Abstract
Over the last decade, the introduction of drug-eluting stents has dramatically reduced restenosis and the need for repeat revascularization after implantation of metallic stents. Numerous concerns still remain, however, because of their permanent nature. Thus, the concept of bioresorbable temporary scaffolds composed of biocompatible materials has emerged as a potential alternative to permanent metal stents. Here we focus on metal alloys & discuss preclinical and clinical experiences with bioresorbable metal scaffolds.
1
Introduction
In the current percutaneous coronary intervention (PCI) era, coronary stenting is the standard strategy. Over the last decade, the introduction of drug-eluting stents (DES) has revolutionized the treatment of coronary artery disease. Nevertheless, serious concerns remain about the long-term safety of DES due to the occurrence of late adverse clinical events, such as very late stent thrombosis. Furthermore, metallic stents impair the diagnostic ability of non-invasive imaging such as magnetic resonance imaging or multi-slice computed tomography to detect contrast inside the vessel lumen. Permanent metal stents are also associated with impairment of vessel geometry and often jailing of side branches, and preclude the stented segment from revascularization options, such as coronary artery bypass surgery.
Fully bioresorbable polymeric vascular scaffolds have emerged to overcome the limitations of metallic stents. Currently, there are several polymeric scaffolds in first-in-man trials. However, only two drug-eluting scaffolds have reached their primary end points and reported clinical data: the everolimus-eluting bioresorbable vascular scaffold (ABSORB BVS; Abbott Vascular, Santa Clara, CA, USA) and the myolimus-eluting bioresorbable scaffold (DESolve, Elixir Medical Sunnyvale, CA, USA); both of which have shown similar angiographic late lumen loss (0.19 mm) at 6 months . As shown in the ABSORB studies, everolimus-eluting poly- l -lactic acid (PLLA) scaffolds have also demonstrated similar efficacy and safety to permanent everolimus-eluting metal stents .
However, bioresorbable scaffold technology has major challenges. By its nature, PLLA is limited in expansion and optimal scaffold apposition. Overexpansion of the scaffold may result in strut fractures that can lead to target vessel failure . Moreover, it is not well known how the PLLA scaffold will behave in bifurcations, calcified lesions , and long, diffusely diseased lesions, or when deploying overlapping multiple PLLA scaffolds.
A bioresorbable metallic alloy is a potential alternative to polymeric scaffolds. The attraction of metallic bioresorbable scaffolds relies on their mechanical similarity to permanent metal stents. So far, two metal alloys, iron and magnesium, have been identified as candidates for this application and have been further evaluated.
Here we review experimental results in animal models and reported clinical experiences with bioresorbable metal scaffolds and discuss the future perspectives.
2
Iron-based bioresorbable scaffold
2.1
Why iron alloy?
Iron is an essential element to human life and acts as a useful component for cytochromes, oxygen-binding molecules (hemoglobin and myoglobin), and many enzymes, although its overload or deficiency can be deleterious . The in vivo degradation rate of a pure iron stent is very slow . This slow degradation rate and the small amount of iron in a stent (stent weight ~ 40 mg) relative to the high iron load of blood (447 mg/L) make systemic iron toxicity less likely . It has been shown that iron ions released from bioresorbable iron stents reduce the vascular smooth muscle cell proliferation rate by influencing growth-related gene expression and may therefore play a beneficial role in inhibiting restenosis in vivo . Iron also has a high radial strength because of its higher elastic modulus. This feature can be useful in making stents with thinner struts . Thus, iron appears to be an attractive candidate for bioresorbable scaffolds.
2.2
Preclinical studies in the animal model with bioresorbable iron scaffolding
Peuster et al. reported on experimental studies with bioresorbable iron scaffolds. They implanted scaffolds made of pure iron (> 99.8% iron) into the native descending aorta of New Zealand white rabbits. There were no thromboembolic complications or any other adverse events during the 6–18 months of follow up. All scaffolds implanted were patent at repeat angiography after 6, 12, and 18 months. In addition, there were no pronounced neointimal proliferation, significant inflammatory response, and systemic iron toxicity.
Another preclinical study was performed to evaluate the safety of iron scaffolds in a peripheral stent design in a slotted tube design similar to a commercially available 316 L stainless steel stents . Iron scaffolds were implanted into the descending aorta of 29 mini-pigs with an overstretch injury. Except for two pigs that died after implantation, the remaining 27 mini-pigs were followed for 1–360 days. With respect to the amount of neointimal proliferation, no significant difference was observed between 316 L and iron scaffold. No signs of iron overload or iron-related organ toxicity were noted. Adjacent to the iron scaffold struts, there was no evidence of local toxicity due to degradation products.
We recently evaluated the short-term effects of bioresorbable iron scaffolds in porcine coronary arteries . At 28 days, iron scaffolds started to show signs of degradation without evidence of stent particle embolization or thrombosis without traces of excess inflammation, or fibrin deposition. There were no significant differences in any of the measured parameters between segments implanted with iron scaffolds and cobalt chromium stents. Because the study was limited by short-term follow-up, no conclusion could be drawn in terms of the degradation rate of iron scaffold.
2
Iron-based bioresorbable scaffold
2.1
Why iron alloy?
Iron is an essential element to human life and acts as a useful component for cytochromes, oxygen-binding molecules (hemoglobin and myoglobin), and many enzymes, although its overload or deficiency can be deleterious . The in vivo degradation rate of a pure iron stent is very slow . This slow degradation rate and the small amount of iron in a stent (stent weight ~ 40 mg) relative to the high iron load of blood (447 mg/L) make systemic iron toxicity less likely . It has been shown that iron ions released from bioresorbable iron stents reduce the vascular smooth muscle cell proliferation rate by influencing growth-related gene expression and may therefore play a beneficial role in inhibiting restenosis in vivo . Iron also has a high radial strength because of its higher elastic modulus. This feature can be useful in making stents with thinner struts . Thus, iron appears to be an attractive candidate for bioresorbable scaffolds.
2.2
Preclinical studies in the animal model with bioresorbable iron scaffolding
Peuster et al. reported on experimental studies with bioresorbable iron scaffolds. They implanted scaffolds made of pure iron (> 99.8% iron) into the native descending aorta of New Zealand white rabbits. There were no thromboembolic complications or any other adverse events during the 6–18 months of follow up. All scaffolds implanted were patent at repeat angiography after 6, 12, and 18 months. In addition, there were no pronounced neointimal proliferation, significant inflammatory response, and systemic iron toxicity.
Another preclinical study was performed to evaluate the safety of iron scaffolds in a peripheral stent design in a slotted tube design similar to a commercially available 316 L stainless steel stents . Iron scaffolds were implanted into the descending aorta of 29 mini-pigs with an overstretch injury. Except for two pigs that died after implantation, the remaining 27 mini-pigs were followed for 1–360 days. With respect to the amount of neointimal proliferation, no significant difference was observed between 316 L and iron scaffold. No signs of iron overload or iron-related organ toxicity were noted. Adjacent to the iron scaffold struts, there was no evidence of local toxicity due to degradation products.
We recently evaluated the short-term effects of bioresorbable iron scaffolds in porcine coronary arteries . At 28 days, iron scaffolds started to show signs of degradation without evidence of stent particle embolization or thrombosis without traces of excess inflammation, or fibrin deposition. There were no significant differences in any of the measured parameters between segments implanted with iron scaffolds and cobalt chromium stents. Because the study was limited by short-term follow-up, no conclusion could be drawn in terms of the degradation rate of iron scaffold.
3
Magnesium-based bioresorbable scaffold
3.1
Why magnesium alloy?
Due to its low thrombogenicity and biocompatibility in the human body, magnesium alloy is another attractive metal for bioresorbable scaffolding. Furthermore, in contrast to PLLA, magnesium has a ten-fold higher tensile strength and is capable of significant elongation at break.
Magnesium is the fourth most common cation within the human body; its physiologic plasma concentration is 1.4 to 2.1 mEq/L (0.70 to 1.05 mmol/L), with 350 mg required daily. It is essential for the synthesis of more than 300 enzymes and is a co-factor for ATPase. The toxicity of magnesium is low. The metabolic conversion of magnesium to its chloride, oxide, sulfate, and phosphate salts is also well tolerated. The by-product in the vessel is hydroxyapatite, which is eventually digested by macrophages. Magnesium acts as a systemic and coronary vasodilator. In addition, it has been shown that magnesium may prevent endothelium-induced vasoconstriction and that intravenous administration of magnesium is feasible and safe in patients undergoing elective PCI .
The bioresorption rate of the magnesium alloy varies from 2 to ≥ 12 months by manipulation of the alloy with alloying elements, such as rare earths . Optimal bioresorption of the magnesium occurs from 6 to 12 months to maintain sufficient radial strength of the scaffold during the healing phase . Of note, the magnesium scaffold is completely radiolucent.
3.2
Preclinical studies in the animal model with bioabsorbable magnesium scaffolding
Heublein et al. first investigated the idea of using magnesium alloys for cardiovascular stent application. They selected AE21 magnesium alloy as a bioresorbable metallic-scaffold platform. Eleven domestic pigs underwent implantation of 20 scaffolds into the coronary artery and were followed at 10, 35, and 56 days after implantation. Although the histological analysis revealed that AE21 magnesium scaffolds induced a significant neointimal proliferation until day 35, this disadvantage was offset by later positive remodeling. There was no evidence of fibrin or thromboembolic events. However, the degradation of AE21 scaffolds occurred faster than the expected rate as the loss of its mechanical integrity.
Subsequently, Biotronik developed a modified WE43 magnesium alloy-based absorbable metal scaffold (AMS) . The scaffold (Magic, Biotronik AG, Bulach, Switzerland) is pre-mounted on a fast-exchange delivery system, compatible with 6 F introducer systems.
Di Mario et al. reported the results of experimental implantation of AMS in the coronary artery of 33 mini-pigs. Quantitative coronary angiography analysis at 4-week follow-up demonstrated greater minimal lumen diameter in the AMS group than the control group (1.49 mm vs. 1.34 mm). At 12 weeks, minimal lumen diameter in the control stent remained unchanged (1.34 mm to 1.33 mm), whereas the minimal lumen diameter in the AMS group increased significantly from 1.49 mm at 4 weeks to 1.68 mm at 12 weeks (p < 0.001). Furthermore, homogeneous and rapid endothelialization of the AMS struts was observed in the animal model.
Later on, we examined the safety and efficacy of bioresorbable WE43 magnesium alloy scaffolds implanted in porcine coronary arteries for a period of 3 months . As a result, there was no evidence of particle embolization, thrombosis, excess inflammation, or fibrin deposition. At 3 months, neointimal area was significantly smaller in the magnesium alloy scaffold segments than in the stainless steel stent segments (1.16 ± 0.19 mm 2 vs. 1.72 ± 0.68 mm 2 , p = 0.02). Despite decreased neointimal proliferation, however, there was no significant difference in terms of lumen area between the AMS and control groups (4.18 ± 1.23 mm 2 vs. 5.05 ± 2.04 mm 2 , p = 0.289).
Recently, Li et al. developed a new type of sirolimus-eluting bioresorbable magnesium alloy stent (SEBMAS) made from AZ31B magnesium alloy, with strut thickness of 155 ± 5 μm and poly (lactic acid-co-trimethylene carbonate) [P(LA-TMC)] containing sirolimus as an antiproliferative drug (mean 140 ± 40 μg/cm 2 per stent) . Both the uncoated BMAS and the coated SEBMAS were deployed 2 cm apart in balloon-injured infra-renal abdominal aortas of 20 New Zealand white rabbits. Some struts had lost their continuity already at 60 days. By 90 days, most struts partially corroded, and by 120 days after deployment, almost all of the struts were completely corroded. The lumen area was significantly larger, but the neointimal area was significantly smaller in SEBMAS segments compared with the uncoated BMAS segments at all time points. There was no significant difference in the injury or inflammation scores between groups. Delayed endothelialization at 30 days was observed in the SEBMAS segments versus the uncoated BMAS segments, but with time, the stent endothelialization became similar in both groups at 60 through 120 days.
3.3
Bioabsorbable magnesium scaffolding for patients with critical limb ischemia
Peeters et al. reported the first results of clinical application using AMS for treatment of infrapopliteal lesions in 20 patients with critical limb ischemia (CLI). Angiographic procedural success was achieved in 100%. Primary clinical patency was 89.5% at 3 months, yielding a limb salvage of 100%. At 12-month follow-up, primary clinical patency and limb salvage rates were 73.3% and 94.7%, respectively . There were no symptoms of allergic or toxic reactions to the scaffold material.
Following the promising results of AMS in this compassionate use trial, the AMS INSIGHT (Bioabsorbable Metal Stent Investigation in Chronic Limb Ischemia Treatment) trial was designed to compare, in a randomized controlled setting, the safety and efficacy of the implantation of a balloon-expandable bioresorbable scaffold in the infrapopliteal bed based on 1- and 6-month clinical follow-up and efficacy based on 6-month angiographic patency . In this study, 117 patients with 149 lesions with symptomatic CLI were randomized to implantation of an AMS (60 patients, 74 lesions) or stand-alone percutaneous transluminal angioplasty (PTA; 57 patients, 75 lesions). Seven PTA group patients ”crossed over” to AMS scaffolds. The first-generation AMS-1 and the Pleon Explorer angioplasty balloon catheter (Biotronik AG) were used. The 30-day complication rate was low and similar in patients randomised for PTA alone (5.3%) or PTA followed by AMS implantation (5.0%). Unfortunately, however, the AMS group showed significantly higher binary restenosis (AMS vs. PTA 68% vs. 42%, p = 0.01) at 6 months, with a double late lumen loss (LLL) (AMS vs. PTA 1.4 mm vs. 0.7 mm, p = 0.001). Findings from AMS INSIGHT do not support the positive clinical outcome of the initial AMS findings in small cohorts and suggest that the current-generation AMS, although safe, does not demonstrate efficacy in long-term patency over standard PTA in the treatment of infrapopliteal lesions .
3.4
Bioresorbable magnesium scaffolding for human coronary arteries
The first bioresorbable metallic scaffold (AMS-1; Biotronik AG) implanted in human coronary arteries is the magnesium alloy scaffold, composed of 93% magnesium and 7% rare earth metals. In the Clinical Performance and Angiographic Results of Coronary Stenting with Absorbable Metal Stents (PROGRESS-AMS) trial, the feasibility of AMS-1 was tested. PROGRESS-AMS was a prospective, multicenter, non-randomized study in which 71 magnesium scaffolds were implanted in 63 patients with a single de novo native coronary artery lesion . All of the 71 scaffolds (3.0–3.5 mm in diameter and 10–15 mm in length) were successfully implanted after pre-dilatation. The immediate angiographic results were similar to those from other metallic stents. However, with this first-generation bare metal device, radial support was lost far too early — within a few weeks after implantation. The premature loss of radial support resulted in a higher than expected rate of late recoil and in early negative remodeling. In addition to the mechanical insufficiency, the device did not release an antiproliferative drug to counter the intimal hyperplasia response. As a result, bioresorbable magnesium scaffolds were associated with a high angiographic restenosis rate of 47.5% and a relatively high in-scaffold LLL of 1.08 ± 0.49 mm at 4 months. Disappointingly, the ischemic-driven TLR rate was 23.8% after 4 months, and the overall TLR rate reached 45% after 1 year. No death, myocardial infarction, or stent thrombosis was noted ( Table 1 ).
