Update on vascular endoprostheses (stents): from experimental studies to clinical practice

REVIEW ARTICLE

Update on vascular endoprostheses (stents): from experimental studies to clinical practice

Luís Henrique Gil França^I; Adamastor Humberto Pereira^II

^IPhD in Surgery, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. MSc. in Surgical Clinic, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil. Specialist in Vascular Surgery, Endovascular Surgery, Angiology and Radiology (SBACV/CBR/AMB).

^IIAssociate professor. Head, Vascular Surgery Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.

ABSTRACT

The treatment of peripheral vascular diseases is one of the most rapidly expanding fields of medicine today. The number of peripheral interventions increased and innovative endovascular techniques are close to the results of traditional vascular surgeries. Although balloon angioplasty alone offers good immediate results, implantation of stents has been proposed to improve the procedural success and extend its application to more patients with peripheral vascular disease. However, stenting is controversial. Use of stents has good results in aortoiliac vessels but its use in femoropopliteal vessels is still in dispute. Moreover, the rapid development of endovascular stents for peripheral applications and their choice have been a complicated task for endovascular surgeons. Many factors influence choice of stent, therefore, knowledge of available stents is mandatory. Appropriate selection depends on adequate preprocedural evaluation of the lesion, choice of primary vs. selective stent placement, and location and characteristics of the lesion. In this article the history of stent development is reviewed, from studies with experimental models to clinical practice, and its application in the treatment of peripheral vascular diseases is discussed.

Keywords: Artery, vascular graft, peripheral vascular diseases.

RESUMO

Atualmente, o tratamento das doenças vasculares periféricas é uma das áreas da medicina de maior expansão. O número de intervenções vasculares aumenta e os resultados das novas técnicas endovasculares estão muito próximos aos das tradicionais cirurgias vasculares. Embora a angioplastia ofereça bons resultados em curto prazo, o implante de stents procura melhorar o sucesso do procedimento e estender o seu uso a um número maior de pacientes com doença vascular periférica. Entretanto, a sua utilização ainda é controversa. O implante de stents no sistema aorto-ilíaco tem bons resultados; porém, a sua indicação para as lesões femoro-poplíteas ainda é discutida. Além disso, o rápido desenvolvimento de stents e sua escolha para uso no sistema vascular periférico têm sido uma difícil tarefa para o cirurgião endovascular. Muitos fatores influenciam a escolha do stent, e um amplo conhecimento desse material é essencial. Tal escolha depende da avaliação pré-operatória, da localização e das características da lesão e também do uso do stent primário ou seletivo. Nesse trabalho, são realizadas revisão do histórico do desenvolvimento dos stents, desde os estudos experimentais até os ensaios clínicos e também discussão sobre a sua aplicação no tratamento das doenças vasculares periféricas.

Palavras-chave: Artéria, prótese vascular, doenças vasculares periféricas.

Introduction

Stents are metal mesh tubes inserted in the vascular lumen, whose function is to maintain arterial lumen open (using mechanical pressure) and avoid restenoses resulting from development of intimal hyperplasia or contraction secondary to treatment of fibroelastic lesions.¹ The term "stent" derives from Charles Thomas Stent (1807-1885), a dentist that created a malleable material with the aim of maintaining skin grafts placed within the oral cavity. According to form of insertion, stents can be classified as: direct stent (device implantation prior to balloon dilatation), primary stent (predetermined insertion after ATP), and selective stent implantation (insertion after suboptimal result of ATP). Most stents are implanted selectively, and are indicated in residual stenosis, elastic recoil, poor result with pressure gradient, complications such as dissection or intimal flap, plaque ulcers, occlusions and restenosis. Primary stents can be used in occlusions, lesions with high risk for restenosis and lesions greater that 8 cm, diffuse, eccentric or ulcerated. Their use is limited in cases of marked vessel tortuosity and in much calcified lesions.^1-3

Stents can be distinguished according to several factors, such as implantation mechanism (self-expandable, expandable balloon or thermal memory), geometry (ring format – "open or closed cells"), type of mesh formed by metal legs, structural design (tube or coil) and metal composition.⁴

Self-expandable stents are compressed by a thin plastic membrane over a small-diameter caliber (example: Wallstent^®) or are compressed inside larger-diameter catheters (example: Craggstent^®). When ejected, they expand into the previously dilated vessel lumen diameter through an angioplasty balloon and reach their normal diameter. Such stents are highly flexible, which allows expansion to a predetermined limit, after removal of the introducing sheath. Their implantation is relatively easy, but they have low resistance to radial compression. There may be shortening and they are not accurately released, like balloon-expandable stents. Such stents are indicated in the following sites: aorto-iliac and femoropopliteal axis, carotid arteries and non-ostial lesions of the subclavian artery.^4,5

Balloon-expandable stents are inserted with greater accuracy and have good resistance to radial compression; however, they have low elasticity and longitudinal flexibility, and can be reinflated using a larger balloon. Due to high radial force, such stents are the first choice in ostial lesions and at sites with calcifications and external compression. Contraindicated sites for such stents are those close to joints, surrounding bones and ligaments and next to flexion points. They usually open from tips to center in order to fixate on the wall. Displacement of the material in the wall is from the periphery to the center of the lesion, reducing the chances of embolization. Such stents are indicated in the following sites: aorto-iliac axis, renal arteries, ostial lesions of the subclavian artery, and orifice lesions of supraaortic trunks. Examples: Palmaz (Cordis), Strecker (Medi-tech).^4,5

Differences and advantages between self-expandable and balloon-expandable stents are widely studied in experimental models. Chuapetcharasopon et al. implanted balloon-expandable stents and self-expandable stents in iliac arteries of pigs submitted to atherogenic diet. It resulted in a much more marked intimal hyperplasia in the group submitted to balloon-expandable stents. Such result was attributed to a larger trauma of the vascular wall caused by balloon expansion.⁶ Mangell et al. compared use of these two types of stents in the growth of swine aorta for 4-18 weeks.⁷ Mean pig weight increased from 20 to 93 kg and aortic diameter increased 60%. Balloon-expandable stents did not show pulsatile movement and were subject to vessel wall detachment, while self-expandable stents followed change in vessel diameter without affecting expansibility after 18 weeks, in addition to good fixation, despite vessel dilatation. Andrews et al. implanted self-expandable stents close to the hip joint in swine femoral arteries and veins and concluded that such stents, when implanted in joint regions and veins, have increased risk for developing intimal hyperplasia and occasionally occlusion when compared with stents inserted in vessels with low mobility and in arteries.⁸

Thermal-expansion stents acquire their original formats after exposure to body temperature. The prototype is the nitinol stent, such as Cragg Nitinol (Mintec), Memotherm (Angiomed Bard), and VascuCoil (Medtronic).⁴

Some authors highlight the so-called ideal properties of an endovascular stent, such as high opacity for better visualization, facilitating implantation; large radial force to resist elastic remodeling; minimal format variation after implantation to increase accuracy; simple and easy-to-handle implantation system; longitudinal flexibility to cross tortuous vessels and aortic bifurcation; radial elasticity to resist external compression with no permanent deformation, especially in joint sites; small profile with large expansion to pass through small sheaths and critical stenoses; minimal shortening after release; easy rescue in case of implantation failure; accessible side branch; minimal induction of intimal hyperplasia; resistance against thrombosis and corrosion; and durability and low cost.^5,9,10

Stent biochemical behavior and design have a major effect on host responses to stent presence. Radial distensibility and longitudinal flexibility affect stent patency in the long term. Increased complacence and flexibility may have a negative effect caused by stimulation of fibroblastic activity and interference with endothelization.⁴

Stent architecture is comprised of rings that can have individual setup or sequence accumulation in a repetition pattern. Individual rings can simply be attached to each other, similarly to the Gianturco Z stent (Cook). This type is currently used in endoprosthesis and for large-diameter vessels, such as the innominate veins and the superior vena cava. Another type is sequence connection of rings, using a variety of connections that also attribute properties to stents. Spaces between rings are called cells, which can be closed (elements are very tight, such as "honeycomb") and open (connections are left open). The original Palmaz stent is a laser-cut tube, an expandable balloon that creates a network of four closed cells. Such cells are geometrically interconnected through non-flexible connectors. The result is geometrically simple and produces a strong and durable structure in areas that are not subject to break forces or that demand flexibility. Such lack of flexibility may cause problems not only in areas of tortuosity, but also in straight targets of hard access (contralateral iliac artery in case of an aortic bifurcation with a much acute angle). Even if a sheath can be successfully inserted, stents may not have ability to progress through sheath twist.^4,5 The first "flexible connectors," designed by Palmaz and Schatz, were simple and straight metallic wires between cell segments that provided a degree of flexibility between sequences of inflexible segments of the cell network, similar to connections of train wagons.¹¹ The specific connection geometry alone provides a degree of longitudinal, radial and twist flexibility. Currently there is a wide range of connectors that stretch in any direction, not only in response to balloon expansion, but also to vessel tortuosity and irregularity. Closed-cell stents usually have the advantage of obtaining a more uniform vessel coverage, and those with open cells have more flexibility; however, the latter provides less support, with probability of inadequate coverage, especially in tortuous vessels, in which stent twist makes some cells more open than others.⁴

Braided stents, such as the Wallstent, have good visibility, flexibility and, prior to total release, have the advantage of retracting up to 87% of the stent in the device; disadvantages include shortening and intimal dissection caused by widening of stent distal limits if the release device was inadvertently pushed during release¹²; although they are flexible, such stents are quite rigid and do not fit well in irregular surfaces, but gradually expand, leaving space between the stent and the arterial wall (low conformity). A better stent conformity with the arterial wall could reduce restenosis. Rolland et al. showed that restenosis rate was lower by inserting compliance matching stent in swine carotid arteries.¹³ Nowadays when self-expandable stents are used, recommendation is to always use laser-cut nitinol stents, which have shortening lower than 3%. Braided nitinol stents have shortening that may reach up to 50% of the original stent length when inside the release sheath.^1,4,5

Stents can also have a spiral form (coil stent) which minimizes elastic recoil and seals dissection points. It is more suitable for flexion points, such as lesions located in the popliteal artery, behind the knee. There was no significant improvement in revascularization rate after 9 months when compared with ATP. However, there was significant improvement in ankle-brachial index and low complication rate.¹⁴ Choice of the best stent to be used in each case is dependent on arterial anatomy and lesion morphology. In the presence of tortuous anatomy, preference is for stents with open cells and more flexible. When there is a significant difference in diameter between the common and internal carotid artery, cobalt-chromium stents (Elgiloy) or nitinol conical stents are selected. Lesions with high emboligenic potential are treated with closed-cell stents, while calcified lesions need to be treated with nitinol stents.¹⁵

Stents can be created from varied materials, such as stainless steel 304 SS, 316 L SS, tantalum, elgiloy (SS), platinum, cobalt alloy, and nitinol.⁴ Dyet & Schurmann report that 316 L stainless steel stents have good biofunctionality (degree to which the metal adapts to execute a given function) and good biocompatibility (degree to which the metal remains inert after being implanted in the arterial system without causing foreign body reaction or releasing toxic ions).¹⁶ Gotman exposes that stainless steel stents are comprised of an alloy of iron, chrome and manganese. It also has traits of other metals, such as molybdenum, manganese, copper and carbon. Although such other elements account for a small sample of the total, they may change the crystalline structure of the metal, such as metallic alloy properties.¹⁷ One of the most important components of stainless steel devices used for medical purposes is chrome. A minimal chromium oxide concentration of 12% is required to cover the external surface of the metal, with the aim of avoiding corrosion to which the metal is exposed in the blood flow.^16,17

Nitinol is a nickel and titanium alloy with properties of thermal memory, which allows it to be firmly compacted within a release system when it gets cold, to quickly expand and acquire its predetermined format and size, after release of its placement system in the blood flow. In addition, it has large elasticity and resistance against fracture. Nitinol stands for Nickel Titanium Naval Ordinance Laboratories, whose metallic alloy was initially developed for military purposes.¹⁸ However, in nitinol stents there is release of nickel, which is responsible for intimal hyperplasia. Nickel is a normal nutritional component, but its exposure to high levels may cause serious respiratory problems, local and systemic allergic reactions and inhibition of cell reproduction. On the other hand, titanium seems to be inert. Nickel and titanium form an extremely strong metallic alloy; nitinol is resistant to nickel oxidation, which could release ions of this metal and increase risk for adverse reactions. Similarly to stainless steel stents, nitinol stents are covered by a thin layer of oxide after implanted in the vascular system. In such case, however, titanium oxide is formed, stabilizing the internal surface of the stent and preventing reaction of nickel ions with human body tissues.¹⁸ Fracture of nitinol stents may be related to the polishing and coverage of the stent surface with amorphous oxides.^19,20

A series of cellular and molecular processes contributes to endovascular healing of stents. Such healing process reflects a programmed response, such as foreign body, to implantation in the vascular system and results in four types of tissue: thrombus, neointima, endothelium, and inflammatory cell infiltrate. Location and extension of each type of tissue are influenced by several factors related to endoprosthesis implantation, such as location of the stent metallic mesh, type of graft covering it, endoprosthesis microstructure and porosity.²¹

Surface roughness, electric load, free surface energy and humidity are physical characteristics of the stent with important determinants of thrombogenicity and tissue interactions. Smoothness of the metallic surface is important because it makes it less thrombogenic. Most metallic surfaces implanted in humans have an electropositive surface load that attracts fibrinogen, thus forming a thin layer a few seconds after stent implantation. Such fibrinogen surface reduced superficial tension of the metal surface, resulting in less thrombogenicity. Over the first weeks after stent implantation, the thrombus surrounding the stent struts is gradually replaced by intimal hyperplasia, and the number of newly formed vessels in each area is associated with the number of myointimal cells.²² Pisco studied the reactions occurring after stent implantation in the aorta of dogs and showed that such neovascularization originates from the vasa vasorum.²³ In dogs neointimal formation reaches its limit 2 months after stent implantation and, consequently, starts becoming thinner, with few cells and is gradually replaced by collagen.

Immediately after exposure of a metallic device to the blood flow, a series of events change its surface, with the aim of preparing it for tissue colonization. Modification of arterial wall morphology after stent implantation has a well defined sequence of events. Initially there is formation of thrombi and occurrence of an acute inflammation soon after stent implantation, and later there is neointimal growth. Increased inflammation after stent implantation is associated with medial layer injury and penetration of the stent mesh into the lipid core.²²

The metallic part of the stent also influences healing. The metallic structure is an important determinant in thrombus formation, which, in turn, serves as niche for neointima formation. A few seconds after implantation there is a deposit of fibrin and other plasmatic proteins in the metallic structure exposed to blood flow.²² Over the first 15 minutes of stent exposure to circulatory flow there is adherence of platelets and leukocytes to the stent surface, which is covered by fibrin, contributing to formation of initial thrombus. The thrombus degree that is formed in the stent mesh in this stage will have large influence on subsequent neointimal growth.²⁴ Palmaz et al. showed that, in 24 hours, there already is a complete fibrin layer in the stent surface, with lines oriented toward blood flow direction. The authors suggest that fibrin lines may serve as structure for the development of endothelial cells.²⁵

When endoprostheses are implanted there is a certain degree of vascular wall lesion. Even self-expandable stents require balloon dilatation to better adhere to the arterial wall. Balloon-expandable stents require a balloon catheter to expand in the arterial system, sometimes causing damage to the arterial wall at implantation, with rupture of the medial layer and internal elastic lamina. A greater response of intimal hyperplasia is reported when there is a lesion of the medial layer and relative stent disproportion in relation to the arterial lumen.²¹ Palmaz suggests that proper stent expansion (usually a diameter 10-15% higher than vessel diameter) is required to ensure fixation of stent struts in the vessel wall, restricting thrombus formation. Under such conditions, endothelial cells may develop from tissues that are projected between stent struts, as long as the endothelium has not been totally stripped.²² The relationship between vessel wall lesion caused by the stent and degree of intimal hyperplasia has been experimentally shown in humans.^26,27 Schwartz et al. demonstrated a very close correlation between degree of stent leg penetration in vessel wall layers and intimal proliferation.²⁶ Sullivan et al. showed that permanence of an intact elastic lamina is an important factor to prevent intimal hyperplasia and restenosis after stent implantation in iliac arteries.²⁸ Although inflammatory infiltrate has been observed in vessels with medial layer rupture and with stent struts in the lipid core,²⁹ some researchers draw attention to contamination by stent particles that generate inflammation.³⁰ Slow release of metal ions in tissues that surround the stent implantation site might be the cause of local inflammatory and hyperplastic response. Corrosive products of metal alloys, commonly used in stent manufacturing, (stainless steel 316 L and nitinol) showed biotoxicity.^19,31 Nitinol proved to have inflammatory effect by causing an increase in interleukin-1 ß secretion by monocytes.³² Reduced nickel concentration was observed in areas with structural failure due to corrosion in aortic nitinol endoprostheses. Structural failure of major stents, subject to a much higher force when compared with smaller stents, may be related to focal heterogeneity and material inclusion, generating galvanic corrosion and occasional fracture.³³

Diameter of stent struts also has an influence, as stents with longer legs are an obstacle to cell migration. Stent mesh density has an influence on intimal hyperplasia response. Stents with few legs apart from each other produce more intimal hyperplasia than a higher number of legs around the circumference, even when they are uniformly distributed. This is related to alignment of vessel wall with few stent struts, which produces a polygonal lumen instead of a circumferential lumen.³⁴

Successful stent implantation is dependent on minimal thrombosis and fast endothelization. After angioplasty there is intimal and medial dissection with exposure of subintimal elements to blood flow elements, resulting in deposition of platelets and formation of thrombus, proliferation of fibroblasts and intimal hyperplasia. At the dissection site, blood flow becomes turbulent due to irregularity of the intimal layer, contributing to excessive deposition of platelets and fibrin.³⁵ Richter et al. showed the need of using heparin to prevent stent thrombosis, and also that low-flow vessels are more subject to a higher rate of restenosis.³⁶

Robinson et al. studied cell response to stents implanted in the aorta and iliac arteries of rabbits. Optical and electronic microscopy revealed that endothelial and pseudoendothelial cells adhere to the stent in the first day after implantation.³⁷ Apparently there is located thrombosis, leading to thrombus organization. Smooth muscle cells and inflammatory cells migrate to implantation site, leading to stent incorporation in the arterial wall. A confluent endothelial layer regenerates within 2-4 weeks. Degree of hyperplasia has been associated with histological evidence of inflammation in the vessel submitted to stent implantation. Neutrophil infiltrates are prevalent a few days after stent implantation,²⁷ and macrophages and lymphocytes are predominant in 6 months.²⁹ However, formation of granuloma close to the stent leg has been observed, regardless of lesion degree.³⁸

Dolmatch showed that, after many days, primitive myointimal cells and inflammatory cells (macrophages and polymorphonuclear leukocytes) are seen inside the thrombus.²¹ The process continues with deposition of collagen matrix, proliferation of myointimal cells and development of an endothelial layer. Although such response is related to exposure at stent implantation, there is no reason to believe this process is different from other endoprostheses that are projected with their metallic structure outside the tissue mesh and not exposed to blood flow.²¹

Endothelization rate is more influenced by migration than by cell proliferation. An important factor affecting degree of endothelization is measure of laminar flow velocity. Under normal flow conditions, cells migrate in the flow direction at a single direction and faster. Such observation demonstrates the fact that in the wall of coronary arteries, after stent implantation, with minimal endothelial lesion, endothelization occurs in a few days. On the other hand, in stents implanted in occluded vessels or after large endothelial lesions, such as in cases of endarterectomy catheters or laser revascularization, endothelization time is extended from several weeks to months.^25,39 Cell migration downstream occurs in a zigzag pattern, and not in a straight line. Such movement increases the probability these cells have of meeting other cells that are migrating and their collision reduces migration due to contact inhibition. If a migratory cell finds a linear trait in the surface, it assumes such migration pattern.³⁹ Palmaz et al. showed that creation of parallel grooves in the internal surface of the stent in swine carotid arteries results in rates of accelerated endothelization 1 week after implantation.²⁵

Because of their great radial force, stents prevent occurrence of elastic retraction and negative remodeling of the vessel wall, thus minimizing two of the main mechanisms responsible for loss of vessel lumen diameter that occurs after angioplasty. However, although stents significantly reduce incidence of restenosis, they were not able to completely solve the problem. Stents remained indefinitely inside the vessel, establishing a complex and lasting interaction with the vascular wall and with blood flow elements. This stent fights elastic recoil and negative vessel remodeling; however, it perpetuates trauma to the arterial wall and has strong stimulation to proliferation of neointimal tissue. The need of reducing occurrence of restenosis after stent implantation has led to the study of new materials for its creation or for the development of covering substances that reduce the thrombogenic potential and avoid intimal hyperplasia. Basically, there are two types of projects aiming to minimize intimal hyperplasia: study on stent configuration structure and on the association of other therapeutic modalities to the stent.^2,4,22,40

Stent fixation to the vessel is basically established from the balance between wall resistance and stent radial force. Close contact of such metals with the vascular wall establishes a character of local reaction that, throughout time, will interfere with its permeability. To reduce such type of change covers using solutions and pellicles were developed (stents covered with carbon or silicon carbide, an inert material of low thrombogenicity, which reduces platelet aggregation by inhibiting migration of electrons into metals). Such stents have the advantage of not inhibiting endothelial growth and reducing inflammatory reaction.⁴¹ The advantages and limitations of the polymeric material should be evaluated by its biomechanical and biological properties for vascular application. An ideal material for implantation should be resistant to thrombosis, mechanically stable and also easily incorporated by the tissue, but not trigger proliferative, inflammatory or degenerative response.⁴¹ For example, resistance to thrombosis and tissue reaction are more important in small-caliber vessels, and durability is important in large-caliber vessels.³⁶

Stents covered with polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), polyester (Dacron^®), polyurethane, carbon alloys, with drugs or polymers containing antithrombotic and antiproliferative drugs have been investigated as an alternative to fight intimal hyperplasia.⁴

PTFE graft is an inert material with very small pores that limit internal growth in tissues. PTFE-covered stents are mainly indicated in long stenoses, but their use is limited in refractory restenoses, and should be carefully used when there are important collateral vessels that, if covered, may cause worsening of limb ischemia. Preliminary results show primary patency of 86% in 9 months in the treatment of long lesions of the superficial femoral artery.^42-44 PTFE-covered stents were tested in pigs, aiming to evaluate healing ability, compared with non-covered stents. Patency was equal in both groups, but PTFE did not prevent progressive neointimal thickening. Structural changes in the PTFE, when dilated, may be associated with increased inflammatory response.^45-47

Polyester is manufactured as an array of fibers (Dacron^®). For that reason, such material has textile forms. Both forms of manufacturing are woven and knitted. The knittedtype is more flexible, especially when manufactured with cross-sectional bridges. The woven type has little elasticity and tends to crease and fold easily, showing difficulty to assume the sinuous and tubular contour of blood vessels. The biological response to Dacron grafts^® is characterized by a fibrous capsule that covers the external surface of the graft; microscopy shows an abundant extracellular matrix that infiltrates tissue mesh. The luminal surface is composed of a compacted fibrinoid material, with absence of endothelial cells, except in areas surrounding the anastomosis. Dacron^® graft, when implanted in small-diameter vessels, induces an intense cell reaction comprised of "foreign body" cells and concentric layers of lymphocytes and eosinophils. Such tissue reaction restricts vascular lumen, leading to thrombosis.^48,49

Angelini et al. found reduction in intimal hyperplasia in saphenous grafts performed in swine with hypercholesterolemia after placement of polyester-covered stents.⁵⁰ Castañeda et al. did not find any difference in intimal and media thickening when comparing polyester-covered stents and non-covered stents.⁵¹ Marty et al. evaluated fixation of two types of stent, one covered with polyester and the other covered with polyurethane, and concluded that polyurethane grafts had a more extensive fixation with granulation tissue.⁴⁹ Avino et al. evaluated placement of Dacron^®-covered nitinol stents in the aorta of dogs and concluded that, although covered stents induce major intimal hyperplasia, the luminal area was not altered.⁵² The authors did not find any difference in patency, in thrombus formation, flow hemodynamics and in luminal endothelization. A similar result was reported by Dutra & Pereira in 2001.⁵³ Polyethylene grafts tend to cause increased thrombogenicity when compared with PTFE grafts, as they induce an increase in procoagulating activity of macrophages.⁴⁹

As to incorporation of stents by vascular wall, the most important difference between stents covered with polymeric materials and non-covered stents is that non-covered stents have higher tendency to endothelization, perhaps related to the favorable surface of metals. Such properties probably determine a stable ligation with proteins, when exposed to blood flow, followed by cell fixation in stent metallic mesh. Covered stents are less biocompatible.^22,47,48

Silicon was also studied due to its elastic property and durability. Fontaine et al. compared the biological effects of silicon-covered stents with non-covered stents in dogs and concluded that the membrane remained inert after 6 weeks, with no occurrence of thrombosis and minimal intimal hyperplasia.⁵⁴ Galloni et al. carried out an experiment with carbon-covered stent, which showed good tissue and hematologic compatibility, and no cases of thrombosis.⁵⁵

In addition to a covered stent, substances can be impregnated with the aim of reducing graft reaction and obtaining faster endothelization. Understanding the physiopathology of stent restenosis renewed the interest on use of antiproliferative agents. However, some factors are required for clinical use of stents with antiproliferative drugs, such as a biologically inert, physiologically solid and deformable matrix. The matrix should be sufficiently rigid to resist against the physiological demands of organization, without suffering cracks or delamination, and should also survive the sterilization process without changing its properties. Another factor is correct time of drug release, limited to 6 weeks or less.⁴

Safe drug fixation to the stent is very important and mechanisms (with many variations and combinations) to do so are: 1) direct fixation; 2) fixation by covered pores; or 3) by dissolvable cover, in which the drug is mixed and released by cover dissolution or by enzymatic break of the substances binding the drugs. A favorable geometry is also important for drug release – the larger the cell size, the more heterogeneous the release site.⁴

Recent publication of preliminary results of rapamycin-covered stents (sirolimus) has brought great enthusiasm by perspective of expressive reduction in restenosis incidence. Rapamycin was originally developed as an antifungal drug, but its use has been questioned due to immunosuppressive effects. In 1999 the FDA approved it for use in patients with rejection in renal transplantation. Studies on heart transplants found an inhibition of myointimal proliferation, making rapamycin the main target in studies on stents covered with antiproliferative drugs.^56,57 Rapamycin acts by inhibiting the G1/S cell cycle through protein-binding tacrolimus (FK506), binding to a molecule called mTOR (mammalian target of rapamycin), inhibiting its activation.⁴

Although initial studies are quite promising, the "Sirius" study did not show satisfactory results when evaluating rapamycin-covered stents implanted in coronary arteries of patients with more complex clinical data, including diabetic patients. There was a special interest related to an increased potential of late thrombosis and, despite reduction in intimal hyperplasia, the hypothesis of delay in endothelization process was raised. The studies Sirocco I and II evaluated results of self-expandable stents covered with rapamycin in patients with chronic lower limb ischemia, due to superficial femoral artery lesion. Results did not show statistical difference between groups; in this type of artery, the main cause of stent failure might be related to mechanical factors with consequent stent fracture in the long term.^58,59 For example, nitinol stents may have fracture related to its covering and to polishing with amorphous oxides.^19,20

Analysis of several studies on different vascular beds tends to show that small-diameter arteries are more subject to intimal hyperplasia and to cellular reactions of the stent/vessel wall interaction and large-diameter arteries are subject to structural and mechanical factors of the stent and vessel wall involved.⁶⁰ Stent structure itself is important to prevent occlusion or restenosis. It is based on many factors, such as release mechanism, manufacturing material, stent geometry, presence of polymers and/or other substances able to induce local inflammation and other mechanical factors.^61-63 Differences between stent models are confirmed by several authors in studies on experimental animals^34,64 and in clinical series.^9,63 Favorable results grow as understanding of reactions involved in the interaction between stent and blood vessel wall increases, as well as due to constant technological advance of materials used.^62,65,66

Paclitaxel is another drug being investigated. It is an antiproliferative, cytostatic and chemotherapeutic agent that prevents migration of smooth muscle cells, works as a microtubular stabilizing agent and stimulates apoptosis or programmed cellular death. Paclitaxel also has anti-inflammatory effects.⁶⁷ Drugs that inhibit reactions before the S stage tend to inhibit cell growth, and those that inhibit late parts of the cycles tend to be more toxic. Sirolimus and everolimus interrupt transition from G1 to S stage of the cell cycle. Paclitaxel has later activity on the mitosis stage, inhibiting microtubular function.⁴

Fontaine et al. showed in dogs that absorption and elution of abciximab on the surface of a covered stent is feasible and that local release of this drug reduced myointimal thickening.⁶⁸ On the other hand, Ansel et al., in a study called BLASTER (Bilateral Lower Arterial Stenting Employing Reopro), did not find difference in use of abciximab with patency results of self-expandable nitinol stents in femoral arteries.⁶⁹

There is no evidence in animal experimental studies to affirm how much and how long the substance should remain in the tissue until the stent/vessel wall complex develops a thin neointimal layer and becomes mechanically stable. It might never become stable. Thus, perhaps a small dose of the released substance for a long period of time can delay tissue growth, increasing stent durability, but never stabilizing the stent/vessel wall complex. After studying the effects of homocysteine following stent implantation in an experimental model, the authors showed that there is less intimal hyperplasia in the aorta of swine with hyperhomocysteinemia, which suggests a possible interaction between homocysteine and development of intimal hyperplasia.⁷⁰

Stents can be covered with substances that create a non-detectable surface by the organism and, therefore, do not cause reactions. Among such substances are collagen, fibrin, heparin, phosphorylcholine and many bioactive molecules.⁴ Cloft et al. obtained favorable results observing fast endothelization and low reactive restenosis after implantation of stents covered with bovine type I collagen in the aorta of rabbits.⁷¹

Heparin is a proteoglycan that inhibits proliferation of smooth muscle cells in vitro. Many studies have shown that expression of adherence molecules is reduced in patients with stents covered with phosphorylcholine and heparin. The inhibiting effect is partly mediated by interactions with cell receptors, growth factors, adherence molecules, and proteinase inhibitors. Given the antiproliferative and anticoagulant properties, many studies were conducted to determine the best strategy for heparin administration after stent implantation, as an attempt to prevent intimal hyperplasia. Lin et al. found that heparin-covered stents by covalent binding induce lower intimal hyperplasia in primates compared with the control group.^72,73 Nakayama et al. studied stents covered with heparin and FK506. Heparin covered the internal part, that is, stent lumen in contact with blood flow (due to its anticoagulating properties) and FK506 covered the external part in contact with the vessel wall (due to its immunosuppressive action). Conclusion was that this type of cover was effective in the prevention of intimal hyperplasia.⁷⁴

Metalloproteases are molecules of the family of proteases dependent on zinc and calcium, which degrade collagen and other matrix proteins, such as elastin and proteoglycans. Vascular lesion results in temporal patterns of increased metalloproteinase activity. Such enzymes, in addition to being related to vascular remodeling and intimal hyperplasia, due to their effect on cell proliferation and migration, also have effects on inflammation and angiogenesis. Thus, hypothetically, inhibition of such enzymes might result in reduced intimal hyperplasia. However, Van Beusekom et al., in a study on the effects of batimastat, an unspecific inhibitor of metalloproteinases, and also an antineoplastic drug with antiangiogenic properties, did not find significant influence in neointimal reaction after stent placement in swine femoral arteries, although there are studies in animals confirming its effects of vessel wall remodeling reduction following percutaneous transluminal angioplasty.⁷⁵

Intraarterial radiotherapy is another therapeutic modality that has been widely studied, aiming at suppression of genes involved in the control of cell proliferation cycle. It acts by bombardment of nuclear core with ionizing radiation, and produces break of two helices that compose DNA. Thus, it blocks its duplication, which is an essential condition for cell proliferation. Using recommended radiation doses, smooth cells remain practicable, but prevented from replicating. Many authors experimentally demonstrated the efficacy of gamma radiation using iridium¹⁹² to inhibit neointimal proliferation.^76-78 The only study on humans published so far uses iridium to inhibit neointimal proliferation in peripheral arteries. In human beings, results of the first clinical studies are encouraging. However, late thromboses and sheath restenoses still limit its application. The Vienna-5 trial, which evaluated effectiveness of brachytherapy to prevent restenosis after stent implantation in femoral arteries of 88 patients concluded, after 12 months, that such therapy was not effective in maintaining patency in 6 months.⁷⁹ Another study, called Paris trial, did not show any benefits of using brachytherapy for the treatment of restenosis.⁸⁰ Some questions on use of radiotherapy in endovascular surgery are still unanswered, for example: What is the effective recommended dose? Radiation should be administered before or after angioplasty? Which radiation should be used – beta, gamma? Which radiation release method is the most effective – catheter, balloon or stent? Does radiation really have a beneficial effect in the prevention of late restenosis^79,80?

In conclusion, endovascular surgery is a specialty that provides a minimally invasive option for the treatment of peripheral vascular diseases. With the increasing development of technology and advance of studies to find the ideal vascular substitute, use of stents has become a promising therapeutic option. However, use of stents is not free from complications (fractures, intimal hyperplasia, etc.), and knowledge of correct use of varied endoprostheses available in the market is crucial to obtain favorable results.

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Correspondence

Publication Dates

• Publication in this collection
  20 Feb 2009
• Date of issue
  Dec 2008

History

• Received
  24 May 2008
• Accepted
  15 Oct 2008