Polyurethane/poly(lactic-co-glycolic) acid composite scaffolds fabricated by thermally induced phase separation
Introduction
Three-dimensional polymeric scaffolds for tissue engineering hold much promise for the regeneration of damaged or diseased tissues. Regenerative therapies offer many advantages over existing replacement therapies, including potentially indefinite life-spans of implants, superior mechanical characteristics and better immuno-acceptance. These artificial structures seek to provide a surrogate for the natural extracellular matrix (ECM) by directing the organisation, growth and differentiation of cells in the process of generating functional tissues and impart both chemical and physical cues [1], [2].
A multitude of approaches to manufacturing three-dimensional porous structures for tissue-engineering applications have been detailed in the literature [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. In this particular work, we have employed a modified thermally induced phase separation (TIPS) method to fabricate scaffolds [21], [22], [23]. The TIPS process utilises changes in thermal energy to induce the demixing of a homogenous polymer-solvent or a polymer-solvent–non-solvent solution either by solid–liquid demixing or liquid–liquid phase separation. In the case of a liquid–liquid phase separation mechanism, two definitively different morphologies may be produced: (1) the solution separates into a polymer-rich and polymer-lean phase (giving rise to an emulsion-like morphology) when cooled below the binodal curve, or (2) the solution separates into a bicontinuous polymer-rich and polymer-lean phase when cooled below the spinodal curve. It is this second process that gives rise, by its very path of formation, to a highly interconnected polymer network, which inherently produces a highly porous structure once the solvent is removed via leaching or freeze-drying. One of the most attractive characteristics of TIPS over other scaffold fabrication techniques is the formation of not only an intrinsically interconnected polymer network, but also an interconnected porous space in one simple process that is scalable, fast and controllable. TIPS is thus a very convenient technique for fabricating porous scaffolds as many scaffold architectures can be formed with ease via the manipulation of various processing parameters and system properties.
Based on previous work by our group [24], [25], as well as that of others [26], [27], it is known that dimethylsulphoxide (DMSO) is a suitable low-toxicity solvent in which to dissolve the known biostable, biocompatible polymers polyurethane (PU) and poly(lactic-co-glycolic acid) (PLGA) [28]. While both biocompatible and biodegradable, as well as FDA approved, PLGA is a fairly rigid solid that exhibits little to no elastic behaviour and is thus not suited for applications that involve high movement or shaping in situ. If blended successfully with a polymer such as polyurethane or poly(ethyleneglycol) (PEG), which have soft, elastic mechanical properties, a hybrid can be formed that exhibits much greater flexibility than a PLGA-only system. Wake et al. [29] described the enhanced pliability of three-dimensional foams made of PLGA/PEG blends and a particulate leaching method, evidenced by the ability to roll them into a tube without macroscopic damage to the scaffold—an impossibility with rigid PLGA-only structures. A PLGA/PU composite matrix is thought to have potential as an artificial ECM as the combination of biodegradable PLGA and a non-degradable PU will produce a unique structure that retains its overall mechanical strength as the PLGA degrades with the genesis of new tissues. However, little research has been carried out into the phase separation behaviour of a PLGA/PU/DMSO system, or its suitability in the fabrication of biocompatible scaffolds. It is was the intent of this study to investigate the use of a PLGA/PU/DMSO system to produce highly porous, biocompatible scaffolds of varying porosity, connectivity, size and shape by phase separation and solvent leaching and thereafter their utility in improving cell attachment to PU which is intrinsically non-cell adhesive.
Section snippets
Materials
75/25 PLGA was supplied by Birmingham Polymers Inc (Birmingham, AL, USA). ElastEon PU 70A pellets were a gift to Dr. Darren Martin from Aortech Biomaterials in Melbourne. The PU used in this study incorporates hard segments of 4,4′-methylenediphenyl diisocyanate, a mixture of butanediol and a short siloxane chain extender. The soft segments are made up of a mixture of bis(hydroxyalkyl) polydimethyl siloxane (PDMS) and poly(hexamethylene oxide) (PHMO). PHMO compatibilises the PDMS with the more
Cloud point measurements
The cloud point temperatures for the different concentration PU samples were found to be 59 °C±2 °C (0.5%, 1.0% and 2.0%) and 66 °C±2 °C (4.0%, 5.0% and 6.0%). The PU/PLGA blend had a cloud point temperature of 67 °C±2 °C. The 5% PLGA solution was found to crystallise at 11 °C±2 °C. Solvent freezing point depression was observed in the cloud point measurements and this is discussed in depth in more detail in the following section.
DSC measurements
According to van Emmerik [30], when a homogenous solution demixes, an
Conclusion
In this work, we have presented a novel composite scaffold fabricated via a thermally induced phase separation process that exhibits morphological, mechanical and cell adhesion and growth supporting properties in-between that of scaffolds fabricated from the two individual polymers. While the blended PLGA/PU scaffold possessed architectural features similar to the PLGA scaffold, the cellular adhesion and growth properties of 3T3 fibroblasts seeded onto these scaffolds showed intermediate
Acknowledgements
This study was supported by the Australian Research Council Discovery Grants Scheme, The University of Queensland and The Australian Institute for Bioengineering and Nanotechnology.
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