Implant of a Medical Device and the Wound Healing Process

Impantation of a device results in an injury to the patient startingthe 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 calledthe pluripotent hematopoietic stem cell

Multiple celltypes

Blood formingCells capable of continuedreplication and differentiation intoother cell types

RBC development ends withthe erythrocyte which hasno nucleus or organelles, justa bag of Hb that carries oxygen

EtPO is the hormone produced in the kidneys that regulatesRBC levels in the blood.

Platelets are the hole pluggers of thevascular system.

Megakaryocytes fragments andforms 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 cascadingactivation process wherein the plateletsdegranulate and release chemicals that result in the recruitment ofmore 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 bloodclot.

Arachidonic Acid Cascade

Produces powerful chemicalswhen the platelet is activatedby stimulation from otherplatelets or the bloodcoagulation process. COX isthe control point, aspirininhibits COX impairing thecoagulation process viahindrance of platelet activation.also stops the release of theother inflammatory chemicals

COX is COX1 and COX2, COX2protects stomach from acid.

Factor V also released by plateletsand is activated by the enzyme thrombin

Makes the clot“a” means activated state

Coagulation of blood is governed by 2 coagulation pathways orcascades that are known as the intrinsic and the extrinsic pathways

Begins with trauma to the vascular walls andsurrounding tissue which releases a collection ofchemicals called tissue thromboplastin

4.25

Clot

Begins when blood is exposed to a foreign surface orby some type of trauma to platelets, starts wheneverblood contacts a biomaterial.

4.25

Clot

Note that extrinsic and intrinsicpathways intersect at factor X activationbecoming then a common pathway

Clot

Deficiency of XIII isCause 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++ playsa key role in almost every step. So one approach is to remove Ca++ (citrates).

Thrombin a key factorin feedback loops ofboth pathways.

Platelets initiate clotting andhave an active surfacethat catalyzes the clottingprocess.

Factor X links the intrinsic and extrinsic pathways

Within the body flow of blood past a site of injury also dilutes the coagulantsand removes them from the site of the injury, these activated clotting factorsare 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 plateletsthus activating factor X.

Platelets when activated also catalyze on their surface the conversion ofprothrombin 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 thesticking of platelets. Also has on its surface a protein called thrombomodulinthat 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 cellsthat lines the interior of blood vessels activates a vitamin K dependentplasma protein called protein C and protein S which then inactivates factorVa and VIIIa (some folks have a clotting disorder known as protein S deficiencywhich leads to DVT’s)

2. Fibrin itself also strongly binds thrombin localizing the clotting reactions to thevicinity of the injury only and not the rest of the body

3. Antithrombin III is a serum protein that binds and inactivates nonadsorbedthrombin

4. Combination of AT III with heparin enhances the thrombin removal rate byup 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 verylow, but by adding heparin one can dramatically enhance theanticoagulation 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 trappedwithin the clot, the injured tissue releases a substance called tissueplasminogen activator (tPA) which converts the plasminogen into plasminwhich 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 doesnot induce coagulation of blood. Blood-material interactions fall into two general categories:

1. Those that affect device performance2. Those that pose a risk to the patient, i.e. thrombi and emboli

Strategies to improve the blood biocompatibility of devices:

1. Very smooth biomaterials2. Add endothelial cell membrane components along with a slight negative

charge to the surfaces3. Hydrophilic surfaces reduce platelet adhesion and thrombus formation4. 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.