Modification of PEGDMA hydrogels for use in the fabrication of peripheral nerve guidance conduits

Abstract

Peripheral nerve injury is a worldwide issue affecting millions. More than 719,000 people are receiving surgical treatment for peripheral nerve injury each year in the US alone. There is presently a market for the repair of peripheral nerve injury using natural or synthetic nerve grafts with the autograft (current gold standard) having well known drawbacks in the form of donor site morbidity and a low rate of success for injuries greater than 3 cm. Therefore, there is an opportunity in the market of peripheral nerve injuries to repair gaps greater than 3 cm while also preventing secondary sites of morbidity. This thesis describes the development of a polyethylene glycol dimethacrylate (PEGDMA) based product to fill this clinical need. Initial work in this thesis focused on comparing the material property profiles of four different monomer concentrations of PEGDMA (600MDa) stored in physiological solutions at 37°C over a 28-day period. To achieve this goal, polymer constructs were prepared (25, 50, 75 and 100 wt. % PEGDMA) in water and cross-linked by UV-induced photopolymerisation. Thereafter the material properties were examined after 0, 2, 14 and 28 days for their swelling characteristics, wettability, surface topography, chemical properties, polymer morphology, mechanical properties, and cell response. From this data, it was decided that the 50 and 100 wt. % PEGDMA hydrogels were most suited to replicate the conditions of peripheral nerve tissue. Electroactive bioglass was selected as an additive to increase the conductivity of PEGDMA to enhance conductivity. The materials properties of the new PEGBio composites were subsequently tested with additional analysis of the conductivity of samples. From these subsequent tests it was determined that the PEGBio 2.5 wt. % samples provided the greatest boost to conductivity. Following on from this the project looked to address PEGDMAs lack of degradability. To improve degradability, PEGDMA was polymerised with ten different thiol monomers, both mercaptopropionates and mercaptoacetates. Following an initial polymerisation check, it was determined that mercaptopropionates were more successfully polymerised than mercaptoacetates. The material properties of the new PEG-thiol composites were subsequently tested as per previous tests with further study determining that dipentaerythritol hexa(3-mercaptopropionate) (DiPETMP) successfully enhanced the biodegradability of PEGDMA. To increase the bioactivity of PEGDMA based hydrogels the introduction of bioactive factors was analysed. A series of high-throughput tests combining three drugs (N-acetyl cysteine (NAC), Ibuprofen (Ibu) and Progesterone (Prog)) were carried out to pick the most synergistic three-drug combination to boost cellular proliferation in PC-12 and Schwann cells. Ultimately concentrations of 75 µM NAC, 16.25 µM Ibu and 30 µM Prog were selected. Following this, a study to determine the rates of NAC, Ibu and Prog release from PEGDMA-DiPETMP found that drug release was completed after 1, 3 and 21 days respectively. In the final section of this thesis, attempts were made to control the 3D architecture of the final composition, leading to a combination of PEGDMA, DiPETMP, Bioglass and the drugs NAC, Ibu and Prog (PEGCombo) being prepared via UV chamber polymerisation. Its properties were monitored over a 28 day period, ultimately it was determined that further adjustments to PEGCombos composition were needed to enhance its potential use as a nerve guidance conduit.