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Research: Blood-Biomaterial Interactions and Biocompatibility.
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Blood
Biocompatibility Catastrophe [1]:
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Despite some fifty years of
research, all materials
used in medical applications today cause thrombotic and/or inflammatory
reactions, necessitating short-term or long-term antiplatelet therapy
that is costly and dangerous to the patient.
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Blood-Biomaterial
Interactions in a Nutshell: molecular mechanism of incompatibility.
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Foreign materials interact
with the body, activating
the three coupled defense systems: coagulation, inflammation,
complement:
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Thrombosis:
Vessel (or stent, or heart valve, etc.) occlusion and emboli.
Inflammation, Complement activation:
Activated platelets, macrophages, leukocytes,
cytokine production, systemic damage.
A key role in this process is thought to be played by plasma
proteins that adsorb on the implant surfaces and by
platelets that in
one way or
another participate in all three systems [2].
The figure is adapted from [2].
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Blood
proteins normally do not interact with blood cells, but
when they
adsorb to foreign surfaces, they undergo conformational changes[3] that
expose cryptic sequences. Below, this is shown using platelet
activation at foreign surfaces as an example:
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Left:
Platelets
(shown in the left drawing as grey circles) circulate in blood in a
resting state and do not interact with
blood proteins.
Middle: Adsorption of blood proteins
to the biomaterial surface is thought to
alter their conformation.
Right: Adsorbed proteins are
then thought to activate platelets.
Platelet activation leads to
changes in their shape and size, secretion
of granules and consequent expression of granule markers (CD62P and
CD63), activation of the GPIIb/IIIa integrin complex, exposure of
phosphatidyl serine (PS) , which catalyzes thrombin production.
Thrombin activates fibrin which polymerizes to form the clot.
When activated, platelets also
secrete over 200 active substances –
growth factors and cytokines – with various, sometimes contradictory
functions.[4] Understanding how the secretion of these factors is
regulated would allow the regenerative potential of the platelets to be
harnessed.
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What we are doing about it:
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In a collaborative project
between three institutions – IFG/KIT,
Department of Chest, Heart, and Vascular Surgery, Universitätsklinikum
Tübingen, and Institute of Biomaterial Science, Helmholtz-Zentrum
Geesthacht, Teltow, we are -
Analyzing coagulatory and immune
responses in blood exposed to materials under static and dynamic
conditions. Unlike previous works on this topic, our approach covers
all three systems.
Analyzing of protein conformation and
protein film composition on surfaces of clinically relevant materials.
Studying molecular mechanisms of
platelet activation at surfaces thus linking 1 and 2 above (changes in
protein conformation to platelet activation and other responses). In
the long-term, our goal is to harness the regenerative potential of the
platelets by controlling their activation at implant surfaces.
In pursuing these studies, we are developing standardized conditions
for material biocompatibility testing by relying on experience from
three laboratories.[5,6]
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References:
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[1] Ratner BD (2007)
The catastrophe revisited: Blood compatibility in the 21st century.
Biomaterials 28: 5144-5147
[2] Gorbet MB, Sefton MV (2004) Biomaterial-associated thrombosis:
roles of coagulation factors, complement, platelets and leukocytes.
Biomaterials 25: 5681-5703.
[3] Sivaraman B, Latour RA (2012) The relationship between platelet
adhesion on surfaces and the structure versus the amount of adsorbed
fibrinogen. Biomaterials 31: 832-839.
[4] Nurden AT (2011) Platelets, inflammation and tissue regeneration.
Thromb Haemost 105 Suppl 1: S13-33.
[5] van Oeveren W (2013) Obstacles in Haemocompatibility Testing.
Scientifica 2013: 392584
[6] Braune S., Grunze M, Straub A, Jung F Biointerphases 2013, 8:33
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