Evaluation of New Meshes, a Cell-based Therapy, and Animal Model for Pelvic Organ Prolapse Repair PDF Download

Author: Daniela Ulrich
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Languages : en
Pages : 416

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Book Description
Pelvic Organ Prolapse (POP) is defined as the descent of one or more of the pelvicstructures and includes uterine prolapse, vaginal vault prolapse, and anterior or posterior vaginal wall prolapse. The resultant symptoms are urinary and bowel dysfunction, incontinence, and sexual dysfunction. POP is primarily caused by childbirth injury, but ageing, obesity and other factors also contribute. Common treatment of POP is surgery and includes native tissue surgical reconstruction alone or with implantation of either synthetic or biological mesh with the former having a higher success rate. However, thelong-term outcome of synthetic mesh augmented surgery is unsatisfactory due to postsurgical complications. The most common problems are mesh exposure and pain possiblydue to scarring, folding and/or contraction of synthetic meshes. Polypropylene (PP) wasrapidly adopted for POP surgery and was not carefully reassessed to determine whether PPmet the criteria for treating the damaged pelvic floor tissues.Mesenchymal Stem Cells (MSC) have been discovered in almost every adult tissue andare highly proliferative, self-renew and differentiate into mesodermal lineages in vitro.MSC also have immunomodulatory and angiogenic properties making them idealcandidates for cell-based therapies. Recently MSC have been discovered in theregenerative endometrial lining of the uterus and specific markers (W5C5/SUSD2) havebeen identified for their prospective isolation. These endometrial MSC (eMSC) fulfil the classical criteria of adult MSC and can be obtained under minimally invasive procedures without anaesthesia or scarring from premenopausal women.Tissue engineering is defined as a combination of cells and materials and is widely used in the field of regenerative medicine. Many cell types from the same or a different individual can be used in combination with a synthetic, biological or composite material. Of the urogenital organs, to date, researchers have only been able to reconstruct the human bladder and urethra using tissue engineering approaches.In this thesis, new meshes designed specifically for POP repair surgery were evaluated in an abdominal wall fascial defect model to evaluate the extent of host tissue response, tissue integration and subsequent mechanical properties. Polyamide (PA), Polyamide plus Gelatin (PA+G) and Polyether-etherketone (PEEK) showed temporal inflammatory responses that were different to that seen with PP meshes with enhancedneovascularisation, collagen production, and decreased inflammation. PA and PA+Gcould be a future treatment option for POP repair surgery.Most women who suffer from POP are postmenopausal and we therefore characterisedeMSC from postmenopausal women treated with or without exogenous estrogen. Similarto premenopausal women, eMSC can be obtained by a curettage procedure followingshort-term estrogen treatment. Postmenopausal eMSC are similar to premenopausal eMSC in terms of cloning efficiency and phenotype but are available in lower numbers and differentiate to a lesser degree.The next step was to test the PA+G meshes and eMSC in a nude rat fascial wound modelas a small preclinical proof of principle animal model. Meshes seeded with eMSCimproved the tissue integration compared to meshes alone by increasing theneovascularisation, altering macrophages from an inflammatory to wound healingphenotype, decreasing the foreign body reaction, and improving the biomechanicalproperties in the long term, without engraftment.This thesis also provides a comprehensive analysis of sheep vaginal tissue to generatebaseline data in this large animal preclinical model, including biochemical, biomechanical and histological analyses. Sheep that have not delivered lambs have similar biomechanical and biochemical properties to parous sheep whereas pregnancy significantly changes both the tissue composition and mechanical properties. We also determined regional differencesin postmenopausal sheep vagina and correlated the biochemical and histological results with postmenopausal women. The ovine vagina showed differences between the upper and lower region whereas human vagina did to a lesser degree but with similar tissuecomposition. These results can help to understand the biochemical tissue composition and passive biomechanical properties of ovine vagina and relate this to the histo-architecture at different reproductive stages as part of the establishment of a large animal preclinicalmodel for evaluating regenerative medicine approaches for surgical treatment of pelvicorgan prolapse. The next step would be to test the above mentioned TE construct in a large animal model; however this was not feasible within the time frame of this thesis.In conclusion eMSC are a promising source of MSC independent of a women's stage oflife and could be used for TE purposes. A Tissue Engineering construct might be thefuture treatment for POP but has yet to be evaluated in a large animal preclinical model.