Implant of a Medical Device and the Wound Healing Process

Impantation of a device results in an injury to the patient starting the wound healing process Blood is usually the first tissue to interact with the device

All blood cells come from one type of cell in the bone marrow called the pluripotent hematopoietic stem cell Multiple cell types Blood forming Cells capable of continued replication and differentiation into other cell types

RBC development ends with the erythrocyte which has no nucleus or organelles, just a bag of Hb that carries oxygen

EtPO is the hormone produced in the kidneys that regulates RBC levels in the blood.

Platelets are the hole pluggers of the vascular system. Megakaryocytes fragments and forms the platelets

Platelets love to adhere to damaged tissues and the walls of blood vessels as well as to biomaterials

Platelet plug formation is a cascading activation process wherein the platelets degranulate and release chemicals that result in the recruitment of more platelets and so on These chemicals released by the platelets are also involved in the blood coagulation process leading to the formation of fibrin and a blood clot.

Arachidonic Acid Cascade Produces powerful chemicals when the platelet is activated by stimulation from other platelets or the blood coagulation process. COX is the control point, aspirin inhibits COX impairing the coagulation process via hindrance of platelet activation. also stops the release of the other inflammatory chemicals COX is COX1 and COX2, COX2 protects stomach from acid.

Factor V also released by platelets and is activated by the enzyme thrombin Makes the clot “a” means activated state Coagulation of blood is governed by 2 coagulation pathways or cascades that are known as the intrinsic and the extrinsic pathways

Begins with trauma to the vascular walls and surrounding tissue which releases a collection of chemicals called tissue thromboplastin 4.25 Clot

Begins when blood is exposed to a foreign surface or by some type of trauma to platelets, starts whenever blood contacts a biomaterial Clot

Note that extrinsic and intrinsic pathways intersect at factor X activation becoming then a common pathway Clot Deficiency of XIII is Cause of hemophilia A

Blood coagulation is a system with many feedback and feedforward control loops Many times the goal is not to have the blood coagulate, note that Ca++ plays a key role in almost every step. So one approach is to remove Ca++ (citrates). Thrombin a key factor in feedback loops of both pathways. Platelets initiate clotting and have an active surface that catalyzes the clotting process. Factor X links the intrinsic and extrinsic pathways

Within the body flow of blood past a site of injury also dilutes the coagulants and removes them from the site of the injury, these activated clotting factors are then removed by the liver. Activation of factors XII and XI occurs when blood contacts foreign surfaces so this tends to be a localized effect. Factors IXa and VIIIa form a complex on the surface of activated platelets thus activating factor X. Platelets when activated also catalyze on their surface the conversion of prothrombin to thrombin. Platelets therefore not only plug the holes but help to localize the clotting reactions to the injury site and act as catalysts. The body is also designed in such a way to have anticoagulant properties. For example, 1.Endothelium surface very smooth and repels clotting factors and the sticking of platelets. Also has on its surface a protein called thrombomodulin that binds thrombin making it unavailable for clotting. The yin and the yang of blood clotting…

The thrombin-thrombomodulin complex at the surface of the endothelial cells that lines the interior of blood vessels activates a vitamin K dependent plasma protein called protein C and protein S which then inactivates factor Va and VIIIa (some folks have a clotting disorder known as protein S deficiency which leads to DVT’s) 2. Fibrin itself also strongly binds thrombin localizing the clotting reactions to the vicinity of the injury only and not the rest of the body 3. Antithrombin III is a serum protein that binds and inactivates nonadsorbed thrombin 4. Combination of AT III with heparin enhances the thrombin removal rate by up to a 1000x ‘s 5. Heparin – ATIII also inactivates factor IXa, Xa, Xia, XII a 6. AT III is present in the blood in large amounts whereas heparin levels are very low, but by adding heparin one can dramatically enhance the anticoagulation especially when using medical devices 7. Blood clots themselves are removed quickly by proteolytic enzymes

For example, plasminogen is another protein in the blood which is trapped within the clot, the injured tissue releases a substance called tissue plasminogen activator (tPA) which converts the plasminogen into plasmin which then digests the clot and also destroys fibrinogen, prothrombin, V, VIII, XII. tPA also used to treat heart attacks and strokes And interestingly, active plasmin is then destroyed by by  2 - antiplasmin. Goal for medical devices is to achieve a surface and a biomaterial that does not induce coagulation of blood. Blood-material interactions fall into two general categories: 1.Those that affect device performance 2.Those that pose a risk to the patient, i.e. thrombi and emboli

Strategies to improve the blood biocompatibility of devices: 1.Very smooth biomaterials 2.Add endothelial cell membrane components along with a slight negative charge to the surfaces 3. Hydrophilic surfaces reduce platelet adhesion and thrombus formation 4. Add anticoagulants to the surface such as heparin or via controlled release Recall the Terumo X Coating for their blood oxygenators, see the PDF file.