Biodegradable stents
From Vinodksingh
Introduction
Despite the development and progression of metallic stents, many concerns still remain because of their permanent nature. Although metallic stents are effective in preventing recoil and late restenosis after coronary angioplasty, they continue to have limitations such as stent thrombosis and mismatch of the stent to the vessel size. Thus, the concept of bioabsorbable stents has emerged as an alternative to permanent metal stents. This review will outline concepts, material designs, preclinical, and initial clinical experimental studies with bioabsorbable stents.
Coronary stenting has become the default device in percutaneous coronary interventions (PCIs). Coronary stents are used as a mechanical means to overcome the major limitations of balloon angioplasty with enabling scaffolding and the prevention of early recoil and late vascular remodeling.[1-3] The major limitations of stents are thrombosis and restenosis. While thrombosis has been controlled with the use of antiplatelet therapy, restenosis has been significantly reduced with the use of drug-eluting stents. Nevertheless, the role of stenting is temporary and is limited to the intervention and shortly thereafter, until healing and reendothelialization is obtained. Beyond that, no utility or advantage for stents has been demonstrated and their presence could be a nidus for late thrombosis and chronic inflammation
Why Bioabsorbable Stents?
Problems With Metallic Stents Solved by Bioabsorbable Stents
Despite the development and progression of metallic stents, they continue to have limitations such as stent thrombosis, which requires prolonged antiplatelet therapy, and mismatch of the stent to the vessel size, which often results in a smaller lumen after stent implantation. Further, metallic stents prevent the lumen expansion associated with late favorable remodeling.[4] Permanent metallic stents impair the vessel geometry and often jail and obstruct side branches. Drug-eluting stents are a breakthrough in the development of stents, with their ability to significantly reduce restenosis rates and the need for repeat revascularization. Nevertheless, they are still associated with subacute and late thrombosis, and necessitate prolonged antiplatelet therapy for at least 12 months. Further, the polymer used as a vehicle for drug delivery may induce vessel irritation, endothelial dysfunction, vessel hypersensitivity and chronic inflammation at the stent site.[5] Excessive use of stents in the coronary vasculature (full metal jacket) may interfere with traditional reinterventional techniques such as bypass graft surgery. Finally, metallic stents pose artifacts with modern imaging technologies such as magnetic resonance imaging (MRI) and multislice computerized tomography (MSCT), which eventually will become the default noninvasive imaging modality for the coronary anatomy.
In contrast, bioabsorbable stents, once they are bioabsorbed, leave behind only the healed natural vessel, allowing restoration of vasoreactivity with the potential of vessel remodeling. Late stent thrombosis is unlikely since the stent is gone, and prolonged antiplatelet therapy is not necessary in this instance. Bioabsorbable stents can also be suitable for complex anatomy where stents impede on vessel geometry and morphology and are prone to crushing and fractures, such as is seen in saphenous femoral and tibial arteries. Bioabsorbable implant stents can be used as a delivery device for agents such as drugs and genes, and will perhaps play a role in the treatment of vulnerable plaque. Transferring genes that code key regulatory pathways of cell proliferation inside the cells of the arterial wall using polymer stents as vehicles is feasible. Regardless of which agent (drug or gene) will finally conquer restenosis, a polymer stent remains an optional vehicle for such delivery. Finally, bioabsorbable stents are compatible with MRI and MSCT imaging.
Polymer Stents for Local Drug and Gene Delivery
Polymeric stents have the potential to act as local drug delivery systems. Polymeric material, especially biodegradable polymers, have been widely utilized for the controlled release of drugs,[6-9] Therefore, it is possible to design a biodegradable polymer stent, not only offering a physical barrier to the vessel wall, but also presenting a pharmacological approach in the prevention of thrombus formation and intimal proliferation. These bioabsorbable polymers are currently loaded on the metallic stent for the purpose of drug or gene delivery, and completely erode by the time the drug has been released; yet the stent itself is still maintained in the vessel wall. The discussion of these bioabsorbable polymers is beyond the scope of this review, however. Bioabsorbable Polymers and Stent Designs
There are several conditions to consider when selecting a polymer or alloy for the bioabsorbable stent. These include the strength of the polymer to avoid potential immediate recoil, the rate of degradation and corrosion, biocompatibility with the vessel wall and lack of toxicity. The change in the mechanical properties and the release profiles of drugs from bioabsorbable stents would directly depend on the rate of degradation of the stent, which can be controlled by selection of the stent alloy, passivation agents and the manufacturing process of the stent. Currently there are two types of materials used for bioabsorbable stents: polymeric-based and metallic-based.
Polymers have been widely used in cardiovascular devices and are currently primarily used as delivery vehicles for drug coatings.[10,11] Among the polymers suggested for bioabsorbable stents are Poly-L-lactic acid (PLLA), polyglycolic acid (PGA), poly (D, L-lactide/glycolide) copolymer (PDLA), and polycaprolactone (PCL). The degradation rates of these polymers are listed in Table 1 . Each of these polymers was designed as either self-expanding or balloon-expandable stents. Another proposed design is the hybrid stent, which combines polymeric absorbable stents with a metallic backbone to enable strength and prevent recoil.
Among the first polymeric stents to be tested was the PLLA bioabsorbable stent designed and tested by Stack et al.[12] and is reported to hold up to 1,000 mmHg crush pressure and maintain its radial strength for 1 month. This stent was almost completely degraded by 9 months with minimal thrombosis, moderate neointimal growth and a limited inflammatory response in porcine coronary arteries. The Igaki-Tamai stent, another polymeric stent, is made of poly-L-lactic acid monofilament (molecular mass = 183 kDa) with a zigzag helical coil design (Figure 1). Another interesting concept is the multilayered biodegradable stent designed by Eury et al.,[13] which is made of various polymers such as poly-L-lactic acid, polyglycolic acid, polycaprolactone, polyorthoesters or polyanhydrides. The unique feature of the stent is that one layer addresses the structural requirements of the stent and an additional layer controls the release of different drugs. The laminated construction allows the combination of a plurality of different drugs containing different materials all within a single stent. By appropriate configuration of the layers, drug release characteristics can be adjusted.
Design of Igaki-Tamai stent.
Preclinical Studies With Polymer Stents
The initial experimental studies with biodegradable polymers using (poly D, L-lactide/ glycolide c-polymer), polycaprolactone, poly (hydroxybutyrate-hydroxyvalerate and polyorthoester) coated as films on the circumferential surface of coil wire stents in the porcine coronary arteries were disappointing. Thirty days postimplantation, histopathology revealed that all these coatings were associated with a significant inflammatory response and neointimal proliferation with extensive cell infiltration of multinucleated giant cells, leukocytes, lymphocytes, monocytes and eosinophils. In addition, there was evidence of medial necrosis and pseudoaneurysm formation.[14] Lincoff et al.[15] demonstrated that poly-L-lactic acid, with a low molecular mass, is associated with an intense inflammatory reaction, whereas a minimal inflammatory reaction occurs with high molecular mass poly-L-lactic acid.
The Igaki-Tamai stent was compared with a Palmaz-Schatz stent and showed no stent thrombosis and no significant differences in minimal lumen diameter at 6 months. Histological examination revealed no inflammation and minimal neointimal hyperplasia on poly-L-lactic acid stent struts.[16]
Using a stent made of copolymer L-and D-lactide (L/D ratio 96/4%), Hietala et al.[17] conducted a 34-month study in rabbits. This is the longest known study using a polymer stent, and reported complete endothelialization at 3 months with no inflammatory reaction observed after 6 months. Hydrolyzation of the stent was evident at 12 months and it was completely disintegrated by 24 months. The stent was gradually replaced by fibrosis. The vessel lumen remained patent at all time points. In contrast, the Kyoto University bioabsorbable stent made of polyglycolic acid and polyhydroxybutyrate stents was associated with thrombosis and intensive inflammatory vascular reactions. Preclinical Studies With Polymer Stents for Local Drug Delivery
Yamawaki et al.[8] incorporated an antiproliferative agent into the high-molecular weight poly-L-lactic acid Igaki-Tamai stent. Stents loaded with ST638 (tranilast, a specific tyrosine kinase inhibitor) or ST494 (an inactive metabolite of ST638) were implanted in porcine coronary arteries. Histological examination showed that the extent of neointimal formation and geometric remodeling were significantly less at the ST638-loaded stent site then at the ST494 site. Vogt et al.[9] used a paclitaxel-eluting poly (D, L)-lactic acid (PDLLA) and reported a slow-release profile of paclitaxel, with an exponential function starting with a daily release from 5–8 µg, which was decreased to 1 µg at 4 weeks and to 0 at 3 months. Overall, the stent demonstrated mechanical stability. The histomorphometric analysis at 3 weeks demonstrated inhibition of neointimal formation by 53% with the paclitaxel-loaded PDLLA when compared to the PDLLA stent, and by 44% when compared to the metal stents. This reduction was durable at 3 months. These studies demonstrated the feasibility of loading drugs on the biodegradable polymeric, which resulted in a reduction in neointimal formation. Preclinical Studies With Polymer Stents for Local Gene Delivery
Ye et al.[18,19] demonstrated the successful transfer and expression of a nuclear localizing β–Gal reporter gene in cells of the arterial walls in rabbits. They used a poly-L-lactic acid/poly-caprolactone blend stent impregnated with a recombinant adenovirus carrying the β–Gal reporter gene. Human Experience With the Polymer Stent
Tamai et al.[20] were the first to report immediate and 6-month results after implanting the Igaki-Tamai stent in 15 patients. A total of 25 stents were electively and successfully implanted in 19 lesions, with angiographic successes in all procedures. The authors provide clinical and angiographic follow-up data at 1 day, 3 months and 6 months. No stent thrombosis or major cardiac event occurred at 30 days. Angiographically, both the restenosis rate and target lesion revascularization rate per lesion were 10.5%, while the rates per patient were 6.75% at 6 months. Even so, the presence of a loss index of 0.48 at 6 months is encouraging. The study showed that the Igaki-Tamai stent may not be associated with more pronounced intimal hyperplasia than stainless steel stents. Interestingly, there was evidence of vascular remodeling at the stented site, with an increase of the stent cross-sectional area from 7.42 mm2 at baseline to 8.18 mm2 at 3 months as evaluated by intravascular ultrasound. This persistent expansion was associated with a decrease in the lumen cross sectional area, although after the third month, no further stent expansion was observed. Tsugi et al.[21] reported 1-year follow-up data in a total of 63 lesions in 50 patients who underwent elective stent implantation with the Igaki-Tamai stent. No complications with regard to stent implantation were reported. Quantitative coronary angiography at 3, 6 and 12 months demonstrated percent diameter stenoses of 12 ± 8, 38 ± 23, and 33 ± 23, respectively. Restenosis rates were 21% (12/58 lesions) at 6 months and 19% (7/36 lesions) at 12 months. The target lesion revascularization rate was 12% (7/58 lesions) at 6 months and 17% (6/36 lesions) at 12 months. A recent report of 4-year follow up on this cohort supported the long-term safety profile of the Igaki-Tamai stent. Further studies in the SFA with this stent demonstrated feasibility and safety in deployment of these stents over a length of 70 mm. Overall, these findings demonstrated feasibility and safety, with acceptable efficacy of the use of biodegradable poly-L lactic acid stents in human coronary arteries. Limitations of the Polymer Stents
Polymeric biodegradable stents have demonstrated several limitations. Their strength is lower when compared to metallic stents, which can result in early recoil postimplantation. They are associated with a significant degree of local inflammation. The bioabsorption rate is relatively slow, and may still result in restenosis. These stents are radiolucent, which may impair accurate positioning. Furthermore, it is difficult to deploy the stent smoothly and precisely without fluoroscopic visualization. The polymer alone has a limited mechanical performance and a recoil rate of approximately 20%, which requires thick struts that impede their profile and delivery capabilities, especially in small vessels.[6,22] Bioabsorbable Metallic Stents
Metal bioabsorbable stents are intuitively attractive since they have the potential to perform similarly to stainless steel metal stents. So far, two bioabsorbable metal alloys have been proposed for this application: iron and magnesium. The biocompatibility of these stents depends on their solubility and their released degradation products. Their local toxicity is related to the local concentration of the elements over time. The tissue tolerance for physiologically occurring metals depends on the change of their tissue concentrations induced by corrosion. Thus metals with high tissue concentrations are the ideal candidates for bioabsorption stents (Figure 2).
Steps in bioabsorption of the magnesium stent.
Preclinical Studies With Corrodible Metallic Stents
Peuster et al.[23] reported on experimental studies with absorbable iron stents. They implanted stents made of 41 mg (equal to the monthly oral intake of iron) of pure iron into the native descending aorta of New Zealand white rabbits. There were no thromboembolic complications or any other adverse events during the 6 to 18 months of follow up. In addition, there was neither pronounced neointimal proliferation nor significant inflammatory response.
Magnesium is considered an attractive alloy for bioabsorption. The stent underwent several design iterations to allow scaffolding and support during stent corrosion. Heublein et al.[24] conducted a series of in vitro and in vivo preclinical trials using stents made of magnesium alloy. These studies demonstrated relatively high rates of degradation from 60 to 90 days, while the overall integrity of the stent remained at 28 days. in vivo studies supported stent integrity during corrosion and biocompatibility with endothelial cells and smooth muscle cells. A series of animal studies in which magnesium alloy stents were implanted in porcine coronary arteries demonstrated a reduction of neointimal formation when compared to the stainless steel stent 316 L, positive vessel remodeling at the stented site from 30 to 56 days, and complete absorption of the stent at 56 days. Animal studies carried out for up to 180 days demonstrated durability of the results at 56 days. In addition, there was no evidence of fibrin or thromboembolic events in the magnesium alloy implanted stents. Further studies showed a minimal degree of inflammation, but less when compared with L316 metallic stents (Figure 3).
Magnesium versus stainless steel stent approximately 30 days after implantation in porcine coronaries.
Initial Clinical Trials With the Mg Alloy Absorbable Stent
The first clinical trial to test the feasibility and safety of the magnesium bioabsorbable stent was performed in 20 patients who presented with claudication due to severe peripheral vascular disease (Rutherford Class IV and V), and who were candidates for amputation. These patients had lesions in the proximal two-thirds of one or more infrapopliteal arteries, and were subjected to PCI with the magnesium stent under a compassionate base protocol. Following predilatation, the 3.0 × 15 and 3.5 × 15 mm magnesium stents were successfully deployed with good angiographic and ultrasound results. There was no evidence of blood or vessel toxicity, and the patency rates at 3 and 6 months postimplantation were 89% and 78%, respectively. Limb salvage was obtained in all patients at 3 months, while at 6 months, 1 patient underwent amputation to the limb intervened upon. Duplex ultrasound and MRI demonstrated complete absorption of the stents at 3 months.
The results of this study have led to a clinical trial with the magnesium stent in coronary arteries. The PROGRESS study is designed as a safety study in 65 patients in 7 European centers. The intravascular ultrasound follow-up scheduled at 4 months will determine whether these stents are indeed disappearing and will indicate what the restenosis rate will be. The initial implantation of these stents in the coronary arteries was successful, with good apposition of the stent imaged by IVUS.
Currently, magnesium stents are not visible by X-ray and are not loaded with drugs for the prevention of restenosis. The need for such a drug will be determined by the results of the clinical trials since the recoil is minimized with the use of a metallic stent and the trigger for continuous inflammation is gone shortly after stent deployment. This stent will result in less restenosis than is seen with bare metal stents. If drugs are essential to control restenosis, they can be loaded with another bioabsorbable polymer or without an additional vehicle using the magnesium as the platform for those drugs. Future Directions
Though biodegradable polymer stents and biocorrodible metallic stents seem to be ultimate candidates for the ideal stent, further research is required before they can substitute the conventional bare metal or drug-eluting stent. If so, they may eliminate the need for prolonged antiplatelet therapy and will be compatible with future noninvasive imaging of the coronary tree.
By controlling the ideal absorption time and rate, they can be useful for other applications such as angiogenesis and gene transfer. Once they deposit the drug locally, the vehicle as a whole will disappear in the surrounding tissue. In the meantime, it would be interesting to follow whether the bioabsorbable stent concept will be adopted and thus eliminate the current practice in which many patients chronically carry metal prostheses in their coronary arteries.
