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PLA thermoplastic elastomers
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Biomaterials 26 (2005) 2297–2305 www.elsevier.com/locate/biomaterials
Designing biodegradable multiblock PCL/PLA thermoplastic elastomers D. Cohn, A. Hotovely Salomon Casali Institute of Applied Chemistry, Hebrew University of Jerusalem, Gival Ram Campus, Jerusalem 91904, Israel Received 13 June 2004; accepted 23 July 2004 Available online 22 September 2004
Abstract A series of poly(e-caprolactone)/poly(L-lactic acid) (PCL/PLA) biodegradable poly(ester-urethane)s, was synthesized and characterized. The first step of the synthesis consisted of the ring opening polymerization of L-lactide, initiated by the hydroxyl terminal groups of the PCL chain, followed by the chain extension of these PLA-PCL-PLA triblocks, using hexamethylene diisocyanate (HDI). The trimers comprised PCL2000 flexible segments, while the length of each PLA block covered the 550–6000 molecular weight range. The morphology of the copolymers gradually changed, as the length of the PLA blocks increased. The multiblock copolymers produced displayed enhanced mechanical properties, with ultimate tensile strength values around 32 MPa, Young’s modulus as low as 30 MPa and elongation at break values well above 600%. The longer the PLA block, the slower the in vitro degradation of the material, with all copolymers degrading faster than the respective homopolymers. r 2004 Elsevier Ltd. All rights reserved. Keywords: Poly(caprolactone); Poly(lactic acid); Biodegradation; Elastomer; Copolymer
1. Introduction Biodegradable polymers are used in traditional applications, such as surgical sutures [1,2] and matrices for drug delivery [3–5], and recently they became also the basis of more advanced biomedical systems. The field of Tissue Engineering, for example, capitalized on their degradability to create the temporary scaffolds required for cell growth and tissue regeneration [6–8]. Mechanical parameters play a crucial role in determining the in vivo performance of biomedical systems, since the healing and remodeling processes are greatly affected by the stress field induced on the surrounding tissue by the implanted device [9,10]. This can be exemplified by the detrimental phenomena (e.g. thrombosis, anastomotic intimal hyperplasia) caused by the significant compliance mismatch existing between the
Corresponding author. Tel.: +972-2-6513755.
E-mail address: [email protected] (D. Cohn). 0142-9612/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2004.07.052
stiff vascular grafts in clinical use and the substantially more compliant host arteries [11,12]. Unfortunately, most of the absorbable polymers available today display a very similar mechanical behavior, with unsuitably high Young’s modulus and rather low elongation at break values. These polymers are, therefore, clearly inappropriate for numerous clinical uses, where strong, highly flexible biodegradable materials are required. The paradox in this area has to do, thus, with the large gap existing between the increasing clinical demand for biodegradable systems for soft tissue applications, on one hand, and the paucity of suitable polymers, on the other hand. It is, therefore, apparent that a new generation of biodegradable polymers, characterized by high strength, low modulus and significant elongation at break values, is called for. The important work conducted by Kohn and coworkers, developing a comprehensive family of tyrosinederived poly(carbonate)s [13,14], should be mentioned. Also, the recent development of poly(glycerol sebacate) (PGS), a thermoset polymer synthesized by the
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condensation of glycerol and sebacic acid, constitutes an important contribution to the field [15,16]. As reported [15], PGS has a Young’s modulus of around 0.3 MPa, an ultimate tensile strength above 0.5 MPa and attains elongation at break values slightly below 350%. In contrast to PGS, our work focused on developing biodegradable thermoplastic elastomers, by capitalizing on their versatility of design, their particular morphology and their superior mechanical properties. We have developed a series of multiblock copolymers in which aliphatic poly(ester) segments created the hard, and typically crystalline, blocks of the copolymer, while flexible chains functioned as the soft blocks along the segmented chains. In earlier studies, we synthesized poly(ethylene oxide)/poly(lactic acid) (PEO/PLA) [17–19] and poly(ethylene oxide)/poly(caprolactone) (PEO/PCL) [20] multiblock copolymers and their properties were investigated. The PEO/PLA (PELA) copolymers performed most satisfactorily as films for the prevention of post-surgical adhesions in various animal models [21,22] and are presently undergoing clinical studies. PELA elastomer performed also as the absorbable component of a highly compliant, selectively biodegradable filament wound arterial prosthesis [23,24], that remained patent and pulsating after 90 days in the canine carotid artery [25,26]. The present article focuses on the synthesis and characterization of PCL/PLA thermoplastic elastomers, where poly(L-lactic acid) generated the hard blocks and poly(caprolactone) created the soft segments along the copolymeric backbone. Following a two-stage synthesis, PLLA-PCL-PLLA triblocks were first synthesized and then chain extended with hexamethylene diisocyanate (HDI), whereby, a family of biodegradable poly(esterurethane) multiblock copolymers was obtained. The polymers comprised PCL2000 flexible segments and increasingly long PLA blocks. Light will be shed on the relationship between their composition, morphology and mechanical properties both at time zero as well as a function of their in vitro degradation.
2. Experimental Materials: PCL2000 and HDI were supplied by Aldrich (Milwaukee, USA), L-lactide was purchased from Boehringer (Ingelheim, Germany), and the stannous octanoate catalyst and dioxane were provided by Sigma (Steinheim, Germany). Drying: PCL2000 was dried under vacuum and magnetic stirring, at 105 1C, for 90 min. Triblock preparation: After drying, the calculated amounts of L-lactide (LD) and stannous octanoate, were added using a 400/1 LD/catalyst molar ratio. The first stage of the synthesis was carried out in 250 ml three-necked flasks, in the molten state (145 1C) for one
hour, under a dry nitrogen atmosphere and mechanical stirring (100 rpm). Chain extension: The second stage of the synthesis was performed by reacting the triblock with hexamethylene diisocyanate, in a 1.0:1.1 Triblock:HDI molar ratio. Twenty grams triblock were dissolved in dry dioxane and HDI was added to the dissolved triblock, followed by 0.3 g of catalyst. The reaction was conducter at 82 1C for 3 h, under a dry nitrogen atmosphere and mechanical stirring (100 rpm). The resulting polymer was precipitated into ether, dried and then dissolved in chloroform to generate a 7 wt% solution. Then, 250 mm thick films were cast from the resulting solution, by evaporating the solvent at room temperature, followed by vacuum drying to optimize solvent removal. In vitro degradation: The in vitro degradation was performed by immersing the samples under hydrolytic conditions (PBS, pH=7.4, 37 1C). The medium was changed at least once a week and the degradation process was monitored by gel permeation chromatography (GPC). Characterization: (a)Gel permeation chromatography (GPC): The average molecular weights and polydispersity were determined by GPC (Differential Separations Module Waters 2690 with refractometer detector Waters 410 and Millenium Chromatography Manager), using polystyrene standards between 472 and 360,000 Da. (b)Nuclear magnetic resonance spectroscopy (NMR): 1 H-NMR spectra were recorded using a Bruker 300 high resolution 1H-NMR spectrophotometer. All spectra were obtained at room temperature from 15% (wt/v) CDCl3 solutions. The composition of the copolymers was determined by ratioing the protons of the methylene group alpha to PCL’s ester moieties at 4.05 ppm (triplet) and the proton of the lactoyl methine peak (quartet), centered at 5.15 ppm. (c)Thermal analysis: The samples were analyzed using a Mettler TA 3000 DSC thermoanalyzer. The thermograms ranged from 120 to 200 1C at a 10 1C/min heating rate, under an inert nitrogen atmosphere. The heat of fusion was ratioed to the content (%wt) of the component crystallizing, PCL or PLA, in each specific copolymer. (d)Mechanical properties: The measurement of the mechanical properties was carried out on dogbone specimens using an Instron Universal Testing Machine (Model 4500), at a crosshead speed of 60 mm/min. A minimum of three specimens per sample were tested. Nomenclature: The poly(ester-urethane)s described in this article will be designated as PCLAs. Since all the PCL chains had the same molecular weight (2000), the copolymers will denote only the length of the PLA block present on each side of the central PCL segment. Therefore, PCLA3000, for example, designates a copolymer based on PLLA-PCL-PLLA triblocks comprising
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a PCL2000 central chain and two PLLA blocks, each of them having a molecular weight of 3000. Also, since this study focused on L-lactide only, PLLA will be denoted in the remaining of this article as PLA.
3. Results and discussion 3.1. The working concept The superior mechanical properties of thermoplastic elastomers are attributed to their unique structure, where flexible soft segments alternate with hard, preferably crystalline blocks [27]. Segmented poly (ether-urethane)s are an important example of this family of polymers [28,29]. The hard blocks generate strong domains that act as non-covalent physical crosslinks, while the flexibility of the soft segments affords the large elongation and elastic recovery, characteristic of these micro-segregated polymers. Our work aimed at developing strong biodegradable elastomers, by combining moieties which induced molecular flexibility, on one hand, and crystalline blocks that markedly strengthened the system, on the other hand, with both components being biodegradable. Poly(caprolactone) is an aliphatic polyester with a glass transition temperature around 60 1C and a low melting point (62 1C) [30]. Because of its low Tg, PCL’s amorphous phase displays high mobility at body temperature. Since short poly(caprolactone) chains are amorphous, they were selected to perform as the flexible segment present along the copolymeric backbone. Poly(L-lactic acid) is a much stiffer aliphatic polyester, with a glass transition around 55 1C and a melting point
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around 180 1C [31]. Due to these structural features, PLA was chosen to create the hard blocks along the copolymeric backbone. The syntheses of the PCL/PLA block copolymers were conducted following a two-stage method, as schematically described in Scheme 1. First, PLA-PCLPLA triblocks were synthesized by the ring opening polymerization of L-lactide, initiated by the hydroxyl terminal groups of the PCL chain. The second stage involved the chain extension of the OH-terminated PLA-PCL-PLA trimers, using hexamethylene diisocyanate (HDI), whereby urethane groups were generated along the polymeric backbone. The distinction between the high molecular weight multiblock copolymers described in this study and the diblocks and triblocks developed by other groups [32–34], is a fundamental one. The chain extension of tailor-made triblocks allowed: (i) to generate the required morphology, mainly derived from the length of the PLA and PCL segments present in the basic triblock, and (ii) to attain remarkably enhanced mechanical properties, largely due to the high molecular weight copolymers obtained after the chain extension step. Moreover, the presence of the urethane groups along the backbone also seems to be contributing to the superior mechanical behavior of these polymers. 3.2. The triblocks The length of the central PCL segment was kept constant (MW=2000), while the molecular weight of the (LA)n blocks spanned from 550 to 6000 Da. The progress of the triblock synthesis, monitored by GPC and NMR, revealed that the reaction was complete after
Scheme 1. Synthesis and structure of PCLA multiblock copolymers.
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Table 1 Molecular weight of the five PCLA copolymers synthesized Copolymer
Mn (g/mol)
Mw (g/mol)
P.D.
2000/550 2000/1100 2000/2000 2000/3000 2000/6000
92,000 109,000 124,000 112,000 89,000
168,000 175,000 187,000 176,000 154,000
1.8 1.6 1.5 1.6 1.7
Fig. 1. 1H-NMR of the PLA-PCL-PLA triblock.
approximately 1 h, a similar time frame being measured for all triblocks, regardless of their composition. GPC analysis demonstrated also that there was no unreacted PCL2000 present at the end of the reaction. The polydispersity of the PLA-PCL-PLA triblocks was narrow, with typical values in the 1.15–1.20 range. 1 H-NMR spectroscopy was used to elucidate their composition, by determining the ratio between the PCL and PLA segments. The peaks selected were the quartet at 5.15 ppm, due to the proton of PLA’s methine groups and the triplet centered at 4.05 ppm, assigned to PCL’s methylene protons alpha to the ester group (see Fig. 1).
Fig. 2. DSC thermograms of the PCLA copolymers.
3.3. The copolymers As shown in Table 1, the molecular weight (MWn) of the polymers synthesized ranged between 89,000 and 124,000, with a polydispersity between 1.5 and 1.8. (a) The morphology: Fig. 2 presents the thermograms of the five copolymers synthesized. It is apparent that their morphology gradually changed, as the length of the PLA blocks increased. PCLA550 was the only polymer comprising a crystalline poly(caprolactone) segment, with PLA generating an amorphous matrix. PLA blocks were too short to crystallize and also to prevent PCL’s crystallization. This copolymer exhibited a Tg around 30 1C and a relatively sharp Tm peak at 42 1C (DH=19 J/g). The pronounced shift of poly(caprolactone)’s glass transition to a higher temperature reflects the stiffening effect the PLA blocks exerted on the PCL chains. Likewise, PCLs melting
endotherm appeared at a lower temperature since the PLA affected PCLs crystallizability. These findings indicate also that some degree of phase blending took place between the two components. As the length of the PLA blocks increased, the phases were able to segregate more efficiently, as exemplified by the comparison between PCLA1100 and PCLA2000. The former was the most amorphous of all copolymers synthesized, with both constituents being essentially amorphous. Two glass transitions at around 27 and 41 1C, attributed to the PCL and PLA phases, respectively, were discernible. Only a small and ill defined melting endotherm around 104 1C, due to the incipient degree of crystallinity of the PLA chains, could be observed. PCLA2000 comprised longer, more crystalline PLA blocks, displaying a broad Tm at 118 1C (DH=27
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J/g). As the molecular weight of the poly(lactic acid) blocks increased further (PCLA3000), no glass transitions could be measured and a sharper melting peak was apparent at 144 1C, characterized by a large heat of fusion (32 J/g). Expectedly, the copolymer comprising the longest PLA segments (MW=6000), exhibited only a sharp and large PLA-derived melting endotherm, centered at 156 1C, with an even higher heat of fusion (39 J/gr). (b) The mechanical properties: It is apparent from the data presented in Figs. 3(a)–(c) that, by dictating their morphology, the composition of the PLA-PCL-PLA triblocks played a key role in determining the mechanical behavior of the copolymers. While a similar ultimate tensile strength was measured for all the copolymers (around 32 MPa), their stiffness and ability to stretch varied markedly as the length of the PLA block increased. PCLA550 and 1100 were strong and extremely flexible elastomers, displaying a Young modulus of around 30 MPa and elongation at break values of 1600% and 600%, respectively. As the molecular weight of the (LA)n blocks raised, the materials became increasingly stiff, with E values climbing up to 800 MPa for PCLA6000. Concomitantly, the strain to failure decreased steadily, from above 1600% for PCLA550, down to around 100% for PCLA6000. The gradual stiffening of the copolymers can be readily attributed to the combined effect of increasingly higher PLA contents comprising progressively more crystalline PLA blocks. Clearly, while the ultimate tensile strength was primarily dictated by the molecular weight of the polymer, the elastic properties were mainly determined by the morphology of the triblock. It is apparent from these data, that PCLA multiblock copolymers displayed mechanical properties markedly superior to those exhibited by other biodegradable elastomers recently developed. For example, while PCLA copolymers attained UTS levels above 30 MPa, poly(glycerol sebacate) (PGS) exhibited a tensile strength slightly above 0.5 MPa [15]. Aiming at creating a highly flexible material that is able to stretch substantially, PGS was designed to have a low crosslinking density. Furthermore, as reported [15], PGS is fully amorphous at body temperature, with no glass transition temperatures being observed above 80 1C. These characteristics of PGS may explain its poor mechanical properties. In clear contrast, PCLA multiblock copolymers were tailored so they generated a micro-segregated morphology, where the PCL amorphous chains performed as a molecular coil, while the crystalline PLA blocks functioned as strong non-covalent crosslinking domains. The high molecular weight multiblock copolymers combined, therefore, high flexibility, enhanced strength and superior extendibility.
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Fig. 3. Mechanical properties of the PCLA copolymers as a function of composition: (a) ultimate tensile strength (MPa); (b) Young’s modulus (MPa); (c) elongation at break (%).
3.4. The degradation process The in vitro degradation of these polymers is exemplified in Fig. 4, by presenting the chromatograms of PCLA2000 as a function of degradation time. The initial molecular weight of the polymer was 190,000,
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Fig. 4. GPC curves for PCLA2000 as a function of their in vitro degradation.
decreasing to 83,000 and 48,000 after 1 and 3 months, respectively, while after 6 months the molecular weight was only 5% of its initial value. The slowest degrading material was PCLA6000, retaining about 50% of its initial molecular weight after 75 days, whereas PCLA2000, for example, reached this point already after 28 days. Expectedly, all the copolymers degraded faster than the two homopolymers, with PLA and PCL losing 50% of their initial molecular weight after 5 and 12 months, respectively. (a) The mechanical properties: Figs. 5(a)–(c) plot the change in the mechanical properties of PCLA copolymers, over a period of 90 days. It is apparent that the polymers retained their initial Young’s modulus, while both the ultimate tensile strength as well as the elongation at break values changed substantially over the same period of time. The tensile strength of PCLA copolymers dropped gradually, from their high initial levels (around 30–34 MPa), reaching the 2–3 MPa level after 3 months, with PCLA3000 and PCLA6000 decreasing at the slowest pace. Predictably, as their molecular weight decreased, the extendibility of the polymers decreased markedly. Its worth stressing, though, that due to their remarkable initial mechanical properties, most of these copolymers remained flexible and tough elastomers for a significant period of time. After 45 days in vitro degradation, for example, PCLA1100 displayed a strength of around 8 MPa, a modulus of approximately 40 MPa and a strain to failure of around 120%. (b) Morphology changes: The thermograms shown in Figs. 6(a)–(c) illustrate the change in the morphology of three PCLA polymers as a function of their degradation. As already shown in Fig. 2(b), poly(caprolactone) is the
Fig. 5. Mechanical properties of the PCLA copolymers as function of their in vitro degradation: (a) ultimate tensile strength (MPa); (b) Young’s modulus (MPa); (c) elongation at break (%).
only component able to crystallize in PCLA550, as demonstrated by the melting endotherm at 42 1C. Given this initial morphology, it was anticipated that the PLA blocks would degrade faster than the PCL segments,
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Fig. 6. DSC thermograms of three PCLA copolymers as a function of their in vitro degradation. (a) PCLA550; (b) PCLA2000; (c) PCLA6000.
resulting in an increasingly crystalline poly(caprolactone) phase. The appearance and growth of an additional PCL melting peak and its gradual shift to higher temperatures (up to 54 1C), as shown in Fig. 6(a), is in full accordance with these considerations. Fig. 6(b) presents the thermograms of PCLA2000 over a 10 month degradation period. Noticeably, the longer PLA blocks present in this copolymer, as opposed to PCLA550, caused a fundamental change in its initial structure, with PLA blocks being the only crystalline component present at time zero. A progressive increase in the degree of crystallinity of the PLA component, took place during the first 5 months, as revealed by the shift of the peak to higher
temperatures, from 118 1C up to 125 1C. As degradation proceeded further, a system with two crystalline phases was produced. At 10 months, for example, two sharp melting endotherms, centered at 58 and 121 1C, due to the PCL and PLA segments, respectively, were apparent. The thermograms shown in Fig. 6(c) demonstrate that a further increase in the molecular weight of the PLA blocks, produced a material where only PLA was able to crystallize to a significant extent, as the polymer degraded. It was only after 8 months degradation, that PCL was able to exhibit some degree of crystallinity, albeit very modest, as revealed by the small and broad endotherm around 50 1C.
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spring, while the crystalline PLA blocks functioned as strong non-covalent crosslinking domains. These thermoplastic elastomers combined remarkable strength (UTS values around 32 MPa), high flexibility (tensile moduli as low as 30 MPa) and enhanced extendibility (above 600%). By tightly controlling the ratio between the PCL and PLA segments and their respective degrees of polymerization, the degradation rate was varied over a wide time range. References
Fig. 7. DSC thermograms of three PCLA copolymers after 15 months in vitro degradation. (a) PCLA550; (b) PCLA2000; (c) PCLA6000.
Fig. 7 compares the morphology of PCLA550, 2000 and 6000, after 15 months degradation. As opposed to the other two copolymers shown, PCLA550 displayed a monophasic crystalline structure, with a large and sharp PCL melting endotherm. PCLA2000 and 6000, on the other hand, generated biphasic morphologies where both constituents were able to crystallize. The composition of the various copolymers changed differently over time, depending on their initial composition and morphology, as determined by NMR spectroscopy (see Fig. 1). In the case of PCLA550, for example, the ratio between the PCL and PLA peaks increased by a factor of five, over 15 months degradation, indicating a substantial poly(caprolactone) enrichment. Most of the mass loss, therefore, was due to short PLA fragments leaving the system by readily dissolving into the aqueous medium. In the case of PCLA6000, on the other hand, a different behavior was apparent, with the basic ratio between the two components being essentially constant, over time.
4. Conclusions Our work aimed at developing biodegradable thermoplastic elastomers, by capitalizing on their particular micro-structure and superior mechanical properties. The morphology of PCLA copolymers was investigated and its dependence on compositional parameters was assessed. These PCL/PLA copolymers generated a micro-segregated morphology, where the poly(caprolactone) amorphous chains performed as a molecular
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Biomaterials 26 (2005) 2297–2305 www.elsevier.com/locate/biomaterials
Designing biodegradable multiblock PCL/PLA thermoplastic elastomers D. Cohn, A. Hotovely Salomon Casali Institute of Applied Chemistry, Hebrew University of Jerusalem, Gival Ram Campus, Jerusalem 91904, Israel Received 13 June 2004; accepted 23 July 2004 Available online 22 September 2004
Abstract A series of poly(e-caprolactone)/poly(L-lactic acid) (PCL/PLA) biodegradable poly(ester-urethane)s, was synthesized and characterized. The first step of the synthesis consisted of the ring opening polymerization of L-lactide, initiated by the hydroxyl terminal groups of the PCL chain, followed by the chain extension of these PLA-PCL-PLA triblocks, using hexamethylene diisocyanate (HDI). The trimers comprised PCL2000 flexible segments, while the length of each PLA block covered the 550–6000 molecular weight range. The morphology of the copolymers gradually changed, as the length of the PLA blocks increased. The multiblock copolymers produced displayed enhanced mechanical properties, with ultimate tensile strength values around 32 MPa, Young’s modulus as low as 30 MPa and elongation at break values well above 600%. The longer the PLA block, the slower the in vitro degradation of the material, with all copolymers degrading faster than the respective homopolymers. r 2004 Elsevier Ltd. All rights reserved. Keywords: Poly(caprolactone); Poly(lactic acid); Biodegradation; Elastomer; Copolymer
1. Introduction Biodegradable polymers are used in traditional applications, such as surgical sutures [1,2] and matrices for drug delivery [3–5], and recently they became also the basis of more advanced biomedical systems. The field of Tissue Engineering, for example, capitalized on their degradability to create the temporary scaffolds required for cell growth and tissue regeneration [6–8]. Mechanical parameters play a crucial role in determining the in vivo performance of biomedical systems, since the healing and remodeling processes are greatly affected by the stress field induced on the surrounding tissue by the implanted device [9,10]. This can be exemplified by the detrimental phenomena (e.g. thrombosis, anastomotic intimal hyperplasia) caused by the significant compliance mismatch existing between the
Corresponding author. Tel.: +972-2-6513755.
E-mail address: [email protected] (D. Cohn). 0142-9612/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2004.07.052
stiff vascular grafts in clinical use and the substantially more compliant host arteries [11,12]. Unfortunately, most of the absorbable polymers available today display a very similar mechanical behavior, with unsuitably high Young’s modulus and rather low elongation at break values. These polymers are, therefore, clearly inappropriate for numerous clinical uses, where strong, highly flexible biodegradable materials are required. The paradox in this area has to do, thus, with the large gap existing between the increasing clinical demand for biodegradable systems for soft tissue applications, on one hand, and the paucity of suitable polymers, on the other hand. It is, therefore, apparent that a new generation of biodegradable polymers, characterized by high strength, low modulus and significant elongation at break values, is called for. The important work conducted by Kohn and coworkers, developing a comprehensive family of tyrosinederived poly(carbonate)s [13,14], should be mentioned. Also, the recent development of poly(glycerol sebacate) (PGS), a thermoset polymer synthesized by the
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condensation of glycerol and sebacic acid, constitutes an important contribution to the field [15,16]. As reported [15], PGS has a Young’s modulus of around 0.3 MPa, an ultimate tensile strength above 0.5 MPa and attains elongation at break values slightly below 350%. In contrast to PGS, our work focused on developing biodegradable thermoplastic elastomers, by capitalizing on their versatility of design, their particular morphology and their superior mechanical properties. We have developed a series of multiblock copolymers in which aliphatic poly(ester) segments created the hard, and typically crystalline, blocks of the copolymer, while flexible chains functioned as the soft blocks along the segmented chains. In earlier studies, we synthesized poly(ethylene oxide)/poly(lactic acid) (PEO/PLA) [17–19] and poly(ethylene oxide)/poly(caprolactone) (PEO/PCL) [20] multiblock copolymers and their properties were investigated. The PEO/PLA (PELA) copolymers performed most satisfactorily as films for the prevention of post-surgical adhesions in various animal models [21,22] and are presently undergoing clinical studies. PELA elastomer performed also as the absorbable component of a highly compliant, selectively biodegradable filament wound arterial prosthesis [23,24], that remained patent and pulsating after 90 days in the canine carotid artery [25,26]. The present article focuses on the synthesis and characterization of PCL/PLA thermoplastic elastomers, where poly(L-lactic acid) generated the hard blocks and poly(caprolactone) created the soft segments along the copolymeric backbone. Following a two-stage synthesis, PLLA-PCL-PLLA triblocks were first synthesized and then chain extended with hexamethylene diisocyanate (HDI), whereby, a family of biodegradable poly(esterurethane) multiblock copolymers was obtained. The polymers comprised PCL2000 flexible segments and increasingly long PLA blocks. Light will be shed on the relationship between their composition, morphology and mechanical properties both at time zero as well as a function of their in vitro degradation.
2. Experimental Materials: PCL2000 and HDI were supplied by Aldrich (Milwaukee, USA), L-lactide was purchased from Boehringer (Ingelheim, Germany), and the stannous octanoate catalyst and dioxane were provided by Sigma (Steinheim, Germany). Drying: PCL2000 was dried under vacuum and magnetic stirring, at 105 1C, for 90 min. Triblock preparation: After drying, the calculated amounts of L-lactide (LD) and stannous octanoate, were added using a 400/1 LD/catalyst molar ratio. The first stage of the synthesis was carried out in 250 ml three-necked flasks, in the molten state (145 1C) for one
hour, under a dry nitrogen atmosphere and mechanical stirring (100 rpm). Chain extension: The second stage of the synthesis was performed by reacting the triblock with hexamethylene diisocyanate, in a 1.0:1.1 Triblock:HDI molar ratio. Twenty grams triblock were dissolved in dry dioxane and HDI was added to the dissolved triblock, followed by 0.3 g of catalyst. The reaction was conducter at 82 1C for 3 h, under a dry nitrogen atmosphere and mechanical stirring (100 rpm). The resulting polymer was precipitated into ether, dried and then dissolved in chloroform to generate a 7 wt% solution. Then, 250 mm thick films were cast from the resulting solution, by evaporating the solvent at room temperature, followed by vacuum drying to optimize solvent removal. In vitro degradation: The in vitro degradation was performed by immersing the samples under hydrolytic conditions (PBS, pH=7.4, 37 1C). The medium was changed at least once a week and the degradation process was monitored by gel permeation chromatography (GPC). Characterization: (a)Gel permeation chromatography (GPC): The average molecular weights and polydispersity were determined by GPC (Differential Separations Module Waters 2690 with refractometer detector Waters 410 and Millenium Chromatography Manager), using polystyrene standards between 472 and 360,000 Da. (b)Nuclear magnetic resonance spectroscopy (NMR): 1 H-NMR spectra were recorded using a Bruker 300 high resolution 1H-NMR spectrophotometer. All spectra were obtained at room temperature from 15% (wt/v) CDCl3 solutions. The composition of the copolymers was determined by ratioing the protons of the methylene group alpha to PCL’s ester moieties at 4.05 ppm (triplet) and the proton of the lactoyl methine peak (quartet), centered at 5.15 ppm. (c)Thermal analysis: The samples were analyzed using a Mettler TA 3000 DSC thermoanalyzer. The thermograms ranged from 120 to 200 1C at a 10 1C/min heating rate, under an inert nitrogen atmosphere. The heat of fusion was ratioed to the content (%wt) of the component crystallizing, PCL or PLA, in each specific copolymer. (d)Mechanical properties: The measurement of the mechanical properties was carried out on dogbone specimens using an Instron Universal Testing Machine (Model 4500), at a crosshead speed of 60 mm/min. A minimum of three specimens per sample were tested. Nomenclature: The poly(ester-urethane)s described in this article will be designated as PCLAs. Since all the PCL chains had the same molecular weight (2000), the copolymers will denote only the length of the PLA block present on each side of the central PCL segment. Therefore, PCLA3000, for example, designates a copolymer based on PLLA-PCL-PLLA triblocks comprising
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a PCL2000 central chain and two PLLA blocks, each of them having a molecular weight of 3000. Also, since this study focused on L-lactide only, PLLA will be denoted in the remaining of this article as PLA.
3. Results and discussion 3.1. The working concept The superior mechanical properties of thermoplastic elastomers are attributed to their unique structure, where flexible soft segments alternate with hard, preferably crystalline blocks [27]. Segmented poly (ether-urethane)s are an important example of this family of polymers [28,29]. The hard blocks generate strong domains that act as non-covalent physical crosslinks, while the flexibility of the soft segments affords the large elongation and elastic recovery, characteristic of these micro-segregated polymers. Our work aimed at developing strong biodegradable elastomers, by combining moieties which induced molecular flexibility, on one hand, and crystalline blocks that markedly strengthened the system, on the other hand, with both components being biodegradable. Poly(caprolactone) is an aliphatic polyester with a glass transition temperature around 60 1C and a low melting point (62 1C) [30]. Because of its low Tg, PCL’s amorphous phase displays high mobility at body temperature. Since short poly(caprolactone) chains are amorphous, they were selected to perform as the flexible segment present along the copolymeric backbone. Poly(L-lactic acid) is a much stiffer aliphatic polyester, with a glass transition around 55 1C and a melting point
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around 180 1C [31]. Due to these structural features, PLA was chosen to create the hard blocks along the copolymeric backbone. The syntheses of the PCL/PLA block copolymers were conducted following a two-stage method, as schematically described in Scheme 1. First, PLA-PCLPLA triblocks were synthesized by the ring opening polymerization of L-lactide, initiated by the hydroxyl terminal groups of the PCL chain. The second stage involved the chain extension of the OH-terminated PLA-PCL-PLA trimers, using hexamethylene diisocyanate (HDI), whereby urethane groups were generated along the polymeric backbone. The distinction between the high molecular weight multiblock copolymers described in this study and the diblocks and triblocks developed by other groups [32–34], is a fundamental one. The chain extension of tailor-made triblocks allowed: (i) to generate the required morphology, mainly derived from the length of the PLA and PCL segments present in the basic triblock, and (ii) to attain remarkably enhanced mechanical properties, largely due to the high molecular weight copolymers obtained after the chain extension step. Moreover, the presence of the urethane groups along the backbone also seems to be contributing to the superior mechanical behavior of these polymers. 3.2. The triblocks The length of the central PCL segment was kept constant (MW=2000), while the molecular weight of the (LA)n blocks spanned from 550 to 6000 Da. The progress of the triblock synthesis, monitored by GPC and NMR, revealed that the reaction was complete after
Scheme 1. Synthesis and structure of PCLA multiblock copolymers.
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Table 1 Molecular weight of the five PCLA copolymers synthesized Copolymer
Mn (g/mol)
Mw (g/mol)
P.D.
2000/550 2000/1100 2000/2000 2000/3000 2000/6000
92,000 109,000 124,000 112,000 89,000
168,000 175,000 187,000 176,000 154,000
1.8 1.6 1.5 1.6 1.7
Fig. 1. 1H-NMR of the PLA-PCL-PLA triblock.
approximately 1 h, a similar time frame being measured for all triblocks, regardless of their composition. GPC analysis demonstrated also that there was no unreacted PCL2000 present at the end of the reaction. The polydispersity of the PLA-PCL-PLA triblocks was narrow, with typical values in the 1.15–1.20 range. 1 H-NMR spectroscopy was used to elucidate their composition, by determining the ratio between the PCL and PLA segments. The peaks selected were the quartet at 5.15 ppm, due to the proton of PLA’s methine groups and the triplet centered at 4.05 ppm, assigned to PCL’s methylene protons alpha to the ester group (see Fig. 1).
Fig. 2. DSC thermograms of the PCLA copolymers.
3.3. The copolymers As shown in Table 1, the molecular weight (MWn) of the polymers synthesized ranged between 89,000 and 124,000, with a polydispersity between 1.5 and 1.8. (a) The morphology: Fig. 2 presents the thermograms of the five copolymers synthesized. It is apparent that their morphology gradually changed, as the length of the PLA blocks increased. PCLA550 was the only polymer comprising a crystalline poly(caprolactone) segment, with PLA generating an amorphous matrix. PLA blocks were too short to crystallize and also to prevent PCL’s crystallization. This copolymer exhibited a Tg around 30 1C and a relatively sharp Tm peak at 42 1C (DH=19 J/g). The pronounced shift of poly(caprolactone)’s glass transition to a higher temperature reflects the stiffening effect the PLA blocks exerted on the PCL chains. Likewise, PCLs melting
endotherm appeared at a lower temperature since the PLA affected PCLs crystallizability. These findings indicate also that some degree of phase blending took place between the two components. As the length of the PLA blocks increased, the phases were able to segregate more efficiently, as exemplified by the comparison between PCLA1100 and PCLA2000. The former was the most amorphous of all copolymers synthesized, with both constituents being essentially amorphous. Two glass transitions at around 27 and 41 1C, attributed to the PCL and PLA phases, respectively, were discernible. Only a small and ill defined melting endotherm around 104 1C, due to the incipient degree of crystallinity of the PLA chains, could be observed. PCLA2000 comprised longer, more crystalline PLA blocks, displaying a broad Tm at 118 1C (DH=27
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J/g). As the molecular weight of the poly(lactic acid) blocks increased further (PCLA3000), no glass transitions could be measured and a sharper melting peak was apparent at 144 1C, characterized by a large heat of fusion (32 J/g). Expectedly, the copolymer comprising the longest PLA segments (MW=6000), exhibited only a sharp and large PLA-derived melting endotherm, centered at 156 1C, with an even higher heat of fusion (39 J/gr). (b) The mechanical properties: It is apparent from the data presented in Figs. 3(a)–(c) that, by dictating their morphology, the composition of the PLA-PCL-PLA triblocks played a key role in determining the mechanical behavior of the copolymers. While a similar ultimate tensile strength was measured for all the copolymers (around 32 MPa), their stiffness and ability to stretch varied markedly as the length of the PLA block increased. PCLA550 and 1100 were strong and extremely flexible elastomers, displaying a Young modulus of around 30 MPa and elongation at break values of 1600% and 600%, respectively. As the molecular weight of the (LA)n blocks raised, the materials became increasingly stiff, with E values climbing up to 800 MPa for PCLA6000. Concomitantly, the strain to failure decreased steadily, from above 1600% for PCLA550, down to around 100% for PCLA6000. The gradual stiffening of the copolymers can be readily attributed to the combined effect of increasingly higher PLA contents comprising progressively more crystalline PLA blocks. Clearly, while the ultimate tensile strength was primarily dictated by the molecular weight of the polymer, the elastic properties were mainly determined by the morphology of the triblock. It is apparent from these data, that PCLA multiblock copolymers displayed mechanical properties markedly superior to those exhibited by other biodegradable elastomers recently developed. For example, while PCLA copolymers attained UTS levels above 30 MPa, poly(glycerol sebacate) (PGS) exhibited a tensile strength slightly above 0.5 MPa [15]. Aiming at creating a highly flexible material that is able to stretch substantially, PGS was designed to have a low crosslinking density. Furthermore, as reported [15], PGS is fully amorphous at body temperature, with no glass transition temperatures being observed above 80 1C. These characteristics of PGS may explain its poor mechanical properties. In clear contrast, PCLA multiblock copolymers were tailored so they generated a micro-segregated morphology, where the PCL amorphous chains performed as a molecular coil, while the crystalline PLA blocks functioned as strong non-covalent crosslinking domains. The high molecular weight multiblock copolymers combined, therefore, high flexibility, enhanced strength and superior extendibility.
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Fig. 3. Mechanical properties of the PCLA copolymers as a function of composition: (a) ultimate tensile strength (MPa); (b) Young’s modulus (MPa); (c) elongation at break (%).
3.4. The degradation process The in vitro degradation of these polymers is exemplified in Fig. 4, by presenting the chromatograms of PCLA2000 as a function of degradation time. The initial molecular weight of the polymer was 190,000,
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Fig. 4. GPC curves for PCLA2000 as a function of their in vitro degradation.
decreasing to 83,000 and 48,000 after 1 and 3 months, respectively, while after 6 months the molecular weight was only 5% of its initial value. The slowest degrading material was PCLA6000, retaining about 50% of its initial molecular weight after 75 days, whereas PCLA2000, for example, reached this point already after 28 days. Expectedly, all the copolymers degraded faster than the two homopolymers, with PLA and PCL losing 50% of their initial molecular weight after 5 and 12 months, respectively. (a) The mechanical properties: Figs. 5(a)–(c) plot the change in the mechanical properties of PCLA copolymers, over a period of 90 days. It is apparent that the polymers retained their initial Young’s modulus, while both the ultimate tensile strength as well as the elongation at break values changed substantially over the same period of time. The tensile strength of PCLA copolymers dropped gradually, from their high initial levels (around 30–34 MPa), reaching the 2–3 MPa level after 3 months, with PCLA3000 and PCLA6000 decreasing at the slowest pace. Predictably, as their molecular weight decreased, the extendibility of the polymers decreased markedly. Its worth stressing, though, that due to their remarkable initial mechanical properties, most of these copolymers remained flexible and tough elastomers for a significant period of time. After 45 days in vitro degradation, for example, PCLA1100 displayed a strength of around 8 MPa, a modulus of approximately 40 MPa and a strain to failure of around 120%. (b) Morphology changes: The thermograms shown in Figs. 6(a)–(c) illustrate the change in the morphology of three PCLA polymers as a function of their degradation. As already shown in Fig. 2(b), poly(caprolactone) is the
Fig. 5. Mechanical properties of the PCLA copolymers as function of their in vitro degradation: (a) ultimate tensile strength (MPa); (b) Young’s modulus (MPa); (c) elongation at break (%).
only component able to crystallize in PCLA550, as demonstrated by the melting endotherm at 42 1C. Given this initial morphology, it was anticipated that the PLA blocks would degrade faster than the PCL segments,
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Fig. 6. DSC thermograms of three PCLA copolymers as a function of their in vitro degradation. (a) PCLA550; (b) PCLA2000; (c) PCLA6000.
resulting in an increasingly crystalline poly(caprolactone) phase. The appearance and growth of an additional PCL melting peak and its gradual shift to higher temperatures (up to 54 1C), as shown in Fig. 6(a), is in full accordance with these considerations. Fig. 6(b) presents the thermograms of PCLA2000 over a 10 month degradation period. Noticeably, the longer PLA blocks present in this copolymer, as opposed to PCLA550, caused a fundamental change in its initial structure, with PLA blocks being the only crystalline component present at time zero. A progressive increase in the degree of crystallinity of the PLA component, took place during the first 5 months, as revealed by the shift of the peak to higher
temperatures, from 118 1C up to 125 1C. As degradation proceeded further, a system with two crystalline phases was produced. At 10 months, for example, two sharp melting endotherms, centered at 58 and 121 1C, due to the PCL and PLA segments, respectively, were apparent. The thermograms shown in Fig. 6(c) demonstrate that a further increase in the molecular weight of the PLA blocks, produced a material where only PLA was able to crystallize to a significant extent, as the polymer degraded. It was only after 8 months degradation, that PCL was able to exhibit some degree of crystallinity, albeit very modest, as revealed by the small and broad endotherm around 50 1C.
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spring, while the crystalline PLA blocks functioned as strong non-covalent crosslinking domains. These thermoplastic elastomers combined remarkable strength (UTS values around 32 MPa), high flexibility (tensile moduli as low as 30 MPa) and enhanced extendibility (above 600%). By tightly controlling the ratio between the PCL and PLA segments and their respective degrees of polymerization, the degradation rate was varied over a wide time range. References
Fig. 7. DSC thermograms of three PCLA copolymers after 15 months in vitro degradation. (a) PCLA550; (b) PCLA2000; (c) PCLA6000.
Fig. 7 compares the morphology of PCLA550, 2000 and 6000, after 15 months degradation. As opposed to the other two copolymers shown, PCLA550 displayed a monophasic crystalline structure, with a large and sharp PCL melting endotherm. PCLA2000 and 6000, on the other hand, generated biphasic morphologies where both constituents were able to crystallize. The composition of the various copolymers changed differently over time, depending on their initial composition and morphology, as determined by NMR spectroscopy (see Fig. 1). In the case of PCLA550, for example, the ratio between the PCL and PLA peaks increased by a factor of five, over 15 months degradation, indicating a substantial poly(caprolactone) enrichment. Most of the mass loss, therefore, was due to short PLA fragments leaving the system by readily dissolving into the aqueous medium. In the case of PCLA6000, on the other hand, a different behavior was apparent, with the basic ratio between the two components being essentially constant, over time.
4. Conclusions Our work aimed at developing biodegradable thermoplastic elastomers, by capitalizing on their particular micro-structure and superior mechanical properties. The morphology of PCLA copolymers was investigated and its dependence on compositional parameters was assessed. These PCL/PLA copolymers generated a micro-segregated morphology, where the poly(caprolactone) amorphous chains performed as a molecular
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