (technetium-99m sulfur colloid) can be combined with bone scanning (technetium-99m methylene diphosphate), within 24 hours, to differentiate between bone infarction and osteomyelitis in children.

i. Bone infarction: decrease on bone marrow scan and increase on bone scan

ii. Osteomyelitis: normal on bone marrow scan and increase uptake on bone scan

2) Gallium-67 Citrate Scan: used to localize areas of inflammation or neoplasia probably because of exudation of labeled serum proteins. a. Specifically is poor when used alone so its commonly used in

conjunction with technetium-99m phosphate scans as a double tracer technique.

b. Requires delayed imaging 24-48 hours c. Less dependent on vascular flow than technetium-99m phosphate

and may identify foci that would have otherwise been missed. d. Difficult to distinguish between cellulitis and osteomyelitis

3) Indium 111-Labeled Leukocyte Scan: suggested for use to differentiate osteomyelitis from neoplasia or reactive bone formation. a. Positive at earlier stages of osteomyelitis than technetium-99m

phosphate (more accurate for osteomyelitis) b. Blood is taken from the patient and PMN separated and labeled

with indium 111 and placed back in the patient and scanned at 24 hours.

c. Hot spots occur in areas where PMN accumulate so helpful for acute osteomyelitis but may not be good for chronic osteomyelitis (lymphocytes predominate)

MRI -T1 images have short TR and TE, bright fat -T2 images have long TR and TE, bright water -STIR (short au inversion recovery) are fat suppression and are almost 100% negative predictive value for osteomyelitis. -In osteomyelitis, marrow fat is replaced with edema and cellular infiltrates that are lower signal on T1 than fat and higher signal that fat on T2 and STIR therefore:

Classic findings of osteomyelitis on MRI are a decrease in normally high marrow signal on T1 and normal or increased signal on T2 images

-Gadolinium contrast helps distinguish an abscess (bright signal involved abscess with no enhancements of the fluid within the abscess) from cellulitis.

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Culture Studies -Cultures should be obtained before antibiotics started. -Cultures of superficial wounds or sinus tracts should be used with caution because not reliable for deep infection and are usually polymicrobial (unless staph. aureus groups) -Preferred specimen is aspiration fluid (joint or pus) -Deep wound biopsy or cultured specimen after cleaning the wound is acceptable -Specimens should be sent from:

1. sinus tract tissue 2. sinus tract pus 3. soft tissue 4. bone from curettage 5. bed of involved bone 6. tissue surrounding implant for aerobic, anaerobic, fungal and TB

-Sinus tract should be sent for histologic evaluation to rule out malignancy Glycocalyx -An exopolysaccaride coating that envelops bacteria -A biofilm is an aggregation of microbe colonies embedded within a glycocalyx matrix that usually develop on implants or devitalized bone surfaces. -Glycocalyx shields bacteria from antibodies and antibiotics Bacterial Types

1. Gram + Bacteria: a. No outer membrane (unlike gram -) b. Have thick cell wall on outside of cell which is where a lot of

antibiotics work on (gram have no cell wall) c. Resistant to antibodies and complement mediated killing

2. Gram Bacteria: a. Have an outer membrane which contains endotoxins (lipid A) which

cause sepsis. b. Have very thin cell wall between the OM and IM c. Susceptible to antibodies and complement mediated killing d. Antibodies must penetrate porins in the outer membrane so not

susceptible to some antibiotics 3. Encapsulated Organisms:

a. Streptococcus pneumoniae b. Neisseria meningitites c. Haemophilus influenzae d. Patients who have splenectomy or hypogammaglobulinemia are at

increased risk for these encapsulated organisms Transient Synovitis of the Hip -May mimic septic arthritis of the hip

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-An immune-mediated mechanism after viral infection. -Less signs of systemic illness -Kocher criteria include:

1. History of fever 2. Non-weight bearing of that side 3. ESR >40 4. WBC > 12,000 - Probability of septic arthritis with positive predictors:

o 1 out of 4: 5% o 2 out of 4: 62% o 3 out of 4: 97% o 4 out of 4: 99.8%

Osteomyelitis -Infection of bone and bone marrow -Bone inflammation secondary to microbial pathogens -May be caused by: hematogenous, direct inoculation or spread from adjacent tissue -May be acute, subacute or chronic -Tibia is the most common location of adult osteomyelitis -Most common pathogen is staph. aureus -Diagnosis is based on clinical findings (pain, erythema, sinus drainage and systemic symptoms), lab values (ESR, CRP, CBC, Blood cultures), imaging (MRI