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(Circulation. 2000;102:371.)
© 2000 American Heart Association, Inc.
Editorial |
Biodegradable Stents
"Fulfilling the Mission and Stepping Away"
From Centro Cuore Columbus, Milan, Italy.
Correspondence to Antonio Colombo, MD, Centro Cuore Columbus, Via Buonarroti 48, 20 145 Milan, Italy. E-mail columbus{at}micronet.it
Key Words: Editorials • stents • absorbable implants • restenosis • thrombosis
In 458 BC, a prominent Roman leader named Lucius Quintius Cincinnatus was unique in his behavior. Cincinnatus served his country when he was needed and, after fulfilling his duty, he returned to his private life.1 We now see a new medical device, a biodegradable stent, that mimics this historical figure.
The 2 main functions of a stent, treatment of dissection and prevention of restenosis, refer to 2 events that occur and progress in a set frame of time. Coronary dissections are effectively contained by stent insertion and undergo a healing process, with the majority of cardiac events occurring in the first 6 months.2 In-stent restenosis also occurs within the first 6 months.3 Therefore, a permanent prosthesis that is in place beyond this initial period has no clear function.
Besides lacking a well-defined function, are there any negative aspects related to the presence of a permanent coronary implant?
Zidar et al4 stated that one of the main reasons to develop a biodegradable stent was the short-term need for a stent and the potential long-term complications of metal stents.
Kimura et al3 demonstrated, with an extended angiographic follow-up of 3 years, that the presence of a metallic stent does not seem to be associated with lesion progression or accelerated atherosclerosis of the treated site after 6 months. In fact, late improvement in luminal diameter seems to occur between 6 months and 3 years. The Belgian Netherlands Stent Study (BENESTENT I) recently extended its follow-up to 5 years and demonstrated a sustained and persistent benefit of the stent.5
If no demonstrable complications exist with a permanent intracoronary implant, can the question be turned around by asking, "What are the benefits of not having a permanent coronary implant?" Two answers can be given.
1. Coronary stenting freezes recoil, but it also freezes remodeling. Chronic arterial responses to metal stents have been studied with intravascular ultrasound, and it seems that metal stents prevent the lumen expansion associated with late favorable remodeling, despite allowing some enlargement of the vessel surrounding the stent.6 The possibility of not having a permanent metallic implant could permit the occurrence of remodeling with lumen enlargement to compensate for the development of new lesions.
2. With the use of long stents and full-lesion coverage, stented segments can now extend for several inches.7 This situation may preclude surgical revascularization, which may become necessary at a later time.
In addition, a biodegradable stent may act as an optimal vehicle for specific local therapy with drugs or genes.8 9 These potential applications have been curtailed by the difficulties associated with the development of biodegradable stents that are not associated with a prominent inflammatory reaction and by the simplicity and low cost associated with manufacturing stainless steel stents.
The containment of the thrombotic complications associated with metallic implants has also reduced the need to search for an alternative.10 11 12 The resurgence of interest in the biodegradable stent that is seen with the publication of the current report by Tamai et al13 has various meanings. This work highlights the fact that a number of former problems with stenting have been resolved and that a new approach in coronary stenting is emerging.
Biodegradable Stents
Stack et al14 at Duke University developed the first biodegradable stent and implanted it in animals. A polymer of poly-L-lactide was used for this prototype stent, which could withstand up to 1000 mm Hg of crush pressure (the Palmaz-Schatz stent can withstand a pressure of 300 to 500 mm Hg) and keep its radial strength for 1 month. The stent was almost completely degraded by 9 months. Subsequent clinical research with this device remained limited, despite the presence of minimal thrombosis, moderate neointimal growth, and a limited inflammatory response in these early animal implants. The Kyoto University biodegradable stent made of polyglycolic acid was frequently associated with thrombus deposition in a canine model.15 The Cleveland Clinic/Mayo/ThoraxCenter biodegradable stent covered a Wiktor tantalum stent with a 90-degree arc of biodegradable polymer.
The polymers used were poly (D, L-lactide/glycolide copolymer), polycaprolactone, poly (hydroxybutyrate-hydroxyvalerate), and polyorthoester. All these coatings were associated with a significant inflammatory response and neointimal proliferation. Extensive cell infiltration of multinucleated giant cells, leukocytes, lymphocytes, monocytes, and eosinophils occurred. In addition, evidence of medial necrosis and pseudoaneurysm formation was found.16 17
In the past 5 years, the interest of the community in biodegradable stents is best expressed by the following: the 1994 edition of the Textbook of Interventional Cardiology dedicated a full chapter to the topic of biodegradable stents,4 whereas the 1999 edition devotes <2 pages to the topic. At the last meeting of the American Heart Association, only 1 of the 154 presentations devoted to stenting dealt with a biodegradable stent.18
The important fact is that the field of biodegradable stents did not
stay still. Lincoff et al19 demonstrated that
poly-L-lactic acid (PLLA) with a low molecular mass (
80
kDa) is associated with an intense inflammatory reaction,
whereas a minimal inflammatory reaction occurs with implants that are
coated with high-molecular-mass (321 kDa) PLLA. These findings are
not conclusive. Discrepancies exist when evaluations of these stents
are performed in different animal models. In dogs, minimal tissue
growth occurs,4 whereas in a pig model, marked cellular
proliferation occurs.8
Yamawaki et al8 were the first to incorporate an antiproliferative agent into the high-molecular-weight PLLA Igaki-Tamai stent. Prostheses loaded with a compound that inhibits the activity of tyrosine kinases were implanted in a pig model. These authors showed that neointimal formation was significantly less at the sites where the PLLA stent was loaded with the specific inhibitor compared with sites treated with the same stent loaded with an inactive compound.
The Present Human Study
Tamai et al13 should be complimented for providing this first report on the immediate and 6-month results after the implantation of a biodegradable PLLA stent in humans. This biodegradable stent combines the features of a thermal self-expandable and a balloon expandable stent. Initially, the stent autoexpands in response to the heat transmitted by a delivery balloon inflated with a 70°C contrast-water mixture (50°C at the balloon site). Subsequent expansion is obtained with inflation at a moderate to high pressure (6 to 14 atm). This stent will continue to expand to its nominal size in the following 20 to 30 minutes at 37°C; it maintains a radial strength similar to or higher than that of the Palmaz-Schatz stent.
The most important and unique innovation these authors made, compared with prior investigators, is the change in stent design from a knitted pattern to a zigzag helical coil design. This design change reduced vessel wall injury at the time of stent implantation,20 which reduced the amount of initial thrombus deposition and tissue proliferation.21 Tamai et al13 report on the first 15 patients treated with the Igaki-Tamai high-molecular-mass PLLA self-expandable stent. A total of 25 stents were electively and successfully implanted in 19 lesions. The authors provide clinical and angiographic follow-up data at 1 day, 3 months, and 6 months. The small number of patients and lesions treated should not elicit any conclusions concerning the 10.5% restenosis rate per lesion at the 6-month angiographic examination. Nevertheless, the presence of a loss index of 0.48 at 6 months is a very encouraging finding; it shows, for the first time in human coronary arteries, that this type of biodegradable stent may not be associated with more pronounced intimal hyperplasia than stainless steel stents.
It is interesting to note that the continuous self-expansion of the stent progresses up to the third month after implantation. The mean stent cross-sectional area as evaluated by intravascular ultrasound was 7.42 mm2 at baseline and 8.18 mm2 at 3 months (P=0.086). This persistent expansion was associated with a decrease in lumen cross-sectional area (7.42 mm2 versus 5.67 mm2, P<0.005). After the third month, no further stent expansion occurs, and the lumen cross-sectional area does not significantly change (5.67 mm2 versus 5.63 mm2, P=0.15). The authors elaborate on this result by stating that this type of stent does not stimulate intimal hyperplasia within the stent between 3 and 6 months.
A possible concern is related to the heat necessary to provide the rapid expansion of this stent. Even mild short-term temperature elevation (65°C to 75°C for few seconds) can cause necrosis of the arterial wall, with subsequent proliferation of smooth muscle cells.22 In addition, platelet adhesion to the vessel wall seems to be increased by a temperature of 55°C, which raises the risk of thrombosis.23 The preliminary experience presented here does not seem to support these possibilities. A large number of patients with more diversified clinical conditions and complex lesions will be necessary to fully eliminate this area of concern. At 6-month evaluation with intravascular ultrasound, the stent struts were still present. This finding shows that, at present, we still lack a demonstration that this stent will be completely reabsorbed within a set number of months. An extended follow-up period with intravascular ultrasound evaluation will be necessary to answer this critical question. In this respect, the report seems not yet complete and fully demonstrative.
As stated, the low number of observations in this early experience should not be considered sufficient to elaborate on the interaction between continuous stent expansion, polymeric biodegradable material, and late loss. For this reason, some of the conclusions of the authors should be tempered.
We believe that even a larger cohort would not be able to demonstrate a major impact of this device on loss index. The trend in late loss seen in the first 3 months suggests that this stent may behave in a manner similar to that of stainless steel stents.
To effectively impact tissue growth, it may be necessary to add specific antiproliferative compounds to this biodegradable stent. The encouraging results after the implantation of a PLLA biodegradable stent loaded with tyrosine kinase inhibitor in pigs8 remain to be confirmed in humans.
Finally, Ye et al9 demonstrated the successful transfer and expression of a nuclear-localizing ß-Gal reporter gene in cells in the arterial wall of rabbits after the implantation of biodegradable polymer stents (PLLA/polycaprolactone blends) impregnated with a recombinant adenovirus carrying that gene. The possibility of transferring genes that code key proteins in the central regulatory pathways of cell proliferation inside the cells of the arterial wall using biodegradable stents as vehicles is exciting. Regardless of which agent (gene or drug) will finally conquer restenosis, a biodegradable stent remains the optimal vehicle for such delivery.
This work is a fresh departure from the traditional view of stents, which considers them permanent prostheses able to withstand decay because they replace a missing part of the body. This effort represents the first move toward a new concept of coronary stenting: "fulfill the mission (with possible local drug or gene delivery) and step away."
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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