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A bioresorbable cardiovascular stent prepared from L-lactide, trimethylene carbonate and glycolide terpolymers.

INTRODUCTION

As cardiovascular incidents are dramatically increasing nowadays, percutaneous transluminal coronary intervention such as stenting has been developed due to its minimal trauma and out-patient treatment [1,2], Although cardiovascular intervention using metal stents has become the standard of care for stenosed vessels, the lifelong persistence of metal stents within the arteries might induce long-term effects, Finally resulting in neointimal hyperplasia [3, 4], Polymeric bioresorbable stents are expected to cause less late stent thrombosis, to shorten the dual antiplatelet therapy, and to favor restoration of the natural vascular integrity because there will be eventually no foreign material exposed to blood if endothelialization is delayed or incomplete. Therefore, more and more attention has been paid to degradable and bioresorbable polymers for the fabrication of cardiovascular stents so as to reduce the restenosis [5-8].

Several polymeric bioresorbable stents have been reported for various applications. Agrawal and Clark investigated a poly(L-lactide) (PLLA) stent based on a slotted polymer fiber design that can withstand up to 1000 mm Hg compression pressure [9], The Igaki-Tamai stent, a coil stent made of PLLA monofilament (molecular weight, 183 kDa) with a zigzag helical design, exhibits a radial force of 11,9%/0.006 MPa and is First used in human coronary arteries [10]. Recently, everolimus-eluting vascular stent ABSORB[TM] has received CE Mark approval for the treatment of coronary artery disease. ABSORB[TM] is made of PLLA, and is the first bioresorbable stent to have clinical and imaging outcomes similar to that metallic drug-eluting stent implantation for 2 years but with the potential advantages of full stent resorption [11].

As a degradable and bioresorbable material, polylactide (PLA) has been widely used in the fields of sutures, drug delivery systems, surgical implants, and cardiovascular stents [12, 13]. Optically pure PLLA possesses sufficient tensile strength, but its high rigidity and crystallinity, slow degradation and acidic degradation products constitute the main obstacles which limit the stent applications [14, 15]. Copolymerization of PLLA with poly(1,3-trimethylene carbonate) (PTMC) is a means to adjust the properties of the copolymers. PTMC is an amorphous elastomer with a glass transition at about -12[degrees]C. High molecular weight PTMC exhibits good mechanical properties, including high flexibility and high tensile strength [16]. It degrades extremely slowly by pure hydrolysis [1, 17, 18]. In contrast, in vivo degradation of PTMC rapidly occurs by surface erosion, probably involving enzymes [17, 19]. The degradation of PTMC yields neutral products, i.e., diols and carbon dioxide.

Various copolymers of LLA and TMC have been reported [19-23]. These copolymers with excellent flexibility have been investigated for applications as heart constructs and nerve regeneration guides [19, 20], cartilage implants and wound dressing [21], sustained drug release carrier [22], and stent cover [23].

In our previous work, various PLLA-TMC copolymers were obtained by varying the chemical composition and chain microstructure [24-26]. The thermal properties, degradation behaviors as well as mechanical properties of the copolymers were considered. It appears that the PLLA-TMC copolymers exhibit a relatively high tensile strength and high crystallinity, but a slow degradation rate. Conversely, low crystallinity could result in loss of tensile strength due to lower LLA content. In fact, the use of cardiovascular stents requires high mechanical strength to withstand the pressure of the vessels, excellent flexibility for in situ expansion, along with appropriate degradation rate. Hence, PLLA-TMC copolymers seem not to meet all the requirements of cardiovascular stents.

Similar to PLLA, polyglycolide (PGA) is also a degradable and highly crystalline polymer (45-55% crystallinity), with a glass transition temperature of ~35[degrees]C and a melting temperature ranging between 220 and 225[degrees]C [27]. PGA is a fast degrading polymer with high tensile strength and low elongation at break. Meanwhile, the GA monomer shows much higher reactivity than the LLA and TMC ones [18, 28]. Therefore, the incorporation of GA units into PLLA-TMC chains should be a promising method of modulating the thermal, physical, and mechanical properties as well as the degradation rate.

Terpolymers of LLA, TMC, and GA with relatively low molecular weights ranging from 2.46 X [10.sup.4] to 5.39 X [10.sup.4] g [mol.sup.-1] were first reported by Zini et al. [29], These terpolymers exhibit a glass transition close to the human body temperature, and display shape memory properties. Nevertheless, the elastic modulus shows an abrupt drop of about three orders of magnitude at the glass transition region, thus making them unable to withstand the pressure of the vessels at body temperature. Similar terpolymers are also used as monofilament sutures [30, 31]. It is well known that the thermal and degradation behaviors of copolymers are directly dependent on the monomer composition and molecular weight. In par ticular, high molecular weight is essential to ensure good mechanical performance.

In this work, high molecular weight terpolymers based on LLA, TMC, and GA covering a broad range of compositions were synthesized and characterized to evaluate their potential in the development of cardiovascular stents. The effect of the composition on the thermal and mechanical properties is investigated. Corresponding PLLA-TMC copolymers as well as PLLA and PTMC homopolymers were synthesized for the sake of comparison. Plasma-treated poly[(L-lactide)-co-glycolide] (PLGA) fibers with excellent mechanical strength were used to reinforce the terpolymer matrix. A minitube was fabricated using a single-screw extruder, and then processed by a CNC engraving machine to form a cardiovascular stent.

EXPERIMENTAL

Materials

L-lactic acid, zinc powder, glycolic acid, antimony trioxide, 1,3-propanediol, diethyl carbonate, sodium metal, dibutyltin dilaurate, and stannous octoate ([SnOct.sub.2]) were obtained from SCRC (China) and used as received. Solvents were of analytical grade and used without further purification. PLGA fibers were kindly supplied by Beijing Textile Research Institute. The fibers were fabricated by melt spinning from a PLGA random copolymer with LLA/GA ratio of 10/90.

Synthesis

LLA was prepared by polycondensation of L-lactic acid followed by thermal decomposition and cyclization. GA was prepared from glycolic acid under similar conditions. Both monomers were purified by five times recrystallization from ethyl acetate. TMC was prepared by using the procedure reported in literature [18]. In brief, 1 M of 1,3-propanediol, 1.2M of diethyl carbonate, 1/1000M of dibutyltin dilaurate, and 0.8 g sodium metal were refluxed at 140[degrees]C for 6 h. Ethanol and residual diethyl carbonate were eliminated by distillation. About 1/1000A/ of [SnOct.sub.2] was then added. Nearly 200 g of crude product were obtained by thermal decomposition at 180[degrees]C for 12 h. Purification was performed five times by recrystallization from acetone/ethyl ether (v/v = 1/3) prior to polymerization. LLA, GA, and TMC were dried under vacuum at room temperature for 72 h.

PLLA, PTMC, PLLA-TMC, and PLLA-TMC-GA homo- and copolymers were synthesized by ring-opening polymerization of appropriate monomer feeds, using [SnOct.sub.2] as catalyst. The monomers/[SnOct.sub.2] mole ratio was kept constant at 2000/1. The monomers and catalyst were charged in a silanized polymerization tube. After degassing, the tube was sealed under vacuum, and polymerization proceeded at 130[degrees]C for 72 h. The resulting polymers were recovered by dissolution in dichloromethane and precipitation in methanol, followed by vacuum drying at room temperature up to constant weight.

Measurements

IR spectra were recorded using a Nicolet Magna-IR 560 spectrometer at a 4 [cm.sup.-1] resolution. [sup.1]H NMR spectra were performed on a Bruker DMX500 spectrometer operating at 400 MHz. Deuterated chloroform (CD[Cl.sub.3]) was used as solvent. Chemical shifts ([delta]) were given with respect to tetramethylsilane (TMS). [sup.13]C NMR spectra were recorded using a BRUKER AMX400 spectrometer at 125 MHz, with CD[Cl.sub.3] as solvent. Gel permeation chromatography (GPC) measurements were performed on a Shimadzu apparatus equipped with a refractive index (RI) detector using tetrahydrofuran (THF) as solvent at a flow rate of 1.0 mL [min.sup.-1]. Nearly 60 [micro]L of 1.0 w/v% solution were injected for each analysis. Calibration was accomplished with polystyrene standards. X-ray diffraction (XRD) spectra were registered with a Philips diffractometer composed of a Cu K[alpha] ([lambda] = 1.54 [Angstrom]) source, a quartz monochromator, and a goniometric plate. Contact angle was determined on solvent-casting films using a Kruss tensiometer K100 at room temperature. Every measurement was repeated three times. DSC was performed with a TA Q2000 instrument. Nearly 5 mg of sample were used for each analysis. All samples were first heated at 10[degrees]C [min.sup.-1] to the temperature well above the glass transition temperature ([T.sub.g]) or the melting temperature ([T.sub.m]) to erase the thermal history, followed by rapid cooling at 50[degrees]C [min.sup.-1]. Finally, a second heating scan was realized at 10[degrees]C [min.sup.-1]. Unless mentioned otherwise, [T.sub.m] and melting enthalpy ([DELTA][H.sub.m]) were determined from the first run, while [T.sub.g] was obtained from the second run. The thermal stability was investigated by thermogravimetric analysis (TGA, TA Q500) from room temperature to 450[degrees]C at a heating rate of 10[degrees]C [min.sup.-1] under nitrogen atmosphere (flow rate of 40 mL [min.sup.-1]).

Tensile Testing

Films were prepared by solution casting for tensile tests. The various homo- and copolymers were dissolved in dichloromethane at a concentration of 10 w/v%. The solutions were poured in a Petri dish. The solvent was allowed to evaporate by air drying overnight, followed by vacuum drying up to constant weight at room temperature and vacuum drying at 80[degrees]C for 72 h. Dumbbell-shaped specimens with dimensions of ASTM D882-02 standard (4 X 75 X 0.3 [mm.sup.3]) were finally cut from the films.

For the preparation of composite films, PLGA fibers were first plasma treated as previously reported [25]. Briefly, the PLGA fibers were treated in a home-made plasma immersion ion implantation machine. The plasma treatment was carried out using a beam voltage of AC 12 kV, an electrode power of 70 W, and the pressure inside the plasma chamber of 0.5 Pa. The surface of the fibers was modified in an atmosphere of oxygen gas at a frequency of 13.6 MHz for predetermined time periods. Predetermined amounts of fibers with average diameter of 11.7 [micro]m and average length of 0.3-0.6 mm were then introduced in copolymer solutions in dichloromethane. The mixed solutions were stirred for a few hours to ensure homogeneous dispersion. Composite films and corresponding tensile specimens were then prepared under the same conditions as in the case of neat polymers.

Tensile tests were carried out at room temperature (20-23[degrees]C) on a DXLL10000 universal tensile testing machine operated at a crosshead speed of 10 mm [min.sup.-1] and a grip-to-grip separation of 25 mm. Tensile strength, strain at break and Young's modulus were calculated from the stress-strain curves. All data present the average of at least four duplicate measurements.

Stent Manufacture

A terpolymer was selected for the fabrication of stent. First, a cylindrical tube with desired wall thickness, inner and outside diameters was extruded through a die, using a single-screw extruder (screw diameter [PHI] = 15 mm, length to diameter ratio L/D - 22). The screw speed was maintained at 40 rpm and the barrel temperature ranged from 150 to 170[degrees]C. The tube was then manufactured using a CNC engraving machine (518 JIG) to yield a cardiovascular stent, on the basis of previously reported design patterns for coronary stents [32], The stent has final dimensions of 5.0 mm in outer diameter, 0.22 mm in wall thickness, and 10 mm in length.

RESULTS AND DISCUSSION

Synthesis and Characterization

The development of cardiovascular stents requires a material with strictly defined characteristics in terms of thermal properties, wettability, mechanical performance, and degradation behavior. A series of homo- and copolymers based on LLA, TMC, and GA were synthesized for the fabrication of a cardiovascular stent which is expected to support the diseased vessels during the healing period. The synthesis was realized by bulk ring-opening polymerization of cyclic monomers, using [SnOct.sub.2] as catalyst (Scheme 1). [SnOct.sub.2] was selected as it is highly efficient and commonly used in the synthesis of polymers for biomedical applications [33].

Five PLLA-TMC-GA terpolymers as well as corresponding PLLA-TMC copolymers with different compositions were obtained by varying the feed ratio. Various acronyms were introduced to designate the copolymers for the sake of clarity (Table 1). For example, PLT95/5 designates PLLA-TMC with LLA/TMC feed ratio of 95/ 5, and PLTG95/5/5 designates PLLA-TMC-GA with LLA/TMC/GA feed ratio of 95/5/5. PLLA and PTMC homopolymers were also synthesized for comparison. All samples were obtained with high yields above 80%.

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Figure 1 presents the FT-IR spectra of PLLA-TMC and PLLA-TMC-GA copolymers, along with PLLA and PTMC homopolymers. PLLA presents characteristic bands at 1757 and 1184 [cm.sup.-1] assigned to carbonyl and ether bonds, respectively. Similarly, the carbonyl and ether bonds of PTMC are detected at 1741 and 1244 [cm.sup.-1]. On the FT-IR spectrum of the PLLA-TMC copolymer (PLT75/25), the vibration of the ether bond is split into two bands at 1190 and 1267 [cm.sup.-1], and only one carbonyl absorption band is detected at 1752 [cm.sup.-1]. These findings suggest that copolymerization occurred between LLA and TMC monomers. In the case of the PLLATMC-GA terpolymer (PLTG90/10/15), a characteristic absorption of -C[H.sub.2] group of PGA is observed around 1423 [cm.sup.-1].

The composition of the copolymers was determined from [sup.1]H NMR spectra. Figure 2 shows the [sup.1]H NMR spectra of PLLA, PLT95/5, and PLTG95/5/5 in CD[Cl.sub.3]. PLLA presents a doublet at 1.4-1.7 ppm (peak 4) and a quartet at 5.0-5.2 ppm (peak 1) which are attributed to the C[H.sub.3] and CH protons, respectively. On the spectrum of PLT95/ 5, signals of both LLA and TMC components are detected. The middle C[H.sub.2] protons of TMC component appear at 2.03 ppm (peak 3). Two lateral C[H.sub.2] protons appear at 4.24 ppm (peak 2) [30, 34], Interestingly, signals in the 5.0-5.2 ppm zone can be divided in two groups: the downfield group around 5.2 ppm belongs to main chain LLA units, and the upfield group around 5.0 ppm is assigned to LLA units linking to TMC units. The terpolymer PLTG95/5/5 presents the signals of all the three components. A multiplet of the C[H.sub.2] protons of GA moiety is detected at 4.6-5.0 ppm (peak 5), which shows the presence of many TMC- or LLA-linking GA units because of its low content and higher reactivity as compared to LLA and TMC [18, 28]. These findings confirm that PLLA-TMC-GA terpolymers were successfully obtained. The composition of the terpolymers is calculated from the integrations of the signals at 4.1-4.3 ppm for TMC units, at 5.0-5.2 ppm for LLA units and at 4.6-5.0 ppm for GA units. As illustrated in Table 1, the composition of the copolymers is very close to the feed ratio, in agreement with good conversion of monomers.

Detailed analysis of the [sup.13]C NMR spectra allows getting insights in the chain microstructures of the copolymers as previously reported [30]. The [sup.13]C NMR spectrum of a typical PLLA-TMC-GA terpolymer (PLTG95/5/5) is presented in Fig. 3. The carbonyl carbon of TMC, GA and LLA moieties is observed at 154.3, 166.5, and 169.5 ppm, respectively. The CH carbon of LLA moiety appears between 69.0 and 71.4 ppm, and the C[H.sub.3] group is detected at 16.6 ppm. The middle C[H.sub.2] carbon of TMC moiety is observed at 27.9 ppm, while the two other C[H.sub.2] carbons appear between 61.8 and 65.0 ppm. The C[H.sub.2] carbon of GA moiety is detected between 60.6 and 60.9 ppm. The enlarged [sup.13]C NMR regions of PLTG95/5/5 are also illustrated in Fig. 3. A downfield multiplet ([delta] = 69.10, 69.19, 69.24, and 69.29 ppm) is detected. Meanwhile, obvious splitting multiplet signals of C[H.sub.2] region of GA are also observed, indicating the presence of different triad sequences of PLLA-TMC-GA terpolymers.

The weight and number average molecular weights ([[bar.M].sub.w] and [[bar.M].sub.n], respectively) and polydispersity ([[bar.M].sub.w]/[[bar.M].sub.n] of the various polymers are determined by GPC as shown in Table 1. All the homo- and copolymers exhibit high molecular weight with [[bar.M].sub.n] above 100,000, except PTMC a little lower. The polydispersity values of all polymers range from 1.9 to 2.6. This is an important feature because stent materials should be able to maintain the original mechanical properties within the first 3-6 months of implantation [10]. It is known that the mechanical properties deteriorate as the molecular weight decreases. A number average molecular weight of ~25, 000 has been proposed as the limiting value below which the tensile properties are lost [16]. Meanwhile, the processing by melt extrusion also induces chain scission [35, 36].

Therefore, the initial molecular weight of polymers should be high enough to ensure good mechanical properties after processing.

Wettability is one of important criteria for evaluating the surface property of biomaterials [37], The results from the contact angle measurements are presented in Table 1. The water contact angle of PLLA is 85.2[degrees]. In the case of the copolymers, the contact angle values vary in the range of 80.6[degrees] to 83.8[degrees], in agreement with the hydrophobic character of the various polymers [38, 39].

The crystalline structure of the selected solution-cast films was examined by X-ray diffraction, as shown in Fig. 4. PLLA, PLT95/5 and PLT95/5/5 films appear semicrystalline with the diffraction peaks at theta = 8.3[degrees], 9.5[degrees], and 11.2[degrees], respectively, which correspond to the crystalline structure of PLLA. It is known that PTMC is an amorphous elastomer. No diffraction peaks of PGA are observed, indicating that PGA blocks are not long enough to crystallize. Different peak intensities are observed. PLLA appears more crystalline than the copolymers, in agreement with different LLA contents.

Thermal Properties of PLLA-TMC-GA Terpolymers

The thermal properties of the LLA-based copolymers can be modulated to a large extent by adjusting the comonomer feed ratio as illustrated in Fig. 5 and Table 2. All copolymers exhibit only one glass transition temperature ([T.sub.g]). The [T.sub.g] of PLLA and PTMC is observed at 61.1[degrees]C and -12.3[degrees]C, respectively. PLLA-TMC copolymers present lower [T.sub.g] than PLLA due to the presence of TMC component. The higher the TMC content, the lower the [T.sub.g]. It is known that [T.sub.g] of PGA homopolymer is around 36[degrees]C [27], lower than that of PLT75/25 (44.4[degrees]C). Thus, with the same LLA/TMC mole ratio, lower [T.sub.g] was obtained for the PLLA-TMC-GA terpolymers as compared to that of PLLA-TMC copolymers with increasing GA content. All the PLLA-TMC-GA terpolymers exhibit a [T.sub.g] above 50[degrees]C.

To rationalize the glass transition temperature changes with composition in the terpolymers, the well-known Fox equation was modified to account for a three-component system as follows:

1/[T.sub.g] = [w.sub.1]/[T.sub.g1] + [w.sub.2]/[T.sub.g2] + [w.sub.3]/[T.sub.g3] (1)

where [w.sub.1]; [w.sub.2], and [w.sub.3] refer to the weight fraction of the three components and [T.sub.g], [T.sub.g2] and [T.sub.g3] refer to the [T.sub.g] of corresponding homopolymers. The results obtained from Fox equation are very close the experimental data as shown in Table 2, indicating that no phase separation occurred for all compositions.

PLLA is an intrinsically semicrystalline polymer which exhibits a melting peak at 176.1[degrees]C with a melting enthalpy ([DELTA][H.sub.m]) of 38.4 J [g.sup.-1], in contrast to PTMC which appears amorphous. PLLA-TMC copolymers are semicrystalline at LLA contents above 85 mol%. A decrease in LLA content results in the lowering of melting temperature [T.sub.m] and a decrease in the heat of fusion. In the case of PLLA-TMCGA copolymers, only PLTG95/5/5 presents a very weak melting peak at 157.2[degrees]C with corresponding [DELTA][H.sub.m] of 0.3 J [g.sup.-1]. The crystallization ability of these LLA-based copolymers is strongly affected by LLA content and its average sequence length. PLTG95/5/5 has a higher LLA content than PLT85/15, but presents slightly lower [T.sub.m] and [DELTA][H.sub.m] values. This finding suggests that the terpolymer exhibits shorter LLA sequence length and more random chain structure. It is now well known that crystalline debris formed during degradation may cause an unexpected late inflammatory response and negatively influencing tissue growth [40]. Therefore, minimal crystallinity is preferable, considering the use of these polymers for biomedical applications.

Thermogravimetric analysis of the polymers was performed to determine the decomposition temperature of polymers. TGA shows that in a range from room temperature to 200[degrees]C all investigated polymers are quite stable with a maximum observed weight loss of 1%. All polymers degrade in a single decomposition step. PLLA and PTMC homopolymers exhibit the best thermal stability, with the temperature at maximum weight loss rate ([T.sub.d max]) about 357 and 363[degrees]C, respectively. The [T.sub.d max] of the PLLA-TMC and PLLA-TMC-GA copolymers varies between 337 and 355[degrees]C (Table 2). It appears that copolymers with very high LLA contents such as PLT95/5 and PLTG95/5/5 exhibit higher thermal stability than those with more TMC and GA comonomers because of more regular chain structures.

Mechanical Properties of PLLA-TMC-GA Terpolymers and Composites

The mechanical properties of the materials are of key importance for stent applications. Grabow et al. developed biodegradable PLLA stents which are able to withstand compression pressure of up to 1.3 bars equivalent to that of the ordinary metal stainless-steel stents [32], Therefore, the mechanical properties of the copolymers were evaluated in comparison with PLLA. The tensile strength ([partial derivative]), strain at break ([[epsilon].sub.break]), and Young's modulus (E) are listed in Table 3. The [T.sub.m] and [DELTA][H.sub.m] of the solution-cast films are also given, considering that the mechanical properties of polymers are strongly dependent on the crystallinity. It is observed that copolymers with different molar ratios possess dramatically different mechanical properties. PLLA exhibits a brittle character, with tensile strength, [[epsilon].sub.break] and modulus values of 61.3 MPa, 8.9% and 2039 MPa, respectively. PTMC presents an elastomeric behavior, with an [[epsilon].sub.break] value of 719% as previously reported [34]. Hence, the tensile strength and Young's modulus of copolymers decrease with increasing TMC content, whereas the [[epsilon].sub.break] gradually increases, in agreement with our previous work [34], PTL75/25 shows the lowest strength (14.1 MPa) and modulus (941 MPa) values among all the selected PLLA-TMC samples, but the highest strain at break (453%). These findings can be explained by the loss of crystallinity of the PLLA-TMC copolymers.

In the case of PLLA-TMC-GA terpolymers, the tensile strength decreases slightly with introducing 5 mol% GA moiety into PLLA-TMC copolymers. Surprisingly, [[epsilon].sub.break] is greatly improved. The typical stress-strain behaviors are illustrated in Fig. 6, taking PLT95/5 and PLTG95/5/5 for examples. The tensile strength of PLTG95/5/5 is 52.3 MPa, i.e., slightly lower than that of PLT95/5 (54.7 MPa). In contrast, the [[epsilon].sub.break] of PLTG95/5/5 (249%) is nearly nine times that of PLT95/5 (28.5%). On the other hand, a gradually decrease of tensile strength and Young's modulus is observed with increasing GA content. Thus, all the PLLA-TMC-GA copolymers exhibit high [[epsilon].sub.break] whereas the tensile strength is slightly lower than that of PLLA. These can be assigned to the lower crystallinity of the PLLA-TMC-GA terpolymers as mentioned above. Hence, a series of PLLA-TMC-GA terpolymers with sufficient tensile strength and better flexibility were obtained in comparison with PLLA homopolymer. According to Venkatraman, a collapse pressure of about 2.5 bars can be obtained for stents made of PLLA with tensile strength above 50 MPa [41], Microporous stents prepared from PLLA/PCL blends exhibit a compression strength of 5581 mm Hg, and the blend film exhibits a tensile strength of 9 MPa [42], Stents made of PLLA and poly(4-hydroxybutyrate) blend with a tensile strength of 36 MPa present a collapse pressure of 1.1 bars [43], Therefore, PLLA-TMC-GA terpolymers should possess sufficient collapse strength when processed into stents, which make them promising candidates for the development of cardiovascular stents.

To further enhance the tensile strength of PLLA-TMC-GA terpolymers, PLGA fibers with LA/GA ratio of 10/90 were selected to reinforce the terpolymer matrices. In fact, PLGA fibers are commonly used as bioresorbable sutures under the trademark of Vicryl[R]. Monofilaments are the basic units of PLGA multifilament whose tensile strength depends upon the monofilament number.

In this work, the tensile strength of the monofilaments is used to represent the mechanical properties of the multifilament short fibers used for reinforcement. As previously reported [25], PLGA monofilaments exhibit a tensile strength of 172.5 MPa which is much higher than that of PLLA-TMC-GA terpolymers. PLTG95/5/5 was selected as the matrix because of its outstanding mechanical properties, and a series of composites were prepared with various contents of short PLGA fibers (average length of 0.3-0.6 mm). The PLGA fibers were plasma-treated for 15 min to improve the affinity with the matrix [25], The strength of the composites strongly increases with increasing PLGA fibers content as shown in Table 3. The tensile strength of the composite with 8 wt% of fibers increases from initial 52.3-69.1 MPa, and the Young's modulus from initial 1877-2855 MPa. But the [[epsilon].sub.break] decreases dramatically from initial 249 to 4%. The poor toughness of the composites is assigned to the poor affinity between the fibers and the matrix, although PLGA fibers were plasma-treated.

According to our previous study, the composite with 5 wt% PLGA fibers degrades much faster than the PLLA-TMC neat copolymer and PLLA because the faster degradation of PLGA fibers speeds up the degradation of the matrix by autocatalysis [26], Meanwhile, composite with 5 wt% fibers exhibit nearly the same tensile strength and flexibility as PLLA, but with much higher modulus. PLGA fiber shows low solubility in organic solvents, and has a melting temperature up to 204[degrees]C, which is about 50[degrees]C higher than that of PLTG95/5/5, which should allow solution or hot processing of the composites. Therefore, PLLATMC-GA terpolymer reinforced with PLGA fibers is also a considerable candidate material for stent applications.

Stent Manufacture

The stent was prepared from PLTG95/5/5 terpolymer for it exhibits a relatively high tensile strength and excellent toughness. Mini-tubes with an outer diameter of 5.0 mm and wall thickness of 0.22 mm were first fabricated by a single-screw extruder, and then stents were obtained using a CNC engraving machine. Figure 7 shows a stent prototype with the length of 10 mm. It is worthy to note that chain scission occurred during extrusion processing. [bar.[M.sub.n]] and [bar.[M.sub.w]] of PLTG95/5/5 strongly decreased from initial 2.36 X [10.sup.5] and 5.16 X [10.sup.5] g [mol.sup.-1] to 1.84 X [10.sup.5] and 3.80 X [10.sup.5] g [mol.sup.-1], respectively, despite extensive vacuum drying of polymers before processing. This finding illustrates the necessity to use high molecular weight polymers, so as to ensure good mechanical performance after heat processing.

Therefore, cardiovascular stents were fabricated the first time from PLLA-TMC-GA terpolymers, using a CNC engraving machine. Further studies are underway to determine the mechanical properties, degradation behavior and biocompatibility of the stents.

CONCLUSIONS

This work aims to design a suitable polymer system for the preparation of cardiovascular stents. Various terpolymers based on LLA, TMC, and GA covering a broad range of compositions were investigated, in comparison with corresponding PLLA-TMC copolymers as well as PLLA and PTMC homopolymers. All the copolymers present high molecular weights, which is essential for the mechanical performance of materials. The thermal behaviors and mechanical properties of the polymers are strongly dependent on the compositions. Only one glass transition temperature is observed for the copolymers. PLLA-TMC copolymers are semicrystalline at TMC contents below 25 mol%, but the crystallinity is lower than that of PLLA. Incorporation of GA units further decreases the crystallinity of PLLA-TMC-GA terpolymers due to more random microstructure. Meanwhile, the toughness of terpolymers is greatly improved, with only a slight loss of tensile strength. Plasma-treated PLGA fibers are used to reinforce the PLLA-TMC-GA terpolymers. Composite with 8 wt% fibers exhibits much higher tensile strength, whereas the toughness strongly decreases. A stent prototype is successfully manufactured from a terpolymer using a CNC engraving machine, thus showing the potential of terpolymers with good mechanical properties for the development of cardiovascular stents. Further studies are underway to investigate the mechanical properties and in vivo degradation behavior of the stents.

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Jianting Dong, (1) Lan Liao, (1) Li Shi, (1) Zaishang Tan, (1) Zhongyong Fan, (1) Suming Li, (2) Zhiqian Lu (3)

(1) Department of Materials Science, Fudan University, Shanghai 200433, People's Republic of China

(2) Department of Interface, Physicochemistry and Polymers, Institut Europeen des Membranes, UMR ENSCM-UM2-CNRS 5635, Universite Montpellier 2, Place Eugene Bataillon, 34095 Montpellier cedex 5, France

(3) Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, People's Republic of China

Correspondence to: Zhongyong Fan; e-mail: zyfan@fudan.edu.cn or Suming Li; e-mail: suming.li@iemm.univ-montp2.fr

Contract grant sponsor: National Natural Science Foundation of China; contract grant number: 51073041; contract grant sponsor: Science and Technology Commission of Shanghai Municipality; contract grant number: 12441903103; contract grant sponsor: Key Technology Research for Strategic Emerging Industry Program of Guangdong.

DOI 10.1002/pen.23662

Published online in Wiley Online Library (wileyonlinelibrary.com).

TABLE 1. Characterization of PLLA, PTMC, PLLA-TMC, and PLLA-TMC-GA
homo-and copolymers.

                   [LLA]/[TMC]/[GA]
                                          [bar.[M.sub.n]] x
Polymer          Feed      Product (a)     [10.sup.-4] (b)

PLLA           100/0/0       100/0/0            30.7
PTMC           0/100/0       0/100/0             9.1
PLT95/5         95/5/0     95.1/4.9/0           28.3
PLT90/10       90/10/0     90.7/9.3/0           21.8
PLT85/15       85/15/0     85.9/14.1/0          20.8
PLT75/25       75/25/0     75.7/24.3/0          11.2
PLTG85/15/5    85/15/5    85.8/14.2/5.7         20.9
PLTG90/10/5    90/10/5    90.6/9.4/5.6          23.7
PLTG95/5/5      95/5/5    95.8/4.2/5.4          23.6
PLTG90/10/10   90/10/10   90.5/9.5/10.8         14.6
PLTG90/1O/15   90/10/15   90.2/9.8/15.8         14.2

               [bar.[M.sub.w]] x    [bar.[M.sub.w]]/
Polymer         [10.sup.-4] (b)    [bar.[M.sub.n]] (b)

PLLA                 81.4                  2.6
PTMC                 17.2                  1.9
PLT95/5              68.9                  2.4
PLT90/10             50.9                  2.3
PLT85/15             50.2                  2.4
PLT75/25             24.3                  2.2
PLTG85/15/5          50.0                  2.4
PLTG90/10/5          54.7                  2.3
PLTG95/5/5           51.6                  2.2
PLTG90/10/10         30.0                  2.0
PLTG90/1O/15         28.2                  2.0

Polymer        Contact angle ([degrees])

PLLA               85.2 [+ or -] 1.8
PTMC                      --
PLT95/5            83.1 [+ or -] 1.2
PLT90/10           81.1 [+ or -] 0.6
PLT85/15           81.8 [+ or -] 2.2
PLT75/25           80.6 [+ or -] 1.2
PLTG85/15/5        82.3 [+ or -] 1.7
PLTG90/10/5        82.7 [+ or -] 0.7
PLTG95/5/5         83.8 [+ or -] 1.1
PLTG90/10/10       83.5 [+ or -] 0.4
PLTG90/1O/15       82.4 [+ or -] 0.4

(a) Determined by [sup.1]H NMR using CD[Cl.sub.3] as solvent.

(b) Determined by GPC.

TABLE 2. Thermal properties of PLLA, PTMC, PLLA-TMC, and
PLLA-TMC-GA copolymers.

                [T.sub.g]      [T.sub.m]     [DELTA][H.sub.m]
Polymer        ([degrees]C)   ([degrees]C)    (J [g.sup.-1])

PLLA               61.1          176.1             38.4
PTMC              -12.3            --               --
PLT95/5            58.2          162.9             5.3
PLT90/10           53.5          159.3             1.7
PLT85/15           50.1          158.1             0.6
PLT75/25           44.4            --               --
PLTG85/15/5        50.9            --               --
PLTG90/10/5        54.0            --               --
PLTG95/5/5         57.3          157.2             0.3
PLTG90/10/10       52.6            --               --
PLTG90/10/15       52.3            --               --

               [T.sub.g-f] (a)   [T.sub.d] max (b)
Polymer         ([degrees]C)       ([degrees]C)

PLLA                 --                 357
PTMC                 --                 363
PLT95/5             57.8                354
PLT90/10            54.8                350
PLT85/15            51.5                348
PLT75/25            44.5                347
PLTG85/15/5         50.7                337
PLTG90/10/5         53.9                340
PLTG95/5/5          56.9                355
PLTG90/10/10        53.0                344
PLTG90/10/15        52.2                343

(a) Calculated from Fox equation.

(b) Determined by TGA.

TABLE 3. Mechanical and thermal properties of PLLA, PTMC, PLLA-TMC,
and PLLA-TMC-GA copolymers and composites.

                                        [[member of].sub.break] (b)
Polymer              [??] (a) (MPa)                 (%)

PLLA                61.3 [+ or -] 3.1        8.9 [+ or -] 1.9
PLT95/5             54.7 [+ or -] 2.3        28.5 [+ or -] 6.5
PLT90/10            50.8 [+ or -] 1.5        128 [+ or -] 24.1
PLT85/15            48.7 [+ or -] 2.0        233 [+ or -] 16.5
PLT75/25            14.1 [+ or -] 1.0        453 [+ or -] 68.4
PLTG85/15/5         34.3 [+ or -] 1.3        342 [+ or -] 60.2
PLTG90/10/5         49.6 [+ or -] 1.4        304 [+ or -] 58.1
PLTG95/5/5          52.3 [+ or -] 1.3        249 [+ or -] 25.4
PLTG90/10/10        47.3 [+ or -] 1.7        345 [+ or -] 35.2
PLTG90/10/15        42.8 [+ or -] 1.6        402 [+ or -] 81.6
PLTG95/5/5-f2 (e)   55.7 [+ or -] 3.9        4.0 [+ or -] 0.8
PLTG95/5/5-f5 (f)   61.2 [+ or -] 3.4        3.1 [+ or -] 1.2
PLTG95/5/5-f8 (g)   69.1 [+ or -] 6.3        4.2 [+ or -] 1.5

Polymer                E (c) (MPa)       [T.sub.m] (d) ([degrees]C)

PLLA                2,039 [+ or -] 154             177.7
PLT95/5             1,804 [+ or -] 58              162.9
PLT90/10            1,784 [+ or -] 179             159.5
PLT85/15            1,769 [+ or -] 91              155.7
PLT75/25              941 [+ or -] 99                --
PLTG85/15/5         1,199 [+ or -] 102             132.5
PLTG90/10/5         1,742 [+ or -] 42              149.3
PLTG95/5/5          1,877 [+ or -] 134             156.2
PLTG90/10/10        1,732 [+ or -] 118             136.5
PLTG90/10/15        1,539 [+ or -] 103               --
PLTG95/5/5-f2 (e)   2,205 [+ or -] 254             -- (h)
PLTG95/5/5-f5 (f)   2,585 [+ or -] 310             -- (h)
PLTG95/5/5-f8 (g)   2,855 [+ or -] 328             -- (h)

Polymer             [DELTA][H.sub.m] (d) (J [g.sup.-1])

PLLA                                37.8
PLT95/5                             27.1
PLT90/10                            23.2
PLT85/15                            16.8
PLT75/25                             --
PLTG85/15/5                          3.8
PLTG90/10/5                         14.5
PLTG95/5/5                          18.9
PLTG90/10/10                        11.0
PLTG90/10/15                         --
PLTG95/5/5-f2 (e)                  -- (h)
PLTG95/5/5-f5 (f)                  -- (h)
PLTG95/5/5-f8 (g)                  -- (h)

(a) Tensile strength.

(b) Strain at break.

(c) Young's modulus.

(d) Determined by DSC (First scan).

(e) Composite with 2 wt% of PLGA fibers.

(f) Composite with 5 wt% of PLGA fibers.

(g) Composite with 8 wt% of PLGA fibers.

(h) Not determined.
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Author:Dong, Jianting; Liao, Lan; Shi, Li; Tan, Zaishang; Fan, Zhongyong; Li, Suming; Lu, Zhiqian
Publication:Polymer Engineering and Science
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Geographic Code:9CHIN
Date:Jun 1, 2014
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