Novel Biodegradable Shape Memory Material Based on Partial

Sep 18, 2008 - A novel shape memory material was prepared based on the formation of inclusion complexes between α-cyclodextrin (α-CD) and poly(ϵ-ca...
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Biomacromolecules 2008, 9, 2573–2577

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Novel Biodegradable Shape Memory Material Based on Partial Inclusion Complex Formation between r-Cyclodextrin and Poly(E-caprolactone) Haiya Luo,† Yan Liu,† Zhijun Yu,† Sheng Zhang,*,† and Bangjing Li*,‡ State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Sichuan University, Chengdu 610065, China, and Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China Received April 30, 2008; Revised Manuscript Received September 9, 2008

A novel shape memory material was prepared based on the formation of inclusion complexes between R-cyclodextrin (R-CD) and poly(-caprolactone) (PCL); the PCL-R-CD inclusion crystallites serve as a fixing phase, while free PCL crystallites serve as a reversible phase. The characteristics of the material were investigated and a mechanism for the shape memory behavior was proposed. This material showed good shape memory properties, with the recovery ratio exceeding 90% and the recovery time being less than 6 s at 90 °C. This PCLR-CD partial inclusion complex lost about 50% (47.4 ( 4.4%) weight within 45 days in presence of lipase, indicating its degradability. The shape memory and biodegradation properties of the well-designed polymer-RCD complexes indicate great promise for this novel shape memory material.

Introduction Shape memory polymers (SMPs) are materials which can remember and recover their original shape after mechanical shaping deformations. The shape memory effect is typically initiated by a change in temperature.1,2 In principle, thermally induced SMPs go through two phases on the molecular level: a thermally reversible phase with lower switch transition temperature (Ttrans) determines the temporary shape and a fixing phase with higher thermal transition temperature fixes the permanent shape.3 A variety of thermoresponsive SMPs have been reported in the literature and have found applications such as sensors, transducers, actuators, and medical treatments.4-6 For medical treatments, the SMPs should be both biodegradable and highly shape recoverable. One example of the application of SMPs is their use as an implant device in minimally invasive surgery. The degradable implant could be inserted into the human body in a compressed (temporary) shape through a small incision. When the device is placed at the correct position, it obtains its application (original) shape after being warmed up to body temperature. After a defined time period, the device is degraded, eliminating the need for a second surgery for its removal. Several kinds of biodegradable SMPs have been developed in the recent decade.2,7-10 To date, most biodegradable SMPs known are block copolymers or cross-linked polymer networks, which are given two-phase structure by covalent linking method. In this study, we constructed a poly(caprolactone)-R-cyclodextrin (PCL-R-CD) partial inclusion complex (IC) using molecular recognition of CDs with PCL. The partial ICs are designed to contain thermally sensitive naked PCL segments and thermally stable PCL-R-CD inclusion segments. PCL was selected as the inclusion guest to form partial ICs because of its biodegradability and tissue compatibility. Furthermore, medical devices containing PCL have been * To whom correspondence should be addressed. Tel.: +86-28-85400266. E-mail: [email protected]; [email protected]. † Sichuan University. ‡ Chinese Academy of Sciences.

used safely in humans. Finally, the low melting temperature of PCL (Tm ) 40-65 °C) is suitable as Ttrans for clinical applications.

Experimental Section Materials. PCL with different molecular weights (Mn ) 1,000 or 80,000), R-CD and lipase from porcine pancrease (type II, 100-400 units/mg protein) were purchased from Aldrich Chemical Co. The PCL samples and R-CD were dried in a vacuum at 60 °C for 4 h before use. All solvents were local commercial products and used without further purification. Preparation of Partial ICs. Films of PCL-R-CD partial IC were prepared by casting solution in a rectangular glass mold (60 × 80 × 30 mm). As an example, the preparation of P8030 is described (the first two digit numbers in abbreviation of samples indicate that the molecular weight of PCL was 80000, while the last two digit numbers in abbreviation of samples indicate the theoretical content of PCL-RCD ICs). Method A (using acetone and water as solvent): 229 mg of PCL (Mn ) 80000) was dissolved in 50 mL of acetone at 60 °C and 83.6 mg of R-CD was dissolved in 10 mL of distilled water. The R-CD aqueous solution was heated to 60 °C and then added to the PCL solution dropwise under stirring. After stirring for 2 h, a film was prepared by casting the solution (casted volume was 60 mL) under atmospheric condition at 60 °C. The solvent was allowed to evaporate for 3 h. With this method, the PCL precipitated quickly after adding the CD aqueous solution to the acetone solution of PCL so that the resulting film was blend of free PCL and uncomplexed R-CD and the film disintegrated after washing with water and tetrahydrofuran (THF). So we used Method B to prepare partial ICs. Method B (using DMF as solvent): 229 mg of PCL was dissolved in 40 mL of dimethylformamide (DMF) and 83.6 mg of R-CD was dissolved in 10 mL of DMF. Both solutions were stirred in an oil bath at 70 °C, and then the R-CD solution was added dropwise to the PCL solution (casted volume was 50 mL) under stirring. After stirring for 2 h, a film was prepared by casting the solution under atmospheric condition at 70 °C. The solvent was allowed to evaporate for 6 h. The

10.1021/bm8004726 CCC: $40.75  2008 American Chemical Society Published on Web 09/18/2008

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Communications After predetermined periods of times, the samples were centrifuged out (1000 r/min for 5 min) from the buffer, then washed with distilled water, and dried in vaccum at 40 °C.

Results and Discussion

Figure 1. X-ray diffraction patterns of (a) R-CD, (b) homoPCL (Mn ) 80000), (c) complete PCL-R-CD, and (d) P8030.

resulting film was washed with water and THF several times to remove the free PCL and uncomplexed R-CD and dried under vacuum at 40 °C for 24 h. The PCL-R-CD (Mn of PCL ) 10000) complete IC was prepared as described by Harada.11 Measurements. Wide angle X-ray diffraction measures were carried out on PHILP X’Pert MPD with nickel filtered Cu KR radiation source (voltage, 50 KV; current, 35 mA; scanning speed, 2°/min). To obtain melting temperature and heats of fusion, differential scanning calorimetry (DSC) was carried out on 5-10 mg samples with a NETZSCH DSC 204 instrument operated at a heating rate of 10 °C/min. Thermogravimetric analyses (TGA) were performed using a Dupont 2100 thermal analysis apparatus. The samples were heated from 25 to 500 °C in a dynamic nitrogen atmosphere at a rate of 10 °C/min. Dynamic mechanical analysis (DMA) was performed using a DMA Q800 V7.1 instrument in the strain mode at a fixed frequency of 1 Hz and under nitrogen gas purging. The measured specimen was heated from 30 to 100 °C. Shape Memory Behavior Test. The shape memory effect was evaluated according to a method described by Liu et al.12 A straight strip (13.0 × 0.5 × 0.1 mm) of the specimen was deformed to an angle θo at 90 °C and then cooled down to room temperature to maintain the deformation (θi). The deformed sample was heated again to 90 °C rapidly and the deformation angle θf was recorded. The ratio of the recovery was defined as (θi - θf)/θi. The fixity ratio was defined as θi/θo. The recovery time is the time required for the deformed shape to recover its original shape. Biodegradability Test. Biodegradability of P8030 was evaluated by an enzymatic test at 37 ( 1 °C.13 The degradation was expressed by the weight loss. A total of 20 mg of sample were immersed in pH 7.4 PBS medium with 2 mg/mL of lipase. The test bottle was shaken at regular intervals and the buffer medium was renewed every 3 days.

CDs are one of the most important host compounds in supramolecular chemistry. The doughnut-shaped geometry of CDs gives a cavity allowing CDs to incorporate guests to form host-guest ICs. Since Harada et al. discovered that R-CD can form a crystalline IC with poly(ethylene glycol) (PEG) in aqueous solution,14 many polymeric guests have been found to form ICs with different types of CDs.11,15-17 For instance, PCL (Mn ) 530-40000) was found to form complete ICs with R-CDs to give a crystalline powder.17,18 Complete ICs are complexes for which the whole polymer chain is covered by CDs. The PCL-R-CD complete ICs are stoichiometric one to one (R-CDs: monomer unit) compounds and show thermal stability (decomposing above 340 °C while melting).18 We have found that if the molecular weight of PCL is high enough (Mn of PCL ) 80000) and the R-CD/PCL is suitable, PCL-R-CD partial IC films (which contain both PCL-R-CD crystallites and uncovered PCL segments) can be obtained by casting solutions at 70 °C using DMF as solvent. After washing with water and THF several times to remove the free PCL and uncomplexed R-CD, the resulting films were analyzed by wide angle X-ray diffraction. As shown in Figure 1, the X-ray diffraction pattern of the P8030 (Mn of PCL ) 80000; theoretical mass proportion of the inclusion segments ) 30%) showed both typical PCL-R-CD inclusion channel crystalline peak (2θ ) 19.9°) and homoPCL crystalline peaks (2θ ) 21.3° and 23.6°), whereas the R-CD crystalline peak (2θ ) 21.8°) was absent.17,18 This indicated that the P8030 was not a blend of R-CDs and PCL, but rather a partial PCL-R-CD IC simultaneously containing channel-type supramolecular crystallite (PCL-R-CD inclusion) and homoPCL crystallite. For the PCL with molecular weight of 10000, however, it was difficult to obtain the complex films. The resulting mixture was very rigid and brittle, even when the theoretical mass proportion of the inclusion segments was only 20%. In contrast to the cases for complex formation between R-CDs and low molecular weight of PCL in the literature,17,18 we could not get the PCL-R-CD partial IC films using acetone and water as solvent. The PCL precipitated quickly after adding the CD aqueous solution to the acetone solution of PCL, which may be due to the fact that the solubility of higher molecular weight PCL decreased sharply after adding water to system. So PCL-R-CD partial IC films were all prepared by using DMF as solvent in this paper. It should also be noted

Figure 2. (A) TGA thermograms of (a) homoPCL, (b) P8030, (c) P8040, (d) P8050, and (e) R-CD; (B) DSC thermograms of (a) PCL-R-CD complete IC, (b) P8030, and (c) homoPCL (Mn ) 80000).

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Table 1. Composition of R-CD-PCL Partial Inclusion Complex Filmsa decomposion temperature (°C)

mass ratio of free PCL/PCL-R-CD inclusion

first step second step theoretical estimated from TGA PCL P8030 P8040 P8050 R-CD

355 331 335 332 271

352 353 354

70/30 60/40 50/50

69/31 66/34 55/45

a The first two digit numbers in abbreviation of samples indicated that the molecular weight of PCL was 80000. The last two digit numbers in abbreviation of samples indicated the theoretical content of PCL-R-CD ICs.

that it is hard to get the complex films when the ratio of R-CD/ PCL is too low or too high. When the theoretical proportion of inclusion segment was less than 30%, the resulting films dissolved totally during purification. When the theoretical proportion of inclusion segment was more than 50%, the films were rigid, brittle, and hard to be shaped. The thermal stabilities of PCL-R-CD partial ICs, homoPCL (Mn ) 80000), and R-CD were investigated by TGA, and the results are shown in Figure 2A. It was seen that all of the PCLR-CD partial ICs showed two-step thermal degradation. The

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first step was attributed to decomposition of R-CD and showed a much higher decomposition temperature than pure R-CDs. The second degradation step was attributed to the free PCL component. This two-step weight loss behavior can be used to estimate the ratio between the R-CD-PCL inclusion and the free PCL. Although the TGA method may not be very accurate due to the partially overlapping of the two weight loss steps, the R-CD contents estimated from TGA were in agreement with the design ratio (as shown in Table 1). Especially for P8030, the composition calculated from TGA was almost consistent with the feed ratio. DSC was carried out to get the thermal information for PCLR-CD partial IC (P8030). In Figure 2B, P8030 presented an endothermic peak at 59 °C, which is similar to the endothermic peak of homoPCL. This indicated that some of the PCL segments in P8030 were uncovered by R-CDs and formed PCL crystallite. In contrast, the PCL-R-CD complete IC showed no thermal transition during the course of heating because every single polymer chain is closely included in the channels formed by R-CDs. As expected, the partial ICs obtained in this study exhibited typical thermoresponsive shape memory function, which was very different from the homopolymer (pure PCL melt above Tm) and complete PCL-R-CD ICs (the complete ICs are

Figure 3. (A) Photographs demonstrating the macroscopic shape memory behavior for P8030: (a) original shape, (b) temporary shape, and (c) recovered shape at 80 °C; (B) The recovery ratio (squares) and fixity ratio (circles) as a function of inclusion ratio (recovery temperature is 90 °C); (C) The recovery time as a function of temperature for the P8030 (recovery time is the time required for the deformed sample to recover its original shape); (D) Temperature dependence of storage modulus E′ for the (a) homoPCL (Mn ) 80000), (b) P8050, (c) P8040, and (d) P8030 measured by DMA.

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Figure 4. Molecular mechanism of shape memory effect of partial PCL-R-CD partial ICs: pure PCL crystallites (ordered lines in small rectangles) as reversible phase and PCL-R-CD inclusion crystallites (filled ovals) as fixed phase.

Figure 5. Degradation behaviors of P8030 (circles) and homoPCL (squares) in presence of lipase at 37 °C.

thermally stable until decomposition above 300 °C). An example of the macroscopic shape memory effect of PCL-R-CD partial ICs was demonstrated in Figure 3A. A band of P8030 was changed into a semicircular shape at 90 °C and then cooled rapidly to room temperature. On heating again to 90 °C, the specimen recovered its original band shape. The same method used to evaluate the shape memory effect of alloys was adopted to investigate that of the partial ICs.13,19 Figure 3B shows the recovery ratio and fixity ratio of different PCL-R-CD partial ICs. All of the recovery ratios were beyond 90%. The recovery ratio of P8030 was 94.4%. The recovery ratio decreased slightly, however, as the inclusion content of specimen increased. This may be due to the fact that the complex with higher inclusion ratio has compositional heterogeneity. It has been reported that high hard content may result in a compositional heterogeneity, which consist of two parts: high hard segment content part and low hard segment content part. The compositional heterogeneity can worsen the shape memory behavior of the complex.12 The fixity ratio of PCL-R-CD partial ICs also decreased slightly as the inclusion content increased. Figure 3C displays the final recovery time of P8030 under different testing temperatures. The original shape was straight strip, and the deformed shape was the folded shape. The recovery time is the time required for the deformed shape to recover its original shape.20 The recovery time of P8030 is shorter at higher temperature than that at low temperature, indicating that the recovery rate increased with temperature. Difference in the modulus below and above the Ttrans is a significant property to describe the shape memory function. A high storage modulus ratio (E′trans-20 °C/E′ trans+20 °C) implies good shape fixity on cooling and large shape recovery upon heating.19 As shown in Figure 3D, a pronounced drop in storage

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modulus (E′) occurred for PCL-R-CD partial ICs as temperature increased. Note that the E′ curve for pure PCL above 70 °C can not be obtained because of melting. Such results indicate that the melting of the free PCL segments in the complex conferred large scale motion to the complex material, which abruptly becomes soft and flexible above the transition temperature (60 °C). The complexes, however, do not disintegrate due to the presence of the thermally stable inclusion segments, which limit the disentanglement of the chains. It can be seen that the E′ of PCL-R-CD partial ICs decreased as the inclusion content increased, which may be also assigned to the compositional heterogeneity for complex with higher inclusion ratio. A mechanism of the shape memory effect found in PCL-RCD partial ICs can be proposed as follows: depending on the designed ratio, R-CD molecules will thread along the PCL chains to form PCL-R-CD inclusion crystallites between CL monomers and R-CD (filled oval) and homoPCL crystallites (the ordered structure in small rectangles), respectively. When heating the specimen above Tm(PCL), the naked PCL segments become flexible following fusion of the PCL crystallites. The PCL-R-CD inclusion crystallites, however, remain stable and act as anchors to prevent the chains from slipping. This material shows entropy elasticity and can readily be deformed by application of an external stress. (Figure 4, process 1). When the deformed specimen is cooled under the external stress, the deformation becomes “frozen” due to the crystallization of the naked PCL segments (Figure 4, process 2). Upon heating the specimen up to Tm(PCL) again, the strength of the “frozen deformed specimen” disappears. As a result of its entropy elasticity, the materials recovered its original shape (Figure 4, processes 3 and 4). The “switch function” of the naked PCL segments is the result of their fusion and crystallization transition. Recently a series of biodegradable shape memory copolymers or polymer networks have been developed by synthetic methods using oligo-PCL as the component.3 The degradation behavior of the supramolecular material (P8030) obtained in this study was determined by weight loss measurements performed after incubating the partial ICs in pH 7.4 phosphate buffer solution with lipase at 37 °C. It was observed that the weight of the sample decreased significantly during 45 days in the enzymatic solution (Figure 5). Furthermore, the weight loss rate of P8030 was faster than that of pure PCL.

Conclusions In conclusion, a novel biodegradable shape memory material based on PCL-R-CD partial IC was developed in this study. Depending on the design ratio, R-CD molecules threaded along the PCL chains to form PCL-R-CD ICs and leave some free PCL crystallites, which accounted for the fixing phase and reversible phase, respectively. We believe that this kind of materials could be optimized for use in medicine. Considering that a wide range of polymers (including many degradable polymers) have been reported to penetrate CDs with cavities of different sizes to form inclusion complexes, the self-assembly inclusion method described in this study is expected to broaden the list of degradable shape memory materials. Acknowledgment. This work was funded by the National Natural Science Foundation of China (Grant Nos. 50703025 and 30600148).

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(13) Shin, K. M.; Dong, T.; He, Y.; Taguchi, Y.; Oishi, A.; Nishida, H.; Inoue, Y. Macromol. Biosci. 2004, 4, 1075. (14) Harada, A.; Kamachi, M. Macromolecules 1990, 23, 2821. (15) Kavaguchi, Y.; Nishiyama, T.; Okada, M.; Kamachi, M.; Harada, A. Macromolecules 2000, 33, 4472. (16) Li, J.; Ni, X.; Zhou, Z.; Leong, K. W. J. Am. Chem. Soc. 2003, 125, 1788. (17) Lee, S.; Kim, J. M. Macromolecules 2007, 40, 9201. (18) Huang, L.; Allen, E.; Tonelli, A. E. Polymer 1998, 39, 4857. (19) Liu, G. Q.; Ding, S. B.; Cao, Y. P.; Zheng, Z. H.; Peng, Y. X. Macromolecules 2004, 37, 2228. (20) Zheng, X. T.; Zhou, S. B.; Li, X. H.; Weng, J. Biomaterials 2006, 27, 4288.

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