ROSE-HULMAN INSTITUTE OF TECHNOLOGY

Department of Biomedical Engineering

BE331-02—BE361-02 Biomechanics & Biomaterials

______________________________________________________________________________
Name: Trevor Nong

CM: 2537

Due: 2/19/18

Biomechanics—Biomaterials Final Project:

Analysis of Cardiovascular Endoprotheses
 Table of Contents

Article Summary: “Endoluminal Stent-Grafts for Infrarenal Abdominal Aortic Aneurysms” ..... 2

Article Summary: “Transluminal Placement of Endovascular Stent-Grafts for the Treatment of

Descending Thoracic Aortic Aneurysms” ...................................................................................... 3

Article Summary: “Analysis of Biomechanical Factors Affecting Stent-Graft Migration in an

Abdominal Aortic Aneurysm Model” ............................................................................................ 4

Article Summary: “Minimally-Invasive Implantation of Living Tissue Engineered Heart

Valves” ............................................................................................................................................ 5

Introduction ..................................................................................................................................... 6

Biomaterial Analysis of Cardiovascular Endoprostheses ............................................................... 7

Biomechanical Analysis of Cardiovascular Endoprostheses .......................................................... 9

Conclusion .................................................................................................................................... 12

Works Cited .................................................................................................................................. 13

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 Article Summary: “Endoluminal Stent-Grafts for Infrarenal Abdominal Aortic Aneurysms”

Abdominal Aortic Aneurysm (AAA) is a local enlargement of the abdominal aorta which
threatens fatal injury when ruptured, as such, treatment is of vital importance. At the time in
which this article was published, major abdominal surgery was a common treatment for AAA
and endovascular stents or stent-graft prostheses were receiving a growing attention as a
minimally invasive and far less traumatic treatment option. Seeking to define clinical value of
the treatment, the use of endoprotheses composed of a self-expanding nitinol stent covered with
polyester fabric in treating AAA is studied by a group of researchers at University Medical
Center Freiburg. Results were obtained from a total of 154 patients across three academic
hospitals. The subjects were selected based on the anatomy of their aneurysms and split into two
groups, those receiving straight stent-grafts and those receiving bifurcated stent-grafts. After the
grafts were implanted, computed tomography and intra-arterial angiography were performed
after an average of 12.5 months as a form of follow-up.
Results found that the primary rate of success, which was defined as the “complete exclusion of
the AAA from circulation”—total redirection of blood flow into the stent-graft—was 86% in the
patients receiving straight grafts and 87% in the patients receiving bifurcated grafts. In three
patients, complications in the installation procedure resulted in an open surgical operation.
Roughly 10% of patients experienced minor and/or major complications during the installation
procedure, resulting in a single death. All patients, however, exhibited a postimplantation
syndrome in which leukocytosis and an elevation in C-reactive protein levels were observed.
Despite promising initial results, the journal did not contain extended follow-up data on device
durability, safety, efficacy, and cost. In previous studies, all AAA treatments utilizing
endoprostheses such as stent-grafts resulted in maintenance of decrease in aneurysmal sac
diameter. There was not, however, a proper study comparing endoluminal to surgical AAA
repair. Durability also remained an issue, as during this study there were significant problems
encountered in creating a total seal between the stent-graft and aorta. Primary failure—
incomplete seal—occurred in 13 patients due to dislodgment of the stent-graft, resulting in leaks.
Secondary failure, arising after the operation, occurred in 7 patients within 6 months of the
procedure due to tears in the polyester component or reperfusion through the lumbar arteries.
The journal article also did not discuss at length what sort of design considerations were utilized
in the construction of the stent-grafts for each patient or aneurysm type [1].

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 Article Summary: “Transluminal Placement of Endovascular Stent-Grafts for the Treatment of
Descending Thoracic Aortic Aneurysms”

A Thoracic Aortic Aneurysm (TAA) is a life-threatening ballooning of the aorta, just above the
heart. As such, when ruptured, a TAA is almost invariably fatal. At the time of this article was
published, the prognosis for TAA was worse than that of the AAA and the typical treatment for
TAAs was a surgical replacement with prosthetic graft. The mortality and morbidity rates,
however, associated with this procedure were quite significant—greater than 50% in patients
requiring emergency treatment, and greater than 12% in patients undergoing the procedure
electively—and as such, a group of researchers from Stanford University School of Medicine
and Stanford University Hospital examined the use of the transluminally implanted
cardiovascular stent-graft as an alternative, much less traumatic and minimally invasive
treatment of TAAs.
The subjects of the study were chosen from a pool of 154 patients undergoing surgical repair of
aortic aneurysm. Thirteen subjects were recruited from the group of the patients who were
seeking treatment for aneurysms suitable for treatment with the stent-grafts, exhibiting adequate
peripheral access to the aneurysms as well as appropriate morphological features. Subjects were
then underwent several imaging processes from which measurements were taken to manufacture
custom stent-grafts tailored to each individual so as to cater specifically to anatomical needs in
each patient. The stent-grafts were composed of stainless steel struts forming Z-shaped features
and a woven Dacron graft.
The stent-graft was deployed by utilizing a series of guidewires and catheters that entered the
body through the femoral artery. As a precaution, vasodilating drugs were administered before
the stent-graft was fully deployed, lowering blood pressure and reducing the mechanical forces
acting upon the stent-graft in a bid to prevent stent migration. The deployment of the stent-graft
was a technical success in all patients. Complete thrombosis surrounding the stent-graft was
present in 12 of 13 patients, sealing off the aneurysms to blood flow. Only one patient required a
second operation to treat any complication associated with the thoracic aortic aneurysm and, as
of the publishing of the article, none of the 13 patients had died or suffered any stroke, infection,
or distal embolization.
This study had not yet collected data on whether or not the self-expanding stent-graft did not
exacerbate the expansion of the aneurysm sac over long durations, so there was no conclusion as
to whether or not this treatment exhibited long-term efficacy. Though, during the deployment
procedure, measures were taken to increase the device’s biomechanical compatibility with the
patient, there was no real discussion into how the mechanics of the stent-graft itself would
interface with the mechanics of the arterial walls [2].

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 Article Summary: “Analysis of Biomechanical Factors Affecting Stent-Graft Migration in an
Abdominal Aortic Aneurysm Model”

In this study, researchers from the Department of Mechanical and Aerospace Engineering, as
well as the Department of Biomedical Engineering at North Carolina State University sought to
utilize a fluid solving model to analyze the effects of stent-graft implementation on aneurysm
wall pressures and stresses, blood flow, and deformation in AAAs. This analysis provides
insight into the efficacy of endovascular aneurysm repair from a mechanical perspective and
allows predictions of stent-graft and AAA behavior to be made.
To numerically simulate the interaction of pulsatile blood flow, bifurcated stent-graft distension,
stagnant blood, and aneurysm wall motion, several partial differential equations were required to
have been solved. This was achieved through the application of the governing equations for
fluid and structure dynamics as well as a modified version of the Quemada blood rheology. It
was also assumed—in order to simplify the model to the point of being solvable—that there were
no blood particle effects, no residual stressed and tissue growth on the walls, and that there was
no slippage of the stent-graft.
Results showed that implanting a stent-graft significantly reduces sac pressure, mechanical
stress, pulsatile wall motion, and maximum diameter increase in the model. It follows that the
implementation of a stent-graft would therefore restore normal blood flow conditions and
prevent rupture of an aneurysm. It was also found that AAA neck angle, iliac bifurcation angle,
the ratio of aorta to iliac diameter in the aneurysmal neck, and blood waveform are of significant
importance in the creation of drag force on the stent-graft that may cause migration and
complications.
The results of the study revealed that then current fixation techniques in self-expandable and
balloon-expandable stent-grafts were possibly inadequate to withstand blood flow, prompting
consideration into improving fixation methods. The study might also be criticized for failing to
address that the blood of the aneurysmal sac would have thrombosed within hours of stent-graft
implementation, limiting the significance of the results obtained from the model. This in-depth
biomechanical analysis, however, did provide insight into how complicated and multifaceted
stent-graft fixation is [3].

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 Article Summary: “Minimally-Invasive Implantation of Living Tissue Engineered Heart
Valves”

Heart valve substitutes are often bioprosthetics, and as such have both limited durability and
compatibility with the body. To combat this limitation, tissue engineering technology may
provide living valve replacements with the potential to regenerate and growth. Researchers from
the University Hospital Zurich, Swiss Center for Regenerative Medicine, Eindhoven University
of Technology, and Tampere University of Technology sought to demonstrate the practicality of
utilizing the technologies of tissue engineering and minimally-invasive implantation based on
autologous cells and self-expandable biodegradable biomaterials to achieve heart valve
replacement.
To conduct this study, dynamic bioreactors were used to generate trileaflet heart valves from
biodegradable synthetic scaffolds. The tissue engineered heart valves (TEHV) were then
integrated in self-expanding stents and seeded with autologous vascular or stem cells (bone
marrow, peripheral blood). The TEHVs were then implanted, utilizing a minimally-invasive
method, as pulmonary heart valve replacements in sheep. The in vivo functionality of the
TEHVs was monitored by echocardiography and angiography for up to 8 weeks.
The implantations were successful in all animals, demonstrating in vivo functionality with
leaflets that were thickened, yet still mobile. An examination of tissue microstructures revealed
the formation of layers of new tissue with endothelialized surfaces and quantitative analysis of
the extracellular matrix (ECM) demonstrated that explanted valve values for deoxyribose nucleic
acid (DNA), collagen, and glycosaminoglycans (GAGs) were greater than or equal to that of
native valves. The mechanical properties of the explanted valves were also shown to have
adequate tissue strength, but less pliability.
This study presents the “proof of principle” for utilizing cell-seeded living TEHVs as opposed to
bioprosthetic heart valves, which are prone to calcification. As such, there is no study of long-
term effects and viability of these TEHVs. An important area of interest that has yet to be
studied would be the long-term outcome of the seeded cells in terms of their state of
differentiation and persistence in the neotissues formed in the interface of the native tissue and
the TEHV. This information would be useful in evaluating the contribution of the seeded cells to
tissue remodeling [4].

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 Introduction

Cardiovascular endoprostheses are prosthetic devices placed inside the cardiovascular system.
These devices are often components of life-sustaining treatments to otherwise highly mortal
medical conditions such as aneurysms of the aorta and, over the last 20 years, have been used in
conjunction with a minimally invasive implantation method to rapidly eclipse open endovascular
surgery as a treatment to aortic aneurysms [3]. As such, cardiovascular endoprostheses must be
optimally designed with the utmost attention to detail; failure in devices of this importance often
lead to serious injury or death. One of the most common types of cardiovascular endoprosthesis,
the cardiovascular stent-graft (CSG), is used to alleviate pressure on the walls of arteries,
interfacing directly with biological tissue of the human body. The idea of a stent-graft may seem
modest enough, but they are not simple metal rings used to hold open blood vessels, they are,
among many other possibilities, devices which utilize a system of self-expanding components
that are interlocked so as to form a mesh. Covering that mesh is a sheath of woven polymers that
fix themselves in place under constant cyclical stresses and constant interactions with the body’s
tissues. A wealth of biomechanical and biomaterial analyses and design considerations must be
utilized in order to design an acceptable device, resulting in cutting-edge stent-grafts that can be
utilized not only to support tissue and redirect blood flow, but be reabsorbed into the body or
serve as a delivery system that elutes pharmaceutical drugs directly into an area of interest.

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 Biomaterial Analysis of Cardiovascular Endoprostheses

Biomaterials, materials that interface with a biological systems, are distinguished by an ability to
coexist with biological tissues in the human body without bringing about significant harm. This
ability is referred to as a material’s biocompatibility. The term biocompatibility, however,
means remarkably little; it doesn’t provide any information other than that, when applied to the
body in some way, it is relatively harmless. None of the biological mechanisms or tissue-
biomaterial interactions can be inferred from a material’s status as biocompatible [5]. It is
essential, then, that a medical device be designed not with a material’s status as biocompatibility
in mind, but with consideration into how the material interacts with the system in which it is
placed. Cardiovascular endoprostheses such as stent-grafts present a significant challenge in this
regard, as they exist in a system that subjects these devices to persistent cyclic forces and
complex biological interactions on the protein, cell, and tissue level.
Bulk and surface material characteristics dictate much of the behavior displayed by a
biomaterial. Implantable medical devices are most often composed of a combination of
materials that confer different desirable properties to the device. The crystalline structure of
materials, determined by the elemental composition and bond types between these elements, is
the primary contributor to the bulk properties of a material [6]. In metal biomaterials, it is often
desirable that the metal structure resist corrosion. Corrosion resistance may be governed by both
elemental composition and surface finish. Titanium alloys, for example, are highly resistant to
corrosion as they undergo passivation. Titanium passivation is the result of a titanium atom’s
high reactivity to oxygen, producing a titanium-oxygen interaction which forms a passive layer
of titanium oxide that shields the underlying material from corrosion. Surface finishing methods
can further enhance corrosion resistance by changing the chemical composition of a material’s
surface. Electropolishing is employed with medical grade stainless steels to produce a surface
with high concentrations of chromium, which will react with oxygen to undergo passivation and
form a chromium oxide layer [6].
A device’s surface material characteristics also influence the degree in which proteins, cells, and
tissues adhere to a material. Cell adherence can both desirable and undesirable. In bioresorbable
stents, it is intended for endothelial cells to interact with the stent and gradually degrade it
throughout the healing process. In many other devices, endothelial cell proliferation over the
stent can result in restenosis, causing atherosclerosis and increasing risk for ischemic conditions
[5]. As a general rule, the rougher a device’s surface finisher, the more likely a cell will adhere
to it and the higher its thrombogenicity, or tendency to produce a blood clot. With respect to
graft material selection, it is desirable to utilize a polymer which forms a layer around the graft
that is impermeable to blood so as to relive all fluid pressure from the blood vessel. In the
context of surface finish, it is undesirable for the graft to have porosity, as thrombosis occurs
within the pores of the polymer weave and initiates an inflammatory response that is associated
with decreased effectivity [5].
Complementary to surface finish, net charge of the surface material can also attract proteins and
cells of the opposite charge, or repel those of the same charge. This combination of net charge

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and surface roughness can be conducive to the formation of a proteinaceous layer that passivates
the device to platelets and white blood cells (WBCs), decreasing thrombogenicity. In metals, yet
another surface property that dictates reactivity to blood is a material’s free surface energy,
which is determined by the number of unfulfilled intermolecular bonds. It is common for
medical grade metals to have high free surface energy, making them thrombogenic in that
respect [6]. Anti-coagulant and anti-platelet agents may also be applied to the surface of the
stent-graft so as to reduce the adherence of platelets and other clotting factors in the area
surrounding the device. Anti-inflammatory agents have also proved useful in reducing intimal
hyperplasia, or overgrowth of the vessel lining [5]. Tissue engineering can further reduce the
incidence of thrombosis and restenosis by employing stem cells to prompt the body to integrate a
device into itself by growing into or around it and regenerating tissue, providing not a tissue-
biomaterial surface interface but a tissue-tissue interaction with scaffolding to be recolonized by
the body’s own cells. This decreases the immunogenicity of the device, reducing the
inflammatory response as well as coagulation that results from immune response [4] [5].
Many of the devices utilized in the summarized articles were composed of stents composed of
either nitinol or medical grade stainless steel and a sheathing graft woven out of Dacron or
polyester [1] [2] [4]. Self-expanding nitinol—nickel titanium—stents enclosed in woven
polyester fabric are particularly useful in treating AAA or TAA as nitinol is a shape memory
alloy; it can be designed to collapsed during delivery and then expand into its final shape when at
or above body temperature, lodging the device into place. Nitinol is also a very fatigue resistant
alloy, which is vital in its use as a cardiovascular stent, as the stent will be subjected to constant
cycling loading from blood circulation and pulsatile motion of the blood vessels. The woven
polyester graft functions to redirect all blood flow through the stent-graft, relieving the aorta of
pressure. The use of polyester in particular grants strength, vital in resisting the fluid forces of
the blood, and hydrophobicity, conferring a resistance to degradation, to the graft. The material
properties of the polyester weave will also depend on the characteristics of the fiber orientation,
such as how closely the fibers are woven together and if they are parallel or intersectional. The
material choices in these studies appear to be relatively conscientious of the needs of the device,
as far as the level of then-present medical knowledge is concerned.
Again, given that the studies on AAA and TAA treatment were conducted during the initial
implementation of intravascular stent-grafts as a medical treatment, the researchers were
unaware of what common issues occur in patients post-treatment. Post-operative restenosis was
not a primary concern at the time, and therefore the design of the devices did not address this
phenomenon but instead focused on remaining fixed to the arterial wall and structural integrity
[1] [2]. Today, it is common for patients of these procedures to adhere to an aspirin (anti-
inflammatory) and anti-platelet/anti-coagulant regiment for up to a year after the operation, so as
to further decrease the chance for restenosis and thrombosis. Possible experiments that could
have led to insight into the effects of inflammation and endothelial cell proliferation might
include a sort of direct contact test to examine cell adherence or extended animal trials to analyze
the long-term implications and effects of cardiovascular endoprotheses.

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 Biomechanical Analysis of Cardiovascular Endoprostheses

Equal in importance to the tissue-biomaterial interaction of a medical device is the

biomechanical impact it has on the body. The body’s inherent response when interfacing with
foreign materials can be modulated by changing the mechanobiological state of the system.
With regard to cardiovascular endoprostheses, research suggests that the main driver behind
restenosis on CSGs is inflammation, which is in part caused by mechanical irritation of tissue
lining the arterial walls [5]. Also, as with chondrocytes that are present in articular cartilage, as
well as with bone, cyclic loading has been shown to improve the health of the neointimal tissue
that forms after stent-graft implantation [6]. Given a stent-grafts need to be firmly fixated in
place for treatment, there is a host of biomechanical factors that affect the fluid forces and flow
of blood as well as internal pressures within the stent-graft.
The use of CSGs for the treatment of AAAs and TAAs provide a canonical example of how
biomechanical factors and physical characteristics must be considered when designing these
medical devices. The arterial walls are composed of three layers of tissue: the tunica externa,
tunica media, and tunica intima, which are the outer, middle, and inner layers of tissue,
respectively. The composition of these tissues must be mechanically robust to as to withstand
the persistent cyclic loading and fluid forces that occur within the cardiovascular system. As
such, tissue layers are comprised of flexible proteins and tissue types such as collagen, smooth
muscle, and elastic fibers [3] [6]. AAAs and TAAs are caused when the tissue undergoes
permanent, plastic deformation. This is probably indicative of microstructural failure, as
proteins such as collagen have a natural elasticity to them so as to resist the pressure within the
artery. CSGs function as a complete bypass of the artery and shield the artery from nearly all
mechanical forces induced by the flow of blood (Figure 1), allowing arterial repair [3] [2].

Figure 1. A rendition of a stented AAA model [3].

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Design considerations for CSGs must include a diameter that is large enough to prevent
occlusions due to blood clotting but also sized correctly so as to minimize stress on the areas of
the arterial walls in which they opening of the stent are firmly fixed. Other design considerations
include frictional forces, sufficient radial strength to support the vessel walls and withstand shear
forces and blood pressure, but also once again minimize undue stress on the arterial walls, as
well as stent-graft flexibility, which is vital in insuring that the device can be collapsed and then
deployed via guidewire system [3] [6]. In the context of the studies previous summarized, the
main criterion for success in each study was the complete bypass of the aortic aneurysm as well
as the absence of stent migration. Results from these studies showed that aneurysm diameter
decreased after treatment with CSGs, suggesting that microstructural failures might be
remodeled or healed when relieved of stresses, visualized in Figure 2. There is, however, no data
on the performance of the aortic aneurysm after it has undergone such healing.

Figure 2. A visualization of the effect of stent-graft implementation on an AAA model.

Though the CSGs were custom designed for each patient, the primary mode of fixation was a
simple system of barbs at the openings of the stent-grafts, opposing the shear drag force due to
blood flow [1] [2].

10
Given that, again, the studies analyzing the treatment of AAAs and TAAs with CSGs were
conducted before the advent of computational models that would allow for detailed
biomechanical examinations of force-device interactions, there do not appear to be any sort of
specialized features which serve to provide extra fixation and resistance against stent migration
over time [1] [2]. Utilizing fluid solving models and simplifying assumptions, later research has
suggested that the methods of stent-graft fixation that are commonly used may in fact be
inadequate to resist the significant drag forces that arise due to pressure within the stent-graft.
This pressure is also shown to have a nearly linear correlation with CSG size. It is also notable
that the assumptions utilized in this study presumed that the inertial effects of platelet
components in the blood were non-existent and that any blood surrounding the stent-graft was
stagnant. These are relatively unrealistic, though necessary to simplify the model, assumptions
that actually create a sort of best-case scenario. It is reasonable to assume the opposite might
actually occur in a real system, though whether or not these assumptions make any significant
difference in results is not known [3].
Tissue engineering may also be used to augment the biomechanical properties of CSGs.
Biodegradable stents seeded with stem cells can be grown to tissue maturity and then
decellularized so as to result in a device that will be recolonized by the body’s native cells. This
ensures that the biomechanical response of the device more closely mimics that of the original
tissue once the stent is resorbed into the body, reducing the chance of restenosis or thrombosis.
The effect of fatigue is also minimized, as biological tissues respond more robustly to fatiguing
than metal or polymeric crystalline structures [4].

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 Conclusion

The studies addressed in this article are examples of early research opportunities that were
successful, yet were not advanced enough in biomedical knowledge to predict some of the more
complex bodily responses to implanted CSGs, or examples of more theoretical, “proof of
concept” behaviors that advance biomedical sciences. As such, with respect to modern design
considerations for CSGs and other intravascular devices, the experimental treatments of AAAs
and TAAs that were performed do not satisfy today’s standard of device efficacy and durability,
as important factors such as risk of restenosis and stent migration are not confronted. Some of
these risks, however, could not have been addressed as the mechanisms and interactions
responsible for them were not yet understood. The treatments did, however, serve to treat an
imminent danger posed by the possibility of a ruptured aneurysm that would almost certainly
prove fatal. They also served to shed light on the bodily response to the treatment of these
aneurysm.

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 Works Cited

[1] U. Blum et al., “Endoluminal Stent–Grafts for Infrarenal Abdominal Aortic Aneurysms,” N.
Engl. J. Med., vol. 336, no. 1, pp. 13–20, Jan. 1997.
[2] M. D. Dake, D. C. Miller, C. P. Semba, R. S. Mitchell, P. J. Walker, and R. P. Liddell,
“Transluminal Placement of Endovascular Stent-Grafts for the Treatment of Descending
Thoracic Aortic Aneurysms,” N. Engl. J. Med., vol. 331, no. 26, pp. 1729–1734, Dec. 1994.
[3] Z. Li and C. Kleinstreuer, “Analysis of biomechanical factors affecting stent-graft migration
in an abdominal aortic aneurysm model,” J. Biomech., vol. 39, no. 12, pp. 2264–2273, Jan.
2006.
[4] D. Schmidt et al., “Minimally-Invasive Implantation of Living Tissue Engineered Heart
Valves: A Comprehensive Approach From Autologous Vascular Cells to Stem Cells,” J. Am.
Coll. Cardiol., vol. 56, no. 6, pp. 510–520, Aug. 2010.
[5] D. F. Williams, “On the mechanisms of biocompatibility,” Biomaterials, vol. 29, no. 20, pp.
2941–2953, Jul. 2008.
[6] J. C. Palmaz, “Intravascular stents: tissue-stent interactions and design considerations.,” Am.
J. Roentgenol., vol. 160, no. 3, pp. 613–618, Mar. 1993.

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