Synthesis, Characterization and 3D Micro-Structuring via 2-Photon Polymerization of Poly(glycerol sebacate)-Methacrylate–An Elastomeric Degradable Polymer

Poly(glycerol sebacate) (PGS) has been utilised in numerous biomaterial applications over recent years. This elastomeric and rapidly degradable polymer is cytocompatible and suited to various applications in soft tissue engineering and drug delivery. Although PGS is simple to synthesise as an insoluble prepolymer, it requires the application of high temperatures for extended periods of time to produce an insoluble matrix. This places limitations on the processing capabilities of PGS and its possible applications. Here, we present a photocurable form of PGS with improved processing capabilities: PGS-methacrylate (PGS-M). By methacrylating the secondary hydroxyl groups of the glycerol units in the PGS prepolymer chains, the material was rendered photocurable and, in combination with a photoinitiator, crosslinked rapidly on exposure to UV light at ambient temperatures. The polymer’s molecular weight and the degree of methacrylation could be controlled independently and the mechanical properties of the crosslinked material tailored. The polymer also displayed rapid degradation under physiological conditions and cytocompatibility with various primary cell types. As a demonstration of the processing capabilities of PGS-M, µm scale 3D scaffold structures were fabricated using 2-photon polymerisation and used for 3D cell culture. The tunable properties of PGS-M coupled with its enhanced processing capabilities make the polymer an attractive potential biomaterial for various future applications.

[1]  Yufeng Zheng,et al.  The application of poly (glycerol-sebacate) as biodegradable drug carrier. , 2009, Biomaterials.

[2]  E. Andrzejewska,et al.  Nanocomposites obtained by photopolymerization of (methacrylate monomer)/(methacrylate functionalized polyhedral oligomeric silsesquioxane) system , 2011 .

[3]  Jason A Burdick,et al.  Review: photopolymerizable and degradable biomaterials for tissue engineering applications. , 2007, Tissue engineering.

[4]  C. Constantinides,et al.  Biosourced Amphiphilic Degradable Elastomers of Poly(glycerol sebacate): Synthesis and Network and Oligomer Characterization , 2013 .

[5]  C. Wilkinson,et al.  New depths in cell behaviour: reactions of cells to nanotopography. , 1999, Biochemical Society symposium.

[6]  R. Nerem,et al.  Poly(glycerol sebacate) supports the proliferation and phenotypic protein expression of primary baboon vascular cells. , 2007, Journal of biomedical materials research. Part A.

[7]  P. Janmey,et al.  Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. , 2005, Cell motility and the cytoskeleton.

[8]  R. Osellame,et al.  Two-Photon Laser Polymerization: From Fundamentals to Biomedical Application in Tissue Engineering and Regenerative Medicine , 2012, Journal of applied biomaterials & functional materials.

[9]  Jason A Burdick,et al.  Biodegradable and radically polymerized elastomers with enhanced processing capabilities , 2008, Biomedical materials.

[10]  Robert Langer,et al.  In vivo degradation characteristics of poly(glycerol sebacate). , 2003, Journal of biomedical materials research. Part A.

[11]  C. Bettinger,et al.  Photocrosslinkable biodegradable elastomers based on cinnamate-functionalized polyesters. , 2013, Acta biomaterialia.

[12]  G. L. Woo,et al.  Synthesis and characterization of a novel biodegradable antimicrobial polymer. , 2000, Biomaterials.

[13]  Mangirdas Malinauskas,et al.  Tuning the refractive index in 3D direct laser writing lithography: towards GRIN microoptics , 2015 .

[14]  R. Langer,et al.  A tough biodegradable elastomer , 2002, Nature Biotechnology.

[15]  Julian H. George,et al.  Exploring and Engineering the Cell Surface Interface , 2005, Science.

[16]  W. Cook,et al.  In vitro enzymatic degradation of poly (glycerol sebacate)-based materials. , 2011, Biomaterials.

[17]  X. Loh,et al.  Poly(glycerol sebacate) biomaterial: synthesis and biomedical applications. , 2015, Journal of materials chemistry. B.

[18]  J. Karp,et al.  Synthesis and characterization of photocurable elastomers from poly(glycerol-co-sebacate). , 2007, Biomacromolecules.

[19]  A. Almarza,et al.  Poly (glycerol sebacate): a novel scaffold material for temporomandibular joint disc engineering. , 2013, Tissue Engineering. Part A.

[20]  N. Tsutsumi,et al.  Synthesis, characterization, and enzymatic degradation of network aliphatic copolyesters , 1999 .

[21]  Nupura S. Bhise,et al.  Direct-write bioprinting of cell-laden methacrylated gelatin hydrogels , 2014, Biofabrication.

[22]  C. Wilkinson,et al.  Reactions of cells to topography. , 1998, Journal of biomaterials science. Polymer edition.

[23]  M. Shibata,et al.  Thermal and mechanical properties of photocured organic–inorganic hybrid nanocomposites of terpene‐based acrylate resin and methacrylate‐substituted polysilsesquioxane , 2010 .

[24]  R. Ross,et al.  The smooth muscle cell in culture. , 1979, Physiological reviews.

[25]  Ali Khademhosseini,et al.  Elastomeric nanocomposite scaffolds made from poly(glycerol sebacate) chemically crosslinked with carbon nanotubes. , 2015, Biomaterials science.

[26]  Kristi S Anseth,et al.  Synthesis and characterization of photocrosslinkable, degradable poly(vinyl alcohol)-based tissue engineering scaffolds. , 2002, Biomaterials.

[27]  K. Woodhouse,et al.  Understanding the biodegradation of polyurethanes: from classical implants to tissue engineering materials. , 2005, Biomaterials.

[28]  Aldo R Boccaccini,et al.  An elastomeric patch derived from poly(glycerol sebacate) for delivery of embryonic stem cells to the heart. , 2010, Biomaterials.

[29]  Saulius Juodkazis,et al.  Ultrafast laser processing of materials: from science to industry , 2016, Light: Science & Applications.

[30]  Jan Feijen,et al.  A poly(D,L-lactide) resin for the preparation of tissue engineering scaffolds by stereolithography. , 2009, Biomaterials.

[31]  Rui L. Reis,et al.  Biodegradable Systems in Tissue Engineering and Regenerative Medicine , 2004 .

[32]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[33]  M. Cima,et al.  Zero-order controlled release of ciprofloxacin-HCl from a reservoir-based, bioresorbable and elastomeric device. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[34]  B. Tighe,et al.  Cellular interactions with synthetic polymer surfaces in culture. , 1985, Biomaterials.

[35]  A. Boccaccini,et al.  Synthesis, properties and biomedical applications of poly(glycerol sebacate) (PGS): A review , 2012 .

[36]  Todd C. McDevitt,et al.  Gelatin methacrylate microspheres for controlled growth factor release. , 2015, Acta biomaterialia.

[37]  M. Frydrych,et al.  Large three-dimensional poly(glycerol sebacate)-based scaffolds - a freeze-drying preparation approach. , 2013, Journal of materials chemistry. B.

[38]  David E. Nye.  From science to industry? Flaws in the linear model , 2006 .

[39]  J. Santerre,et al.  Differential synthesis of cholesterol esterase by monocyte-derived macrophages cultured on poly(ether or ester)-based poly(urethane)s. , 1998, Journal of biomedical materials research.

[40]  B. Boyan,et al.  Culture surfaces coated with various implant materials affect chondrocyte growth and metabolism , 1994, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[41]  J. Santerre,et al.  Enzyme induced biodegradation of polycarbonate-polyurethanes: dose dependence effect of cholesterol esterase. , 2003, Biomaterials.

[42]  L. Koch,et al.  Laser printing of cells into 3D scaffolds , 2010, Biofabrication.

[43]  A. Muhlebach,et al.  New water-soluble photo crosslinkable polymers based on modified poly(vinyl alcohol) , 1997 .

[44]  Z. Cui,et al.  Adipose-derived stem cell: A better stem cell than BMSC , 2008, Cell Research.

[45]  Mangirdas Malinauskas,et al.  Preclinical study of SZ2080 material 3D microstructured scaffolds for cartilage tissue engineering made by femtosecond direct laser writing lithography , 2015, Biofabrication.

[46]  Saulius Juodkazis,et al.  Three-dimensional laser micro-sculpturing of silicone: towards bio-compatible scaffolds. , 2013, Optics express.

[47]  A. Göpferich,et al.  Mechanisms of polymer degradation and erosion. , 1996, Biomaterials.

[48]  Scott J. Hollister,et al.  Tailoring the mechanical properties of 3D-designed poly(glycerol sebacate) scaffolds for cartilage applications. , 2010, Journal of biomedical materials research. Part A.

[49]  Wei Cai,et al.  Shape-memory effect of poly (glycerol–sebacate) elastomer , 2008 .

[50]  Ali Khademhosseini,et al.  PGS:Gelatin nanofibrous scaffolds with tunable mechanical and structural properties for engineering cardiac tissues. , 2013, Biomaterials.

[51]  Gordana Vunjak-Novakovic,et al.  Biodegradable fibrous scaffolds with tunable properties formed from photo-cross-linkable poly(glycerol sebacate). , 2009, ACS applied materials & interfaces.

[52]  Eric Mazur,et al.  3D Cell‐Migration Studies using Two‐Photon Engineered Polymer Scaffolds , 2008 .

[53]  Yadong Wang,et al.  Fast degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neo-artery , 2011, Nature Medicine.

[54]  I. H. Jaafar,et al.  Spectroscopic evaluation, thermal, and thermomechanical characterization of poly(glycerol-sebacate) with variations in curing temperatures and durations , 2010 .

[55]  Hyoungshin Park,et al.  Pre-treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue. , 2008, Journal of biomedical materials research. Part A.

[56]  F A Auger,et al.  Modulated response to cytokines of human wound healing myofibroblasts compared to dermal fibroblasts. , 1998, Experimental cell research.

[57]  Laurent E. Prat,et al.  Real time monitoring of the quiescent suspension polymerization of methyl methacrylate in microreactors—Part 1. A kinetic study by Raman spectroscopy and evolution of droplet size , 2015 .

[58]  L G Griffith,et al.  Effect of pore size and void fraction on cellular adhesion, proliferation, and matrix deposition. , 2001, Tissue engineering.

[59]  Christopher D. Pritchard,et al.  Retinal transplantation using surface modified poly(glycerol-co-sebacic acid) membranes. , 2010, Biomaterials.

[60]  Rm Wie.  Spectrometric Identification of Organic Compounds , 1974 .

[61]  Kee-Won Lee,et al.  Substantial expression of mature elastin in arterial constructs , 2011, Proceedings of the National Academy of Sciences.

[62]  Joseph P Vacanti,et al.  Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material. , 2005, Biomaterials.

[63]  Scott J Hollister,et al.  A comparison of the influence of material on in vitro cartilage tissue engineering with PCL, PGS, and POC 3D scaffold architecture seeded with chondrocytes. , 2010, Biomaterials.

[64]  S. MacNeil,et al.  Biomimetic poly(glycerol sebacate)/poly(l-lactic acid) blend scaffolds for adipose tissue engineering. , 2015, Acta biomaterialia.

[65]  Aldo R Boccaccini,et al.  Characterisation of a soft elastomer poly(glycerol sebacate) designed to match the mechanical properties of myocardial tissue. , 2008, Biomaterials.

[66]  Kristi S. Anseth,et al.  Fundamental studies of a novel, biodegradable PEG-b-PLA hydrogel , 2000 .

[67]  J. Park,et al.  Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. , 2007, Journal of dermatological science.

[68]  Aleksandr Ovsianikov,et al.  Laser Fabrication of 3D Gelatin Scaffolds for the Generation of Bioartificial Tissues , 2011, Materials.

[69]  Jennifer H Elisseeff,et al.  Synthesis and characterization of a novel degradable phosphate-containing hydrogel. , 2003, Biomaterials.

[70]  J. Gimble,et al.  Adipose-derived stem cells for regenerative medicine. , 2007, Circulation research.

[71]  D. Williams,et al.  The enzymatic degradation of polymers in vitro. , 1987, Journal of biomedical materials research.

[72]  M. Grinstaff,et al.  Recent advances in glycerol polymers: chemistry and biomedical applications. , 2014, Macromolecular rapid communications.

[73]  Yang Gao,et al.  Two-photon polymerization: investigation of chemical and mechanical properties of resins using Raman microspectroscopy. , 2014, Optics letters.

[74]  Jennifer L West,et al.  Photocrosslinkable polyvinyl alcohol hydrogels that can be modified with cell adhesion peptides for use in tissue engineering. , 2002, Biomaterials.

[75]  W. Cook,et al.  Synthesis, characterization and properties of biocompatible poly(glycerol sebacate) pre‐polymer and gel , 2013 .