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Magnesium catalyzed polymerization of end functionalized poly(propylene maleate) and poly(propylene fumarate) for 3D printing of bioactive scaffolds James A. Wilson, Derek Luong, Alex P Kleinfehn, Sahar Sallam, Chrys Wesdemiotis, and Matthew L. Becker J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09978 • Publication Date (Web): 13 Dec 2017 Downloaded from http://pubs.acs.org on December 13, 2017
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Journal of the American Chemical Society
Magnesium catalyzed polymerization of end functionalized poly(propylene maleate) and poly(propylene fumarate) for 3D printing of bioactive scaffolds James A. Wilson†, Derek Luong†, Alex P. Kleinfehn†, Sahar Sallam‡, Chrys Wesdemiotis‡ and Matthew L. Becker*† †
Department of Polymer Science, University of Akron, Akron, Ohio 44325, USA of Chemistry, University of Akron, Akron, Ohio 44325, USA
‡ Department
KEYWORDS Magnesium, ring-opening copolymerization, poly(propylene fumarate), additive manufacturing, polyester. ABSTRACT: The ring-opening copolymerization of maleic anhydride and propylene oxide, using a functionalized primary alcohol initiator and magnesium 2,6-di-tert-butyl phenoxide as a catalyst, was investigated in order to produce high end-group fidelity poly(propylene maleate). Subsequent isomerization of the material into 3D printable poly(propylene fumarate) was utilized to produce thin films and scaffolds possessing groups that can be modified with bioactive groups post-polymerization and postprinting. The surface concentration of these modifiable groups was determined to be 30.0 ± 3.3 pmol.cm-2 and copper-mediated azide-alkyne cycloaddition was used to attach a small molecule dye and cell adhesive GRGDS peptides to the surface as a model system. The films were then studied for cytotoxicity and found to have high cell viability before and after surface modification.
INTRODUCTION Advances in additive manufacturing have the potential to change medicine.1-3 However, these advances will be highly dependent on the availability of printable materials that meet the chemical, mechanical and biological requirements of the specific application. Various forms of additive manufacturing, more colloquially known as 3D printing, have been demonstrated in the literature.4 Fused deposition modelling (FDM) is a layer-by-layer method of extrusion molding solid filaments, such as poly(urethane)s (PUs), poly(L-lactic acid) (PLLA) or poly(ester urea)s (PEUs).5-7 Polymeric resins can also be printed using continuous digital light processing (cDLP), wherein photo-crosslinking in specific regions is achieved through high resolution stereolithography.8-11 Inkjet methods have also been demonstrated in 3D printing and can be used with either powders or resins.12-14 In order to produce 3D scaffolds that are compatible with biological systems, the polymer should be non-toxic, implantable without rejection and completely resorbable upon degradation. While the first two criteria are achieved in a multitude of polymer systems, there are relatively few examples that are also bioresorbable; polylactides,15-18 poly(ε-caprolactone) (PCL)19, 20 and poly(propylene fumarate) (PPF).21 Each of these examples are polyesters and thus, able to degrade either enzymatically or through hydrolysis in vivo. However, as a consequence of the rapid degradation of PLLA, acidosis and inflammation of the surrounding tissue area are regularly observed.22 Conversely, the slow degradation of PCL in the human body limits its use in tissue repair, particularly with regards to reforming vascular tissue. 19, 23
Both PLLA and PCL can be extruded through FDM to produce 3D scaffolds capable of undergoing in vitro degradation.1, 24-27 While the materials exhibit moderate mechanical and tensile properties, the majority of defects in the material are observed at the interface between deposited layers.26, 27 Furthermore, as a consequence of the achievable width of the extrusion nozzle in FDM, the resolution of the 3D printed scaffold is limited.1, 2, 28 Stereolithographic methods, such as cDLP, have been shown to exhibit much higher resolution compared to FDM techniques, as they are limited by the light source of the printer rather than the materials used. This enables 3D scaffolds to be printed with a controlled porosity that can be tailored to match physiological conditions. PPF is an unsaturated polyester that degrades in vivo to form fumaric acid and propylene glycol, which are excreted naturally. First reported by Mikos and coworkers in 1994,29 PPF has been used for a variety of medical applications, such as vascular stents,30 nerve grafts,31 cartilage,32 drug release vehicles,33 blood vessel engineering,34 and bone tissue engineering.10, 35-37 As a consequence of the unsaturated alkene in the polymer backbone, intermolecular crosslinking can be achieved in order to strengthen the mechanical properties of the material. The development of a printable PPF resin by dissolving the polymer into the reactive diluent diethyl fumarate (DEF), which acts as both solvent and crosslinking agent, has been extensively studied and shown to be able to produce 3D scaffolds with compressive moduli comparable to bone.8, 10, 11, 21, 38 The current method of PPF production is through the stepgrowth polycondensation of DEF and propylene glycol
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(Scheme 1). However, this is not an industrially viable method of production for PPF for 3D printing purposes. Only low molecular mass PPF (
