3. Implant of a Medical Device and the Wound Healing Process

4. 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

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

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

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

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

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

10. 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.

12. 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.

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

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

15. Begins when blood is exposed to a foreign surface or
by some type of trauma to platelets, starts whenever
blood contacts a biomaterial.
Clot
4.25

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

17. 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

18. The yin and the yang of blood clotting…
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,
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.

19. 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

20. 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:
Those that affect device performance
Those that pose a risk to the patient, i.e. thrombi and emboli

21. Strategies to improve the blood biocompatibility of devices:
Very smooth biomaterials
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.