Sequence of local events following device implantation

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Sequence of local events following device
implantation

• 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
Figure 16-12 Platelet plug formation
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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
Figure 16-12 Platelet plug formation
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Fibrin Clot Formation-Thrombogenesis
Two principle pathways converge on the same end
product-fibrinogen? 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

• Prothrombin
• Ca
• Fibrinogen
• Fibrin
• Polymerization

Figure 16-13 The coagulation cascade
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Primary Factors
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Fibrin Clot Formation
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Dissolving the Clot and Anticoagulants
Figure 16-14 Coagulation and fibrinolysis
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Complement Activation

• Blood-materials interactions-protein adsorption
• The Complement system is a complex cascade
  involving approximately 30 glycoproteins present
  in serum as well as cell surface receptors
• Activation of the inflammation and immune related
  function.

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Cytokines and Growth Factors

• 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

• 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
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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
• rapid dilation of local capillaries
• increase in the permeability of their endothelial
  cell linings
• Dilation?
• 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
• 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

• 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
  (TNF-alpha) 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
• Tissue remodeling-elastin synthesis