Synthesis of biodegradable photocrosslinkable polymers for stereolithography-based 3D fabrication of tissue engineering scaffolds and hydrogels

Aalto University, P.O. Box 11000, FI-00076 Aalto www.aalto.fi Author Laura Elomaa Name of the doctoral dissertation Synthesis of biodegradable photocrosslinkable polymers for stereolithography-based 3D fabrication of tissue engineering scaffolds and hydrogels Publisher School of Chemical Technology Unit Department of Biotechnology and Chemical Technology Series Aalto University publication series DOCTORAL DISSERTATIONS 165/2015 Field of research Polymer Technology Manuscript submitted 7 May 2015 Date of the defence 2 December 2015 Permission to publish granted (date) 23 June 2015 Language English Monograph Article dissertation (summary + original articles) Abstract Stereolithography (SLA) has become popular in 3D fabrication of tissue engineering (TE) scaffolds due to its high resolution, mild building conditions, and fast production times. However, the availability of biodegradable polymers for SLA is very limited. The aim of this thesis was to synthesize new biodegradable, photocrosslinkable polymers for SLA-based scaffold fabrication, and to increase the understanding of how polymer properties and fabrication parameters affect the properties of the resulting TE scaffolds and hydrogels. Star-shaped polycaprolactone (PCL) oligomers were synthesized via ring-opening polymerization and functionalized with methacrylic anhydride to yield photocrosslinkable macromers. The macromers were crosslinked by free radical polymerization using radicalforming photoinitiators. First, a photocrosslinkable, solid PCL macromer was used in SLA by simultaneously heating the macromer to decrease its viscosity. The PCL scaffolds prepared by SLA closely resembled their mathematically defined 3D models. To improve the bioactivity of the scaffolds, a liquid, low-molecular PCL macromer was next combined with bioactive glass (BG) in SLA at room temperature. BG particles were homogeneously distributed within the resulting SLA fabricated scaffolds, increasing their mechanical strength. The formation of calcium phosphate deposits on the scaffold surface in simulated body fluid indicated the in vitro bioactivity of the composite material and increased the cell proliferation on the scaffold surface. To tune the properties of the PCL macromer, a new photocrosslinkable poly(ester amide) was synthesized based on PCL and L-alanine-derived depsipeptide. Copolymerization of PCL with the depsipeptide increased the glass transition temperature and hydrophilicity of the polymer and accelerated its hydrolytic degradation. Also the compressive strength of the SLA fabricated scaffolds increased with depsipeptide content. The new copolymer significantly extended the repertoire of biodegradable polymers suitable for SLA-based scaffold fabrication. Last, a photocrosslinkable poly(ethylene glycol-co-depsipeptide) was synthesized for SLA fabrication of cell-laden hydrogels. The stiffness of the hydrogels increased with increasing crosslinking time while the swelling degree and mass loss decreased. The encapsulated cells showed proliferation in the hydrogels, and tubular hydrogels were successfully fabricated as vascular graft models. Due to its good cell encapsulation capacity and printability, the new polymer was a highly desired addition to the very limited group of biodegradable polymers available for SLA fabrication of cell-laden TE hydrogels.Stereolithography (SLA) has become popular in 3D fabrication of tissue engineering (TE) scaffolds due to its high resolution, mild building conditions, and fast production times. However, the availability of biodegradable polymers for SLA is very limited. The aim of this thesis was to synthesize new biodegradable, photocrosslinkable polymers for SLA-based scaffold fabrication, and to increase the understanding of how polymer properties and fabrication parameters affect the properties of the resulting TE scaffolds and hydrogels. Star-shaped polycaprolactone (PCL) oligomers were synthesized via ring-opening polymerization and functionalized with methacrylic anhydride to yield photocrosslinkable macromers. The macromers were crosslinked by free radical polymerization using radicalforming photoinitiators. First, a photocrosslinkable, solid PCL macromer was used in SLA by simultaneously heating the macromer to decrease its viscosity. The PCL scaffolds prepared by SLA closely resembled their mathematically defined 3D models. To improve the bioactivity of the scaffolds, a liquid, low-molecular PCL macromer was next combined with bioactive glass (BG) in SLA at room temperature. BG particles were homogeneously distributed within the resulting SLA fabricated scaffolds, increasing their mechanical strength. The formation of calcium phosphate deposits on the scaffold surface in simulated body fluid indicated the in vitro bioactivity of the composite material and increased the cell proliferation on the scaffold surface. To tune the properties of the PCL macromer, a new photocrosslinkable poly(ester amide) was synthesized based on PCL and L-alanine-derived depsipeptide. Copolymerization of PCL with the depsipeptide increased the glass transition temperature and hydrophilicity of the polymer and accelerated its hydrolytic degradation. Also the compressive strength of the SLA fabricated scaffolds increased with depsipeptide content. The new copolymer significantly extended the repertoire of biodegradable polymers suitable for SLA-based scaffold fabrication. Last, a photocrosslinkable poly(ethylene glycol-co-depsipeptide) was synthesized for SLA fabrication of cell-laden hydrogels. The stiffness of the hydrogels increased with increasing crosslinking time while the swelling degree and mass loss decreased. The encapsulated cells showed proliferation in the hydrogels, and tubular hydrogels were successfully fabricated as vascular graft models. Due to its good cell encapsulation capacity and printability, the new polymer was a highly desired addition to the very limited group of biodegradable polymers available for SLA fabrication of cell-laden TE hydrogels.