Designing and synthesis of shape memory polymers for biomedical application

DESIGNING AND SYNTHESIS OF SHAPE-MEMORY POLYMERS FOR BIOMEDICAL APPLICATION XUE LIANG NATIONAL UNIVERSITY OF SINGAPORE 2010 DESIGNING AND SYNTHESIS OF SHAPE-MEMORY POLYMERS FOR BIOMEDICAL APPLICATION XUE LIANG (Msc in Chemistry, Zhejiang University, China ) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHYLOSOPHY DEPARTMENT OF CHEMICAL & BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2010 To My Family ACKNOWLEDGEMENTS First of all, I would like to express my sincere gratitude to my supervisor, Professor Li Zhi, for his patient supervision, encourage and continuous support. He is always helping me to solve the problems and sharing his inspiring ideas, the most important thing he makes me understand is how to research. He also seizes every tiny problem and tries to solve it promptly. Such kind of critical attitude and rigorous scholarship in research will accompany me in the rest of my life. This thesis has benefited by many other people’s efforts. I would like to acknowledge Professor Hong Liang and Prof. George Zhao for their helpful advices and discussions. I would specially thank Dr. Lou Xian Jun for his help in doing cytotoxicity test. The kind helps from Mdm. Li Fengmei, Mdm. Li Xiang, Ms. Chew Su Mei, Mdm. Han Yanhui, Mr. Wong Chee Ping, Mr. Cheung Augustine, Dr. Dharmarajan Rajarathnam, Mr. Ng Kim Poi, Mr. Boey Kok Hong, Ms. Tay Kai Si, and Ms. Xu Yanfang, are really appreciated. Without their help, this thesis would never have been so successful. The financial support provided by National University of Singapore was also gratefully acknowledged. Additional thanks go to my colleagues, Dr. Dai shiyao, Dr. Zhang Wei, Dr. Christine Schutz, Ms. Tang Weng Lin, Dr. Wang Zunsheng, Dr. Xu Yi, Mr. Jia Xin, Ms. Wang Wen, Mr. Mojtaba Binazadeh, Mr. Pham Quang Son, Ms. Ngo Nguyen Phuong Thao, and Dr. Mou Jie, for their friendship and valuable discussion during the study. Special thanks go to my friends, Ms. Lai Siok Lian, and Ms. Chieng Yu Yuan. You always patiently answer the questions for me and helped me a lot at the beginning of my Ph.D. study. You are also good listeners whenever I met any troubles in life or i researches. I really spent a great time with all of you. I would also thank my other friends: Ms. Wang Yanyan and Ms. Lou Liping. Last but not least, I would like to express my gratitude from to my parents, husband and brother. Thank you very much for your continuous and invaluable support in my life. I could not finish the whole study without the great love and care from you. ii TABLE OF CONTENT ACKNOWLEDGEMENTS . I LIST OF FIGURES . VII LIST OF TABLES XI LIST OF SCHEMES XIII NOMENCLATURE XIV SUMMARY XVII CHAPTER INTRODUCTION .1 1.1 Shape-memory alloys 1.2 Shape-memory polymers 1.3 Thermally-induced shape-memory polymers . 1.4 SMPs with PCL as switching segment and polyurethane as hard segment 1.5 SMPs with PCL as switching segment and macrodiol as hard segment . 1.6 Biodegradable SMP as fast self-expandable stent 1.7 Biodegradable SMP as self-expandable drug-eluting stent 1.8 Objective . 1.9 Thesis organization . CHAPTER LITERATURE REVIEW 2.1 Parameters for Characterization of Shape-Memory Properties 2.2 Indirect Actuation of Thermally-Induced SMPs . 11 2.3 Direct Actuation of Thermally-Induced SMPs . 12 2.4 Chemically Cross-linked SMPs 13 2.4.1 Tg-dependent chemically cross-linked SMPs . 14 2.4.2 Tm-dependent chemically cross-linked SMPs . 16 2.5 Physically Cross-linked SMPs 18 2.5.1 Tg-dependent SMPs .20 2.5.2 Tm-dependent physically cross-linked SMPs .23 2.5.2.1 PCL-based SMPs with non-crystallizable polyurethane as hard segment 23 iii 2.5.2.2 PCL-based SMPs with crystallizable macrodiol as hard segment 27 2.6 Chemically and Physically Double Cross-linked SMPs . 28 2.7 Shape-Memory Composites and Blends . 28 2.8 Biodegradable Shape-Memory Systems . 29 2.8.1 Biodegradable thermoplastic elastomers with shape-memory effect . 30 2.8.2 Poly(ε-caprolactone) as biomaterials in biomedical applications . 31 2.9 Application of SMPs . 31 2.9.1 The application of SMPs as smart suture . 32 2.9.2 The application of SMPs as stent . 33 2.9.3 The application of SMPs as actuator 34 2.10 Enzymatic ring-opening polymerization . 35 2.10.1 The general aspect of ring-opening polymerization of lactones . 35 2.10.2 Mechanism of lipase-catalyzed ring-opening polymerization of cyclic lactones . 36 2.11 Poly[(R)-3-hydroxyalkanoate]s (PHAs) . 37 2.11.1 General concept of PHAs . 37 2.11.2 Poly[(R)-3-hydroxybutyrate] (PHB) 38 2.11.2.1 Production of PHB 39 2.11.2.2 Physical properties of PHB . 39 2.11.3 Poly(3-Hydroxybutyrate-co-3-Hydroxyvalerate) . 40 2.12 Stents in the treatment of coronary arteries 42 2.12.1 Metallic stent 42 2.12.2 Polymeric stents 43 2.12.2.1 Biostable polymeric stent 43 2.12.2.2 Biodegradable polymeric stent 43 2.12.3 Drug-eluting stents . 45 2.12.3.1 Paclitaxel-eluting stent 46 CHAPTER MATERIALS AND CHARACTERIZATION METHODS .47 3.1 Materials . 47 3.2 Material synthesis . 47 3.2.1 General procedure for the preparation of three-arm PCL-triols by enzymatic ring-opening polymerization of ε-caprolactone with glycerol 47 3.2.1.1Preparation of three-arm PCL (Tm of 47 oC, Mn of 4200 g/mol) 48 3.3 Characterization of materials 48 3.3.1 Characterization of molecular weight and structure . 48 3.3.1.1 Gel Permeation Chromatography (GPC) 49 3.3.1.2 Nuclear Magnetic Resonance (NMR) . 49 3.3.2 Characterization of thermal property 49 3.3.2.1 Differential Scanning Calorimetry (DSC) . 49 3.3.3 Characterization of mechanical and shape-memory properties 50 3.3.3.1 Tensile Stress Test 50 iv 3.3.3.2 Collapsed pressure 50 3.3.3.3 Shape-Memory Properties .50 3.3.4 Cell culture, cytotoxicity, and biocompatibility of materials . 51 3.3.5 Evaluation of SMPs as self-expandable stent . 52 3.3.6 Preparation drug-eluting stent and drug release profiles 52 CHAPTER SYNTHESIS AND CHARACTERIZATION OF THREEARM POLY(ε-CAPROLACTONE)-BASED POLY(ESTER-URETHANES) WITH SHAPE-MEMORY EFFECT AT BODY TEMPERATURE … 54 4.1 Introduction . 54 4.2 Experimental Section 57 4.2.1 General procedure for synthesis of three-arm PCL-based poly(ester-urethane)s (tPCLPUs). 57 4.2.2 Preparation of three-arm PCL-based poly(ester-urethane) (tPCL-PU) (sample M). 57 4.3 Results and Discussion . 59 4.3.1 Enzymatic synthesis of three-arm PCL-triols. 59 4.3.2 Preparation and structure analysis of three-arm PCL-based polyesterurethanes (tPCLPUs). 65 4.3.3 Thermal properties of tPCL-PUs. . 70 4.3.4 Mechanical and shape-memory properties of tPCL-PUs. 71 4.4 Conclusion 75 CHAPTER BIODEGRADABLE SHAPE-MEMORY POLYMR AS FAST SELF-EXPANDABLE STENT .76 5.1 Introduction . 76 5.2 Experiments 79 5.2.1 Preparation of PHBV-diol. . 79 5.2.2 Synthesis of poly(PCL-PHBV)urethanes (PCTBV)s. 79 5.3 Results and Discussion . 80 5.3.1 Synthesis of poly (PCL-triol/PHBV-diol) urethanes (PCLBVs). . 80 5.3.2 Mechanical properties of PCTBVs. 86 5.3.3 Shape-memory properties of PCTBVs. 86 5.3.4 Cytotoxicity test of PCTBVs. . 89 5.3.5 Evaluation of PCTBV-25 as self-expandable stent. . 91 5.4 Conclusion 93 CHAPTER EVALUATION OF BIODEGREDADABLE SHAPEMEMORY POLYMERS AS FULL POLYMERIC AND SELFEXPANDABLE DRUG-ELUTING STENT 95 v 6.1 Introduction . 95 6.2 Materials and methods 98 6.2.1 Synthesis of 2-Oxepane-1,5-dione (OPD) 98 6.2.2 Synthesis of poly(2-Oxepane-1,5-dione)-diol (POPD) 98 6.2.3 Synthesis of poly(ester-urethane)s (PCTOPD)s containing hyperbranched three-arm PCL block and POPD block 98 6.3. Result and Discussion 100 6.3.1 Synthesis of poly(2-Oxepane-1,5-dione)-diol (POPD) . 100 6.3.2 Synthesis of poly(ester-urethane)s (PCTOPD) containing hyperbranched three-arm PCL block and POPD block 104 6.3.3 Mechanical properties of PCTOPDs 106 6.3.4 Shape-memory properties of PCTOPDs. 108 6.3.5 Cytotoxicity and biocompatibility of PCTOPDs 109 6.3.6 Evaluation of PCTOPD-27 as self-expandable stent. . 110 6.3.7 In vitro drug release of PCTOPD stents. 112 6.3.8 Collapsed pressure of PCTOPD-27 stents. . 113 6.4 Conclusions . 115 CHAPTER CONCLUSION AND RECOMMENDATIONS . 117 7.1 Conclusion 117 7.2 Future Work 120 REFERENCES . 124 LIST OF PUBLICATIONS……………………………………………….141 vi LIST OF FIGURES Figure 1.1 A simplified scheme for shape-changes of SMP from deformation to recovery upon application of external stimulus. Figure 2.1 Characterization of shape-memory properties with cyclic thermomechanical tensile test. Figure 2.2 Characterization of shape-memory properties with bending test. 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Li, Synthesis and characterization of three-arm poly(epsiloncaprolactone)-based poly(ester-urethanes) with shape-memory effect at body temperature. Macromolecules, 2009, 42(4) 964. L. Xue, S. Dai and Z. Li, Biodegradable shape-memory block co-polymers for fast self-expandable stents. Biomaterials, 2010, 31, 8132. L. Xue, S. Dai and Z. Li, Evaluation of biodegradable shape-memory polymers as full polymeric and self-expandable drug-eluting stent. (Submitted to Adv. Func. Mat.) S. Dai, L. Xue, Z, Manfred, Z. Li, Enzyme-catalyzed polycondensation of polyester macrodiols with divinyl adipate: a green eethod for the preparation of thermoplastic block copolyesters. Biomacromolecules, 2009, 10(12), 3176. 141 [...]... properties of PCTBVs and PCDBVs xi Table 5.2 Shape- Memory Properties of PCTBVs and PCDBVs Determined by Cyclic Thermomechanical Tensile Test Table 6.1 The reaction condition and results of the preparation of poly(2-oxepane-1,5dione)-diol Table 6.2 Molecular weight and thermal properties of PCTOPD Table 6.3 The mechanical and shape- memory property of PCTOPDs xii LIST OF SCHEMES Scheme 2.1 Reaction routes for. .. The prepared three-arm biodegradable shape- memory polymers with switching temperature at body temperature are potentially useful materials for biomedical applications Expecially, due to their good shape- memory property and fast shape- recovery, these SMPs could be used as fast selfexpandable stents For the application as fast self-expandable stent, novel block co -polymers PCLtriol-co-PHBV PU (PCTBVs)... and desired thermal properties are prepared from the enzymatic syntheses Novel poly(ester–urethanes) are then synthesized from three-arm PCL-troil The effect of switching segment (PCL-triol) on the thermal, mechanical and shape- memory properties of SMPs is examined The characterization of polymers structure, thermal, and mechanical properties, and the investigation of shapememory behavior of star polymers. .. temperature (Ts) of tPCL-PUs could be adjusted by using PCL-triols with different Tm Ts of 36-39 oC was achieved by using PCL-triols with Tm of 45-47 oC and Mn of 2720-4200 g/mol Excellent shape- memory properties of tPCL-PU were demonstrated in cyclic thermomechanical tensile tests at 38 oC, with shape recovery in 10 second, shape fixity rate (Rf) of 91-92%, shape recovery rate (Rf) of 95-99% The prepared... The drug release profiles of paclitexal from PCTOPD stents The biodegradable and self-expandable chitosan material was used to make sirolimus-eluting stent with 2.5 wt% of sirolimus Figure 6.11 Compression curve for stent from PCTOPD-27 with the thickness of 0.22 mm and out diameter of 3.45 mm x LIST OF TABLES Table 1.1 Comparison of the properties of SMPs with SMAs Table 2.1 Overview of chemically cross-linked... demanding processing and traditional conditions,14 appreciable toxicity15, 16 and non- biodegradability This provides motivation for the development of alternative shapememory materials 1.2 Shape- memor y polymer s The most important alternative is shape- memory polymers (SMPs) The first SMP was developed by CDF Chimie Company in the mid of 1980s.17 Later on, tremendous attraction and efforts have been paid... combination of overall polymer structure and morphology together with a tailored programming technology Therefore, the shape- memory performance not only depends 2 on the molecular structure but also on the mode of deformation as well as the programming of stimulus application process The shape- change process, shown in Figure 1.1, includes: i) the original shape A of SMP is formed by traditional process, extruding... especially in biomedical fields Figure 1.1 A simplified scheme for shape- changes of SMP from deformation to recovery upon application of external stimulus 1.3 Ther mally-induced shape- memor y polymer s Polymers, exhibiting shape- memory effect, are classified into physically crosslinked thermoplastics and chemically cross-linked thermosets Since chemically crosslinked thermosets are unable to be reshaped after... elastic memory of materials For this reason, SMPs should be the most promising materials because SMPs exhibit very good elastic memory and can complete shape changes within a minute Thus far, no biodegradable SMP for the reponse at body temperatue has been reported for such application New SMPs containing hyperbranched PCL and PHBC may be prepared for such application 1.7 Biodegr adable SMP as self-expandable... shape- memory property from the phase separation between the hard and the switching segements, which also leads to the property related to blood compatibility Thus, the studing of shapememory segmented polyurethane for various biomedical applications becomes more and more meaningful and important In this sense, the aim of this PhD project is to develop multifunctional SMPs, combining thermoplastic and . DESIGNING AND SYNTHESIS OF SHAPE- MEMORY POLYMERS FOR BIOMEDICAL APPLICATION XUE LIANG NATIONAL UNIVERSITY OF SINGAPORE 2010 DESIGNING AND SYNTHESIS OF SHAPE- MEMORY. biomaterials in biomedical applications 31 2.9 Application of SMPs 31 2.9.1 The application of SMPs as smart suture 32 2.9.2 The application of SMPs as stent 33 2.9.3 The application of SMPs as. EVALUATION OF BIODEGREDADABLE SHAPE- MEMORY POLYMERS AS FULL POLYMERIC AND SELF- EXPANDABLE DRUG-ELUTING STENT 95 vi 6.1 Introduction 95 6.2 Materials and methods 98 6.2.1 Synthesis of 2-Oxepane-1,5-dione