New multi-material formulations for vat-photopolymerisation and their application in manufacturing ocular implants

Konta, Andrea Alice (2022) New multi-material formulations for vat-photopolymerisation and their application in manufacturing ocular implants. PhD thesis, University of Nottingham.

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Additive Manufacturing (AM), often referred to as 3D printing, encompasses a series of processes that build structures in an additive fashion, layer by layer. This is usually possible by translating a 3D computer-aided design (CAD) into a standard tessellation language (STL) file that is then directly manufactured into a physical structure. The process that manufactures structures illuminating liquid photosensitive resins with a light source is called vat-photopolymerisation. From the different vat-photopolymerisation techniques, two-photon polymerisation is the technique that allows micro- and nano-printing at the highest resolution. Besides high resolution, it also offers the possibility of manufacturing complex structures without need for support. And it also allows to select degrees of porosity, defined shapes, or intricate topologies. These features had made the technique attractive for several applications like microfluidics, metamaterials, cell culture, or drug delivery.

However, there are several challenges that need to be resolved for the technique to reach its full potential and be embraced on a commercial basis outside the research community. This thesis aims to tackle two of the disadvantages of this technique. First, the lack of suitable materials available for it. Currently, there are few materials that are 2PP processable that are also of interest for biological applications. Second, the research developed on the technique has mainly focused on mono-material formulations. Therefore, the work presented in this thesis addresses both drawbacks by developing new materials that could be potentially used for biological applications and optimises them for 2PP processing in multi-material formulations.

This was achieved by initially synthesizing a new mono–functional poly(trimethylene carbonate) acrylate (PTMCA) polymer and optimizing it for 2PP printing in several multi-material formulations. The optimisation was done by mixing the biodegradable PTMCA with a hydrophilic (poly(ethylene glycol) diacrylate (PEGDA)) and hydrophobic (tricyclo [,6] decanedimethanol diacrylate (TCDMDA)) cross-linker monomer at different concentrations. The multi-material formulations containing the mono–functional PTMCA were successfully processed in the 2PP system, and the structures manufactured with them showed a sharp increase in reacted vinyl groups (RVG) compared to structures manufactured with only commercial monomer (between 20% and 50% increase depending on the formulation used). The addition of PTMCA to the monomers also significantly expanded the polymerisation threshold of the formulations when compared to thresholds of only cross-linkers. The presence and disposition of both materials in structures manufactured with multi-material formulations were confirmed via Time-of-Flight Secondary Ion Mass Spectrometry (TOF – SIMS). PTMCA + PEGDA samples showed a continuous single phase. PTMCA + TCDMDA samples showed phase separation at certain concentrations. This phase separation could be controlled by the formulation concentration or the processing parameters of the 2PP system.

The library of 2PP materials was also expanded by synthesizing two new hyperbranched polymers: Hyperbranched poly(PEGDA) (HBpPEGDA) and Hyperbranched poly(TCDMDA) (HBpTCDMDA). This would allow to manufacture with highly functionalised materials with a high molecular weight, compared to the mono-functional low molecular weight PTMCA. The hyperbranched materials were optimized for 2PP manufacturing in mono-material (HBpTCDMDA based) or multi-material (HBpPEGDA based) formulations. Structures manufactured with HBpTCDMDA also showed a sharp increase in RVG (>50 %) when compared to structures manufactured with TCDMDA monomer. The hyperbranched formulations also significantly broadened the polymerization threshold when compared to thresholds of formulations prepared with commercial PEGDA and TCDMDA monomers. The presence of both materials in multi-material formulations was confirmed via ToF-SIMS, with a single continuous phase. Scaffolds printed with HBpTCDMDA also showed high viability on LIVE/DEAD assay with mouse fibroblasts, indicating the potential biocompatibility of this material.

Last, to show the potential of one of the formulations developed in this thesis for a biological application, one of the PTMCA + PEGDA mixtures was selected and further optimised to fabricate a proof-of-concept intravitreal implant for sustained release of fluocinolone acetonide (FA). Different implant designs based on a diamond lattice were created to study the influence of implant geometry on drug release. Printing optimisation was initiated in the 2PP system to determine the initial feasibility of lattice design printing at small scale while using small amounts of formulation, but micro projection stereolithography (PμSLA) was chosen as the technique for scale-up and final implant manufacturing due to faster printing times compared to 2PP while still maintaining adequate resolution. N – vinyl pyrrolidone (NVP) was added to the formulation to facilitate drug release from the implant matrix. The percent of NVP needed was optimised by studying the release of model drug Rhodamine B from Ultraviolet (UV) cast samples. The concentration that allowed for a sustained release of ~80 % of model drug over 39 days was 25 wt% NVP, which was the formulation selected to manufacture the FA intravitreal implants. Cylindrical lattice implants (1.85 ± 0.05 mm in length, 0.5 mm in diameter) loaded with 6.25 wt% of FA were manufactured via PμSLA using the optimised formulation containing 25 wt% NVP. They showed high cell viability and no cytotoxicity in in vitro assays with human corneal epithelial cells. All lattice implants showed ~60 % of cumulative drug release over 35 days. The profile of release varied depending on the geometry of the implant, indicating an influence of the pore size and surface area over release. The microstructure analysis of samples indicated some phase separation and a possible preference of the drug for Poly - vinyl pyrrolidone (PVP), which further facilitated the drug release from the polymer matrix when it dissolved into aqueous media.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Irvine, Derek
Ruiz-Cantu, Laura
Wildman, Ricky
Alexander, Cameron
Keywords: 3D printing, Additive Manufacturing, Vat-photopolymerization, Two-photon polymerization, Biomaterials, Hyperbranched polymers, Multi-material printing, Intravitreal implant
Subjects: R Medicine > RS Pharmacy and materia medica
T Technology > TS Manufactures
Faculties/Schools: UK Campuses > Faculty of Engineering
Item ID: 69553
Depositing User: Konta, Andrea
Date Deposited: 31 Jul 2022 04:42
Last Modified: 31 Jul 2022 04:42

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