Semi-crystalline terpolymers prepared from L-lactide, trimethylene carbonate, and glycolide are promising materials for cardiovascular stents.
As cardiovascular incidents increase dramatically, drug-eluting stents (DES) have been used widely because they cause minimal trauma and can be employed on an out-patient basis. Metal stent implants remain the gold standard of care for clogged vessels, but their lifelong persistence within the arteries might induce long-term effects, ending a recurrence of the narrowing. Polymeric bioresorbable stents are expected to restore blood flow by opening a clogged vessel and supporting it until the device is gradually resorbed, within approximately two years, leaving patients with a healed vessel free of a permanent metal implant. Therefore, more attention is being paid to degradable and bioresorbable polymers for fabricating cardiovascular stents. Polylactide (PLA) is a proven biocompatible and bioresorbable material commonly used in medical implants such as resorbable sutures and internal fixation devices for bone fracture. Biodegradable stents based on optically pure poly(L-lactide) (PLLA) have been investigated intensively over the past decade, and PLLA Absorb-brand stents with European CE approval have been used recently in human coronary arteries.1 However, PLLA is too brittle and degrades very slowly in vivo.2 In addition, the acidity and high crystallinity of its degradation byproducts often provoke inflammatory reactions.Copolymerizing LLA with 1,3-trimethylene carbonate (TMC) can modulate the thermal properties, degradation behavior, and mechanical properties of PLLA.3 Poly(1,3-trimethylene carbonate), or PTMC, is an amorphous elastomer with excellent flexibility and high tensile strength. In vivo degradation of PTMC yields neutral products like diols and carbon dioxide. It appears that the PLLA-TMC copolymers with high LLA content exhibit a relatively high tensile strength and high crystallinity, but a slow degradation rate. Conversely, low crystallinity could result in tensile strength loss due to lower LLA content. In fact, cardiovascular stents requires high mechanical strength to withstand the pressure of the vessels, excellent flexibility for in situ expansion, and an appropriate degradation rate. PLLA-TMC copolymers cannot meet all these requirements. We further modulated the properties of PLLA-TMC copolymers by incorporating glycolide (GA) monomer as a third component. Similar to PLLA, polyglycolide (PGA) is a highly crystalline polymer with high tensile strength, but it degrades much faster than PLLA. And GA monomer shows much higher reactivity than LLA or TMC.Table 1.Characterization of PLLA, PLLA-TMC, and PLLA-TMC-GA homo- and copolymers. Mn: Number average molecular weight. PDI: Polydispersity index. Tm: Melting temperature. ΔHm: Melting enthalpy. б: Tensile strength. εbreak: Strain at break. MPa: Megapascals.Polymer[LLA]/[TMC]/[GA]PDIb)Tm(°C)ΔHm(J/g)б (MPa)εbreak (MPa)FeedProducta)PLLA100/0/0100/0/03.12.6176.138.461.3±3.18.9±1.9PLT95/595/5/095.1/4.9/02.82.4162.95.354.7±2.328.5±6.5PLT90/1090/10/090.7/9.3/02.22.3159.31.750.8±1.5128±24.1PLT85/1585/15/085.9/14.1/02.12.4158.10.648.7±2.0233±16.5PLTG95/5/595/5/595.8/4.2/126.96.36.1997.20.352.3±1.3249±25.4PLTG90/10/590/10/590.6/9.4/188.8.131.52––49.6±1.4304±58.1PLTG85/15/585/15/585.8/14.2/184.108.40.206––34.3±1.3342±60.2aDetermined by proton nuclear magnetic resonance with deuterated chloroform as solvent.bDetermined by gel permeation chromatography.We synthesized a series of PLLA-TMC-GA terpolymers as well as corresponding PLLA-TMC copolymers by ring-opening polymerization of appropriate monomer feeds (see Table 1).4 All the polymers exhibit high number molecular weights even exceeding 210,000, which is essential for good mechanical performance. The PLLA-TMC-GA terpolymers present much lower melting temperature, Tm, and melting enthalpy, ΔHm, than the corresponding PLLA-TMC copolymers (see Table 1). Only PLTG95/5/5 presents a very weak melting peak at 157.2°C with corresponding ΔHm of 0.3J/g. This minimal crystallinity is preferable, considering the use of these polymers for biomedical applications.Figure 1.Stress-strain curves of pure poly (L-lactide) (PLLA), PLLA-TMC copolymer with an LLA/TMC feed ratio of 95/5 (PLT95/5) and PLLA-TMC-GA terpolymer with an LLA/TMC/GA feed ratio of 95/5/5 (PLTG95/5/5). TMC: Trimethylene carbonate. GA: Glycolide.Figure 2.A stent prototype prepared from a PLLA-TMC-GA terpolymer.Table 1 also lists the various polymers’ mechanical properties. Compared with PLLA-TMC copolymers, the tensile strength (б) of PLLA-TMC-GA terpolymers decreases slightly due to the presence of GA moieties. However, the strain at break (εbreak) is greatly improved. As shown in Figure 1, the tensile strength of PLTG95/5/5 is 52.3 megapascals (MPa), slightly lower than that of PLT95/5 (54.7MPa). In contrast, the εbreak of PLTG95/5/5 (249%) is nearly nine times that of PLT95/5 (28.5%). A collapse pressure of about 2.5 bars, which is much higher than that of ordinary metal stents (1.3 bars), can be obtained for stents made of PLLA with tensile strength above 50MPa.5 Therefore, PLLA-TMC-GA terpolymers should possess sufficient collapse strength when processed into stents. We successfully manufactured a cardiovascular stent from PLLA-TMC-GA terpolymer (see Figure 2).In summary, we synthesized totally bioresorbable PLLA-TMC-GA terpolymers via ring-opening polymerization of LLA with TMC and GA. The terpolymers exhibit a rational ability of crystallization and outstanding mechanical properties. We also manufactured a stent prototype, showing the feasibility of terpolymers for the development of bioresorbable cardiovascular stents. Further studies are under way to investigate the in vivo degradation behavior of the stents.AuthorsJianting DongFudan UniversityLan LiaoFudan UniversityZhongyong FanFudan UniversitySuming LiEuropean Membrane Institute University of Montpellier 2Zhiqian LuSixth People’s Hospital Shanghai Jiaotong UniversityReferencesG. W. Stone, A. Rizvi, W. Newman, K. Mastali, J. C. Wang, R. Caputo and J. Doostzadeh, Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease, N. Engl. J. Med. 362, pp. 1663-1674, 2010. Y. Onuma, J. Ormiston and P. W. Serruys, Bioresorbable scaffold technologies, Circ. J. 75, pp. 509-520, 2011. Y. R. Han, X. Y. Jin, J. Yang, Z. Y. Fan, Z. Q. Lu, Y. Zhang and S. M. Li, Totally bioresorbable composites prepared from poly(L-lactide)-co-(trimethylene carbonate)
copolymers and poly(L-lactide)-co-(glycolide) fibers as cardiovascular stent material, Polym. Eng. Sci. 52, pp. 741-750, 2012. J. T. Dong, L. Liao, L. Shi, Z. S. Tan, Z. Y. Fan, S. M. Li and Z. Q. Lu, A bioresorbable cardiovascular stent prepared from L-lactide, trimethylene carbonate, and
glycolide terpolymers, Polym. Eng. Sci., 2013. First published online: 25 JulyS. Venkatraman, T. L. Poh, T. Vinalia, K. H. Mak and F. Boey, Collapse pressures of biodegradable stents, Biomaterials 24, pp. 2105-2111, 2003. DOI: 10.2417/spepro.005019