Int Urogynecol J (2012) 23:669–679 DOI 10.1007/s00192-012-1718-y

REVIEW ARTICLE

Polypropylene mesh and the host response

Hiren Patel & Donald R. Ostergard & Gina Sternschuss

Received: 28 September 2011 /Accepted: 9 February 2012 /Published online: 20 March 2012 # The International Urogynecological Association 2012

Abstract The use of (PP) mesh for pelvic satisfaction. Surgeons are approached regularly by industry floor repair has been increasing dramatically over the past with efforts to implement newer technologies and products. decade; however, tissue response in humans has not been Whether any one product is superior remains unclear, as extensively studied. This review discusses PP mesh and evidence-based outcome and safety data lag far behind the postimplantation host tissue response. Emphasis is placed introduction of medical implants. As surgeons strive to im- on studies investigating the relationship between individual prove outcomes, they offer patients these new innovations mesh properties and specific responses. There is an imme- without the benefit of knowing long-term outcomes and safe- diate inflammatory response after PP mesh implantation that ty. Nowhere is this dilemma more apparent than in the field of lays the framework for tissue ingrowth and subsequent mesh female pelvic floor reconstruction. Over the past 10 years, the integration. This response varies based on physical proper- market has been flooded with numerous medical devices ties of individual mesh, such as pore size, weight, coatings, touted to improve outcomes in transvaginal pelvic floor re- bacterial colonization, and biofilm production. construction. Despite an absence of long-term randomized trials, the use of in female pelvic floor recon- Keywords Biocompatibility. Host response . Inflammatory struction is more prevalent, as these products have been mar- response . Polypropylene mesh keted to the surgeon as innovations that reduce operative time, allow for quicker recovery, and increase revenues. The use of biomaterials during repair, mostly Introduction polypropylene (PP) mesh, is commonplace in the general discipline. The use of transvaginal PP mesh to In nearly every field of medicine, physicians are constantly augment the pelvic floor repair remains controversial, as searching for ways to improve surgical outcomes and patient evidence of quality of life and symptom improvement is lacking [1]. Along with long-term efficacy, patient safety H. Patel : G. Sternschuss needs to be determined. The United States Food and Drug Long Beach Memorial Medical Center, Women’s Hospital, Administration (US FDA) and UK’sNationalInstitutefor 2801 Atlantic Ave, Health and Clinical Excellence (NICE) have issued warn- Long Beach, CA 90806, USA ing statements regarding the use of synthetic mesh in D. R. Ostergard vaginal surgery for pelvic floor reconstruction in light of Department of Obstetrics, Gynecology and Women’s Health, the absence of level I evidence supporting its efficacy and Division of Female Pelvic Medicine and Pelvic Reconstructive safety [2, 3]. NICE has even created a detailed patient Surgery, University of Louisville, School of Medicine, 550 South Jackson St, Second Floor, information document highlighting its findings from a Louisville, KY 40202, USA recent review of the efficacy and safety of vaginal mesh in pelvic floor reconstruction [4]. In this article, we review H. Patel (*) the impact of mesh implantation on host tissue and the 5710 Crescent Park East, 418, Playa Vista, CA 90094, USA resulting inflammatory responses associated with tissue e-mail: [email protected] ingrowth and mesh integration. 670 Int Urogynecol J (2012) 23:669–679

Pathophysiology strength and extensibility of the mesh designs differed con- siderably. Not all meshes behave the same way in vivo and Pelvic floor prolapse is a relatively common problem in which perhaps once implanted also continue to exhibit unique the underlying pathophysiology remains unclear. The strength characteristics. Mesh architecture may not only affect its of the pelvic floor depends on the interplay of properly inner- biomechanical properties but also tissue response. In 1997, vated muscles, ligaments, and connective tissue. The etiology Amid devised a classification based primarily on pore size of prolapse is likely multifactorial, developing from obstetric for meshes used in hernia repairs (Table 1). Different syn- trauma and denervation to the pelvic floor. It has been pro- thetic materials behave in unique ways in vivo [8, 9]. Mesh posed that altered collagen and connective tissue metabolism characteristics, such as material, pore size, and weave, may in pelvic floor tissues contribute to the pathogenesis of pelvic not only dictate their biocompatibility but also the in situ organ prolapse (POP) [5, 6]. Jackson et al. found that prolapse tissue response. was associated with a reduction in total collagen content and a decrease in collagen solubility by showing that collagen turn- over in prolapse tissue, as indicated by matrix metalloprotei- Quality of scar formation nase (MMP-9) activity, occurred at four times the rate of controls [5]. In a recent review, Kerkhof also described find- After implantation, the host tissue reaction ings from multiple studies confirming that altered collagen begins with an acute inflammatory response, ultimately metabolism, as evidenced by an increased expression of col- leading to collagen production and scar formation. The lagen type III and MMP-9, was associated with prolapsed amount and type of collagen production stimulated by dif- tissue [6]. Traditionally, it is this in situ weakened supportive ferent materials may vary owing to their respective proper- connective tissue that is used to perform native tissue repairs ties and environment [10, 11]. Using an animal model, de during pelvic floor reconstruction. Several studies have shown Almeida et al. noted that at day 60, both Prolene® (1,500- high recurrence rates with traditional native tissue repairs, μmpores)andMarlex®(PP,600-μmpores)induceda hence the introduction of biomaterials to augment repairs. similar inflammatory response. However, Prolene® pro- The use of PP mesh in pelvic floor reconstruction has duced a greater amount of collagen type III, whereas Mar- increased dramatically over the past several years. The mesh lex® had no difference in collagen production compared is intended to serve as scaffolding onto which tissue in- with sham [12]. Junge et al. used the rat abdomen to study growth occurs. Studies evaluating the pelvic floor tissue the influence of various mesh materials on collagen deposi- response are limited to small case series. A greater number tion [13]. Three different materials were used: Marlex®, of studies involving larger numbers are available for abdom- Mersilene® (polyester), and Vypro® (PP/polyglactin com- inal hernia repairs, and most investigations have used an posite). On day 90, the Marlex® group was found to have a animal model. It is important to understand that individual significantly higher ratio of collagen to overall protein com- tissue responses at these different locations will differ. For pared with the other groups. The study also showed that all example, hernia meshes are inserted under sterile condi- groups experienced an increase in the ratio of collagen type tions, whereas prolapse repair meshes are exposed to a I/III over time. However, within the scar of the sham group, clean-contaminated environment. Also, biomechanics in the type I/III collagen ratio was significantly elevated com- the abdominal wall may differ significantly from that of pared with the mesh group. There were no significant differ- the pelvic floor. However, there may exist many similarities ences in type I/III collagen ratios between mesh groups. and overlapping physiologic responses. Pore size and mesh weight may also influence collagen production and maturation. In an animal study using the abdominal wall, Pascual et al. investigated the influence of Biocompatibility Table 1 Classification of synthetic biomaterials Biocompatibility is generally accepted to be the ability of a Biomaterial type Characteristic material to perform with an appropriate host response. As such, biomaterials should be physically and chemically in- Type I Totally macroporous mesh with pores >75 μm, ert. The ideal biomaterial for use in pelvic floor reconstruc- the size required for infiltration of macrophages, tion is yet to be determined. The most widely used mesh in fibroblasts, blood vessels pelvic floor repair is a monofilamentous, macroporous PP Type II Totally microporous mesh with pores <10 μminat least one of three dimensions mesh. Krause et al. assessed the in vitro biomechanical Type III Macroporous material with multifilamentous or properties of raw meshes commonly used in pelvic floor microporous components surgery [7]. They examined material properties of eight Type IV Materials with submicronic pore size different types of surgical meshes using tensile tests. The Int Urogynecol J (2012) 23:669–679 671 pore size and mesh weight on collagen production and its Postimplantation local inflammatory responses can also subsequent impact on tensile strength [14]. Four different elicit a stronger systemic rise in proinflammatory markers PP meshes were used: At 14 days, lighter-weight meshes [22]. Di Vita et al. showed that the use of PP mesh for with larger pore size induced more collagen type III depo- inguinal is associated with a higher production sition and faster conversion to type I than heavy-weight of inflammatory cytokines [serum Interleukin-6 (IL-6) and meshes. They also found that the most porous light-weight Interferon (IFN)] compared with conventional hernia repair. mesh (Optilene®) achieved the greatest tensile strength. In another study by Di Vita et al., patients who had under- Given the short (14 day) duration of this study, the long- gone hernia repair with larger mesh had the highest levels of term effects regarding tensile strength remain unclear. Po- IL-6, suggesting a direct relationship between mesh size and tential confounders in this study may be the vast differences degree of inflammatory response [23]. In both studies, se- in the material characteristics of the individual meshes. rum was collected up to 168 h postimplantation only, so the long-term systemic response still needs to be determined in this population. Host response at a cellular level Whereas inflammatory reaction is necessary for connec- tive tissue deposition, a state of enhanced immunological A well-known host response to foreign-body implantation activity may also be the source of postoperative complica- occurs immediately after introduction of the biomaterial into tions. Recently, Rechberger et al. investigated the role be- the body [15]. Immediately upon implantation, blood–ma- tween preoperative cytokine levels and PP mesh erosion terial interactions lead to the development of a blood-based after suburethral sling placement [24]. Preoperative serum transient matrix that forms surrounding the biomaterial [16]. IFN concentrations in a group of patients without mesh This matrix formation is aided by the immune response that erosion were compared with preoperative levels for patients is triggered by injury to vascularized connective tissue. The with mesh erosion. They found that women with mesh matrix is rich in cytokines, chemoattractants, and growth erosion had significantly higher preoperative IFN levels factors important for enhancing cellular activity and the than women with normal vaginal . subsequent activation and proliferation of other mediators These findings may suggest that an exaggerated systemic in the early wound-healing response [17]. In other words, response may play a role in the pathogenesis of mesh the matrix lays the framework upon which subsequent complications. Some studies investigated modulators of phases will respond. the immune response to see if they play a role in mesh An acute inflammatory response follows matrix forma- integration [25, 26]. In an animal study, Orenstein et al. tion. Histamine-mediated phagocyte recruitment and adhe- demonstrated the role of mast cells in host tissue response sion to implant surfaces is facilitated by proteins adsorbed in to PP mesh [25]. They found that mice implanted with PP the matrix. Enhanced neutrophil activity along with hista- meshes and treated with a mast cell suppressant exhibited mine and interleukin release from mast cells plays an im- less inflammation and foreign-body reaction. However, in portant role in this subsequent phase [18]. The chronic another animal study, Junge et al. were unable to find a inflammatory response starts when monocytes and lympho- difference in the amount of inflammatory tissue formation cytes are recognized at the implant site, leading to eventual between mice that had specific cytokine receptor knockouts foreign-body giant-cell (FGBC) formation through fusion of and controls [26]. these cells. Migration of macrophages to the implant site is heavily influenced by cytokine activity [19], with subse- quent fusion dependent on the material surface itself [20]. Anatomic location and tissue response The process of tissue ingrowth into the mesh is a result of the local inflammatory response upon implantation. This is Animal and human studies have used both the abdomen and characterized by macrophage activation and fibroblast pro- vagina to evaluate tissue response to graft materials. The liferation, the activity of which is mediated by cytokines and abdominal wall and pelvic floor clearly represent two dis- growth factors [14]. The response also varies depending on tinct anatomic regions, and so whether the foreign-body the particular surface characteristics. Brodbeck et al. found response in pelvic floor tissues follows the same course that surface characteristics of biomaterials (hydrophobic/ and timeline as the abdominal wall remains a matter of hydrophilic) influence local cytokine response [21]. They debate. Using a rabbit model, Pierce et al. used PP mesh and showed that cytokine responses from cells adherent to hy- porcine dermis to evaluate the histologic response based on drophobic biomaterials, such as PP, were much more pro- site of implantation 9 months postimplantation [27]. They nounced, whereas hydrophilic surfaces caused lower levels found that implantation of the same material in two different of cytokine production and leukocyte adhesion independent anatomic locations—abdomen and vagina—resulted in differ- of one another. ent histologic responses. Tissues surrounding vaginal grafts 672 Int Urogynecol J (2012) 23:669–679 had significantly higher scores for inflammation and neovas- cularization and lower scores for fibroplastic proliferation than tissues surrounding abdominal grafts. Clearly, anatomical fac- tors need to be considered when interpreting and applying study findings to any particular clinical situation.

Bacterial colonization

Acontaminatedorinfectedsurgicalsiteisconsidereda contraindication for placement of permanent synthetic ma- terial. In an animal model, Ott et al. showed that implanta- tion of PP meshes in an abdominal wall contaminated with bacteria may lead to suppurating infections [28]. The vagina is considered a clean-contaminated field. Mesh complica- tions, such as erosion, may be linked to bacterial contami- nation at the time of mesh insertion. During vaginal Fig. 1 Medical biofilm. a Planktonic bacteria can be cleared by anti- bodies and phagocytes and are susceptible to antibiotics. b Adherent hysterectomy, Culligan et al. found that 52% and 25% of bacterial cells form biofilms preferentially on inert surfaces, and these patients had≥5,000 bacterial colonies at 30 and 150 min sessile communities are resistant to antibodies, phagocytes, and anti- after surgical scrub prep, respectively [29]. Efforts at reduc- biotics. c Phagocytes are attracted to biofilms. Phagocytosis is frustrat- ing the vaginal bacterial load include the use of preoperative ed but phagocytic enzymes are released. d Phagocytic enzymes damage tissue around the biofilm, and planktonic bacteria are released prophylactic antibiotics, vaginal prep with antiseptic media, from the biofilm. Release may cause dissemination and acute infection and the use of antibiotic irrigation. Even repeated surgical- in neighboring tissue. From [34], with permission site disinfection prior to placement of PP mesh vaginally did not reduce bacterial colonization or clinical infection when Biofilms provide antimicrobial resistance through delayed compared with standard disinfection [30]. Furthermore, out- penetration of the antimicrobial agent and altered growth side of preoperative antibiotics, there exist no clear rate of biofilm microorganisms. Suci et al. showed a delayed evidence-based guidelines regarding the choice of antiseptic penetration of ciprofloxacin into Pseudomonas biofilms or antibiotic irrigant during implantation of PP mesh. compared with a sterile surface [35]. Antibiotic therapy to Differences in host responses exist given that bacterial treat biofilm-associated infections can restrain bacteria but contamination of the surgical field during vaginal surgery not completely eradicate them [36]. Hoyle et al. also found happens frequently, whereas infectious complications occur that dispersed bacterial cells were more susceptible to tobra- less frequently. Furthermore, aside from infection of the mycin than were cells in intact biofilms [37]. Evans et al. implanted mesh itself, some authors suggest an infected found that the slowest growing Escherichia coli cells (in mesh as being a key component in de novo urge symptoms biofilms) were the most resistant to cetrimide, showing that after placement of a midurethral sling [31]. In that study, altered growth rate of biofilm microorganisms also confers 83% of patients with urge symptoms had bacteria identified antimicrobial resistance [38]. in the excised tissue, compared to 5% in controls.

Biofilms Composite meshes

A key determinant in the postimplantation infectious pro- Per the Amid classification, composite meshes are designat- cess may be the formation of a biofilm. A biofilm is an ed as type III. It is thought that by adding a partially aggregate of microorganisms existing within a self- absorbable monomer to the mesh weave, the graft can be produced matrix surrounding the implanted foreign body. constructed using less PP, thereby reducing the total amount Microorganisms within the biofilm exist in a state of dor- of PP placed in the body. Surgeons have for several years mancy, with growth activity potentially changing based on used PP meshes that have been combined with other ab- nutrient availability [32]. Biofilms that form after biomate- sorbable synthetic monomers. Other reasons for combina- rial implantation can shield bacteria from antibiotics and tion PP mesh use include easier intraoperative handling, less may lead to subacute and chronic infections [33, 34]. Bio- foreign-body load leading to favorable host response with films can make it difficult for host immune responses to good tissue ingrowth, and fewer postoperative complica- counter the microbial invasion and proliferation (Fig. 1). tions. In the hernia literature, a recent meta-analysis Int Urogynecol J (2012) 23:669–679 673 comparing the effectiveness of Vypro II® (PP-Vicryl com- studies. Whether partially absorbable PP meshes offer any bination) and PP mesh for repair found advantage over pure PP meshes remains largely unknown. that there was no significant difference between the two Another issue to address is the potential for a greater number [39]. However, use of Vypro II® mesh was associated of infections and erosions with the use of multifilamentous with a reduced foreign-body sensation felt by the patient. compared with monofilament prosthesis. It is believed that The materials more commonly used in combination with multifilamentous meshes have a greater chance of becoming PP include Vicryl® (polyglactin) and Monocryl® (poly- infected due to an impaired immune response. Amid sug- glecarpone 25). gested that pore size <10 μm may prevent macrophages Polyglactin by it itself is well known to induce a vigorous from entering spaces infiltrated by the much smaller bacteria inflammatory and fibrotic reaction [40]. Rosch et al. per- [8]. However, Papadimitrou et al. recently found that at 2 formed immunohistochemical analysis of PP and PP/Vicryl weeks after implantation, mononuclear phagocytes and mul- mesh tissues explanted after 7 and 90 days [41]. Despite a tinucleated giant cells were seen in close apposition to the higher initial macrophage index on day 7, indices for the individual filaments of the multifilamentous tape [46]. macrophage subpopulation decreased in the sham and PP/ Vicryl® groups but persisted in the PP mesh group at 90 days. Mast cell indices were significantly higher in the PP mesh Coated PP meshes group compared with the PP/Vicryl® group at 90 days. Combining Vicryl® with lightweight PP mesh to improve Titanium is considered to be an inert material and has been intraoperative handling may also result in a favorable host used for decades in orthopedic and dental implants. As a response in the long term. In an animal study, Rosch et al. coating, it is thought to resist degradation at ambient tem- compared tissue responses to lightweight PP mesh and perature due to a thin and stable protective oxide layer that lightweight PP mesh combined with Vicryl® [42]. They forms on its surface. Titanium-coated PP meshes have more noted an initially increased inflammatory tissue reaction recently come into use in the field of pelvic reconstructive and a simultaneous enhancement of fibrosis around the surgery and hernia repair [47]. They are marketed as meshes implanted PP/Vicryl® mesh. After day 56, both groups had with a high degree of biocompatibility, as suggested by the similar inflammatory responses. No residual polyglactin manufacturer [48]. It is unclear whether titanium coating was found 84 days after implantation. However, another offers any significant advantages over a nontitanized PP study examining the inflammatory response to various type mesh. Studies of titanized meshes used for hernia repair in I and III meshes found that PP/Vicryl® composite mesh animal models have not clearly shown any superior benefit. implantation led to a greater inflammatory response of giant Scheidbach et al. studied the inflammatory response of two cells and histiocytes than other type I heavyweight meshes identical heavyweight PP mesh constructs, one coated with after 12 weeks [43]. titanium and the other uncoated [49]. At 3 months post- Junge et al. studied the influence of polyglecaprone 25 implantation, the titanium mesh was found to have less monofilament supplementation to a pure monofilament PP shrinkage than the uncoated mesh (8.8% vs. 14.9%; p0 mesh on the inflammatory response in an animal model 0.031). However, there were no significant differences in [44]. They looked at material absorption, inflammatory tis- inflammatory cell infiltration or proliferation. In a similar sue reaction, fibrosis, and granuloma formation. Total ab- study, Junge et al. compared the tissue inflammatory re- sorption of the polyglecarpone 25 monofilaments occurred sponse between two lightweight PP meshes, one coated with between 56 and 84 days of implantation. Although not titanium and the other without [50]. The tissues were statistically significant, implantation of Monocryl®-supple- assessed at 56, 84, and 182 days postimplantation. No mented mesh resulted in a lower host inflammatory and significant differences were found 56 days after implanta- fibrotic response. Monocryl®-supplemented mesh incited a tion; however, the uncoated PP mesh induced a significantly significantly lower rate of apoptosis. Concerning hernia lower amount of inflammation after 84 and 182 days when repair and peritoneal adhesions, PP/Vicryl® meshes may compared with the titanized mesh. There was no difference induce a greater inflammatory response, leading to dis- in cell proliferation between groups at any time point. Based organized scar and greater adhesion formation when on these findings, titanium coatings do not necessarily en- placed in direct contact with visceral peritoneum [45]. hance the biocompatibility of PP meshes and may, in fact, The authors proposed that this finding may have more to increase the host inflammatory response. do with the reticular and multifilamentous structure of The safety of titanium should also remain a concern when Vicryl® and the resulting exaggerated inflammatory re- considering its use in biomedical implants. In the orthopedic sponse after implantation. and dental literature, it is well known that titanium induces In pelvic floor tissues, the foreign-body response to com- changes in osteoblast cells. Ku et al. proposed that ion bination meshes is difficult to ascertain due to a lack of release at the cell–biomaterial interface played a significant 674 Int Urogynecol J (2012) 23:669–679 role in genetic expression of both cellular growth factors and postimplantation, gene expression analysis revealed upregu- apoptosis [51]. Titanium may up and down regulate various lation of four inflammatory cytokines in the collagen-coated genes associated with functional activities, including apo- group compared with the uncoated group. Relative to suture ptosis, vesicular transport, and structural function [52]. The repair, coated PP mesh induced differential expression release of titanium particles after implantation may also be (greater than fourfold difference; p<0.01) of six genes, cytotoxic. Using in vitro and in vivo methods, Kumazawa et whereas uncoated PP induced the differential expression of al. found an indirect size-dependant proinflammatory cyto- two genes. No differences in expression were found at kine response [47]. The authors suggest that phagocytosis 90 days. leading to release of superoxide anions and tumor necrosis Another factor to consider in the use of collagen-based factor (TNF)-α further enhanced the inflammatory response. biomaterials is the postimplantation safety in the host. Part Whether such changes are present after implantation of of the manufacturing process involves collage cross-linking. titanized meshes in humans remains unstudied. This is performed using chemicals such as hexamethylene Collagen-based biomaterials have been available for sev- diisocyanate or glutaraldehyde. Washing may remove most eral decades and are becoming increasingly popular due to but not all the remnants of cross-linking agents [58]. Using their perceived biocompatibility and low immunogenicity. an in vitro model, van Luyn et al. studied the cytotoxic Collagen can be added to a polymer and then cross-linked to effects of cross-linked and non-cross-linked dermal sheep enhance mechanical properties using a variety of techni- collagen (DSC) [58]. They proposed that cytotoxicity was a ques, such as UV irradiation, chemical, or enzymatic pro- result of not only the cross-linking agent but was also due to cesses [53]. Some authors suggest that use of a collagen- activity of the of the cross-linked collagen by-products coated PP mesh for vaginal prolapse repair may help reduce obtained through host enzymatic breakdown of the DSC. erosions and dyspareunia [54]. As with titanium-coated During the immediate postimplantation period, it appears meshes, the host tissue response in humans has not been that collagen-coated PP meshes induce a more severe in- extensively studied. Huffaker et al. used a rabbit vagina flammatory response. By 12 weeks, the inflammatory re- model to compare tissue responses to two PP meshes: one sponse is similar to uncoated PP mesh. Given these in vivo uncoated PP mesh (Gynemesh PS®) and one collagen- findings, it remains unclear whether collagen coating pro- coated PP mesh (Pelvitex®) [55]. At 12 weeks postimplan- vides any clinical benefit. It can be argued that the intense tation, mesh implant sites were harvested and examined for inflammatory response early in the postimplantation period histologic changes. Both meshes induced a chronic mild may, in fact, cause greater local complications, such as pain inflammatory response and received similar scores for in- or erosion. flammation, neovascularization, and fibroblastic prolifera- tion. Overall, low numbers of apoptotic cells were noted surrounding all implants (<1%), but there was higher apo- ptotic activity in the collagen-coated group (0.39% vs. Individual mesh characteristics and host response 0.1%; P00.04). It is important to note that although this study had a relatively small sample size (five in each group), Morphologic and mechanical properties of various two meshes of similar density and pore size were used. meshes have been discussed extensively [59, 60]. The Other studies looking at host response to collagen-coated properties of an implanted mesh may not be always meshes have studied the same two commercially available assumed on the basis of its preimplantation character- meshes, Gynemesh PS® and Pelvitex®. These studies istics. There is data to suggest that once implanted, PP showed no superior host response to collagen-coated PP mesh may exhibit different postimplantation biomechan- meshes. de Tayrac et al. used a sheep vagina model to study ical properties, specifically stiffness [61, 62]. The re- the host response to collagen-coated and uncoated PP sponse may also be dependant on the particular implant meshes [56]. The host response was assessed at 1 and itself, as variations may be due in part to different host 12 weeks. They noted a delayed and poorer tissue integra- inflammatory responses to the implanted material. Dif- tion of collagen-coated mesh at week 1 despite finding a ferent PP constructs may induce inflammatory responses nonsignificant higher rate of vaginal erosions in the uncoat- and fibrosis unique to their respective architecture. ed group (33% vs. 16.7%; p00.4). There were no differ- Components of this architecture include mesh weight, ences in inflammatory response at 12 weeks. pore size, and filament type. For the most part, com- The early inflammatory response associated with parative studies investigating the impact of these indi- collagen-coated meshes may be even greater. A more recent vidual characteristics do not always control for other study using the same types of meshes evaluated and com- potential confounding characteristics. For example, a pared the response to collagen-coated and uncoated PP study comparing the impact of pore size may use two meshes at the molecular level [57]. At day 7 meshes with different pore sizes but that also have Int Urogynecol J (2012) 23:669–679 675 different weights or weaves. This may ultimately affect inflammatory changes at 4 months and 1 year postimplan- the results of that study. tation [69]. The heavyweight PP mesh was associated with significantly higher cell proliferation, apoptosis, and turnover at both time points, indicating an ongoing inflammatory pro- Weight cess and scar remodeling even 1 year after implantation. They also showed an increased and persistent presence of apoptotic Mesh weight (g/m2) is directly related to the amount of cells in tissues surrounding the heavyweight PP mesh, where- mesh material implanted within the host. Earlier- as levels in the lightweight mesh were close to physiologic generation PP meshes are now dubbed heavyweight meshes, at 1 year. as newer, lighter meshes are being introduced. Heavyweight The enhanced inflammatory response may have more to do meshes have an increased material surface area, whereas with total mesh surface area than mesh weight itself. Klinge et lightweight meshes typically have a larger pore size or al. studied the effect of surface area on bacterial adherence and smaller diameter fibrils, resulting in a smaller surface area. tissue response [70]. They found that in vitro bacterial adher- However, surface area also depends on the weave, which ence to multifilament mesh was significantly greater when may result in more or less actual surface area. It is thought compared with monofilament mesh. The persistence of bac- that by reducing weight, meshes may provide adequate teria did not lead to a clinically higher infection rate, although support with fewer associated side effects. However, no meshes were explanted from rats after only 7 days. In practice, stringent criteria or cutoffs define mesh weight. In a recent bacterial contamination of a surgical wound that contains a international expert roundtable discussion, the panelists foreign body may be responsible for late infections months could not concur on the specifications for the respective and years from the initial operation. characteristics [63]. They did agree that use of a lightweight mesh with a laparoscopic approach to repair is associated with the lowest rates of chronic pain, stiff abdomen, Pore size and foreign-body sensation. Comparative studies of heavy- weight and lightweight mesh use in inguinal hernia repair Pore size is an important factor in achieving a favorable host show equally low recurrence rates with less pain and discom- response. Earlier studies have shown greater vascular pene- fort [64, 65]. The use of heavyweight meshes for abdominal tration and collagen deposition with materials of larger pore hernia repair has been associated with adhesions and fistula size [71, 72]. Taylor et al. found that small pore material [66]. With regard to vaginal prolapse, studies comparing prevented capillary penetration and led to a greater and more heavyweight to lightweight PP mesh are scant. However, sustained giant cell reaction [71]. Chvapil et al. found that one study showed no difference in erosion rates between highly porous biomaterials achieved a greater ingrowth of Gynemesh® (90 g/m2) and Gynemesh PS® (42.7 g/m2)[67]. connective tissue rich in capillaries and collagen [72]. Porosity In vitro animal studies have shown a significantly greater may affect both the degree of mechanical interlock and the and prolonged inflammatory response with heavyweight intrinsic quality and subsequent strength of such ingrown compared with lightweight meshes [68, 69]. Using a rat tissue. Bobyn et al. used implanted metal plates of varying abdominal wall model, Klinge et al. compared functional pore sizes to study the peel strength of ingrown fibrous tissue and tissue responses of heavyweight and lightweight meshes [73]. Mechanical testing revealed that implants with a greater [68]. Observations were carried out on days 3, 7, 14, 21, and pore surface achieved higher attachment strength. However, 90. Over that time period, the heavyweight mesh induced a histologically, tissue-surface configuration at the interface of significant amount of collagen production, enclosing the mesh the more porous implant was more irregular. and forming a thick scar plate. Conversely, the scar tissue The initial postimplantation response involves interaction surrounding the lightweight mesh was limited to the perifila- between macrophages, neutrophils, and bacteria. The average mentary region, with pores filled with fat forming only a loose size of bacteria is about 1 μm. Macrophages and neutrophils scar net. At 90 days, apoptotic cells were almost absent in the are unable to enter the interstices or pores <10 μm. Bacteria lightweight group but still significantly elevated in the heavy- can enter and proliferate in pores <10 μm in size, rendering weight group, indicating increased cell turnover. Textile anal- them safe from the host’s defense mechanisms [8]. Hence, ysis revealed that the incorporated lightweight mesh exhibited pore size may contribute to the initiation and persistence of sufficient maximum tensile strength with double the elasticity mesh-related infections. Pore size may also dictate the histo- of the heavyweight mesh at 16 N force. logical response and subsequent ingrowth after mesh implan- The long-term, chronic inflammatory response induced tation. Using a canine model, Greca et al. compared the by PP meshes is also of concern, as many believe that this behavior of two different PP meshes (Prolene® 164 μm× enhanced response is responsible for complications. Novit- 96 μm; T mesh 4 mm×3 mm) [74]. The T mesh incorporated sky et al. used a rabbit abdominal wall model to quantify the significantly more mature collagen (type I) than the Prolene® 676 Int Urogynecol J (2012) 23:669–679

Table 2 Polypropylene (PP) mesh characteristics influencing Tensile properties cellular response Architecture Pore size Weave of fibrils Weight Surface characteristics Total implantation size Monofilamentous vs. multifilamentous Shrinkage Stiffness Surface area Fibril diameter Elasticity Degradation

mesh. It is important to note that the geometries of the two meshes differed considerably. In a more recent study by Greca et al., Prolene® was compared with an ultralightweight macroporous PP mesh (Mpathy®; pore size 1.6 –2mmwithinterstitialpores 100 μm) [75]. Prolene® had a preimplantation burst strength that was 3.6 times greater than that of Mpathy®; however, at 90 days postimplantation, both meshes demonstrated similar tensile strengths. The Mpathy® mesh also had a significant- ly higher incorporation of mature type I collagen. In general, macroporous PP meshes are preferred due to a more favorable host response; however, the ideal pore size is yet to be determined. Ideal pore size is one that results in the incorporation of mature collagen while maintaining tissue- appropriate tensile strength and minimizing bacterial colonization.

Degradation of PP mesh

PP has long been considered an inert material in vivo. Ex vivo, in extreme circumstances such as high temperature and mechanical stress, PP can degrade to form volatile compounds [76]. The presence of oxygen in addition to

Table 3 Nonmesh factors influencing cellular response

Fig. 2 Scanning electron microscopy (SEM) of polypropylene fila- Anatomical location of implant ments. a Polypropylene component of a pristine Composix® E/X Exposure to bacteria mesh; b explanted polypropylene mesh with blisters on the fibers; c explanted polypropylene mesh with transverse cracks. From [79], with Individual patient characteristics permission Persistence of dormant bacteria Presence of bacterial biofilms Combinations with other materials mesh. Despite the Prolene® mesh having significantly higher Coatings burst strength prior to implantation, at 30 days postimplant, Release of cytotoxic chemicals the T mesh showed similar tensile strength to the Prolene® Int Urogynecol J (2012) 23:669–679 677 extreme temperature can also give rise to thermal oxidation. significance may be due to shorter implantation times of One of the earliest looks into PP degradation within the some of the implants. human body was performed by Jongebloed et al. who re- Ultimately, the impact of these degradation compounds moved a broken PP suture 6.5 years postimplantation from on the human is of significant clinical importance. Degra- the human eye and compared it to a pristine suture of the dation products may adversely affect exposed humans. Fros- same kind [77]. Using scanning electron microscopy tling et al. studied the effects of PP degradation in animals (SEM), the suture showed cracks perpendicular to the axis [81], comparing levels of glutathione, an abundant antioxi- of the suture, with significant breakage and missing frag- dant found in high concentrations in the liver. The authors ments. There was significantly more degradation in areas found significantly lower concentrations of glutathione in where the suture was in contact with tissue. Given this the liver, lung, and brain of exposed rats. Hepatic micro- finding, the authors attributed the degradation to a host somal enzyme activity was significantly higher in rats ex- enzymatic response while acknowledging the role of UV posed to degradation products. Despite these findings in light in contributing to or enhancing the host response. animal studies, the effect of PP degradation products on The construction of a PP mesh begins with processing of humans remains unstudied. the PP resin or compound. This occurs during a multistep process in which the PP compound is heated, melted, ex- truded, and cooled to form filaments. Filaments are then woven into a given configuration and heat treated so as to Conclusion retain the desired configuration and stiffness. Once implanted, the PP mesh is subjected to the host’s foreign- Despite its long-term and widespread use, there is little body response. Many investigators now believe that post- known about the tissue response to PP in the human vagina. implantation mesh contracture is a result of direct host- Multiple variables, both directly and indirectly related to PP induced changes to the conformation and structure of the mesh characteristics, may ultimately affect the host response preimplanted material [78]. (Tables 2, 3). Studies characterizing the host tissue response One factor that may contribute to tissue response may be are heterogenous with respect to methodology, study sub- the individual hosts’ unique inflammatory response. Studies jects (animal vs. human), and duration of follow-up. It comparing the effect of different materials on tissue re- appears that minor changes in mesh characteristics can have sponse often implant the different study materials in sepa- a major impact on subsequent tissue response. Based on rate patients or animals. By studying a single host’s response animal studies, there exists a fine balance between inflam- to two different materials, this bias can be eliminated. Cost- matory response during tissue incorporation and scar forma- ello et al. characterized the degree of oxidative degradation tion. Variables of this inflammatory response include of heavyweight and lightweight PP within a single host [79]. implant architecture, duration (i.e., sustained, chronic), bac- Using various techniques, they found that physical changes terial introduction, and individual host response. In order to in the explanted materials may be due to host-induced determine the ideal mesh for use in vaginal reconstructive oxidation. On SEM, the explanted heavyweight PP showed surgery, more controlled studies are needed to assess each greater surface cracks and peeling than the lightweight PP. individual mesh characteristic and their independent effects However, it is important to note that the heavyweight PP on the host pelvic floor response. had remained in vivo for substantially longer. In a separate study, the same authors examined 14 sam- ples of explanted PP mesh [80]. Adherent tissue was re- moved from the meshes using a chemical process. Even Conflicts of interest Patel: None; Ostergard: American Medical after removal of host tissue, the mesh remained contracted Systems, consultant; Sternschuss: None and folded, suggesting a permanent change in mesh confor- mation. Explanted samples were compared with pristine samples of the same material treated in the same manner. References Using the same techniques as before, the authors analyzed the explant degradation. With SEM, 85% of the explanted 1. Maher C, Feiner B, Baessler K, Glazener CMA (2010) Surgical specimens possessed two or more cracks, fissures, peeling, management of pelvic organ prolapse in women. Cochrane Data- or increased surface roughness (Fig. 2). Further physio- base of Systematic Reviews, issue 4 chemical analysis revealed greater differences between 2. U. S. Food and Drug Administration. FDA Safety Communication: explanted and pristine meshes, indicating in vivo degrada- UPDATE on Serious Complications Associated with Transvaginal Placement of Surgical Mesh for Pelvic Organ Prolapse. July 2011. tion, although not all comparisons were statistically signif- From: http://www.fda.gov/medicaldevices/safety/alertsandnotices/ icant. The authors acknowledged that the lack of statistical ucm262435.htm 678 Int Urogynecol J (2012) 23:669–679

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