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"*Failure modes of endovascular grafts that may be simulated through
pre-clinical testing and clinical characteristics that need additional
consideration in these tests"*

# By Michael Lawrence- Brown, MD

DR. LAWRENCE-BROWN: Thank you for inviting me here. I don\'t know if I
am going to lift this to a higher level. I have taken quite a beating
already on this, and I wasn\'t really sure how to put the clinical
characteristics, and so if I have taken some license, I hope you will
forgive me, but it was the only way I could put it together.

So what I looked at was proximal fixation versus seal, to prevent \--
and we have looked at that, and the distal landing zone attachment and
seals, I have put that separate, because it had separate problems.

And they can be dealt with in a different way, and access is an image
for failure, and graft and limb occlusion, and I will show you some of
the testing that we did with that.

And deployment failure, and a device defect, either in short or long
term, and it is the long term issues that are really coming to the fore
now. And we cannot divorce any of that from the physician induced
problems which apply to the failure mode.

And its inappropriate usage, and its technique defect, which can be an
education defect on their part, or it can be a memory lapse, or it can
just be a human factor.

And inadequate infrastructure, especially with imaging, and I have been
to different places, and some of the imaging that I have seen, I can\'t
see a dam thing on what is going on, and so how they can see where they
are going I don\'t know. But it is a real matter for failure.

And then inadequate support. So do you have someone there to give you
the extra ancillary devices that you need to fix a problem that you
can\'t fix at the time.

And planning. If you plan it wrong, you get it wrong, and that is
probably one of the most common failure modes. And we all have a problem
because this slide illustrates that the death rate per 100,000 has been
reduced to almost half in Australia, but mainly through the work of the
National Heart Foundation.

And so you can see that all causes comes down by 46 percent, and
pulmonary heart disease comes down by 68, and then it is followed by a
stroke, which has a lesser impact.

But for all cardiovascular disease, people are living longer, and
aneurysmal disease emerges as an age related factor, and the heart for
aneurysmal disease is age.

And this was the paper presented in 1986 at the RSNA, with Jim and
Lawrence, and it showed the stent with the graft, and the work was done
in dogs. We followed on with that to some extent, but we were limited by
the materials that were available to be used.

Now, there may be new materials, but it is not easy to use new
materials. So it was back on the polyester versus PDFE, and stainless
steel versus notanole (phonetic), versus polyurethane, and the sutures
were polypolprine and polyester nylon, and then the metal markers that
existed.

Now, people said that the better polyesters or better materials such as
cylar and mylar, and it is my understanding that we can\'t use those
because Dupont says that they are never to be implanted in a human
being.

So there are limitations imposed on us from all sides, and I stand
corrected if necessary, but that was our understanding. We found working
on dogs and animals impossible, in terms of devising something that was
feasible, and to be able to do something.

And so we developed a model with a gelatin aneurysm from a real life
model, a cast, a

3-D CT scan, and day by day we lay it in resin, and then we attached the
various ports, and constructed valves, because the first thing we needed
was hemostatic valve.

So this was our first simulated model, and this was an x-ray phantom,
and so of course we called on Mr. Walker. And there is the x-ray
machine, and there was the pressure pump.

And that is just a closer picture, and it was a fairly ideal sort of
aneurysm. It was the model of the first one that we ever treated with a
tube graft. But what we were looking at was to try and make a bifurcated
graft.

And what we needed to do was to test different methods to see if we
could actually feasibly deliver a bifurcated graft, and see if we could
do it and now lose total blood volume in the process.

So that was the first simulated test model that we had, and I am sure
that we can make much better ones, but it is a start. Then we looked at
what metal we should use, and we looked at cyclic colonization, one hour
equals one year.

And this is the simple diagrammatic method. You put the sample in the
solution, and you connect it to a variable potential, and you measure
the electrode potential across it.

And then this would be ideal, and so you would at the breakdown point
when you start to get equilibrium, it moves all the way up, and it
deforms at the breakdown point, and then it comes down along the same
line.

It is not a metal that we could use for lots of reasons. So the next one
was stainless steel, which comes along on a relative straight line up
and down, but you get mesenteric curve once you go past the elastic
point. So you get a permanent deformation.

And the notanols, there are different kinds of notanols, as it has been
stated today. The only one available to us showed some deformity right
from the beginning, and so it never really came back along the same
line, which meant that it would change its crystalline structure, which
meant in the long term that it would probably fracture.

So we were only left with stainless steel to use, and that\'s why we
used stainless steel, but it a simulated pre-clinical test, and I am
sure that it could be extended so that other metals or materials could
be used pre-clinically to do that.

And then we tried to improve on that by \-- there is the stainless
steel, and we had to look to see how we would join it. So we looked at a
welded sleeve, and we looked at soldering, and the welded sleeve was
somewhat better than the soldering we could produce.

But we were convinced by the engineers that the soldering could be
improved and we went back to soldering, but it also shows that these
things can be tested on how they get joined and so on.

And we looked to see if we could improve it by plating it with gold, and
we made it worse, which was interesting, and which was a surprise. And
so you can look at the various potentials and you can assess it, and we
can go way above the corrosive time span for the lifetime of the people
that we are dealing with.

We are not dealing with pediatric patients. We are dealing with people
in the last \-- probably 15 or 20 years of their lives. So having done
that, we then proceeded and used a graft, and after a period of time, we
had a failure.

It was a failure of the migration, and it fell down into the aneurysm
and it was explanted, and having a look at it, you can see there the
stress fracture lines, and until it breaks.

And it didn\'t break at the joint or at the soldering point. It broke at
the stress point, and so it was a stress point fracture, a deep
fracture. And this is the point where it broke. You can see the
corrosion around it where it had occurred.

But the fracture occurred here, and that was a stress-strain
relationship. The stress-strain relationship migration is very important
as Dr. Parodi has done some very elegant experiments with this.

And this was a very early sample that we used, and it was sent to me by
a colleague, and he showed that the pressure wave inside the false lumen
of a dissected aneurysm with no outflow was this, and with the true
lumen it was this.

And what it means is that in the false lumen where there is no outflow,
but you have pressure, the pulse wave is higher, and the diastolic

\-- the pulse rate is wider, and the diastolic is higher.

So the main pressure is somewhat higher in the false lumen than in the
true lumen. So we were very worried at that stage about endoleaks, and
where there was no outflow, because if you increase the mean pressure,
you increase the risk of rupture, and I think we all believe that now.

So migration became a very important issue for us in that. So with that,
we got permission to change the hook structure. You can see a long hook
and there was a stress point there which fractured, and it got changed
to a different soldering or hooks, stronger hooks, et cetera.

And then it was tested, and so you can do some pre-clinical testing. It
is very simple. Here is a spring gage, and the aorta is tied to a
syringe top, and that is a cadaver aorta, and sometimes we use pigs in
the beginning, but then we got permission to use cadaver aortas.

And then the graft is affixed to an animal and it has an attachment
device to the hooks, or no hooks as it may be inside, and we just
pulled. And the friction force alone to pull out is along here, and so
it is 16 gage wire, or I\'m sorry, 14 gage wire, and 16, 18, and 20.

And you get to 20 gage wire, and it becomes pretty bulky. So it is not
desirable, but you don\'t get much extra regular force anyway. But if
you add another attachment system, depending on the strength of the
hook, and the number of hooks, you can lift your displacement detachment
force from 10 or 12, and up to 40 or whatever, depending on what you
want to put in there. So you can test for that.

But you can\'t \-- whatever you are doing in designing that, you cannot
forget about the problems of planning, and how the graft is going to
fall. So, a graft is always going to fall at right angles to the access.

And this is just a mirror image of that, in terms of where the renal
arteries are, and you can see that \-- well, not the mirror image of.
I\'m sorry. I have moved the renal arteries relative to the right and to
the left.

But the wall distance, or the length that you would assess the neck to
be on an axial CT is the same, but the effect of putting a graft in is
very different, because your wall contact area is very short here,
whereas it is very long there. So you can simulate that in any
situation.

And the diameter is important because just simple mathematics tells you
that you have got a 28 millimeter diameter, and you can pull it at right
angles and it is goes under the curve, you are going to lose at 45
degrees approximately 19.8 millimeters.

So you can lose just about your whole wall on one side, and that is the
minimum contact wall length that you require. And here is an example.

This is the 18th case that we ever did, and it is sharply angulated
forward, and we thought that everything was fine, but on the posterial
wall, you can see that the top crown of the cover stent has fallen into
the sac of the aneurysm, and therefore, there is not adequate wall
contact at that point.

And that hole is sufficient to cause a rupture, and a rupture occurred
in a large aneurysm, and it occurred in a couple of weeks.

So migration and seal and all contact became issues, and that was the
reason that we decided to go across the renal artery, because the region
of the mesenteric and renal vessels is the strongest part of the aorta,
and the last bit to start to dilate.

And durability demands a secure fixation without migration, because
migration as we said may repressurize. But if you put a Y across the
renal artery, you go across its surgical principle.

And you can see why here across the renal, and all the vortex shedding
and so on that occurs, and all the canoeist is doing is keeping his
canoe straight with the paddles. He is not paddling up against that. He
is just balancing.

So we were concerned obviously of putting a Y across a renal artery. So
we did some mathematical modeling, and then we did some computer
computational flow dynamics, and then finally we put it into a flow
model and looked at it.

And they all come out fairly close for a 7 millimeter tube and a 5
millimeter Y, and as long as you don\'t get accretions on it, then you
get a three percent decrease in flow, about that range.

We have to look in the clinical characteristics and you cannot put that
in our selection, because as people age, not only do they lose brain
cells and can\'t remember things, but they also lose a certain number of
neutrons, and so the creatinine levels are going to rise with age.

And so you have to put it into some form of normal human context if you
are going to follow these people over a period of time. And you also
have to look at the tortuosity as we discussed, and two issues arise.

The first is that as soon as you put a rigid device, or send a rigid
device in there, you are getting a knitting needle effect if there is
severe tortuosity.

And the more rigid there is, the more that will occur, and that will
change all your length assessments. And then when you release it, it may
take up its previous shape or it may not.

Here is the issue of a kink and this is a very good examine of a kink,
but the problem is that the following stent overrides the preceding
stent. And that is a major problem, and it was not an anticipated
problem for that degree of deformity.

And we could have avoided that and I admit that by just doing some
better testing on what angle we wanted it to take, and the argument is
that you have to put a gap in this type of stent arrangement to allow
you to go around the curve. It is a box car on a train effect.

And it can be calculated, and so you can actually do that, and so you
can calculate, say, to go around an angle on an aorta, or you can
clinically test this.

You can make a design with a certain angle and you can do that, and plan
it to go around, which brings up a really important issue, and that is
that if you are simulating pre-clinically to design or make something,
what limit are you going to put on it, because you are going to have to
put some limit at some stage, and thereafter you are going to have to
adapt.

And you adapt before you put it, rather than trying to fix the problem
afterwards. So if you say, okay, we will set these limits, and so we
will only use a device at these limits, and we have all done that, and
we set guidelines.

And we found that 69 percent of the devices inserted were outside the
guidelines. Now, to be fair, many of those that were inserted outside
the guidelines had been custom made or adapted for the deviation from
the guidelines.

But we thought that the neck was the most critical part if we are going
to get a failure, because it is the hardest to fix, and 63 percent were
outside that.

So it does mean that we have a clinical problem, and the clinical
characteristics of the people that we are treating, or the clinical
characteristics of the people we are treating are going to impact on
what you design to test.

And we found when we looked at how it was \-- how the failure being an
endoleak rate, the flair and contour of greater than 3 millimeters was
the greatest risk.

And then length for the reasons that we described, and they are affected
by diameter. We found that angles up to 30 degrees was not a problem,
and up to 60 degrees, you could cater for them with customizing, and
after that, we had a problem.

But the failing defect within the other limits, which is within 28
millimeters, didn\'t affect the situation, in terms of migration or
endoleak. But the contour was very important, and it is probably device
specific.

So there is a finite link to the graft and that is ideal, but in this
one, if it were to fit to there, and just cover that length, then it
would probably be okay. And pre-clinical testing on the model on the
bench would show conformity to that shape.

But if it fits across there, then it is not going to have wall contact.
It is going to be separated here and there, and that is just the reverse
of this. So you might say that is the safe thing from the point of view
of resisting detachment, but it is not, because if it fits in here, then
you could have 30 graft flow here.

And that is just a combination and that is just a dangerous situation as
was already alluded to, because you don\'t get wall contact. Now,
compliance may come into it, because you may push the graft out and
compliance of the aorta is going to be important.

These points are often related to the number of arteries, and that\'s
where a number of arteries come out. So the point of narrowing as far as
that top pair of arteries, you may be able to push it out, or you may
not.

And that is going to depend on other factors, such as calcification, and
as people go outside two parameters, then they increase the risk of
failure. So in this situation, if there is contour with diameter, it is
highly significant.

And contour length is the next most significant thing, and neck diameter
affects a contour change in angle, of course, and is important, but less
significant.

This is an issue of imaging, and our first priority was to make sure
that the imaging was the first prerequisite. And we had to take the
balance of imaging and infection.

And you should be able to angle, and so you get the best angle, and you
get the best length, and so on and so forth. And since I have had the
pleasure of staying two days in Washington, I have seen some enormous
people in Washington, and if you haven\'t got a good machine to get
through them, it is going to be hard whether you operate on them or
whether you \-- or whatever you do, it is going to be really difficult.

So imaging is essential and that is a clinical characteristic related to
infrastructure. Now, this is where I got beaten up today, and I don\'t
know what the force is, but the force is going to be here, and it is
going to move until it hits the wall.

Or it is going to hit something that stops it, and when it moves, it is
going to pull from the other two ends. Pressure, of course, is something
I accept as important, but pressure would change with exercise.

So if you are going to pre-clinically test, you have got to be able to
test by changing your pressure, and every time we exercise, people in
exercise tests with endovascular disease, the pressure always goes up,
especially when there is no compliance in the aortic wall with aging,
because you lose the capacity.

And we were concerned, rightly or wrongly, but we were concerned that if
this was the area that was going to be a problem, and just maybe you
could say it was intuition, but it was going to be at the bottom end and
it was going to lift out. And we still have that problem.

And so we decided that if you are going to use a modular device, you
have got to get the joint as close to the exit point as possible, and
preferably inside the exit vessel.

So you can see that there are many forces at work, and as we said, there
is a drag force, and if we have a 30 millimeter diameter neck at the top
here, and 10 millimeters down at the bottom, the drug force is 10
Newtons.

Now, if you use regular force alone, you are going to drag it out,
because the radial force alone, the stainless steel anyways, is an extra
10 Newtons. And you are going to need a little bit of exercise, and it
is going to pop out.

In a thorastic aorta, you don\'t get that problem because just the flow
through there doesn\'t give you a drag force. If you come down below 26
millimeters, then the Newton pullout is only 3 to 4.

So there is a huge difference if you change your diameter, and the
relative diameters of the top and the bottom. There is the perception of
difficulty, and so you would think that people would go up the right
side here to get a straight line, but that is merely the mirror image.

So in implanting, people can use the same thing in a mirror image, and
change their whole access of procedural plans. So, perception is
important. And in open surgery, you can modify. We tailor.

To think that we go in there and do a specific operation every time and
not have changes is naive. We have the ability to tailor. So if you are
going to work from a remote site, you should have the ability to tailor
in principle.

And if we are going to pre-clinically test or set up these things, we
have got to set it up for the different situations that we are going to
encounter. So we have to anticipate those situations. You can\'t expect
one device to perform all functions.

And here is an example of tortuosity. If you have tortuosity of the top
and the bottom, you cannot orientate the top and the bottom at the same
time, because as you deploy, it will take on a different twist.

So why not separate them so that then you can do different things with
this one, and you can orientate that one separately. It also means that
you can \-- that you don\'t have to worry about lengths so much, and so
you can bring this one right down and put it into the other side if
necessary and get stability.

We talk about thrombosis and clotting, and here is a pre-clinical test
that we did very early. We soaked this in hundred-thousand units per
liter, which is not a lot really. It is only 5,000 units in 50 mils.

And we put this bit of graft material into a bowl, and harvested it with
some blood, in which the patient had 5,000 units of heparin, and this
one was free of clot, and this one wasn\'t.

Now, if you read the literature, there is no heparin bounding to that
one, but experimentally it makes a difference. So if people take a long
time and they don\'t prime it properly, there is the potential for
thrombosis, and we have had that problem.

Animal testing is not to be forgotten, because it does have a place, but
it depends on what you want to test, and in this situation we wanted to
test what happens in a growing pig when we put Y\'s and things across
orifices or vessels, and to see how much time it takes to narrow off the
vessel.

And there are limits. You can only use the animal once, and if something
goes wrong, or the anesthetic is wrong, or whatever, then it doesn\'t
work.

In this case, we could only go on for six months, because the pig got so
big because it was growing that they wouldn\'t feed it anymore.

We need to be able to test the different devices in a situation, one
against the other. So you might test ancillary devices. And you can see
that this is just a simple experiment of putting a balloon expandable
stent and putting one through a self-expanding stent.

But it shows you different properties, and that is so we can use these
properties. This is the current test rig that we are trying to set up to
simulate these tests, and here is an artificial heart, and it goes
through an artificial aneurysm, and there is an in-flow and out-flow,
and we can change that.

And we can position the graft in different situations inside there, and
have a look to see what happens when we put pulsatile flow in through
that area. It is pretty crude, but it is a start that we didn\'t have a
long time ago.

We talked about laminated thrombus today, and I don\'t think we came up
with any specific things, and lots of things have been written about it,
but I don\'t think we understand it too much.

Essentially, we regard it as having no structural strength whatsoever,
and it will change. Now, this is an experiment and we just put a little
bit of the current through the laminated thrombus, and you can see after
you run it for a while that it starts to cavitate.

Now, maybe your artificial thromboses is not the same as laminated
thromboses, and it has a slightly different structure. They have tried
the angi-fluid dynamics, and engineers are not allowed to work with
human material.

And so we have simulated thrombus and we can\'t use real thrombus. But
it does suggest that if you start to get channels through laminated
thrombus that it behaves in a strange way.

And we all know what the physics are to make an aneurysm expand, but
this business of aneurysm contraction, especially length contraction,
and compression length-wise, we didn\'t see any physical or mechanical
reason why that should occur.

So that is still debated and I left this morning feeling that that was
probably the agreement around here. And this is just Einstein, but I
guess you all know that he died at the age of 75, and it was in 1955,
and open surgery had been available since 1952.

And having had a procedure that was open surgery with a graft, and
having had a graft before and it hadn\'t worked too well, he turned down
surgery even though he knew his aneurysm was ruptured and he lay in bed
for about three days, and he was still working away with his
mathematical formulas.

So he is almost the patron of many thing, including aneurysmal disease.
But I want to put him up for another reason, and that is that he is a
Northern European and he is old.

If he were Chinese, his common iliacs would be very different, and
because we are in Southeast Asia, when we are starting to look at that
situation, we have to have a whole new set of pre-clinical tests, and so
on and so forth, on the ethnic changes in the common iliacs. And lift
out from the common iliacs is a real problem, which is why we dwelt on
it. Thanks.