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Development of an engineered tissue designed for pelvic floor repair

Roman Regueros, Sabiniano (2014) Development of an engineered tissue designed for pelvic floor repair. PhD thesis, University of Sheffield.

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Abstract

Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are diseases related to weakness of supportive tissues of the pelvic floor due to altered collagen production in middle-aged women and traumatic processes in younger women such as pregnancy and vaginal delivery. Currently there is no recommended material for use in the surgical management of these disorders. Synthetic non-absorbable materials, such as polypropylene mesh produce a vigorous inflammatory response followed by dense fibrosis and have been associated with serious complications such as exposure. By contrast acellular biological materials have a tendency toward rapid absorption with questionable long-term mechanical integrity and concerns regarding early failure. Our approach aims to develop a tissue engineered repair material (TERM) to provide the long-term durability of synthetic non-absorbable materials whilst avoiding complications such as exposures and pain. The TERM is composed of a scaffold designed to degrade slowly whilst the inclusion of autologous cells is anticipated to produce a new extracellular matrix (ECM) to remodel fascial tissue for long-term restoration of the mechanical properties. Biodegradable poly-(L)-lactic acid (PLA) scaffolds were identified as the candidate material being more cell compatible in vitro than materials currently used to treat SUI and POP, and with mechanical properties close to the range of native tissues of the pelvic floor. A comparison of oral fibroblasts and adipose-derived stem cells (ADSCs) showed similar results when these cells were cultured on PLA scaffolds to develop a TERM in terms of metabolic activity, ECM production and mechanical properties. Of the two, ADSCs were chosen for further experiments since these cells have been shown in the literature to have regenerative potential and also to be immunosuppressive and to stimulate angiogenesis. The number of cells seeded on the scaffolds, the period of culture and culture conditions were optimized for the production of the best TERM candidate. On the other hand, no significant effects were found when exploring chemical and mechanical stimulation with the aim of increasing ECM production. The host response against the PLA scaffolds implanted cell-free and with ADSCs was studied in rats. The acute host response showed that after an inflammatory response, new collagen ingrowth and blood vessels were developed in all samples. Work was then focussed on the modification of the electrospinning rig to develop a variety of PLA scaffolds with different mechanical properties due to different fibre configuration. Finally, the potential of ADSCs to develop the TERM was assessed using cells from different donors, as well as examining whether this potential was preserved when these cells were rapidly isolated from fat using an enclosed system. In summary, we identified a suitable candidate material, cell candidate and culture conditions to develop a TERM designed for pelvic floor repair. Then, an initial animal study suggested a host response against our TERM leading to constructive remodelling for integration into the native tissues. Finally, a range of PLA scaffolds were produced with improved mechanical properties and preliminary data showed the potential to rapidly isolate ADSCs which were used to develop a TERM in vitro.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Engineering (Sheffield) > Materials Science and Engineering (Sheffield)
Identification Number/EthosID: uk.bl.ethos.617219
Depositing User: Mr Sabiniano Roman Regueros
Date Deposited: 22 Aug 2014 09:01
Last Modified: 03 Oct 2016 11:17
URI: http://etheses.whiterose.ac.uk/id/eprint/6651

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