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Introduction to Modern Biomaterials
Gabriel Luna BarcenasCinvestav Queretaro
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Sequence of local events following device implantationl Injury
l Injection, implantation, blood vessel damagel Acute inflammation
l Polymorphonuclear leukocytesl Chronic inflammation
l Monocytes and Macrophagesl Granulation tissue
l Fibroblasts and new blood capillariesl Foreign body reaction
l Macrophages and FBGCs at the material-tissue interfacel Fibrosis
l Fibrous capsule
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Hemostasis: Vasoconstriction & Plug Formation
Figure 16-12: Platelet plug formation
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HemostasisThe 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 fibrinogenis 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 ActivationPlatelets bind to matrix and spread to cover the damaged
surface; aggregation to form temporary plug;
l 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);
l 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-fibrinogenà 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
Figure 16-13: The coagulation cascade
l Prothrombinl Ca++l Fibrinogenl Fibrinl Polymerization
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Factor Trivial Name(s) Pathway Characteristic
I Fibrinogen Both -
II Prothrombin Both Contains N-term. gla segment
III Tissue Factor Extrinsic -
IV Calcium Both -
V Proaccelerin, labile factor, accelerator (Ac-) globulin Both Protein cofactor
VI (Va) Accelerin - This is Va, redundant to Factor V
VII Proconvertin, serum prothrombin conversion accelerator (SPCA), cothromboplastin Extrinsic Endopeptidase with gla residues
VIII Antihemophiliac factor A, antihemophilic globulin (AHG) Intrinsic Protein cofactor
IX Christmas Factor,antihemophilic factor B,plasma thromboplastin component (PTC) Intrinsic Endopeptidase with gla residues
X Stuart-Prower Factor Both Endopeptidase with gla residues
XI Plasma thromboplastin antecedent (PTA) Intrinsic Endopeptidase
XII Hageman Factor Intrinsic Endopeptidase
XIII Protransglutamidase,fibrin stabilizing factor (FSF), fibrinoligase Both Transpeptidase
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 Activationl Blood-materials interactions-protein adsorption;
l The Complement system is a complex cascade involving approximately 30 glycoproteins present in serum as well as cell surface receptors;
l Activation of the inflammation and immune related function.
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Cytokines and Growth Factorsl Autocrine (affect function of the cell that releases it)l Paracrine (affect the function of adjacent or nearby cells
of the same or different phenotype)
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TGF-bChemoattractant for monocytes and fibroblastsl Pro-fibrogenic
l stimulates fibroblast proliferationl Stimulates fibroblasts to secrete matrix (collagen,
fibronectin, and glycosaminoglycans) and therefore aids in the development of wound strength
l Stimulates angiogenesis (new blood vessel development)
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Cellular Terminology:l granulocyte: any blood cell containing specific granules
(e.g. neutrophils, eosinophils, basophils)l leukocyte: a colorless blood cell capable of ameboid
movement (e.g. lymphocytes, monocytes, granulocytes)l macrophage: large phagocytic mononuclear cell
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Figure 16-2: The blood count
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10/8/18 27Figure 16-1: Composition of blood
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Clinical Signs of Inflammation:l redness (rubor), swelling (tumor), pain (dolor), heat (calor)Why rubor? erythrocytesWhy swelling? Permeability:
l pressure difference between capillary and external tissue bed l endothelium is tight permits very slow flow of water and small
molecules into surrounding tissueNORMALLY: lymphatic vessels drain away this fluid maintaining
constant tissue volumeINFLAMMATION: permeability increases and larger molecules move
into the tissuel increased fluid influx not promptly balanced by the lymphatic
system l swelling (tumor)
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Acute InflammationLasts from minutes to days depending on the injuryInitial stages:
l rapid dilation of local capillariesl increase in the permeability of their endothelial cell linings
Dilation?l foreign protein or material coagulation factor (factor XII)
kinins dilation and endothelial permeationDilation leads to an increase in blood entry into the
capillary bedsl loss of plasma through the capillary wallsl platelets and erythrocytes become stickyl blood flow slower and sludgy
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Neutrophil (a granulocyte) First Cells to Appear at Injury Site
l stick to capillary endothelium, penetrate between the endothelial cells and move into the surrounding damaged tissue;
l neutrophil emigration (diapedisis) begins minutes to hours after insult and may continue for as long as 24h;
l neutrophil activates when engages foreign particle such as a damaged cell, pathogen, damaged matrix, or a biomaterial; and, they
l 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 Continuuml Initiation by mechanical injury/damage to vasculaturel Blood coagulation-clot formationl Platelet activation and degranulationl Inflammation-edema l Removal of damaged matrix and necrotic cell
componentsl Cell proliferation and recruitment including endothelial,
epithelial, stromal and inflammatory cellsl Continued removal of matrixl Angiogenesisl Matrix synthesis and deposition
l Epithelialization and wound contractionl Decrease in cellularity-apoptotic pathwayl Tissue remodeling-elastin synthesisl