Synthesis and characterization of “Clickable” triazine-trione based thermosets and composites via Thiol-Ene and Thiol-Yne Photochemistry

QC 20240506

Embargo godkänt av skolchef Amelie Eriksson Karlström via e-post 2024-05-05

Abstract

Triazine trione (TATO)-based thiol-ene and thiol-yne (TEC and TYC) thermosets and hydroxyapatite (HA) composites have proven their potential as bone fracture fixation implants for use in open reduction internal fixation (ORIF), a field which is currently dominated by metal implants which usually require a second operation for removal. These composites demonstrate high flexural modulus and strength as well as excellent biocompatibility. As injectable implants they are well-aligned with the surgeons needs for more patient-customized solutions to treat bone fractures. While promising, the non-degradable properties of current systems hinder their full potential to fully resorbable implants after complete bone healing. Hence, the foundation of this thesis was to expand the family of TATO thermosets and composites targeting key requirements on future biomaterials suited for bone tissue regeneration. 

Two different approaches were adopted in this thesis, namely the formulation of composites based on newly synthesized TATO-based monomers, and infusing polyester dendrimers into the existing TATO-HA formulation. The rationale behind both approaches was that the introduction of hydrolysable groups, from either the new TATO monomers or the dendrimers, would increase degradation but also impact the mechanical properties of the composite. The potential clinical applications of these new formulations were investigated through the evaluation of their mechanical, processability, biocompatibility and degradation properties.

In the first approach, TATO-based alkene and alkyne monomers, containing either ester or amide linkages, were synthesized via fluoride promoted esterification (FPE) chemistry. Thermosets and composites were formulated with the resulting triester TATO monomers (TESTATO), commercially available triester TATO thiol (TEMPIC) and biocompatible hydroxyapatite (HA) filler. These formulations generated photo-initiated TEC and TYC crosslinked composites containing hydrolysable ester groups. These ester-rich materials displayed soft and flexible properties, differing from the previouspreviously formulated rigid and strong TATO-based composites. Cytotoxicity testing showed the new composites did not negatively affect cell viability. The high customizability of the TESTATO based composites was demonstrated through the drop-casting of objects such as rings, rods, tubes, and thin films (Paper I). These soft and flexibility composites were not suitable for bone fixation; however, they were investigated for their applications as tissue engineering (TE) scaffolds (Paper III) and anti-soft tissue adhesion coatings on metal implants (Paper IV). In the work of Paper III, numerous characterizations were applied to study the potential of the TESTATO based thermosets as tissue-engineering scaffolds, including mechanical testing, surface analysis, enzymatic degradation testing, and biocompatibility with bone marrow mesenchymal stromal cells (BMSCs). Collected results suggested that these ester-rich TEC and TYC thermoset materials showcased competitive properties to medical grade PCL, especially in the sense of biocompatibility and flexibility. Meanwhile, their convenient viscosity and ability to be cured on demand with light-initiated TEC and TYC chemistry allowed them to be fabricated into TE devices using different methodologies including drop-casting, salting leaching, thin filming and 3D printing. Moreover, the merits of flexibility and high processability of TESTATO based HA composites were applied to create flexible anti-soft tissue adhesion coatings on metal implants (Paper IV). Initial studies demonstrated that these soft TATO-HA composite coated metal plates were hydrophilic and able to withstand flexural displacement of 2 mm, under both dry and wet conditions, which is advantageous for potential future in vivo studies.

In the second approach, polyester dendrimers with 1 and 3 generations were successfully integrated into the previously established rigid and strong TATO-HA composites in small weight percentages via HEV light-initiated TEC reactions. The addition of the dendrimers did not negatively affect the composites’ flexural modulus and strength under both dry and wet conditions. Moreover, the addition of these dendrimers was found to impact the viscosity of the resins of all formulations and reduce the size distribution of trapped bubbles in the composite cross sections.

Both approaches aimed at introducing hydrolysable linkages into the TATO based systems. The inclusion of the G1 dendrimer significantly improved degradation while the TESTATO-alkene based composite showed the best hydrolytic degradation. However, the improvements to the degradation kinetics were more modest than expected, demonstrating that additional work, such using fillers that are more degradable than HA, will be required in the future.

urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-346065