Willem
Flameng
Cardiac
Surgery, University Clinic Gasthuisberg Leuven, Belgium.
Tissue
engineering is aiming to create viable tissue or organ grafts that do self
propagate and repair
(Grikscheit
and Vacanti, 2002)
.
Three strategies to achieve this goal have been proposed: implantation of cells,
in situ tissue regeneration and implantation of in vitro assembled constructs
from cells and scaffolds
(Griffith
and Naughton, 2002)
.
In the field of cardiac valve tissue engineering the last mentioned strategy has
been generally opted for
(Bader
et al., 1998;Grikscheit and Vacanti, 2002;Terada et al., 2000)
.
Considering
the matrix materials again two directions have been followed since the first
paper by Shinoka and coworkers
(1995)
on tissue engineering of a replacement heart valve. A first choice was the
construction of heart valves from biodegradable materials. Here again, Shinoka
(1995)
and some other groups
(Sodian
et al., 2000;Hoerstrup et al., 1998)
focused on seeding of scaffolds comprised of artificial biodegradable material
such as polyglycolic acid meshes and polyhydroxyalkanoate, a bacterium-derived
thermoplastic polyester. Whereas the first scaffold was highly porous, too stiff
to create a complete valve
(Shinoka
et al., 1995)
and potentially immunogenic, the second was more flexible but required special
salt leaching preparations to obtain an acceptable porosity. Different
approaches either using no scaffold
(Ye
et al., 2000b)
or human fibrin gel based scaffold
(Ye
et al., 2000a)
have also been examined since they would overcome the specific problems of the
artificial scaffold materials. Yet another branch of cardiac valve tissue
engineering is using acellularised human
(Dohmen
et al., 2002a;Dohmen et al., 2002b)
or porcine aortic root
(Bader
et al., 1998;Dohmen et al., 2002b;Dohmen et al., 2001)
as a matrix material. This
material has the great advantage that it is a functional valve in itself and
does not has to be manufactured. Some groups have been seeding these matrices in
vitro
(Bader
et al., 1998)
,
whereas others have mainly focused on the acellularisation process, claiming
that these matrices show spontaneous repopulation in vivo
(O'Brien
et al., 1999)
.
Although
all these matrices showed promising results, serious drawbacks have also been
reported. Considering the artificial scaffolds rapid hydrolysation can result in
construct breakdown
(Cebotari
et al., 2002;Shinoka et al., 1998)
whereas implantation of xenogeneic acellular aorta in animals resulted in
aneurysmal dilatation
(Allaire
et al., 1994)
.
Also
recent clinical trials using implants of non-seeded but acellularised porcine
valves showed catastrophic results
(Simon
et al., 2002)
related to early degeneration of these matrices.
In
vitro seeding has major methodological problems besides those of cell seeding
itself (eg. sterility, cell culturing, etc.). The loss of seeded cells is one of
the major problems when in vitro seeding is used
(Jansson
et al., 2001;Rademacher et al., 2001)
and to overcome these problems different types of flow/pressure systems have
been designed. They range from stretching devices or simple flow systems
(Ziegler
and Nerem, 1994)
to fully functional bioreactors gradually imitating the real haemodynamic flow
and pressure stresses
(Hoerstrup
et al., 2000;Sodian et al., 2002;Dumont et al., 2002)
.
At
present our group has addressed another approach, originating from a first
attempt to grow an artificial artery graft out of granulation tissue
(Simmons
et al., 1975)
.
This graft, the Sparks mandril prosthesis, was constructed from the tissue
encapsulating a subcutaneously implanted plastic/glass rod. Although the
cellular component was removed and the remaining tissue tanned, this is to our
knowledge the first attempt to construct a vascular prosthesis from granulation
tissue. More recently Campbell and coworkers
(1999)
showed the construction of a functional vascular graft from a capsule generated
from an intraperitoneally deposited capsule around an implanted silastic tube.
The everted the capsule to internalise the exterior mesothelial layer and
implanted the grafts in the abdominal aorta of both rats and rabbits. The type
of capsule that is deposited, is comprised out of an internal layer of
macophages, some layers of (myo)fibroblasts and an external layer of mesothelial
cells and is generally described as ‘Foreign Body Reaction’
(Butler
et al., 2001a;Butler et al., 2001b)
.
At
present it has already been proven that the entire layer of (myo)fibroblasts is
of haematopoietic origin
(Campbell
et al., 2000)
,
as was shown by reconstituting the bone marrow of female irradiated mice with
male derived transplanted cells. In a later stage of their research the same
group
(Bayes-Genis
et al., 2002)
claimed that the myofibroblasts were derived from the macrophages, but also
reported the presence of an undifferentiated cell population in the explants.
This was done by studying the cell morphology and colocalisation of ASMA and
CD172a. Although ASMA is a generally used marker for myofibroblast
(Della
Rocca et al., 2000;Taylor et al., 2000;DeRuiter et al., 1997)
,
the CD172a is not an exclusive marker for macrophages but is also expressed in a
subpopulation of haematopoietic stem cells
(Kuci
et al., 2003;Vogel et al., 2003)
.
Considering
these findings we feel that at this stage we can not exclude the possibility of
the presence of stem cells in the granulation tissue. Therefore we chose to
pursue this approach further and study the use of “immature” foreign body
reaction as a means to repopulate a biological but stabilised matrix. This
approach avoids but does not exclude the use of a bioreactor since the seeding
is done by the valve recipient itself.
Therefore
our group has been working on an alternative matrix comprised of a cross-linked
scaffold and an autologous neomatrix covering the foreign scaffold. As a
cross-linked scaffold we have used a non cytotoxic photooxidated bovine
pericardium
(Moore,
2001)
,
which is shown to tolerate in vitro cell seeding
(Jansson
et al., 2001)
.
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