Elsevier

Biomaterials

Volume 29, Issue 22, August 2008, Pages 3185-3194
Biomaterials

Synthesis and water-swelling of thermo-responsive poly(ester urethane)s containing poly(ε-caprolactone), poly(ethylene glycol) and poly(propylene glycol)

https://doi.org/10.1016/j.biomaterials.2008.04.015Get rights and content

Abstract

Thermo-responsive multiblock poly(ester urethane)s comprising poly(ε-caprolactone) (PCL), poly(ethylene glycol) (PEG), and poly(propylene glycol) (PPG) segments were synthesized. The copolymers were characterized by GPC, NMR, FTIR, XRD, DSC and TGA. Water-swelling analysis carried out at different temperatures revealed that the bulk hydrophilicity of the copolymers could be controlled either by adjusting the composition of the copolymer or by changing the temperature of the environment. These thermo-responsive copolymer films formed highly swollen hydrogel-like materials when soaked in cold water and shrank when soaked in warm water. The changes are reversible. The mechanical properties of the copolymer films were assessed by tensile strength measurement. These copolymers were ductile when compared to PCL homopolymers. Young's modulus and the stress at break increased with increasing PCL content, whereas the strain at break increased with increasing PEG content. The results of the cytotoxicity tests based on the ISO 10993-5 protocol demonstrated that the copolymers were non-cytotoxic and could be potentially used in biomedical applications.

Introduction

In the field of biomaterials, there is great interest in the development of degradable materials. Synthetic biodegradable polymers can be used as materials for temporary scaffolds for tissue engineering purposes, as sutures, drug delivery devices, orthopedic fixation devices or temporary vascular grafts. These polymers need to possess the desired biocompatibility, suitable mechanical properties and predictable biodegradability. For application in the body, materials with a high water affinity offer the added advantage of compatibility with the internal environment of the body, which has high water content. Hydrogels are such materials and are the first materials to be developed for application in the human body [1], [2]. There are three classes of hydrogels: (i) chemical crosslinked, (ii) physical crosslinked and (iii) ‘pulley’ gels. Chemically crosslinked hydrogels are formed by the copolymerization of a monomer having one polymerizable double bond with a crosslinking agent having at least two polymerizable double bonds. Physical hydrogels are self-assembled three-dimensional structures which are held together by non-covalent junctions, these include Coulombic, dipole–dipole, van der Waals, hydrophobic, and hydrogen bonding interactions [3], [4], [5]. The latest addition to the family of hydrogels is a class of hydrogels known as ‘pulley’ gels [6]. By chemically crosslinking two cyclodextrin molecules, each threaded on a different poly(ethylene glycol) (PEG) chain that is end-capped with a bulky group, a sliding double ring crosslinking agent was produced. These topologically crosslinked gels possess sliding crosslinks and have been demonstrated to have excellent swellability [6].

Our work focuses on the synthesis of water swellable thermo-responsive hydrogel-like materials. The main mode of crosslinking is by physical interactions between the hydrophobic segments and does not rely on toxic crosslinking agents to form a hydrogel. An added advantage is that, unlike crosslinked hydrogels, this copolymer is solution-processable and can be applied as thin film ‘smart’ coatings. This material is water-insoluble and shows stability in large amounts of water that other thermogelling copolymers do not. This work focuses on the synthesis of a copolymer incorporating three materials which are widely regarded as candidate materials for biomedical applications. They are poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG) and poly(ε-caprolactone) (PCL). These materials are linked to form linear multiblock poly(ester urethane)s. Polyurethanes are widely applied in various biomedical applications such as heart valves [7], dialysis membranes [8] and pacing leads insulation [9], [10]. Moreover, polyurethanes have good elastic properties due to the hydrogen bonding between the urethane bonds, making them attractive for applications where elasticity is required, such as ligament tissue engineering [11], [12], [13]. However, polyurethanes have been reported to undergo slow hydrolytic degradation [14]. In order to render the polyurethanes more hydrolytically degradable, biodegradable hard segments such as poly[(R)-3-hydroxybutyrate] (PHB) have been introduced into the polyurethane backbone to form poly(ester urethane)s [15], [16]. These poly(ester urethane)s have been shown to degrade within two weeks under accelerated hydrolytic degradation conditions [17].

PCL is a biocompatible polyester which has been extensively investigated for use as a biomedical material. The degradation product of PCL is 6-hydroxyhexanoic acid, which is a naturally occurring metabolite in the human body. Sutures having PCL as a main component have been approved by the Food and Drug Administration (FDA) for use in surgeries, attesting to its safe application in humans [18], [19], [20]. In other applications, PCL is used in Capronor, a commercially available 1-year implantable contraceptive device [21]. The toxicology of poly(ε-caprolactone) has been thoroughly studied in the safety evaluation of Capronor and the material has been generally regarded as safe.

On the other hand, Pluronics or the PEG–PPG–PEG triblock copolymer is a well known FDA approved polymer and has been applied in drug delivery systems as a thermogelling system [22], [23]. The main reason for the thermosensitivity is due to the presence of the PPG block in the polymer. PPG is water-soluble at low temperatures and reverts into the insoluble form at higher temperatures [24]. This behavior is similar to the behavior of poly(N-isopropyl acrylamide) (PNIPAAm), another extensively studied ‘smart’ polymer. Smart hydrogels comprising PNIPAAm have been synthesized for various applications and these gels respond to external stimuli, such as temperature [25], [26], [27], [28]. When the temperature is raised, the gel shrinks, expelling its contents. When the temperature is lowered, the gel swells, absorbing the fluid from its external environment. However, safety concerns remain over the use of PNIPAAm in materials for biomedical applications due to the possible presence of the monomeric acrylamide-based residues, which is a neurotoxin [29], [30].

This paper will highlight on the synthesis and the characterization of a new class of poly(ester urethane)s comprising PEG, PPG and PCL. This material forms a hydrogel-like material when it absorbs water and does not require the use of toxic crosslinking agents. We demonstrate for the first time, the reversible cyclical thermo-responsive behavior of this ‘smart’ material. The promising results shown by this new material make it a highly attractive candidate for use in biomedical devices that require regulation of behavior by temperature control.

Section snippets

Materials

Poly(ethylene glycol) (PEG) with Mn of ca. 2000 and poly(propylene glycol) (PPG) and poly(ε-caprolactone)-diol (PCL-diol) with Mn of ca. 1000 were purchased from Aldrich. Purification of the PEG was performed by dissolving in dichloromethane followed by precipitation in diethyl ether and vacuum-dried before use. Purification of PPG was performed by washing in hexane three times and vacuum-drying before use. The Mn and Mw of PEG were found to be 1890 and 2060, respectively. The Mn and Mw of PPG

Synthesis and characterization of poly(PEG/PPG/PCL urethane)s

Poly(PEG/PPG/PCL urethane)s were prepared by the randomly coupling PCL, PEG and PPG segment blocks using the isocyanate of 1,6-hexamethlyene diisocyanate (HMDI) with dibutyltin dilaurate as the catalyst. The synthesis of the poly(PEG/PPG/PCL urethane)s is presented in Scheme 1. This synthesis procedure can be replicated in any polymer synthesis laboratory. The starting materials are all commercially available and are relatively cheap.

A series of random multiblock poly(PEG/PPG/PCL urethane)s

Conclusions

Thermo-responsive and biodegradable poly(PEG/PPG/PCL urethane)s were successfully synthesized from PEG, PPG and PCL-diol using HMDI as a coupling agent. Their chemical structure and molecular characteristics were studied with GPC, 1H NMR, 13C NMR and FTIR, which confirmed the architecture of the poly(PEG/PPG/PCL urethane)s. The GPC results indicated that the synthesized poly(PEG/PPG/PCL urethane)s had high molecular weights. The thermal stability of the poly(PEG/PPG/PCL urethane)s was studied

Acknowledgements

The authors acknowledge the financial support from Institute of Materials Research and Engineering, A*STAR, Singapore (IMRE/06-1R0529) and National University of Singapore (R-397-000-019-112). The authors thank M.J. Loh and J.G. Lim for kindly proofreading the manuscript. X.J. Loh would like to acknowledge the A*STAR Graduate Scholarship from A*STAR.

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