Chapter 14
Thermo-Sensitive Gels: Biodegradable Hydrogels from Enantiomeric Copolymers of Poly(lactide) and Poly(ethylene glycol) 1
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Tomoko Fujiwara and Yoshiharu Kimura
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Department of Chemistry, Boise State University, 1910 University Drive, Boise, ID 83725 Department of Polymer Science and Engineering, Kyoto Institute of Technology, Matsugasaki, Kyoto 600-8585, Japan 2
Biodegradable hydrogels have been developed by using block copolymers of poly(lactide) (PLA) and poly(ethylene glycol) (PEG). Here, a novel thermo-sensitive formation of hydrogel is demonstrated by mixing micellar solutions of enantiomeric block copolymers of P L A and P E G in which the specific interaction o f the enantiomeric P L A chains and that o f the P E G chains connected with them are responsible for the hydrogel formation. This unique helix-induced gel is potentially useful for use as injectable drug carrier and implantable scaffold for tissue engineering.
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© 2006 American Chemical Society
In Degradable Polymers and Materials; Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.
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Introduction Polymer gels are classified by their crosslinking mechanism into two types - chemical and physical gels. The physical gels are crosslinked by physical bonds such as van der Waals interaction, hydrogen bond, hydrophobic interaction, and molecular entanglement. Poly(N-isopropylacrylamide) (PNIPAM), which is one of the most widely known physical gels, has a low critical solution temperature (LCST) around 32°C and forms a gel above the LCST as the both results of dehydration of the hydrophobic isopropyl groups and hydrogen bonding to the carbonyl groups (1-4). A triblock copolymer of poly(ethylene oxide) and poly(propylene oxide) (PEO-PPO-PEO), which is utilized as non-ionic surfactant by the trade names of Pluronic® and Poloxamer®, also exhibits sol-gel phase transition in water. Many researchers have studied the mechanism of this gelation (5-9) to conclude that the micelles are formed and packed to induce sol-to-gel transition near LCST and the PEO corona blocks shrink to lead gel-to-sol transition at higher temperature. In other cases, helix formation is responsible for the gel formation of gelatin and agarose in a cooled aqueous medium (10), while hydration of poly(oxyethylene) that grafted onto a substrate forms a gel (/ /). Recently, these polymer gels have been applied as biomedical materials with achieving remarkable advances in medical science and biotechnology (12). The applications involve cell culture, tissue engineering, drug delivery system (DDS), medical sensing, and so on, for which the biocompatibility, biodegradability and safety of the gels are extremely important as well as the physicochemical properties. Particularly, biodegradability of the gels is essential in their in vivo use, and accordingly they must be prepared from biodegradable polymers having good biocompatibility. Among the biodegradable polymers thus developed, polylactides (PLA) have been receiving a special interest not only as eco-plastic materials (13) but also as biomedical materials (14). Since lactic acid, the starting material of PLA, can be derived from renewable natural resources such as cornstarch, PLA is regarded as one of the sustainable materials. The PLA consisting of the enantiomeric L- and D-lactic acids are called poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA), respectively. Only PLLA is now being produced in industrial scale by ring-opening polymerization of L-lactide that can be synthesized from L-lactic acid, a renewable feedstock manufactured by large-scale fermentation. It is also known that the polymer blend of PLLA and PDLA forms a stereocomplex whose melting temperature (r ) is 230°C, approximately 50°C higher than that of the respective PLLA and PDLA (15-19). Therefore, the improved properties are expected with the stereocomplex of PLLA and PDLA. Based on these backgrounds many trials have been done to obtain polymer gels from PLA derivatives. m
In Degradable Polymers and Materials; Khemani, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.
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In this chapter, thermo-sensitive hydrogels of block copolymer systems consisting of enantiomeric PLA and poly(ethylene glycol) (PEG) will be described. Particularly, mechanistic studies will be stressed for the insight into the specific interaction of the enantiomeric PLA blocks and the role of PEG blocks in the hydrogel formation.
Hydrogels from various PLA-PEG block copolymers: ABA and BAB triblock and AB diblock One of the preparative approaches to the hydrogels is to synthesize block copolymers consisting of the hydrophobic "hard" Α-block, PLA and the hydrophilic "soft" B-block, PEG as the block components. Since both PLA and PEG are highly biocompatible and bioresorbable, the PLA-PEG block copolymers can provide various biomedical applications as temporary devices for clinical and pharmaceutical purposes. Zhu et al. first prepared a block copolymer, poly(DL-lactide)-6/ocA-polyoxyethylene (PDLLA-PEG) for use as a drug carrier in 80's (20,21). The typical chemical structures of ABA, BAB, and A B block copolymers are shown in Figure 1. The A B A type block copolymer, PLA-PEG-PLA, has been most extensively studied since late 80's in regard to its synthesis (22-27), properties (28,29), and degradability (30-34). In the A B A system, PEG works as an intermolecular plasticizer in processing implant pastes, films, and scaffolds. Its hydrogels have also been studied mainly for their biomedical application (35,36). Vert et al. have recently reported the utilization of the hydrogels to the protein release (37). Microspheres have been prepared from the A B A block copolymers by W/O or W/O/W emulsion technique (38-40), and utilized for
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