Synthesis of biocompatible segmented polyurethanes from aliphatic diisocyanates and diurea diol chain extenders

Abstract

Many polyurethane elastomers display excellent mechanical properties and adequate biocompatibility. However, many medical-grade polyurethanes are prepared from aromatic diisocyanates and can degrade in vivo to carcinogenic aromatic diamines, although the question of whether the concentrations of these harmful degradation products attain physiologically relevant levels is currently unresolved and strongly debated. It is therefore desirable to synthesize new medical-grade polyurethanes from less toxic aliphatic diisocyanates. In this paper, biocompatible segmented polyurethane elastomers were synthesized from aliphatic diisocyanates (1,4-diisocyanatobutane (BDI) and lysine methyl ester diisocyanate (LDI)), novel diurea diol chain extenders based on tyrosine and tyramine, and a model poly(ethylene glycol) (PEG) diol soft segment. The objectives were to design a hard segment similar in structure to that of MDI-based polyurethanes and also investigate the effects of systematic changes in structure on mechanical and biological properties. The non-branched, symmetric polyurethane prepared from BDI and a tyramine-based chain extender had the highest modulus at 37 °C. Introduction of symmetric short-chain branches (SCBs) incorporated in the tyrosine-based chain extender lowered the modulus by an order of magnitude. Polyurethanes prepared from LDI were soft polymers that had a still lower modulus due to the asymmetric SCBs that hindered hard segment packing. Polyurethanes prepared from tyramine and tyrosine chain extenders thermally degraded at temperatures ranging from 110 to 150 °C, which are lower than that reported previously for phenyl urethanes. All four polyurethanes supported the attachment, proliferation, and high viability of MG-63 human osteoblast-like cells in vitro. Therefore, the non-cytotoxic chemistry of these polyurethanes make them good candidates for further development as biomedical implants.

Introduction

Segmented polyurethane elastomers have been incorporated in a number of biomedical devices [1] due to their excellent mechanical properties and adequate biocompatibility [2]. These materials are composed of alternating hard and soft blocks that can microphase separately under appropriate conditions to form hard and soft domains. The diisocyanate and chain extender comprise the hard segment while the polyester, polyether, or polycarbonate diol generally comprises the soft segment. By varying the structure of segmented polyurethanes, the mechanical properties can be tuned to targeted values for a specific clinical indication. Typical applications include blood-contact materials [3], heart valves [4], insulators for pacemaker electrical leads [5], cardiovascular catheters [6], and implants for the knee-joint meniscus [7], [8]. Commercial medical-grade segmented polyurethanes, such as Biomer^®, Elasthane™, and ChronoFlex^® AR [9], are typically synthesized from 4,4′-methylenebis(phenylisocyanate) (MDI). Carcinogenic and mutagenic aromatic diamines have been reported as degradation products from polyurethanes incorporating aromatic diisocyanates; however, the question of whether the concentrations of these harmful degradation products attain physiologically relevant levels is currently unresolved and strongly debated [10], [11], [12]. To avoid the potential release of toxic degradation products to the extracellular matrix, it is desirable to synthesize new medical-grade polyurethanes from less toxic intermediates.

As alternatives to MDI, lysine methyl ester diisocyanate (LDI) and 1,4-diisocyanatobutane (BDI) have been used to synthesize biomedical polyurethanes. Potential degradation products from these aliphatic diisocyanates are the amino acid lysine and the biological diamine putrescine, respectively. Degradation products from segmented poly(ester-urethane)urea elastomers comprising BDI, lysine ethyl ester and putrescine chain extenders, and poly(ε-caprolactone) (PCL) diols demonstrated no toxic effects on human endothelial cells cultured in vitro [13], [14]. Porous polyurethane scaffolds synthesized from LDI, glucose, and poly(ethylene glycol) (PEG) supported the attachment, proliferation, and differentiation of rabbit bone marrow stromal cells and degraded to non-toxic decomposition products (e.g., lysine and glucose) in vitro [15], [16]. These materials also induced a minimal foreign body response in vivo, with the formation of a capsule around the degrading implant [16], [17].

Although polyurethanes prepared from BDI and LDI mitigate the risk associated with toxic degradation products from MDI polyurethanes, the hard segments of polyurethanes prepared from these aliphatic diisocyanates lack some of the important structural features associated with MDI-based hard segments, such as aromatic rings in the backbone. In the paper presented here, novel aromatic diurea diol chain extenders were synthesized from amino acid derivatives. The objectives were to design a hard segment similar in structure to that of MDI-based polyurethanes and also to investigate the effects of systematic changes in structure on mechanical and biological properties. Tyrosine ethyl ester and tyramine were chosen as amino acid derivatives because they contain a phenyl group in the backbone, which has been reported to strengthen inter-chain hard segment attraction due to π-electron interactions between adjacent aromatic rings [18]. The urea linkages in the chain extender were incorporated to strengthen hard segment interactions through bidentate hydrogen bonding of urea groups in adjacent chains. To investigate the structure–property relationships, segmented polyurethanes were synthesized from the novel diurea diol chain extenders, a 1000-Da PEG diol (selected as a model soft segment), and aliphatic diisocyanates. BDI and LDI were chosen as diisocyanates because they have been reportedly used as intermediates for the synthesis of biocompatible polyurethanes [16], [19], [20]. Attachment and proliferation of MG-63 osteosarcoma cells on polyurethane films was investigated to evaluate the potential of the materials for bone tissue engineering applications. By systematically varying the structure of the hard segment using the components described above, the effects of backbone structure, such as symmetry and branching, on mechanical and biological properties were investigated.