Immunobiology of foreign body response to composite PLACL/gelatin electrospun nanofiber meshes with mesenchymal stem/stromal cells in a mouse model: Implications in pelvic floor tissue engineering and regeneration

Abstract

Pelvic Organ Prolapse (POP) is a common gynaecological disorder where pelvic organs protrude into the vagina. While transvaginal mesh surgery using non-degradable polymers was a commonly accepted treatment for POP, it has been associated with high rates of adverse events such as mesh erosion, exposure and inflammation due to serious foreign body response and therefore banned from clinical use after regulatory mandates. This study proposes a tissue engineering strategy using uterine endometrium-derived mesenchymal stem/stromal cells (eMSC) delivered with degradable poly L-lactic acid-co-poly ε-caprolactone (PLACL) and gelatin (G) in form of a composite electrospun nanofibrous mesh (P + G nanomesh) and evaluates the immunomodulatory mechanism at the material interfaces. The study highlights the critical acute and chronic inflammatory markers along with remodelling factors that determine the mesh surgery outcome. We hypothesise that such a bioengineered construct enhances mesh integration and mitigates the Foreign Body Response (FBR) at the host interface associated with mesh complications. Our results show that eMSC-based nanomesh significantly increased 7 genes associated with ECM synthesis and cell adhesion including, Itgb1, Itgb2, Vcam1, Cd44, Cdh2, Tgfb1, Tgfbr1, 6 genes related to angiogenesis including Ang1, Ang2, Vegfa, Pdgfa, Serpin1, Cxcl12, and 5 genes associated with collagen remodelling Col1a1, Col3a1, Col6a1, Col6a2, Col4a5 at six weeks post-implantation. Our findings suggest that cell-based tissue-engineered constructs potentially mitigate the FBR response elicited by biomaterial implants. From a clinical perspective, this construct provides an alternative to current inadequacies in surgical outcomes by modulating the immune response, inducing angiogenesis and ECM synthesis during the acute and chronic phases of the FBR.

Keywords: Electrospining; Foreign body response; Interface; Mesenchymal stem cells; Nanofibers; Pelvis; Tissue engineering.