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A holistic tissue engineering approach from laboratory to small and large animal models for treatment of pelvic organ dysfunction

Jerome A. Werkmeister1, 2, Sharon Edwards1, Chris Su1, Shanti Gurung2, 3, Aditya Vashi1, Jacinta White1, Daniela Ulrich3, Anna Rosamilia2 and Caroline E. Gargett2, 3
  • 1 CSIRO, CSIRO Manufacturing, Australia
  • 2 Monash University, Obstetrics and Gynaecology, Australia
  • 3 Hudson Institute, Medical Research, Australia

Introduction: Pelvic Organ Prolapse (POP) is the herniation of the pelvic organs into the vagina due to childbirth injury, causing incontinence and sexual dysfunction.  It occurs in 25% of all women and upto 50% of parous women with ageing.  Surgical intervention is required in 19% of women suffering from POP, often with mesh augmentation.  Unfortunately, mesh-related problems, FDA concerns and commercial withdrawal of some meshes, have necessitated new approaches to POP treatment.  In this study, we have engineered new mesh designs with better mechanical properties and combined these with a novel source of stem cells isolated from the endometrium (eMSC).  We have developed in vitro assays to amplify stem cells effectively, assessed cell proliferation, differentiation capacity and macrophage tissue responses in vitro, and used both small and large animal models to assess the tissue response and regenerative healing of eMSC seeded on these new mesh types. 

Materials and Methods: A number of mesh type were developed, primarily knitted from polyamide (PA) coated with varying pore sizes and densities and a stabilised gelatin/fibronectin coating (PA + G/Fn).  Uncoated meshes and commercial polypropylene meshes were used in vitro and in vivo.  eMSC were isolated from biopsies obtained without anaesthesia from pre-menopausal and estrogen-treated post-menopausal women by magnetic bead (W5C5/SUSD2+) cell sorting.  Cells were treated and assessed as described below.  For small animal assessment a standard rat fascial defect model was used and eMSC were labelled with DiO.  For large animal functional eMSC assessment, autologous ovine eMSC were isolated as CD273+/CD49b- and transduced with mCherry; cells were seeded on PA +G/Fn meshes and implanted transvaginally in a sub-clinical POP model described below.

Results and Discussion: Undifferentiated eMSC could be amplified independent of age and passage number in the presence of a TGF-β receptor inhibitor (A83-01) which blocked apoptosis and maintained the W5C5+ phenotype.  These amplified cells proliferated on PA + G/Fn meshes and could be differentiated to SMCs (with TGF β1, PDGFB) or fibroblasts (with CTGF) appropriate for tissue elasticity and mechanical integrity.  In addition, meshes seeded with human macrophages induced a transient TNF-α inflammatory M1 response as well as IL-10 secretion indicative of a M2 tissue regenerative response.  eMSC could modulate the M1/M2 response in vitro.  In nude rats, eMSC did not persist yet promoted strong paracrine effects, promoting early neovascularisation and a rapid influx of M1 macrophages which switched to M2 with time; in the long term macrophages were reduced and fibrosis was minimal around cell-seeded meshes compared with un-seeded control meshes, resulting in better tissue integration and less stiff more complaint tissue regeneration.  In flocks of multiparous sheep, a subpopulation of sub-clinical POP sheep was selected using a new fibre optic pressure vaginal probe and a clinical assessment of vaginal laxity.  In these functional autologous studies eMSC were shown to persist longer and were associated with greater SMC tissue regeneration.

Conclusions: We have shown that our novel tissue engineering approach using mesh designs combined with eMSC may be an alternative approach for treating POP with potential to improve surgical outcomes.

Keywords: Regenerative Medicine, Tissue Engineering, stem cell, in vivo tissue engineering

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: New Frontier Oral

Topic: Biomaterials to modulate biological processes involved in host response

Citation: Werkmeister JA, Edwards S, Su C, Gurung S, Vashi A, White J, Ulrich D, Rosamilia A and Gargett CE (2016). A holistic tissue engineering approach from laboratory to small and large animal models for treatment of pelvic organ dysfunction. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.00888

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.