Transcript Document

Sequence of local events following
device implantation
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Injury
 Injection, implantation, blood vessel damage
Acute inflammation
 Polymorphonuclear leukocytes
Chronic inflammation
 Monocytes and Macrophages
Granulation tissue
 Fibroblasts and new blood capillaries
Foreign body reaction
 Macrophages and FBGCs at the material-tissue interface
Fibrosis
 Fibrous capsule
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Hemostasis: Vasoconstriction
& Plug Formation
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Figure 16-12: Platelet plug formation
Hemostasis
The process of blood clotting and then the subsequent dissolution
of the clot, following repair of the injured tissue.
Composed of 4 major events that occur in a set order following
the loss of vascular integrity:
1. vascular constriction. This limits the flow of blood to the area of
injury.
2. platelets become activated by thrombin and aggregate at the
site of injury, forming a temporary, loose platelet plug. The protein
fibrinogen is primarily responsible for stimulating platelet
clumping. Platelets clump by binding to collagen that becomes
exposed following rupture of the endothelial lining of vessels.
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Hemostasis (continued)
Upon activation, platelets release ADP and TXA2 (which activate
additional platelets), serotonin, phospholipids, lipoproteins, and other
proteins important for the coagulation cascade. In addition to induced
secretion, activated platelets change their shape to accommodate the
formation of the plug.
3. To insure stability of the initially loose platelet plug, a fibrin mesh (also
called the clot) forms and entraps the plug.
4. Finally, the clot must be dissolved in order for normal blood flow to
resume following tissue repair. The dissolution of the clot occurs through
the action of plasmin.
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Overview of Hemostasis:
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Platelet Activation
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SEM of Platelets
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Platelet Activation
Platelets bind to matrix and spread to cover the damaged
surface; aggregation to form temporary plug;
 Initiates the wound healing process through the
secretion of soluble small molecules from cytoplasmic
granules called growth factors and cytokines (Platelet
derived growth factor (PDGF), Fibronectin, von Willebron
Factor and Transforming Growth Factor-beta (TGF-b);
 These substances are sticky and bind to matrix,
chemotactic (draw cells up the concentration gradient
through migration) and /or mitogenic agents for
leukocytes, endothelial cells and fibroblasts;
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Hemostasis: Vasoconstriction
& Plug Formation
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Figure 16-12: Platelet plug formation
Fibrin Clot FormationThrombogenesis
Two principle pathways: converge on the same end productfibrinogen fibrin
Intrinsic pathway: clot in response to an abnormal vessel wall
superficial injury in the absence of tissue injury
Extrinsic pathway: clot formation in response to tissue injury ,
actual breakage of blood vessels.
Both pathways are complex and involve numerous proteolytic
enzymes called clotting factors.
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zymogens
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Hemostasis
The intrinsic pathway is the longer, slower pathway when compared
to the extrinsic pathway. The intrinsic pathway can take between a
few seconds or even minutes to produce Factor X. The extrinsic
pathway reacts almost instantaneously by producing Factor X. The
benefit of the intrinsic pathway is that more Factor X is
produced. The extrinsic pathway's main function is to augment the
intrinsic pathway by slowing the flow of blood outside the vessel by
producing little Factor X, but quickly. The extrinsic pathway
completes the clot and allows for the blood vessel to be repaired
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Hemostasis: Coagulation &
Clot Stabilization
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Prothrombin
Ca++
Fibrinogen
Fibrin
Polymerization
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Figure 16-13: The coagulation cascade
Primary Factors
Factor
Trivial Name(s)
I
Fibrinogen
II
Prothrombin
III
Tissue Factor
IV
Pathwa
y
Both
Characteristic
Contains N-term. gla segment
Calcium
Both
Extrinsi
c
Both
V
Proaccelerin, labile factor, accelerator (Ac-) globulin
Both
VI (Va)
Accelerin
Proconvertin, serum prothrombin conversion accelerator (SPCA),
cothromboplastin
Antihemophiliac factor A, antihemophilic globulin (AHG)
Extrinsi
c
Intrinsic
Protein cofactor
This is Va, redundant to
Factor V
Endopeptidase with gla
residues
Protein cofactor
VII
VIII
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X
Stuart-Prower Factor
Both
XI
Plasma thromboplastin antecedent (PTA)
Intrinsic
Endopeptidase with gla
residues
Endopeptidase with gla
residues
Endopeptidase
XII
Hageman Factor
Intrinsic
Endopeptidase
Both
Transpeptidase
IX
XIII
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Christmas Factor,
antihemophilic factor B,plasma thromboplastin component (PTC)
Protransglutamidase,
fibrin stabilizing factor (FSF), fibrinoligase
Intrinsic
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Fibrin Clot Formation
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Dissolving the Clot and
Anticoagulants
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Figure 16-14: Coagulation and fibrinolysis
Complement Activation
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Blood-materials interactions-protein adsorption;
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The Complement system is a complex cascade involving
approximately 30 glycoproteins present in serum as well
as cell surface receptors;
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Activation of the inflammation and immune related
function.
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Cytokines and Growth Factors
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Autocrine (affect function of the cell that releases it)
Paracrine (affect the function of adjacent or nearby cells
of the same or different phenotype)
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TGF-b
Chemoattractant for monocytes and fibroblasts
 Pro-fibrogenic
 stimulates fibroblast proliferation
 Stimulates fibroblasts to secrete matrix (collagen,
fibronectin, and glycosaminoglycans) and therefore
aids in the development of wound strength
 Stimulates angiogenesis (new blood vessel
development)
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Cellular Terminology:
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granulocyte: any blood cell containing specific granules
(e.g. neutrophils, eosinophils, basophils)
leukocyte: a colorless blood cell capable of ameboid
movement (e.g. lymphocytes, monocytes, granulocytes)
macrophage: large phagocytic mononuclear cell
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Figure 16-2: The blood count
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Figure 16-1: Composition of blood
Clinical Signs of Inflammation:
redness (rubor), swelling (tumor), pain (dolor), heat (calor)
Why rubor? erythrocytes
Why swelling? Permeability:
 pressure difference between capillary and external tissue bed
 endothelium is tight permits very slow flow of water and small
molecules into surrounding tissue
NORMALLY: lymphatic vessels drain away this fluid maintaining
constant tissue volume
INFLAMMATION: permeability increases and larger molecules move
into the tissue
 increased fluid influx not promptly balanced by the lymphatic
system
 swelling (tumor)
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Acute Inflammation
Lasts from minutes to days depending on the injury
Initial stages:
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rapid dilation of local capillaries
increase in the permeability of their endothelial cell linings
Dilation?
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foreign protein or material coagulation factor (factor XII)
kinins dilation and endothelial permeation
Dilation leads to an increase in blood entry into the
capillary beds
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loss of plasma through the capillary walls
platelets and erythrocytes become sticky
blood flow slower and sludgy
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Neutrophil (a granulocyte) First
Cells to Appear at Injury Site
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stick to capillary endothelium, penetrate between the
endothelial cells and move into the surrounding
damaged tissue;
neutrophil emigration (diapedisis) begins minutes to
hours after insult and may continue for as long as 24h;
neutrophil activates when engages foreign particle
such as a damaged cell, pathogen, damaged matrix,
or a biomaterial; and, they
release interleukin-1 and tumor necrosis factor (TNFalpha) called proinflammatory cytokines because they
recruit monocytes to the injury site.
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The Wound Healing Continuum
Initiation by mechanical injury/damage to vasculature
 Blood coagulation-clot formation
 Platelet activation and degranulation
 Inflammation-edema
 Removal of damaged matrix and necrotic cell
components
 Cell proliferation and recruitment including endothelial,
epithelial, stromal and inflammatory cells
 Continued removal of matrix
 Angiogenesis
 Matrix synthesis and deposition
 Epithelialization and wound contraction
 Decrease in cellularity-apoptotic pathway
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 Tissue remodeling-elastin synthesis
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