EndoVascular Stent GraftsBy Paul Arsenovic

An endovascular stent graft is a hallow tube composed of fabric and supporting metal mesh that is inserted inside blood vessels. Typically, these stents are used to reinforce weak spots in arteries, known as aneurysms. The leading causal factors associated with aneurysms are smoking, hypertension, aging, congenial defects, and atherosclerosis. Typically, endovascular stents are used surgically to repair either thoracic or abdominal aortic aneurys (1)ms, sometimes referred to as EVAR (endovascular aortic repair). At least 7 different companies offer FDA approved stents to treat aneurysms, however the dominant market players are Medtronic, Cook Medical, WL Gore & Associates, and Endologix. Due to its success, EVAR  has led to a dramatic shift from open heart surgery to endovascular repair. While EVAR has successfully lowered the risk of lethal aneurysms, a number of complications are associated with stent grafts, namely endoleak and mechanical failure.

To understand the design and function of endovascular stents, a basic understanding of vascular anatomy and physiology is necessary. The left ventricle pumps blood out of the heart into the aorta, the main artery of the body (Figure 1A). The main function of the aorta is to distribute oxygenated blood to the systemic circulation (everywhere except the lungs). The aorta can be divided into 3 anatomical sections: the ascending aorta, the aortic arch, and the descending aorta (Figure 1B). The ascending aorta has only two branches that supply oxygenated blood to heart tissue, commonly referred to as the coronary arteries. The aortic arch has three main branches, the innominate artery, the common carotid, and the left subclavian. Collectively, these arteries supply blood to the arms, head, and neck. The descending aorta runs through the chest and abdomen and is divided further subdivided into the thoracic and abdominal aorta.1

Figure 1: Anatomy of the Heart (A) and the Aorta (B). Images from Wikipedia Commons.

The thoracic aorta enters the chest cavity, where it supplies blood to the chest and organs in the chest cavity. The two main arterial outputs of the thoracic aorta are either visceral (supplying internal organs) or parietal (supplying walls of cavities or organs) branches. Subbranches from the visceral portion supply blood to the lungs, the esophagus, and pericardium. Subbranches from the parietal portion supply blood to the ribs, and the thoracic wall muscles.2  The typical diameter of the thoracic aorta ranges from 2.4-3.3cm.3

After the aorta passes through the diaphragm, it becomes the abdominal aorta. This arterial portion supplies blood to many of the largest internal organs, including the liver, stomach, pancreas, kidneys, spleen and genital organs. More than half of the bodies cardiac output branches off these visceral arteries from the aorta. The other parietal branches supply the adrenal glands, the lumbar, the abdominal wall, the skin, and the spinal cord. At the end of the abdominal aorta, the artery bifurcates into the left and right common iliac arteries. The common iliac arteries split into the internal iliacs that supply the pelvic region and the femural arteries which supply the lower extremeties. The typical diameter of the abdominal aortia is 2-3cm, depending on the age and sex of the patient.4

Histologically, the aorta can be divided into three layers from the lumen outward: 1)  the tunica intima,  2) the tunica media and,  3) the tunica adventitia (Figure 2). The first layer of intima is made of endothelial cells, followed by smooth muscle cells and connective tissue. At the border of the intima and media lies the internal elastic membrane, composed largely of elastin and collagen. The media is the thickest layer of the aorta, largely composed of smooth muscle cells and elastic fibers that are arranged spirally. Elastic fibers are secreted by smooth muscles cells, forming wavy sheets that are known as lamellae. In between the media and the adventitia is another elastic membrane made of collagen and elastin called the external elastic layer. The outer layer or the adventia is dominated by collagen fibers and contains some elastin fibers. Because of the high collagen content in the adventia, it is the strongest layer of the aorta. Since the aorta is such a thick vessel, the adventitia contains small blood vessels that supply the outer layers with nutrients known as the vasa vasorum.

Physiologically, the aortas primarily function is to deliver blood to the systemic circulation and dampen the pulsatile blood flow from the heart. This dampening is achieved from the elastic properties of the vessel. In addition to the passive function of the aorta, large arteries may actively restrict or increase blood flow. To restrict flow, smooth muscles cells in the media and adventitia contract by stimulation from the autonomic nervous system. Conversely, vasodilation or relaxation may occur through relaxation of the muscle tissue by the nervous system. The endothelial layer can also

Figure 2: Histological Section of an Artery. Image from Britannica Encyclpaedia.

play an important role by releasing nitric oxide, which reduces clotting and the viscosity of the blood.

Diseases of Vascular System:

There are numerous interrelated factors that contribute to arteriosclerosis, or the thickening, hardening and loss of elasticity of arterial walls. These factors include smoking, hypertension, aging, congenial defects. Ultimately, these risk factors contribute to a change in the material properties of the arteries, which render them susceptible to failure particularly in regions of high stress, such as the aorta. Failures at the aorta (aortic aneurysm) are critical events that often lead to a lethal loss of blood due to the high blood flow in this region.

Atherosclerosis is a particular disease of the arteries that leads to a buildup of plaques on the luminal wall of blood vessels. Theses plaques are generally ‘fatty-deposits’ composed of cholesterol, fat, and calcium. The cause of atherosclerosis is thought to be related to mechanical changes in the endothelial layer combined with inflammatory responses, leading to the buildup of plaques (Figure 3). The process begins with the retention of lipid-protein complexes containing LDL in the subendothelial layer. As the LDL interacts with the extracellular matrix of the subendothelial layer, it undergoes oxidation. This oxidation leads to a recruitment of inflammatory macrophages that engulf the oxidized LDL molecules. As fat accumulates inside the macrophages, they are referred to as foam cells. Eventually, the foam cells die by apoptosis or necrosis, leaving behind an indigestible oxidized lipid rich mass that forms the basis of arterial plaque.5

Figure 3: A diagram of molecular events that cause the formation of atheromas. Diagram from Lusis, 2000.

Atherosclerosis is a prominent feature of many aortic aneurysms. In a risk analysis study of abdominal aortic aneurysms, the authors found the presence of atheromas to be the leading correlative factor to abdominal aneurysms.  Previous history of a abdominal aneurym was related to the presence of atheromas in 93% of patients examined. Over 80% of patients with abdominal aneurysm also had detectable atheromas in the descending aorta.6  

The process of aging plays a large role in the changing material properties of the aorta, independently of atherosclerosis. The physical changes that take place in the aorta include

collagenous remodeling, intima thickening, vascular smooth muscle cell migration, narrowing lumen, and aortic elongation (Figure 4). Due to aging and fatigue from the billions of heart cycles, the elastic lamellae begin to fail around 40 years of age. As a consequence, the tunica media stiffens as collagen fibers begin to bare most of the cyclic load. As the collagen fibers experience greater stresses, they rearrange and become thicker. Additionally, the expression of elastin decreases throughout aging, limiting the body’s ability to repair the fatigued elastic lamellae. These stiffness changes are typically measured by an increase in systolic and pulse pressure by 40mm Hg between ages 20-80. Over time as the ratio of collagen to elastin increases, aortic compliance decreases. The decreased compliance of the aorta generally leads to a thickening of the intima.7

Intimal thickening further exacerbates the pathology of the arteries and the aorta. This is thought to be related to a change in the endothelial layer. Over time, endothelial cells undergo shape changes and smooth muscle cells migrate from the media to the intima. The coupling of these two events cause the endothelium and the intima layer to thicken, decreasing the size of the aortic lumen. Luminal reduction effectively decreases the cross section of fluid flow in the artery. Both the reduction of the lumen diameter and the thickened intima decrease the compliance of the aorta. Consequently, these changes increase the systolic blood pressure as aging progresses.8

Aortic elongation, particularly at the ascending portion, leads to a widening of the arch. The law of Laplace dictates that as the diameter increase, the wall tension increases. If the ascending aorta reaches 6cm in diameter, the yearly rate of death approaches 11%.9 .Dimensional changes of the abdominal aorta also take place during aging. Typically, the abdominal aorta dilates over time. The increasing diameter of the abdominal region has been associated with an increased risk of aneurysm. The systolic diameter of the abdominal region increases roughly 0.64 mm/decade. The abdominal aortic stiffness increases more than any other region of the aorta, at a rate of .9m/s/decade as measured by pulse wave velocity.10

Comparison of Stent types:If the diseased aorta grows in size to a critical diameter, the risk of rupture grows too

large, necessitating surgical intervention. Prior to the introduction of endovascular stents, large abdominal aortic aneurysms (>5cm diameters) were treated by open surgical repair (OSR). This requires a highly invasive procedure where the abdominal wall is incised to get access to the aorta. The problems with OSR are related to the risks of the operation. The 30-day mortality rate ranges from 4-8%. Furthermore, older patients or patients with different forms of cardiovascular disease are often too risky to undergo OSR. To overcome this challenge, aortic stents were

Figure 4: A Model of the Aging Aorta. Figure from Collens et. al.

introduced in the early 1990s, offering a less invasive and less risky procedure to treat aneurysms of the descending aorta.11

The goal of an endovascular stent graft is to reduce the pressure on the walls of an aneurysm to prevent rupture. If properly attached, the stent graft acts as a functional blood vessel that enables healthy blood flow while protecting the weak walls on the aneurysm site.

A variety of different vascular graft devices exist on the market, from simple tube designs to more complex bifurcated stents. All stent grafts are composed of two general elements:  1) metal supporting mesh and 2) grafting fabric. The grafting fabric is typically made of woven polyester or polytetrafluoroethylene (PTFE).12 The metal supporting mesh is made of either nitronol or stainless steel. The devices are sealed in place by radial expansion or barbs. Devices are either self expanding or require balloon inflation for radial sealing. 13 For the abdominal aortic aneurysms (AAA), there are at least three types of stent graft shapes: 1) tube, 2) bifurcated, and aorta-uni-iliac. For thoracic aortic aneurysms (TAAs), the current FDA approved devices are all simple tubes. However, there are experimental stents that have incorporated the branching arteries, such as the Medtronic’s Thoracic Branch Stent Graft.14

Gold Standard Graft Stent:

There are two important characteristics of an ideal stent graft: 1) biocompatibility and 2) material properties. Ideally, the stent graft should have excellent compatibility with the human body. This means the graft should not be toxic, allergic, or carcinogenic. The main concerns are clotting (thrombosis) and the rupture of red blood cells (hemolysis). Additionally, the immune system must be able to tolerate the device.

Second, the device needs to have very specific material properties. Ideally, the stents compliance should match the properties of a normal aorta. It needs to be ductile or flexible to adapt to the curvatures and irregularities of patient anatomy. The material needs to be dto tolerate the pulsatile nature of blood flow. The stent should not corrode or permanently

Figure 5: Various Types of Endovascular Stents Grafts for TAA or AAA EVAR. (A) Parodi Graft; (B) EVT Endograft; (C) Investigator ESG; (D) BostonScientific Vanguard stent graft; (E) W.L. Gore Excluder stent graft; (F) W.L. Gore thoracic stent graft; (G) Medtronic/World MedicalTalent abdominal aortic stent graft; (H) Medtronic/World Medical Talent thoracic aortic stent graft; (I) Teramed/Cordis abdominal aortic stent graft; (J) Guidant Ancure stent graft; (K) Medtronic AneuRx stent graft.

deform over time. The endothelial layer should incorporate the fabric into the arterial layer to prevent blood flow through the fabric pores (endoleak). Finally, the device should be firmly anchored in place without exerting too much radial force on the artery or causing injury at attachment barbs.

Types of Materials in Stents:As stated previously, the grafting fabric of stents are made of either polyester or PTFE. The polyesters used are made of polyethyleneterephthalate (sometimes referred to as PET), and is commercially known as Dacron. PET is relatively strong compared to PTFE, with a higher yielding strength, elastic modulus, and superior fatigue strength. 15

Graft FabricsPET fabrics are manufactured as either woven or knitted materials. Woven PET is more commonly used, and the fabric thickness is less than the knitted types. Due to the rigidity of woven PET, it does not stretch easily. Alternatively, knitted fabrics stretch easily, however they are thicker which makes them difficult to insert through the endovasculature.16 Although knitted fabrics are flexible, they are porous due to the gaps introduced in the manufacturing process.

Figure 6: A woven (A) and knitted (B) type of PET fibers. Images from Santos et. al.

PTFE, also known commercially as Teflon, is an alternative polymer to PET based fabric. To be used in a vascular application, PTFE has to stretch out in the manufacturing process or expand to retain the correct material characteristics. During expansion, the material porosity can be controlled. For this reason, stent graft PTFE is referred to as ePTFE (expanded PTFE). The biocompatibility of PTFE is excellent as exhibited by its bacterial resistance, low propensity to form blood clots and low inflammatory response. The major disadvantages of PTFE are its inferior strength and greater fatigue when compared with PET fabric. 17

Stent Metals:Three different types of metals are used to support graft fabrics and hold stents in the correct position in the aorta. First, Nitinol (used by Vanguard, Gore, Talent, and Medtronic) is a metal alloy composed of nickel and titanium (49.5 and 57.5 percent respectively). It is considered superelastic, meaning it can undergo large deformations (up to

Figure 7: An SEM image of PTFE fibers showing the node and fiber morphology. Image from Santos et. al.

10%) and still recover its shape.The superelastic property of Nitinol is particularly useful during the insertion of the stent, which requires large deformation of the graft before it is expanded at the site of aneurysm. Nitinol is considered to have good biocompatibility, however it is somewhat an allergen and toxic. The major disadvantages of Nitrinol are its fatigue behavior and corrosion relative to stainless steel and Elgiloy.18

316L stainless steel (marine-grade steel) is an alternative to Nitinol alloy made of 18% chromium and 10% nickel. 316L is highly resistant to corrosion due to the low carbon content (0.03%). Much like implant metals, 316L does slightly corrode into the body over time. To limit the amount of corrosion in the blood, the surfaces of 316L steels can be modified by electropolishing or other surface treatments. The major disadvantage of 316L steel is its biocompatibility when compared to Nitinol and its strength when compared with Elgiloy.19

Elgiloy is a metal alloy composed of 39% cobalt, 19% chromium, 14% Ni, 8% molybdenum, 1.5% manganese. It is very ductile and strong. When compared to 316L steel, elgiloy is stronger with better fatigue resistance. The major drawback to Elgiloy is its biocompatibility, which is lower than either 316L or Nitinol.20

Complications with Vascular Stent Grafts:The two major complications of EVAR surgeries associated with the stent device are

endoleak and mechanical failure. Endoleak refers to blood flow into the extragraft portion of the aneurysm. Endoleak can lead to blood flow into the aneurysmal sac, which increases the risk of rupture. Endoleaks can occur four different ways: 1) incomplete attachment to the artery or 2) backward blood flow, 3) defects in the graft structures or 4) fabric porosity. In surveillance study, the authors found that after EVAR surgery, 7.8% had type II and 12% had type I, type III or a combination of all four.

Another common mode for failure is device fatigue. In a survey of AAA and TAA surgeries, 7.8% of the devices demonstrated fatigue. Of these fatigues, the most common was longitudinal metal fractures.21

Future Trends:All stent metals undergo corrosion that is related to the stents grafts toxicity and

biocompatibility. Engineering various surface coatings and corrosion resistant metals will be an important part of the evolution of stent grafts. Some metals which may possibly fill this void include tantalum, platinum, and cobalt alloys.22

Another material that has yet to be used in an EVAR device is ultra high molecular weight polyethylene (UHMWP). In orthopedic applications, UHMWP showed great biocompatibility, strength, and resistance to fatigue. The immune system tolerates UHMWP much better than PET fabrics and its material strength is at least as good. The surface of UHMWP is also very smooth, reducing the chances of clotting or harmful blood interaction. 23

References:

1 Grays Anatomy

2 Human Cardiovascular System. (2015). In Encyclopædia Britannica. Retrieved fromhttp://www.britannica.com/EBchecked/topic/95628/human-cardiovascular-system/33570/The-arteries

3 Wolak, A. et al. Aortic size assessment by noncontrast cardiac computed tomography: normal limits by age, gender, and body surface area. JACC Cardiovasc Imaging 1, 200–9 (2008).

4 Erbel, R., and Eggebrecht, H. (2006) Aortic dimensions and the risk of dissection, Heart 92, 137–142.

5 Lusis, A. Atherosclerosis. Nature 407, 233–241 (2000).

6 Reynolds, H. et al. Abdominal aortic aneurysms and thoracic aortic atheromas. Journal of the American Society of Echocardiography 14, 11271131 (2001).

7 Collins, J., Munoz, J., Patel, T., Loukas, M. & Tubbs, R. The anatomy of the aging aorta. Clin. Anat. 27, 463–466 (2014).

8 Ibid.9 Nataf, P. & Lansac, E. Dilation of the thoracic aorta: medical and surgical management. Heart92, 1345–1352 (2006).

10 Hickson, S. et al. The relationship of age with regional aortic stiffness and diameter. JACC Cardiovasc Imaging 3, 1247–55 (2010).

11 Dangas, G. et al. Open Versus Endovascular Stent Graft Repair of Abdominal Aortic Aneurysms : A Meta-Analysis of Randomized Trials. JACC Cardiovasc Interv 5, (2012).

12 Katzen, B., Dake, M., MacLean, A. & Wang, D. Endovascular Repair of Abdominal and Thoracic Aortic Aneurysms. Circulation 112,1663–1675 (2005).

13 Marin, M. et al. Endovascular Stent Graft Repair of Abdominal and Thoracic Aortic Aneurysms.Transactions of the ... Meeting of the Amer

14

15 Santo, Isa. Mechanical properties of stent graft materials, ‐ Instituto de Engenharia Mecânica e Gestão Industrial, Faculdade de Engenharia, Universidade do Porto, Portugal

16 Ibid17 Ibid18 Ibid19 Ibid20 Ibid21 Marin, M. et al. Endovascular Stent Graft Repair of Abdominal and Thoracic Aortic Aneurysms.Transactions of the ... Meeting of the American Surgical Association 121, 279288 (2003).

22 Collins, J., Munoz, J., Patel, T., Loukas, M. & Tubbs, R. The anatomy of the aging aorta. Clin. Anat. 27, 463–466 (2014).

23 Ibid