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Title: Improving tissue engineered repair materials used in the treatment of pelvic floor diseases
Author: Hillary, Christopher
ISNI:       0000 0004 7230 4310
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Introduction: Tissue engineering and regenerative medicine techniques may offer improved outcomes for patients suffering from pelvic organ prolapse (POP) and stress urinary incontinence (SUI) compared to polypropylene mesh, which is associated with significant complications. Complications with polypropylene are purported to occur due to an excessive immunological reaction and a mismatch of mechanical properties. Aim: To produce scaffolds with improved biomechanical properties using electrospun degradable and non-degradable scaffolds and to produce oestradiol- releasing scaffolds, which will to improve tissue integration. Methods: Electrospinning was used to produce poly-L-lactic acid and polyurethane scaffolds. Oestradiol-releasing poly-L-lactic acid scaffolds were produced by dissolving the drug in the polymer solution prior to electrospinning. Mechanical properties of these materials were measured using a BOSE tensiometer both before and after cyclical distension. Cell metabolic activity and total collagen production were measured using AlamarBlue assay and Sirius red assay respectively. Oestradiol was incorporated into scaffolds and its release measured fluorimetrically over a 5 month period. The effects of oestradiol on cells in culture were measured (AlamarBlue and Sirius red), and differentiation assays were performed using specific induction media. Specific extracellular component production was assessed using immunohistochemistry. Cell penetration was assessed using confocal microscopy techniques. Poly-L-lactic acid and polyurethane scaffolds were implanted into abdominal wall defect rabbit models over a 3 month period, with histologial, mechanical and immunological outcomes measured. Results: Poly-L-lactic acid scaffolds demonstrated a greater ability of cells to penetrate and showed greater outcomes for cell viability assays and collagen production when stem cells were cultured on them. Meanwhile, polyurethanes demonstrated significantly greater elastic properties, that remained unchanged following periods of cyclical distension. Commercially available polypropylene mesh became plastically deformed following even short periods of cyclical distension to 25% displacement of the original length of the material. Oestradiol-releasing scaffolds were produced, that released the drug over a 5-month period in a dose dependent fashion. Scaffolds that release oestradiol demonstrated a significantly greater total collagen production, which resulted in a stronger biomaterial. Following implantation in animal models, polypropylene mesh was associated with tissue exposure. Poly-L-lactic acid scaffolds became well integrated into the host and became replaced with host cells. Both poly-L-lactic acid and polyurethane scaffolds demonstrated a predominantly M2 macrophage response, while polypropylene mesh showed an M1 macrophage phenotype. The biomechanical properties of tissues that were repaired by either of poly-L-lactic acid, polyurethane, or polypropylene were stronger than tissues that were not reinforced with repair materials. Conclusions: Poly-L-lactic acid scaffolds demonstrate excellent tissue integration and regeneration, while polyurethanes offer mechanical properties that are more closely related to healthy fascia. Oestradiol-releasing scaffolds can support greater proliferation and collagen production of cultured cells, which can be associated with better integration into the host following implantation. Meanwhile, polypropylene mesh exhibits plastic deformation following cyclical distension and is associated with an excessive immunological reaction, which could explain the complications that are observed with this material in patients undergoing mesh surgery.
Supervisor: MacNeil, Sheila Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available