1. 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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2. Hemostasis: Vasoconstriction & Plug Formation
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Figure 16-12: Platelet plug formation

3. 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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4. 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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5. Overview of Hemostasis:
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6. Platelet Activation
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7. 4/23/2017

8. SEM of Platelets
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9. 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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10. Hemostasis: Vasoconstriction & Plug Formation
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Figure 16-12: Platelet plug formation

11. 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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12. zymogens
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13. 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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14. Hemostasis: Coagulation & Clot Stabilization
Prothrombin
Ca++
Fibrinogen
Fibrin
Polymerization
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Figure 16-13: The coagulation cascade

15. Primary Factors Factor Trivial Name(s) Pathway Characteristic I
Fibrinogen
Both - II
Prothrombin
Contains N-term. gla segment
III
Tissue Factor
Extrinsic IV
Calcium V
Proaccelerin, labile factor, accelerator (Ac-) globulin
Protein cofactor
VI (Va)
Accelerin
This is Va, redundant to Factor V
VII
Proconvertin, serum prothrombin conversion accelerator (SPCA), cothromboplastin
Endopeptidase with gla residues
VIII
Antihemophiliac factor A, antihemophilic globulin (AHG)
Intrinsic IX
Christmas Factor,  antihemophilic factor B,plasma thromboplastin component (PTC) X
Stuart-Prower Factor XI
Plasma thromboplastin antecedent (PTA)
Endopeptidase
XII
Hageman Factor
XIII
Protransglutamidase,  fibrin stabilizing factor (FSF), fibrinoligase
Transpeptidase
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16. 4/23/2017

17. Fibrin Clot Formation
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18. 4/23/2017

19. 4/23/2017

20. Dissolving the Clot and Anticoagulants
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Figure 16-14: Coagulation and fibrinolysis

21. 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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22. 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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23. 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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24. 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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25. Figure 16-2: The blood count
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Figure 16-2: The blood count

26. Figure 16-1: Composition of blood
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Figure 16-1: Composition of blood

27. 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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28. 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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29. 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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30. 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
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