CHAPTER

1313Biomaterials andThrombosis

13-1 Introduction: Overview of Hemostasis Blood-Biomaterials Interaction via protein coats ---- blood coagulation controlInjury ---- Hemostatic mechanism

vascular constriction / platelet plug / blood coagulation (thrombosis)

13-2 Role of Platelets 13.2.1 Platelet Characteristics and Functions Non-nucleated fragment of megakaryocyte (no proliferation) Mitochondria, ER, Golgi -granule: platelet factors, b-thromboglobulin, fibrinogen, factor V and VIII Dense granule: ADP, Calcium, serotonin Lysosomal granules: hydrolytic enzymes

Platelet plug formation / activation of blood coagulation cascade

13.2.2 Platelet Activation (1)Means of activation collagen, von Willerbrand factor (vWF), proteins on biomaterials (2) Sequelae

shape change --- contraction of cytoskeletons --- granule release (ADP/thrombin/thromboxane A2)

activated platelets ---- ECM adhesion --- platelet stimulation and coagulationplatelet aggregation with fibrinogen (GPIIb/IIIa) platelet plug formation --- localized blood coagulation PL memb. of platelet --- factor X activation --- thrombin activation

Platelet Activation

13-3 Coagulation Cascade intrinsic pathway

HMWK, prekallikrein, factor XI (proteolysis by factor XII) positive feedback

extrinsic pathway tissue factor from macrophage and endothelial cells

common pathway thrombus (attached through fibronectin)

-carboxyglutamate with vit. K

13-4 Means of Limiting Clot Formation (1) Physiologic factors

normal blood flow surface (membrane) by activated platelets or platelet fragments

(2) Soluble and insoluble biochemical factors a) heparin/antithrombin III (ATIII) complex b) 2-macroglobulin c) thrombomodulin on the endothelial surface

thrombin sequestration --- protein C activation --- V & VIII inactivation d) clot dissolution process (fibrinolysis)

plasmin tissue plasminogen activator (t-PA)2-plasmin inhibitor

13-5 Role of the Endothelium Endothelium --- glycocalyx / integrin and other receptors (1) Anticogaulatory properties

heparin sulfate / thrombomodulin / prostaglandin I2 / tPA (2) Composition of the endothelium

protective glycocalyx / exposure of endothelial ECM molecules decrease in thrombomodulin and release of TFvWF secretion for platelet aggregation

inflammation and thrombosis

13-6 Tests for Hemocompatibility thrombosis, coagulation, platelets, hematology + immunology 13.6.1 General Testing Concerns (1) Hemocompatibility test local effects systemic effects

a. thrombus embolization (stroke) b. soluble products (inflammation) c. implants (reduced blood coagulation response)

(2) Causes (biomaterials) blood characteristics

혈액종류 , 항응고제 , blood pumping flow regime

transport of platelets and plasma proteins / low FR (thrombus formation) material surface characteristics

(plasma protein adsorption and physicochemical properties) 13.6.2 In Vitro Assessment

a. coagulation time b. amount of adhered platelets c. mass of adherent thrombusd. amount of platelet granule release (PF-4 and -thromboglobulin)

limits: use of anticoagulants and control materials

13.6.3 In Vivo Assessment - Choice of animals / length of study and choice of time points / control materials

(1) Histology at the end of the experiments(2) Biochemical Assay (3) Blood flow conditions in animal models

and tissue trauma during implantation procedure

Shunt test (Ex vivo) blood flow control / native blood / long-term responseno evaluation due to the trauma of surgery

Final application of biomaterials