Host response to synthetic mesh in women with mesh complications

Abstract

Background: Despite good anatomic and functional outcomes, urogynecologic polypropylene meshes that are used to treat pelvic organ prolapse and stress urinary incontinence are associated with significant complications, most commonly mesh exposure and pain. Few studies have been performed that specifically focus on the host response to urogynecologic meshes. The macrophage has long been known to be the key cell type that mediates the foreign body response. Conceptually, macrophages that respond to a foreign body can be dichotomized broadly into M1 proinflammatory and M2 proremodeling subtypes. A prolonged M1 response is thought to result in chronic inflammation and the formation of foreign body giant cells with potential for ongoing tissue damage and destruction. Although a limited M2 predominant response is favorable for tissue integration and ingrowth, excessive M2 activity can lead to accelerated fibrillar matrix deposition and result in fibrosis and encapsulation of the mesh.

Objective: The purpose of this study was to define and compare the macrophage response in patients who undergo mesh excision surgery for the indication of pain vs a mesh exposure.

Study design: Patients who were scheduled to undergo a surgical excision of mesh for pain or exposure at Magee-Womens Hospital were offered enrollment. Twenty-seven mesh-vagina complexes that were removed for the primary complaint of a mesh exposure (n = 15) vs pain in the absence of an exposure (n = 12) were compared with 30 full-thickness vaginal biopsy specimens from women who underwent benign gynecologic surgery without mesh. Macrophage M1 proinflammatory vs M2 proremodeling phenotypes were examined via immunofluorescent labeling for cell surface markers CD86 (M1) vs CD206 (M2) and M1 vs M2 cytokines via enzyme-linked immunosorbent assay. The amount of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) proteolytic enzymes were quantified by zymography and substrate degradation assays, as an indication of tissue matrix degradation. Statistics were performed with the use of 1-way analysis of variance with appropriate post hoc tests, t-tests, and Fisher's Exact test.

Results: Twenty-seven mesh-vaginal tissue complexes were excised from 27 different women with mesh complications: 15 incontinence mid urethral slings and 12 prolapse meshes. On histologic examination, macrophages surrounded each mesh fiber in both groups, with predominance of the M1 subtype. M1 and M2 cytokines/chemokines, MMP-9 (pro- and active), and MMP-2 (active) were increased significantly in mesh-vagina explants, as compared with vagina without mesh. Mesh explants that were removed for exposure had 88.4% higher pro-MMP-9 (P = .035) than those removed for pain. A positive correlation was observed between the profibrotic cytokine interleukin-10 and the percentage of M2 cells (r = 0.697; P = .037) in the pain group.

Conclusion: In women with complications, mesh induces a proinflammatory response that persists years after implantation. The increase in MMP-9 in mesh explants that were removed for exposure indicates degradation; the positive association between interleukin-10 and M2 macrophages in mesh explants that are removed for pain is consistent with fibrosis.

Keywords: cytokine; inflammatory response; macrophage phenotype; polypropylene mesh.

FIGURE

Immunofluorescent labeling of pan-macrophage marker CD68 (red), M1 proinflammatory marker CD86 (orange), M2 proremodeling macrophage marker CD206 (green), and 4’,6-diamidino-2-phenylindole (blue). A, A mesh-tissue section from a patient with an exposure who had been implanted with the AMS Perigee prolapse mesh (American Medical Systems, Minnetonka, MN) for 93 months; B, a mesh-tissue section from a patient with pain who had been implanted with the Gynecare TVT Secur (Ethion, Inc., Somerville, NJ) for 6 months; C, control tissue from patients without graft implantation. An asterisk indicates a predominance of proinflammatory M1 macrophages surround mesh fibers that is consistent with a prolonged immune response could be observed in both A and B; however, this response is limited to the area immediately adjacent to mesh fibers. Control tissue contained few or no macrophages as compared with mesh patient tissue. Original magnification ×200. Nolfi et al. Vaginal macrophage profile in women with mesh complications. Am J Obstet Gynecol 2016.