Host response to synthetic mesh in women with mesh complications.

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.

Characterization of the host inflammatory response following implantation of prolapse mesh in rhesus macaque.

OBJECTIVE: We sought to determine the predominant cell type (macrophage, T lymphocyte, B lymphocyte, mast cell) within the area of implantation of the prototypical polypropylene mesh, Gynemesh PS (Ethicon, Somerville, NJ); and to determine the phenotypic profile (M1 proinflammatory, M2 antiinflammatory) of the macrophage response to 3 different polypropylene meshes: Gynemesh PS (Ethicon), and 2 lower-weight, higher-porosity meshes, UltraPro (Ethicon) and Restorelle (Coloplast, Humblebaek, Denmark). STUDY DESIGN: Sacrocolpopexy was performed following hysterectomy in rhesus macaques. Sham-operated animals served as controls. At 12 weeks postsurgery, the vagina-mesh complex was excised and the host inflammatory response was evaluated. Hematoxylin and eosin was used to perform routine histomorphologic evaluation. Identification of leukocyte (CD45(+)) subsets was performed by immunolabeling for CD68 (macrophage), CD3 (T lymphocyte), CD20 (B lymphocyte), and CD117 (mast cell). M1 and M2 macrophage subsets were identified using immunolabeling (CD86(+) and CD206(+), respectively), and further evaluation was performed using enzyme-linked immunosorbent assay for 2 M1 (tumor necrosis factor-alpha and interleukin [IL]-12) and 2 M2 (IL-4 and IL-10) cytokines. RESULTS: Histomorphologic evaluation showed a dense cellular response surrounding each mesh fiber. CD45(+) leukocytes accounted for 21.4 ± 5.4% of total cells within the perimesh area captured in a ×20 field, with macrophages as the predominant leukocyte subset (10.5 ± 3.9% of total cells) followed by T lymphocytes (7.3 ± 1.7%), B lymphocytes (3.0 ± 1.2%), and mast cells (0.2 ± 0.2%). The response was observed to be more diffuse with increasing distance from the fiber surface. Few leukocytes of any type were observed in sham-operated animals. Immunolabeling revealed polarization of the macrophage response toward the M1 phenotype in all mesh groups. However, the ratio of M2:M1 macrophages was increased in the fiber area in UltraPro (P = .033) and Restorelle (P = .016) compared to Gynemesh PS. In addition, a shift toward increased expression of the antiinflammatory cytokine IL-10 was observed in Restorelle as compared to Gynemesh PS (P = .011). CONCLUSION: The host response to mesh consists predominantly of activated, proinflammatory M1 macrophages at 12 weeks postsurgery. However, this response is attenuated with implantation of lighter-weight, higher-porosity mesh. While additional work is required to establish causal relationships, these results suggest a link among the host inflammatory response, mesh textile properties, and clinical outcomes in the repair of pelvic organ prolapse.

Distinct macrophage phenotype and collagen organization within the intraluminal thrombus of abdominal aortic aneurysm.

OBJECTIVE: Little is known about the etiologic factors that lead to the occurrence of intraluminal thrombus (ILT) during abdominal aortic aneurysm (AAA) development. Recent work has suggested that macrophages may play an important role in progression of a number of other vascular diseases, including atherosclerosis; however, whether these cells are present within the ILT of a progressing AAA is unknown. The purpose of this work was to define the presence, phenotype, and spatial distribution of macrophages within the ILT excised from six patients. We hypothesized that the ILT contains a population of activated macrophages with a distinct, nonclassical phenotypic profile. METHODS: ILT samples were examined using histologic staining and immunofluorescent labeling for multiple markers of activated macrophages (cluster of differentiation [CD]45, CD68, human leukocyte antigen-DR, matrix metalloproteinase 9) and the additional markers α-smooth muscle actin, CD34, CD105, fetal liver kinase-1, and collagen I and III. RESULTS: Histologic staining revealed a distinct laminar organization of collagen within the shoulder region of the ILT lumen and a spatially heterogeneous cell composition within the ILT. Most of the cellular constituents of the ILT were in the luminal region and predominantly expressed markers of activated macrophages but also concurrently expressed α-smooth muscle actin, CD105, and synthesized collagen I and III. CONCLUSIONS: This report presents evidence for the presence of a distinct macrophage population within the luminal region of AAA ILT. These cells express a set of markers indicative of a unique population of activated macrophages. The exact contributions of these previously unrecognized cells to ILT formation and AAA pathobiology remains unknown.

In vivo assessment of a biological occluder for NOTES gastrotomy closure.

BACKGROUND: The objective of this study is to evaluate the closure of a transgastric natural orifice transluminal endoscopic surgery (NOTES) access using a multilayer extracellular matrix (ECM) occluder in a canine model. MATERIALS AND METHODS: Mongrel dogs (n = 4) underwent a transgastric NOTES peritoneoscopy and the gastrotomy was closed by deploying a 2-sided ECM occluder. Animals were killed at 7 days (n = 2) and 8 weeks (n = 2) for macroscopic and microscopic assessment. RESULTS: All procedures were completed without any complications. No air leaks were detected immediately after the procedure and at 48 hours postoperatively. At 7 days, ECM appeared to be resolved and mild mucosal inflammation was found at the site of gastrotomy. At 8 weeks, the gastrotomy site was macroscopically and microscopically covered with a normal-appearing gastric mucosa. There was an absence of inflammatory cells and no evidence of the ECM. CONCLUSION: The ECM occluder is safe and effective in this "proof-of-concept" preclinical model.

Extracellular matrix as an inductive scaffold for functional tissue reconstruction.

The extracellular matrix (ECM) is a meshwork of both structural and functional proteins assembled in unique tissue-specific architectures. The ECM both provides the mechanical framework for each tissue and organ and is a substrate for cell signaling. The ECM is highly dynamic, and cells both receive signals from the ECM and contribute to its content and organization. This process of "dynamic reciprocity" is key to tissue development and for homeostasis. Based upon these important functions, ECM-based materials have been used in a wide variety of tissue engineering and regenerative medicine approaches to tissue reconstruction. It has been demonstrated that ECM-based materials, when appropriately prepared, can act as inductive templates for constructive remodeling. Specifically, such materials act as templates for the induction of de novo functional, site-appropriate, tissue formation. Herein, the diverse structural and functional roles of the ECM are reviewed to provide a rationale for the use of ECM scaffolds in regenerative medicine. Translational examples of ECM scaffolds in regenerative are provided, and the potential mechanisms by which ECM scaffolds elicit constructive remodeling are discussed. A better understanding of the ability of ECM scaffold materials to define the microenvironment of the injury site will lead to improved clinical outcomes associated with their use.