Saudi Cultural Missions Theses & Dissertations
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Item Restricted Development of Local Drug Delivery Device for The Treatment of Pancreatic Cancer Resection Margin(University of Birmingham, 2024-02-02) Amin, Manna; McConville, ChristopherPancreatic cancer is a significant cause of cancer-related deaths worldwide, characterised by a 5-year survival rate that is notably low, typically ranging from 7-8%. Currently, the accepted norm for medical treatment is the surgical removal of the affected tissue, followed by administration of chemotherapy, particularly the highly potent one, FOLFIRINOX regimen. Due to the high toxicity associated with systemic delivery of FOLFIRINOX, and the intricate nature of the microenvironment of pancreatic cancer within the pancreas, there is a need for a more safer drug delivery method such as local delivery to treat the resection margin and prevent tumour recurrence. The study aimed at developing a local drug delivery device (Chemo Patch) composed of 3-dimensional printed catheter import part, a gelatine sponge and an ethylene vinyl acetate releasing membrane. Various sponges manufactured utilizing freeze-drying technique were prepared and characterized to ascertain the effects of gelatine concentration, blending with sodium alginate, and crosslinking with glutaraldehyde on the physical and mechanical properties of the sponges. The selection of the best sponge was based on its desirability, primarily determined by its mechanical properties. These properties are influenced by the characteristics of the control sponge, Gelfoam®. The results demonstrated that the dry Gelfoam® sponge had hardness value of 2.703Kg/mm2 ±35, whereas the hydrated sponge had 8.698 Kg/mm2 ±117.7. The dry Gelfoam® sponges had an elasticity ratio (the ratio between the force of retraction and the maximum force) of 78.71%±1.9, whereas hydrated sponges had 12.14%±1.7. The results showed that increasing gelatine content increases sponge hardness, with 1% and 2% lower than Gelfoam® sponge and 4% and 10% higher. Oppositely, an increase in gelatine concentration resulted in a decrease in the elasticity of the prepared sponges. This study examined how gelatine concentration and blending with sodium alginate affect precursor hydrogel rheology. The results revealed that as gelatine concentration increased, both viscoelastic moduli increased and that the storage modulus Gʹ dominated the loss modulus Gʺ, indicating more robust hydrogel behaviour. Similarly, as sodium alginate concentration increases, storage modulus G' surpasses loss modulus G", indicating a stronger hydrogel behaviour. The results demonstrated that for both dry and hydrated sponges, gelatine concentration increases hardness and decreases elasticity. Porosity and swelling ratio decrease as gelatine content increases. Similarly, with increasing the polymer blends concentration, the hardness increases, elasticity decreases, swelling ratio and porosity decrease. Also, for dry and hydrated sponges, glutaraldehyde concentration increases hardness and elasticity. Additionally, increased glutaraldehyde content decreases the porosity and swelling ratio. The optimum sponge was (4% gelatine, 4% sodium alginate, 0.5% glutaraldehyde), which was further characterised in comparison to Gelfoam®. The results revealed that a diverse pore structure in scanning electron microscopy for both sponges with an average pore size of 100μm. Raman mapping revealed non homogenous distribution for ironitican in both sponges. Fourier transform infrared spectroscopy analysis confirmed successful crosslinking with an Amide I shift peak associated with crosslinking. Differential scanning calorimetry showed a glass transition temperature of 125.24°C for the optimum sponge which was greater than Gelfoam® one (110°C). The hydrolysis degradation was more than 6 weeks for the optimum sponge, and the drug release exhibited a biphasic profile over 7 days. Linearity, range, accuracy, limit of detection, and limit of quantification validated the high liquid chromatography irinotican method. Ethylene vinyl acetate melt rheology was used to determine processing temperature for fused deposition three-dimensional printing chemo patch device. Melt rheology predicted a printing temperature of 84°C to 132°C, later confirmed by the greatest printed quality achieved at 120°C. A feasibility study tested two designs—square and oblong. The square-shaped device was 4 cm by 4 cm, while the elongated device was 15mm by 30mm and fits the cadaver pig’s surgical margin. After characterisation of different membranes in thickness, infill percentage, number and size of pores, the best one chosen was 1mm thickness and 75% infill based on drug release ,which was included as part of the Chemo Patch device. The three-dimensional printing parameters were, print speed 15 mm/s, print temperature 110 °C, build plate 55 °C, zig zag infill pattern, 120mm/sec travel speed, 35% flow rate, and 0.15mm layer height. Furthermore, the mechanical testing results indicated that the catheter attachment to Chemo Patch was satisfactory, and there was no evidence of any leakage from the walls of the device. Additionally, the in vitro FOLFIRINOX release was sustained over one week. The study's in vivo testing demonstrated that the Chemo Patch did not exhibit any significant incompatibility issues in the pig model. However, it was observed to elicit some immune response and fibrosis, which is a typical occurrence in implantable drug delivery devices. Furthermore, the study proved the effectiveness of the Chemo Patch device in delivering FOLFIRINOX locally in murine model, hence suppressing tumour growth.48 0