Surg Endosc DOI 10.1007/s00464-014-3936-5
and Other Interventional Techniques
Long-term evaluation of adhesion formation and foreign body response to three new meshes R. R. M. Vogels • K. W. Y. van Barneveld • J. W. A. M. Bosmans • G. Beets • M. J. J. Gijbels M. H. F. Schreinemacher • N. D. Bouvy
•
Received: 30 July 2014 / Accepted: 3 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Introduction Mesh-related adhesions are a significant clinical problem following intraperitoneal mesh placement. In this study, we evaluated adhesion formation to three relatively new meshes for intraperitoneal use. Methods Three new meshes for intraperitoneal use (OmyraÒ mesh, PhysiomeshÒ, and Hi-Tex Endo-IPÒ) were implanted intraperitoneally in rats and compared with a polypropylene control mesh (ParieteneÒ) after 7 or 90 days. Adhesion formation, incorporation (tensile strength), shrinkage, and foreign body reaction were scored. Results Hi-Tex Endo-IP and PhysiomeshÒ showed significantly less adhesion formation when compared to R. R. M. Vogels K. W. Y. van Barneveld J. W. A. M. Bosmans G. Beets M. H. F. Schreinemacher N. D. Bouvy Department of Surgery, Research Institute NUTRIM, Maastricht University Medical Centre, Maastricht, The Netherlands R. R. M. Vogels (&) N. D. Bouvy (&) Department of General Surgery, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands e-mail: [email protected] N. D. Bouvy e-mail: [email protected] M. J. J. Gijbels Department of Molecular Genetics, Research Institute CARIM, Maastricht University Medical Centre, Maastricht, The Netherlands M. J. J. Gijbels Department of Pathology, Research Institute CARIM, Maastricht University Medical Centre, Maastricht, The Netherlands M. J. J. Gijbels Department of Medical Biochemistry, Amsterdam Medical Centre, Amsterdam, The Netherlands
Parietene at both time points (p \ 0.05). Shrinkage was highest in Omyra mesh after 90 days, which was significantly more compared to ParieteneÒ (p \ 0.001). PhysiomeshÒ only showed a significant reduction in craniocaudal mesh length, compared to Parietene and Hi-Tex Endo-IP (p \ 0.05). After 90 days, Hi-Tex Endo-IPÒ showed significantly higher and PhysiomeshÒ significantly lower incorporation strengths compared to all other groups (p \ 0.05). Microscopic evaluation revealed massive foreign body reaction to Hi-Tex Endo-IPÒ, leading to an extensive and thick collagenous scar adherent to the abdominal wall. Fractioning of the PhysiomeshÒ coating over time led to an increase in interfilamentary granuloma formation, leading to scar plate formation, but with only minimal to no abdominal wall adherence. Both ParieteneÒ and OmyraÒ showed a mild foreign body response. Conclusion Although clear distinctions can be made between meshes and some meshes excel, none of the meshes are superior in all aspects required for effective and safe incisional hernia repair. Keywords Ventral hernia Adhesions Rat model Foreign body reaction Mesh With an incidence of more than 10 % after abdominal surgery, the development of incisional hernias is one of the most common surgical complications [1]. Considering that, one in every three patients with an incisional hernia will develop symptoms leading to inevitable hernia repair and these defects pose a major impact on postoperative outcome [1]. Since the use of a mesh in reconstruction of abdominal wall hernias is seen as the gold standard for hernia repair, research on the behaviour of these mesh materials and improvement of currently available materials
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remains a very important research topic [2, 3]. Focus of this research should lie on improving patient outcome through the reduction and prevention of mesh-related morbidity [4]. Due to the increased popularity of laparoscopic repair which in experienced hands is believed to lead to fewer postoperative complications and earlier recovery, meshes need to be designed for intraperitoneal placement [1, 5, 6]. One of the complications especially important for intraperitoneal mesh placement is the formation of adhesions to the mesh [7, 8]. These adhesions may lead to significant clinical problems like small bowel obstruction and fistula formation [9]. Furthermore, during later operations, these adhesions give rise to an increased risk of perioperative complications like enterotomies [10, 11]. Hence, there is a need for research on the effectiveness of meshes designed for adhesion prevention [7]. The effectiveness and safety of many of the available meshes for intraperitoneal use, mainly through slow resorbable coatings, have been proven in previous research [12, 13]. As the variety of meshes aimed at adhesion prevention keeps rising and new materials and coatings are being presented on the market, the need for preclinical research to prove effectiveness and safety of these newest meshes remains important. Moreover, it needs to be proven that these new meshes are still capable of providing adequate hernia repair, neither without an increased risk of recurrence due to shrinkage or migration of the mesh nor an increased risk of adhesion formation [4]. In this study, we evaluated the anti-adhesive characteristics of three new anti-adhesive meshes for intraperitoneal use in an established intraperitoneal mesh model in rats [12]. Adhesion formation was compared to a standard non-coated polypropylene mesh with a follow-up of 7 and 90 days in view of adhesion formation. Furthermore, we investigated the ingrowth and shrinkage of meshes, and host response to these new materials as further measures for mesh performance.
Table 1 Overview of meshes used in this study Mesh
Basic material
Surface modification
Manufacturer
Parietene (control)
Macroporous polypropylene
None
Covidien, Mansfield, MA, USA
Omyra Mesh
Macroporous cPTFE
None
B.Braun, Tuttlingen, Germany
Hi-Tex Endo-IP
Non-woven polyester/PET
One-sided thin aliphatic poly(ether urethane) coating
THT Bioscience group, Montpellier, France
Physiomesh
Macroporous polypropylene
Double-sided Poliglecaprone 25 polymer coating
Ethicon, Johnson & Johnson, Somerville, NJ, USA
Materials and methods
compared with a standard polypropylene control mesh (ParieteneÒ, Covidien, Mansfield, MA, USA). OmyraÒ mesh (B. Braun, Tuttlingen, Germany) is a non-coated, macroporous cPTFE mesh, designed to be anti-bacterial and anti-adhesive. Hi-Tex Endo-IPÒ (THT Bioscience group, Montpellier, France) is a non-woven polyester/PET mesh with a single-sided polyurethane coating designed for intraperitoneal placement. PhysiomeshÒ (Ethicon, Johnson & Johnson, Somerville, NJ, USA) is a macroporous polypropylene mesh with a double-sided poliglecaprone 25 coating, designed for intraperitoneal ventral hernia repair. All pieces were cut to size (3 9 2 cm) and implanted in accordance with the manufacturer’s instructions, in direct contact with the viscera. Rats (n = 10/mesh/time point) were euthanized at either 7 or 90 days after implantation. After sacrifice, meshes were scored for adhesions, shrinkage, and tensile strength. Subsequently, meshes were harvested for histological analysis.
Animals
Surgical procedure
Eighty male Wistar rats weighing 250–300 g were housed at the Central Animal Facilities of Maastricht University and were cared for according to local standards. The experimental protocol was approved by the Animal Ethics committee of Maastricht University and complied with the Dutch Animal Experimental Act.
Surgery was performed as described earlier by Schreinemacher et al. [12, 13]. In brief, prior to surgery, all rats received Buprenorphine 0.05 mg/kg subcutaneously as analgesic. Anaesthesia was induced through inhalation of an air mixture of 5 % isoflurane and maintained with 2.5 % isoflurane gas. Subsequently, the abdomen was shaved and disinfected using a 2 % iodine solution prior to covering with sterile drapes. Abdomen was opened through a 4 cm midline incision. Sterile pieces of mesh were implanted intraperitoneally and fixed to the abdominal wall using four interrupted polypropylene 4–0 sutures (ProleneÒ, Ethicon, Johnson & Johnson, Sommerville NJ, USA). After
Materials Three new commercially available anti-adhesive meshes (Table 1) were tested in our animal mesh model and
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Surg Endosc Table 2 Adhesion score
Characteristics of adhesions
Score (0–11)
Type No adhesions
0
Filmy
1
Dense
2
Capillaries present
3
Larger vessels present
4
Tenacity No adhesions Adhesions fall apart easily
0 1
Traction required
2
Sharp dissection required
3
Extent No adhesions
0
0–25 % covered 26–50 % covered
1 2
51–75 % covered
3
76–100 % covered
4
implantation, the midline incision was closed using polyglactin 4–0 (VicrylÒ; Ethicon, Johnson & Johnson) sutures. Skin was closed using an intracutaneous runningsuture of poliglecaprone (MonocrylÒ; Ethicon, Johnson & Johnson). After 7 or 90 days, animals were euthanized by inhalation overdose of carbon dioxide. The abdominal cavity was opened using a U-shaped incision for macroscopic scoring. Adhesion scoring Adhesions were scored macroscopically, and both adhesion quality and quantity were scored. Qualitative scoring was done using a previously described 11-point scale for adhesion type, tenacity, and extent (Table 2) [12, 14]. Pictures were taken of the meshes covered in adhesions and the percentage o mesh covered with adhesions was calculated. To do this, areas with and areas without adhesions were defined and marked using image processing software and calculated as percentage of the mesh surface covered with adhesions.
surface area and other mesh dimensions were recorded as a percentage of preoperative size. Mechanical strength Explanted abdominal wall was divided into two strips 1 cm wide. The first piece was used for tensile strength testing; the other was used for histological examination. For tensile strength measurement, part of the mesh was carefully dissected from adherent tissue, leaving exactly 1.5 cm2 of mesh fixed to the abdominal wall musculature. All sutures fixing the mesh were cut and removed. Incorporation strength was defined as maximum uniaxial tensile strength required to disrupt 1.5 cm2 of mesh from the abdominal wall at a constant pulling rate of 60 mm/min. A digital Tensiometer was used (Advanced Force Gauge, Mecmesin, Slinfold, UK) to record tensile strength. Histology The second piece of abdominal wall was fixed in formaldehyde 4 %, dehydrated, and embedded in paraffin. Tissue Sections 4 lm thick were cut and haematoxylin-eosin stained. An experienced animal pathologist (MG) blinded to the assigned groups reviewed and evaluated stained sections. A semi-quantitative score was used as described earlier [12, 13]. Scoring was done as follows: not present, slightly present (only directly around mesh material), moderately present (also between mesh material), or abundantly present (thick layer of reactive tissue around all mesh material). Statistical analysis Normality tests using the Kolmogorov–Smirnov test were performed. Parametric variables (adhesion scoring and tensile strength) were expressed as mean ± SD and analysed by t tests and one-way ANOVA. Else, data were expressed as median ± range and analysed by Mann– Whitney and Kruskal–Wallis tests. In order to compensate for type-1 error inflation, LSD and Dunn’s post-hoc correction were used to compensate in case of multiple comparisons between parametric and non-parametric variables, respectively. A corrected p value \ 0.05 was considered statistically significant. All analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL, USA).
Mesh shrinkage Following adhesion scoring, the abdominal wall was explanted en bloc and the dimensions of the mesh were recorded in mm. Total surface area, as well as mesh width and length were recorded, and the percentage of loss in
Results Two animals died during operations; one in the PhysiomeshÒ group and one in the Hi-Tex Endo-IP groupÒ, both
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Fig. 1 Adhesions formed to mesh surface. A percentage of mesh covered in adhesions. B Total adhesion scores per mesh. Data are presented as mean ± SD. *p \ 0.001, **p \ 0.01, ***p \ 0.05
were scheduled for a follow-up of 7 days. Most likely, cause of death was an overdose of anaesthetic. All other animals showed normal postoperative recovery. At the time of euthanasia, none of the animals showed signs of infection or discomfort due to mesh implantation. Adhesions After 7 days, both OmyraÒ (71.9 % ± 27.64) and ParieteneÒ (86.0 % ± 12.86) groups show significantly more adhesion coverage when compared to Hi-Tex Endo-IP (12.9 % ± 9.82) and PhysiomeshÒ (22.2 % ± 12.15) (p \ 0.001). ParieteneÒ mesh (8.7 ± 0.5) showed the highest total adhesion score at this time point, which was significantly higher than in all other groups (p \ 0.001). The total adhesion score for OmyraÒ mesh (6.4 ± 1.6) was significantly higher than that for both Hi-Tex Endo-IP (4.3 ± 1.0, p = 0.002) and PhysiomeshÒ (4.4 ± 0.88, p = 0.003) (Fig. 1). After 90 days, OmyraÒ mesh (65.5 % ± 19.71) and ParieteneÒ (78.6 % ± 19.04) again showed highest adhesion coverage when compared to Hi-Tex Endo-IPÒ (23.4 ± 22.56) and PhysiomeshÒ (17.9 ± 11.54) (p \ 0.001). Total adhesion scores for OmyraÒ (7 ± 2.2) and ParieteneÒ (8.4 ± 2.0) were significantly higher than in Hi-Tex Endo-IPÒ (5.1 ± 0.88) (vs. OmyraÒ p = 0.004, vs. ParieteneÒ p \ 0.001) and PhysiomeshÒ (4.4 ± 1.26) (vs. OmyraÒ p \ 0.001 vs. ParieteneÒ p \ 0.001). Furthermore, the difference between OmyraÒ and ParieteneÒ in adhesion quality was statistically significant (p = 0.029) (Fig. 1).
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Fig. 2 Total shrinkage in %. Graph only shows total shrinkage, Physiomesh showed significantly more shrinkage in the craniocaudal direction when compared to other groups. This shrinkage was compensated by an increase in mesh width. *p \ 0.001
Shrinkage After 7 days, no significant differences could be detected between the different groups. After 90 days, total shrinkage in the OmyraÒ mesh (24.2 % range: 10.0–41.5 %) was significantly larger (p = 0,011) than in ParieteneÒ mesh (0 %, range: 0.0–25.0 %). The other groups showed no significant differences in change of total mesh area. However, when looking at the loss of mesh length
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of both PhysiomeshÒ (p = 0.008) and OmyraÒ (2.25 N ± 1.03, p = 0.045). Both OmyraÒ and Hi-Tex Endo-IPÒ show a significant increase in tensile strength after 90 days (resp. 7.52 N ± 2.47 and 10.89 N ± 2.38, p \ 0.001). Hi-Tex Endo-IP meshes showed the highest incorporation strength after 90 days when compared to all other meshes (vs. OmyraÒ p = 0.011, vs. ParieteneÒ p \ 0.001, vs. PhysiomeshÒ p \ 0.001). Lowest incorporation strength was found in PhysiomeshÒ (1.83 N ± 0.71), the tensile strength in this group was significantly lower than that in all other groups (vs. OmyraÒ p \ 0.001, vs. ParieteneÒ p = 0.01, vs Hi-Tex Endo-IPÒ p \ 0.001) (Fig. 3). Histology
Fig. 3 Tensile strength as an indicator for mesh ingrowth. Maximum force required to disrupt a 1.5 cm2 piece of mesh from the abdominal wall muscle is expressed in N. §: significant increase of tensile strength (p \ 0.05) when comparing the same mesh between both time points. *p \ 0.001, **p \ 0.01, ***p \ 0.05
(craniocaudal length), PhysiomeshÒ showed significantly more shrinkage (13.3 % range: 6.7–30 %) than that of both Hi-Tex Endo-IPÒ (0 %, range: 0.0–20.0 %, p = 0.007) and ParieteneÒ (0 %, range: 0.0–16.7 %, p = 0.043). Due to a small increase in the width of the PhysiomeshÒ samples (5.0 %, range: -10 to ?15 %), the total surface area did not differ significantly from other groups (Fig. 2). Tensile strength At 7 days, PhysiomeshÒ showed the lowest incorporation strength (0.43 N ± 0.35) which was significant when compared to both ParieteneÒ (4.06 N ± 2.11, p = 0.008) and Hi-Tex Endo-IP (4.87 N ± 4.50). The highest incorporation strength was reached by the Hi-Tex Endo-IPÒ (4.87 N ± 4.50), which was significantly higher than that
Results of histology scoring are presented in Table 3. After 7 days, both the ParieteneÒ and OmyraÒ mesh showed only mild to moderate inflammation consisting of mostly macrophages and granulocytes. Contrastingly, the Hi-Tex Endo-IPÒ showed massive fibrosis throughout the filamentary structure of the mesh. Foreign body giant cells were abundantly present surrounding the mesh filaments with a moderate to intense inflammatory reaction to the mesh. This results in a thick fibrotic plaque surrounding the mesh and each individual fibre. Implantation of PhysiomeshÒ resulted to a near absent fibrotic and inflammatory reaction. Inflammation was primarily directed at the coating with almost no reaction near the mesh filaments. The mesh was clearly separated from the abdominal wall muscle, indicating poor ingrowth of the mesh. After 90 days, the inflammatory reaction diminished in both ParieteneÒ and Omyra mesh. Only few giant cells and granulocytes were present surrounding both meshes. Although the amount of fibrosis in the OmyraÒ mesh samples was similar to that in the ParieteneÒ group, there seemed to be some bridging of fibrotic strands between the mesh pores (Fig. 4 A–D). Again, the fibrotic and inflammatory response was massive in the Hi-Tex Endo-IPÒ forming a thick collagenous plate covering the entire mesh thickness. Foreign body giant cells were abundantly present surrounding individual filaments with pronounced
Table 3 Results for histology 7 days
90 days
Fibrosis
Inflammation
Giant cells
Granulocytes
Fibrosis
Inflammation
Giant cells
Granulocytes
Parietene
?
?/??
-
?
?/-
?/-
?/-
?/--
Omyra mesh
?/??
?/??
?/-
?/-
?/-
?/--
?
?/--
Hi-Tex Endo-IP
???
???
?/??
?/-
???
?/??
???
?
Physiomesh
?/-
?/-
-
?/--
??
?
?
?/-
Histology is scored as not present (-), slightly present (?), moderately present (??), or abundantly present (???)
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Surg Endosc Fig. 4 HE staining after 90 days (A, C, E, G, 940 magnified; B, D, F, H, 9100 magnified). Only minor inflammatory reaction can be seen in Parietene (A–B) and Omyra (C–D). Omyra meshes show some degree of mesh bridging. Hi-Tex Endo-Ip (E– F) mesh shows massive fibrosis with scar plate formation and many foreign body giant cells surrounding mesh filaments. Foreign body reaction towards Physiomesh (G–H) is primarily aimed at the coating, creating a scar plate bridging between mesh pores. There is a clear separation between mesh and associated reaction and the abdominal wall, indicating poor ingrowth
inflammation (Fig. 4 E–F). In Physiomesh samples, the coating appeared fragmented and was positioned between mesh fibres. Again the inflammatory reaction was primarily
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aimed at the coating with formation of fibrotic granulomas surrounding the fragmented coating, forming a fibrotic bridge between mesh fibres. Unlike in other groups, there
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still was a clear separation between the foreign body reaction surrounding the mesh and the abdominal wall, indicating poor ingrowth (Fig. 4 G–H).
Discussion Intraperitoneal placement of synthetic meshes has long been associated with mesh-related adhesion formation. [7, 9] Although the placement of meshes in the extraperitoneal position prevents most adhesions from forming, the increased popularity of laparoscopic hernia repair leads to a need for intraperitoneal mesh placement [7, 15]. In addition, also in open repair, the direct contact between mesh and intraperitoneal content can frequently not be avoided. Therefore, many different meshes specifically aimed at intraperitoneal adhesion reduction have been constructed and tested [12, 13]. Since the already wide range of currently available meshes keeps increasing and many manufacturers claim to have developed superior meshes, the need for continuous and consistent research testing of these new meshes remains important [1, 8, 12]. For this reason, we evaluated three, new, potentially effective meshes for intraperitoneal use in a validated intraperitoneal mesh model [12, 13]. A polypropylene mesh was added in concordance with our previous research, to serve as a standardized control group [12, 13]. Clearly, the Hi-Tex Endo-IPÒ mesh showed the best macroscopic results for all investigated parameters at both time points. In view of adhesion reduction, the polyurethane coating seems to effectively prevent ingrowth of visceral structures and thus formation of adhesions. Hi-Tex Endo-IPÒ consists of a non-woven, non-porous material, yet the strength of incorporation of this material was significantly higher than all other materials. This is remarkable since the presence of large pores is generally considered to be necessary for adequate ingrowth [16, 17]. This seems to indicate that this material shows superior properties for intraperitoneal mesh placement. However, the microscopic examination of the implanted Hi-Tex Endo-IPÒ meshes elucidates the extensive ingrowth. The mesh seemed to be fixed or even integrated into the abdominal wall with extensive collagenous and fibrotic infiltration throughout the mesh structure as a whole. Although the extensive ingrowth seems beneficial in terms of recurrence risk, an inflammatory and fibrotic reaction of this extent could give rise to other complications after mesh implantation. Formation of a fibrotic dense scar plate of this extent can lead to a rigid mesh, limiting abdominal wall movement and possibly causing chronic pain in the longterm [18–20]. Theoretically, the collagen content in these, otherwise, healthy rats might be of far better quality than in hernia patients, possibly leading to less favourable results.
However, the coating does seem effective in preventing adhesions to the mesh. Potentially, changing the underlying mesh structure to one with a more favourable host response may lead to a better mesh product. Although the PhysiomeshÒ seemed to provide comparable improvement in adhesion prevention to the Hi-Tex Endo-IPÒ after 90 days, the properties necessary for hernia repair are below average. First of all, the ingrowth of the PhysiomeshÒ was up to ten times lower than that of all other meshes. Since adequate ingrowth and high tensile strength is one of the necessities for effective hernia repair, this lack of abdominal wall integration could be detrimental for the risk of recurrence [21, 22]. We hypothesized that the reason for this lack of tissue integration is the application of an anti-adhesive coatings on both sides of the mesh. Barrier coatings are considered to prevent ingrowth of visceral organs into the mesh and thus prevent adhesions, the application of such a barrier between the mesh and the abdominal wall could in theory lead to a reduced ingrowth into the abdominal wall [9, 13]. Furthermore, since the barrier acts through separation of the mesh material and the abdominal wall, the effect of large pores in a mesh is non-existent [8]. This is supported by histological samples where we see a clear separation between the encapsulated mesh and the abdominal wall, without any signs of abdominal wall ingrowth. Another important risk factor for hernia recurrence after PhysiomeshÒ implantation is the significant loss of craniocaudal mesh size after 90 days. Although the loss in total mesh size was minimal and not significant to control groups, there was a significantly higher reduction in mesh length of up to 30 %. This reduction in size can cause considerable problems when attempting to repair abdominal wall hernias as sufficient overlap of healthy tissue is more difficult to achieve [23, 24]. Furthermore, mesh shrinkage is thought to be associated with increased risk of postoperative pain, although the results on this topic seem to be inconclusive [23, 25]. We believe this mesh shrinkage is due to the extensive fibrotic bridging between the mesh fibres for which the fragmented coating seemed responsible. This combined with the active inflammatory process towards the coating fragments, could lead to contraction of the fibrotic capsule resulting in loss in mesh size. This specific reaction to the small parts of the coating minimizes the effect of large pores through formation of a continuous fibrotic capsule. Potentially this could, subsequently, lead to an extensive scar plate, as seen in the Hi-Tex Endo-IPÒ, with risk of postoperative pain and loss of abdominal wall flexibility [18, 20]. Unfortunately, the OmyraÒ mesh showed inadequate performance on all tested parameters. Although the quality of adhesions was significantly lower than that in ParieteneÒ group at both time points, adhesions were considerably more abundant in numbers than in the other experimental meshes.
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Adding to this, the significant loss of surface area, we believe the effectiveness of this material as an intraperitoneal mesh cannot be proven in this model. Most likely, this lack of effective adhesion prevention is due to the design of the mesh and absence of a tissue separating material. Some studies suggest that even though a material itself can be antiadhesive, the absence of a separating barrier can lead to adhesion formation, possibly due to adhesion formation to the abdominal wall through the mesh pores [26]. Interestingly, most adhesions seem to occur in the region of the cut edges. This phenomenon has previously been described by Schreinemacher et al. [12]. Cutting of the meshes seems to expose underlying mesh fibres and interrupt the coating, leading to bare mesh materials exposed to visceral organs. Manufacturers of all three meshes used in this study claim that they can reduce the amount of adhesions after placement in the intraperitoneal position. However, very few data supporting this claim have been published in the past years. Since the wide range of both mesh materials and animal models makes definitive statements on new meshes very difficult to interpret, we think it is important to test them in a validated model with a validated control group, to gain consistent results on new meshes [27]. Since the prevention of recurrent hernia and adhesion is equally important, we added the shrinkage and ingrowth as additional parameters as described in our previous research [6, 7, 12]. There were some limitations to the present study, warranting further clinical and preclinical research to provide definitive results on presented materials. First of all, this research was performed in an experimental rat model, without any predisposing collagen disease or hernia defect. It is suggested that the presence of an abdominal wall defect has influence on wound healing [28]. The absence of such a defect in our model could possibly influence our results. However, current International Endo hernia Society guidelines advise on reconstruction of the linea alba to improve abdominal wall function [29]. This leads to the assumption that an experimental intraperitoneal mesh model without a defect is adequate for mesh testing. Furthermore, a rat model does not allow for evaluation of postoperative pain and quality of life after mesh implantation. Although this research shows clear differences between meshes implanted, the true impact of the severe inflammatory reaction elicited by the Hi-Tex Endo-IPÒ and the foreign body reaction to the fragmented PhysiomeshÒ coating cannot be evaluated in this model.
Conclusion Although clear distinctions could be made between the meshes used in this study, none of the investigated meshes
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showed superior results in all aspects necessary for hernia repair. Regarding macroscopic results, the Hi-Tex EndoIPÒ clearly showed superior characteristics when compared to all other meshes. However, the extensive foreign body reaction should be taken into account and care should be taken when implanting this mesh in humans. Perhaps modification of the mesh to a large pore construct could improve outcome. For adhesion prevention, PhysiomeshÒ also seemed to give superior results. However, the lack of adequate ingrowth and major loss in mesh length might lead to an increased risk for hernia recurrence, warranting extensive fixation of these meshes to use them effectively. Furthermore, the extensive fibrotic response to the coating material might lead to discomfort and pain on the long-term. More clinical and preclinical studies are thus required to find the ideal intraperitoneal mesh and to test new meshes introduced on the market. Acknowledgments We would like to thank B. Braun and Sto¨pler BV for providing two of the meshes required for this research. Furthermore, we would like to thank S. Hartmans for her assistance to this project. Disclosure Two of the meshes were kindly provided by B. Braun (OmyraÒ mesh) and Sto¨pler BV (Hi-Tex Endo-IPÒ). Authors R.R.M. Vogels, K.W.Y. van Barneveld, M.H.F. Schreinemacher, J.W.A.M. Bosmans, G. Beets, M.J.J. Gijbels, and N.D. Bouvy declare no conflict of interest and have no financial ties.
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21. Sanders DL, Waydia S (2013) A systematic review of randomised control trials assessing mesh fixation in open inguinal hernia repair. Hernia 18:165–176 22. Hollinsky C, Kolbe T, Walter I, Joachim A, Sandberg S, Koch T et al (2010) Tensile strength and adhesion formation of mesh fixation systems used in laparoscopic incisional hernia repair. Surg Endosc Interv Tech 24:1318–1324 23. Beldi G, Wagner M, Bruegger LE, Kurmann A, Candinas D (2011) Mesh shrinkage and pain in laparoscopic ventral hernia repair: a randomized clinical trial comparing suture versus tack mesh fixation. Surg Endosc 25:749–755 24. Zogbi L, Trindade EN, Trindade MRM (2013) Comparative study of shrinkage, inflammatory response and fibroplasia in heavyweight and lightweight meshes. Hernia 17:765–772 25. Eriksen JR, Gogenur I, Rosenberg J (2007) Choice of mesh for laparoscopic ventral hernia repair. Hernia 11:481–492 26. Fortelny RH, Petter-Puchner AH, Glaser KS, Offner F, Benesch T, Rohr M (2010) Adverse effects of polyvinylidene fluoridecoated polypropylene mesh used for laparoscopic intraperitoneal onlay repair of incisional hernia. Br J Surg 97:1140–1145 27. Schreinemacher MHF, Henatsch D, van Barneveld K, Bouvy N (2010) The need for standardised animal models and scoring systems in assessing mesh biocompatibility. Hernia 14:335–336 28. Dubay DA, Wang X, Adamson B, Kuzon WM Jr, Dennis RG, Franz MG (2005) Progressive fascial wound failure impairs subsequent abdominal wall repairs: a new animal model of incisional hernia formation. Surgery 137:463–471 29. Bittner R, Bingener-Casey J, Dietz U, Fabian M, Ferzli GS, Fortelny RH et al (2014) Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias (International Endohernia Society (IEHS)—part 1. Surg Endosc 28:2–29
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and Other Interventional Techniques
Long-term evaluation of adhesion formation and foreign body response to three new meshes R. R. M. Vogels • K. W. Y. van Barneveld • J. W. A. M. Bosmans • G. Beets • M. J. J. Gijbels M. H. F. Schreinemacher • N. D. Bouvy
•
Received: 30 July 2014 / Accepted: 3 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Introduction Mesh-related adhesions are a significant clinical problem following intraperitoneal mesh placement. In this study, we evaluated adhesion formation to three relatively new meshes for intraperitoneal use. Methods Three new meshes for intraperitoneal use (OmyraÒ mesh, PhysiomeshÒ, and Hi-Tex Endo-IPÒ) were implanted intraperitoneally in rats and compared with a polypropylene control mesh (ParieteneÒ) after 7 or 90 days. Adhesion formation, incorporation (tensile strength), shrinkage, and foreign body reaction were scored. Results Hi-Tex Endo-IP and PhysiomeshÒ showed significantly less adhesion formation when compared to R. R. M. Vogels K. W. Y. van Barneveld J. W. A. M. Bosmans G. Beets M. H. F. Schreinemacher N. D. Bouvy Department of Surgery, Research Institute NUTRIM, Maastricht University Medical Centre, Maastricht, The Netherlands R. R. M. Vogels (&) N. D. Bouvy (&) Department of General Surgery, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands e-mail: [email protected] N. D. Bouvy e-mail: [email protected] M. J. J. Gijbels Department of Molecular Genetics, Research Institute CARIM, Maastricht University Medical Centre, Maastricht, The Netherlands M. J. J. Gijbels Department of Pathology, Research Institute CARIM, Maastricht University Medical Centre, Maastricht, The Netherlands M. J. J. Gijbels Department of Medical Biochemistry, Amsterdam Medical Centre, Amsterdam, The Netherlands
Parietene at both time points (p \ 0.05). Shrinkage was highest in Omyra mesh after 90 days, which was significantly more compared to ParieteneÒ (p \ 0.001). PhysiomeshÒ only showed a significant reduction in craniocaudal mesh length, compared to Parietene and Hi-Tex Endo-IP (p \ 0.05). After 90 days, Hi-Tex Endo-IPÒ showed significantly higher and PhysiomeshÒ significantly lower incorporation strengths compared to all other groups (p \ 0.05). Microscopic evaluation revealed massive foreign body reaction to Hi-Tex Endo-IPÒ, leading to an extensive and thick collagenous scar adherent to the abdominal wall. Fractioning of the PhysiomeshÒ coating over time led to an increase in interfilamentary granuloma formation, leading to scar plate formation, but with only minimal to no abdominal wall adherence. Both ParieteneÒ and OmyraÒ showed a mild foreign body response. Conclusion Although clear distinctions can be made between meshes and some meshes excel, none of the meshes are superior in all aspects required for effective and safe incisional hernia repair. Keywords Ventral hernia Adhesions Rat model Foreign body reaction Mesh With an incidence of more than 10 % after abdominal surgery, the development of incisional hernias is one of the most common surgical complications [1]. Considering that, one in every three patients with an incisional hernia will develop symptoms leading to inevitable hernia repair and these defects pose a major impact on postoperative outcome [1]. Since the use of a mesh in reconstruction of abdominal wall hernias is seen as the gold standard for hernia repair, research on the behaviour of these mesh materials and improvement of currently available materials
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remains a very important research topic [2, 3]. Focus of this research should lie on improving patient outcome through the reduction and prevention of mesh-related morbidity [4]. Due to the increased popularity of laparoscopic repair which in experienced hands is believed to lead to fewer postoperative complications and earlier recovery, meshes need to be designed for intraperitoneal placement [1, 5, 6]. One of the complications especially important for intraperitoneal mesh placement is the formation of adhesions to the mesh [7, 8]. These adhesions may lead to significant clinical problems like small bowel obstruction and fistula formation [9]. Furthermore, during later operations, these adhesions give rise to an increased risk of perioperative complications like enterotomies [10, 11]. Hence, there is a need for research on the effectiveness of meshes designed for adhesion prevention [7]. The effectiveness and safety of many of the available meshes for intraperitoneal use, mainly through slow resorbable coatings, have been proven in previous research [12, 13]. As the variety of meshes aimed at adhesion prevention keeps rising and new materials and coatings are being presented on the market, the need for preclinical research to prove effectiveness and safety of these newest meshes remains important. Moreover, it needs to be proven that these new meshes are still capable of providing adequate hernia repair, neither without an increased risk of recurrence due to shrinkage or migration of the mesh nor an increased risk of adhesion formation [4]. In this study, we evaluated the anti-adhesive characteristics of three new anti-adhesive meshes for intraperitoneal use in an established intraperitoneal mesh model in rats [12]. Adhesion formation was compared to a standard non-coated polypropylene mesh with a follow-up of 7 and 90 days in view of adhesion formation. Furthermore, we investigated the ingrowth and shrinkage of meshes, and host response to these new materials as further measures for mesh performance.
Table 1 Overview of meshes used in this study Mesh
Basic material
Surface modification
Manufacturer
Parietene (control)
Macroporous polypropylene
None
Covidien, Mansfield, MA, USA
Omyra Mesh
Macroporous cPTFE
None
B.Braun, Tuttlingen, Germany
Hi-Tex Endo-IP
Non-woven polyester/PET
One-sided thin aliphatic poly(ether urethane) coating
THT Bioscience group, Montpellier, France
Physiomesh
Macroporous polypropylene
Double-sided Poliglecaprone 25 polymer coating
Ethicon, Johnson & Johnson, Somerville, NJ, USA
Materials and methods
compared with a standard polypropylene control mesh (ParieteneÒ, Covidien, Mansfield, MA, USA). OmyraÒ mesh (B. Braun, Tuttlingen, Germany) is a non-coated, macroporous cPTFE mesh, designed to be anti-bacterial and anti-adhesive. Hi-Tex Endo-IPÒ (THT Bioscience group, Montpellier, France) is a non-woven polyester/PET mesh with a single-sided polyurethane coating designed for intraperitoneal placement. PhysiomeshÒ (Ethicon, Johnson & Johnson, Somerville, NJ, USA) is a macroporous polypropylene mesh with a double-sided poliglecaprone 25 coating, designed for intraperitoneal ventral hernia repair. All pieces were cut to size (3 9 2 cm) and implanted in accordance with the manufacturer’s instructions, in direct contact with the viscera. Rats (n = 10/mesh/time point) were euthanized at either 7 or 90 days after implantation. After sacrifice, meshes were scored for adhesions, shrinkage, and tensile strength. Subsequently, meshes were harvested for histological analysis.
Animals
Surgical procedure
Eighty male Wistar rats weighing 250–300 g were housed at the Central Animal Facilities of Maastricht University and were cared for according to local standards. The experimental protocol was approved by the Animal Ethics committee of Maastricht University and complied with the Dutch Animal Experimental Act.
Surgery was performed as described earlier by Schreinemacher et al. [12, 13]. In brief, prior to surgery, all rats received Buprenorphine 0.05 mg/kg subcutaneously as analgesic. Anaesthesia was induced through inhalation of an air mixture of 5 % isoflurane and maintained with 2.5 % isoflurane gas. Subsequently, the abdomen was shaved and disinfected using a 2 % iodine solution prior to covering with sterile drapes. Abdomen was opened through a 4 cm midline incision. Sterile pieces of mesh were implanted intraperitoneally and fixed to the abdominal wall using four interrupted polypropylene 4–0 sutures (ProleneÒ, Ethicon, Johnson & Johnson, Sommerville NJ, USA). After
Materials Three new commercially available anti-adhesive meshes (Table 1) were tested in our animal mesh model and
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Surg Endosc Table 2 Adhesion score
Characteristics of adhesions
Score (0–11)
Type No adhesions
0
Filmy
1
Dense
2
Capillaries present
3
Larger vessels present
4
Tenacity No adhesions Adhesions fall apart easily
0 1
Traction required
2
Sharp dissection required
3
Extent No adhesions
0
0–25 % covered 26–50 % covered
1 2
51–75 % covered
3
76–100 % covered
4
implantation, the midline incision was closed using polyglactin 4–0 (VicrylÒ; Ethicon, Johnson & Johnson) sutures. Skin was closed using an intracutaneous runningsuture of poliglecaprone (MonocrylÒ; Ethicon, Johnson & Johnson). After 7 or 90 days, animals were euthanized by inhalation overdose of carbon dioxide. The abdominal cavity was opened using a U-shaped incision for macroscopic scoring. Adhesion scoring Adhesions were scored macroscopically, and both adhesion quality and quantity were scored. Qualitative scoring was done using a previously described 11-point scale for adhesion type, tenacity, and extent (Table 2) [12, 14]. Pictures were taken of the meshes covered in adhesions and the percentage o mesh covered with adhesions was calculated. To do this, areas with and areas without adhesions were defined and marked using image processing software and calculated as percentage of the mesh surface covered with adhesions.
surface area and other mesh dimensions were recorded as a percentage of preoperative size. Mechanical strength Explanted abdominal wall was divided into two strips 1 cm wide. The first piece was used for tensile strength testing; the other was used for histological examination. For tensile strength measurement, part of the mesh was carefully dissected from adherent tissue, leaving exactly 1.5 cm2 of mesh fixed to the abdominal wall musculature. All sutures fixing the mesh were cut and removed. Incorporation strength was defined as maximum uniaxial tensile strength required to disrupt 1.5 cm2 of mesh from the abdominal wall at a constant pulling rate of 60 mm/min. A digital Tensiometer was used (Advanced Force Gauge, Mecmesin, Slinfold, UK) to record tensile strength. Histology The second piece of abdominal wall was fixed in formaldehyde 4 %, dehydrated, and embedded in paraffin. Tissue Sections 4 lm thick were cut and haematoxylin-eosin stained. An experienced animal pathologist (MG) blinded to the assigned groups reviewed and evaluated stained sections. A semi-quantitative score was used as described earlier [12, 13]. Scoring was done as follows: not present, slightly present (only directly around mesh material), moderately present (also between mesh material), or abundantly present (thick layer of reactive tissue around all mesh material). Statistical analysis Normality tests using the Kolmogorov–Smirnov test were performed. Parametric variables (adhesion scoring and tensile strength) were expressed as mean ± SD and analysed by t tests and one-way ANOVA. Else, data were expressed as median ± range and analysed by Mann– Whitney and Kruskal–Wallis tests. In order to compensate for type-1 error inflation, LSD and Dunn’s post-hoc correction were used to compensate in case of multiple comparisons between parametric and non-parametric variables, respectively. A corrected p value \ 0.05 was considered statistically significant. All analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL, USA).
Mesh shrinkage Following adhesion scoring, the abdominal wall was explanted en bloc and the dimensions of the mesh were recorded in mm. Total surface area, as well as mesh width and length were recorded, and the percentage of loss in
Results Two animals died during operations; one in the PhysiomeshÒ group and one in the Hi-Tex Endo-IP groupÒ, both
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Fig. 1 Adhesions formed to mesh surface. A percentage of mesh covered in adhesions. B Total adhesion scores per mesh. Data are presented as mean ± SD. *p \ 0.001, **p \ 0.01, ***p \ 0.05
were scheduled for a follow-up of 7 days. Most likely, cause of death was an overdose of anaesthetic. All other animals showed normal postoperative recovery. At the time of euthanasia, none of the animals showed signs of infection or discomfort due to mesh implantation. Adhesions After 7 days, both OmyraÒ (71.9 % ± 27.64) and ParieteneÒ (86.0 % ± 12.86) groups show significantly more adhesion coverage when compared to Hi-Tex Endo-IP (12.9 % ± 9.82) and PhysiomeshÒ (22.2 % ± 12.15) (p \ 0.001). ParieteneÒ mesh (8.7 ± 0.5) showed the highest total adhesion score at this time point, which was significantly higher than in all other groups (p \ 0.001). The total adhesion score for OmyraÒ mesh (6.4 ± 1.6) was significantly higher than that for both Hi-Tex Endo-IP (4.3 ± 1.0, p = 0.002) and PhysiomeshÒ (4.4 ± 0.88, p = 0.003) (Fig. 1). After 90 days, OmyraÒ mesh (65.5 % ± 19.71) and ParieteneÒ (78.6 % ± 19.04) again showed highest adhesion coverage when compared to Hi-Tex Endo-IPÒ (23.4 ± 22.56) and PhysiomeshÒ (17.9 ± 11.54) (p \ 0.001). Total adhesion scores for OmyraÒ (7 ± 2.2) and ParieteneÒ (8.4 ± 2.0) were significantly higher than in Hi-Tex Endo-IPÒ (5.1 ± 0.88) (vs. OmyraÒ p = 0.004, vs. ParieteneÒ p \ 0.001) and PhysiomeshÒ (4.4 ± 1.26) (vs. OmyraÒ p \ 0.001 vs. ParieteneÒ p \ 0.001). Furthermore, the difference between OmyraÒ and ParieteneÒ in adhesion quality was statistically significant (p = 0.029) (Fig. 1).
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Fig. 2 Total shrinkage in %. Graph only shows total shrinkage, Physiomesh showed significantly more shrinkage in the craniocaudal direction when compared to other groups. This shrinkage was compensated by an increase in mesh width. *p \ 0.001
Shrinkage After 7 days, no significant differences could be detected between the different groups. After 90 days, total shrinkage in the OmyraÒ mesh (24.2 % range: 10.0–41.5 %) was significantly larger (p = 0,011) than in ParieteneÒ mesh (0 %, range: 0.0–25.0 %). The other groups showed no significant differences in change of total mesh area. However, when looking at the loss of mesh length
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of both PhysiomeshÒ (p = 0.008) and OmyraÒ (2.25 N ± 1.03, p = 0.045). Both OmyraÒ and Hi-Tex Endo-IPÒ show a significant increase in tensile strength after 90 days (resp. 7.52 N ± 2.47 and 10.89 N ± 2.38, p \ 0.001). Hi-Tex Endo-IP meshes showed the highest incorporation strength after 90 days when compared to all other meshes (vs. OmyraÒ p = 0.011, vs. ParieteneÒ p \ 0.001, vs. PhysiomeshÒ p \ 0.001). Lowest incorporation strength was found in PhysiomeshÒ (1.83 N ± 0.71), the tensile strength in this group was significantly lower than that in all other groups (vs. OmyraÒ p \ 0.001, vs. ParieteneÒ p = 0.01, vs Hi-Tex Endo-IPÒ p \ 0.001) (Fig. 3). Histology
Fig. 3 Tensile strength as an indicator for mesh ingrowth. Maximum force required to disrupt a 1.5 cm2 piece of mesh from the abdominal wall muscle is expressed in N. §: significant increase of tensile strength (p \ 0.05) when comparing the same mesh between both time points. *p \ 0.001, **p \ 0.01, ***p \ 0.05
(craniocaudal length), PhysiomeshÒ showed significantly more shrinkage (13.3 % range: 6.7–30 %) than that of both Hi-Tex Endo-IPÒ (0 %, range: 0.0–20.0 %, p = 0.007) and ParieteneÒ (0 %, range: 0.0–16.7 %, p = 0.043). Due to a small increase in the width of the PhysiomeshÒ samples (5.0 %, range: -10 to ?15 %), the total surface area did not differ significantly from other groups (Fig. 2). Tensile strength At 7 days, PhysiomeshÒ showed the lowest incorporation strength (0.43 N ± 0.35) which was significant when compared to both ParieteneÒ (4.06 N ± 2.11, p = 0.008) and Hi-Tex Endo-IP (4.87 N ± 4.50). The highest incorporation strength was reached by the Hi-Tex Endo-IPÒ (4.87 N ± 4.50), which was significantly higher than that
Results of histology scoring are presented in Table 3. After 7 days, both the ParieteneÒ and OmyraÒ mesh showed only mild to moderate inflammation consisting of mostly macrophages and granulocytes. Contrastingly, the Hi-Tex Endo-IPÒ showed massive fibrosis throughout the filamentary structure of the mesh. Foreign body giant cells were abundantly present surrounding the mesh filaments with a moderate to intense inflammatory reaction to the mesh. This results in a thick fibrotic plaque surrounding the mesh and each individual fibre. Implantation of PhysiomeshÒ resulted to a near absent fibrotic and inflammatory reaction. Inflammation was primarily directed at the coating with almost no reaction near the mesh filaments. The mesh was clearly separated from the abdominal wall muscle, indicating poor ingrowth of the mesh. After 90 days, the inflammatory reaction diminished in both ParieteneÒ and Omyra mesh. Only few giant cells and granulocytes were present surrounding both meshes. Although the amount of fibrosis in the OmyraÒ mesh samples was similar to that in the ParieteneÒ group, there seemed to be some bridging of fibrotic strands between the mesh pores (Fig. 4 A–D). Again, the fibrotic and inflammatory response was massive in the Hi-Tex Endo-IPÒ forming a thick collagenous plate covering the entire mesh thickness. Foreign body giant cells were abundantly present surrounding individual filaments with pronounced
Table 3 Results for histology 7 days
90 days
Fibrosis
Inflammation
Giant cells
Granulocytes
Fibrosis
Inflammation
Giant cells
Granulocytes
Parietene
?
?/??
-
?
?/-
?/-
?/-
?/--
Omyra mesh
?/??
?/??
?/-
?/-
?/-
?/--
?
?/--
Hi-Tex Endo-IP
???
???
?/??
?/-
???
?/??
???
?
Physiomesh
?/-
?/-
-
?/--
??
?
?
?/-
Histology is scored as not present (-), slightly present (?), moderately present (??), or abundantly present (???)
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Surg Endosc Fig. 4 HE staining after 90 days (A, C, E, G, 940 magnified; B, D, F, H, 9100 magnified). Only minor inflammatory reaction can be seen in Parietene (A–B) and Omyra (C–D). Omyra meshes show some degree of mesh bridging. Hi-Tex Endo-Ip (E– F) mesh shows massive fibrosis with scar plate formation and many foreign body giant cells surrounding mesh filaments. Foreign body reaction towards Physiomesh (G–H) is primarily aimed at the coating, creating a scar plate bridging between mesh pores. There is a clear separation between mesh and associated reaction and the abdominal wall, indicating poor ingrowth
inflammation (Fig. 4 E–F). In Physiomesh samples, the coating appeared fragmented and was positioned between mesh fibres. Again the inflammatory reaction was primarily
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aimed at the coating with formation of fibrotic granulomas surrounding the fragmented coating, forming a fibrotic bridge between mesh fibres. Unlike in other groups, there
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still was a clear separation between the foreign body reaction surrounding the mesh and the abdominal wall, indicating poor ingrowth (Fig. 4 G–H).
Discussion Intraperitoneal placement of synthetic meshes has long been associated with mesh-related adhesion formation. [7, 9] Although the placement of meshes in the extraperitoneal position prevents most adhesions from forming, the increased popularity of laparoscopic hernia repair leads to a need for intraperitoneal mesh placement [7, 15]. In addition, also in open repair, the direct contact between mesh and intraperitoneal content can frequently not be avoided. Therefore, many different meshes specifically aimed at intraperitoneal adhesion reduction have been constructed and tested [12, 13]. Since the already wide range of currently available meshes keeps increasing and many manufacturers claim to have developed superior meshes, the need for continuous and consistent research testing of these new meshes remains important [1, 8, 12]. For this reason, we evaluated three, new, potentially effective meshes for intraperitoneal use in a validated intraperitoneal mesh model [12, 13]. A polypropylene mesh was added in concordance with our previous research, to serve as a standardized control group [12, 13]. Clearly, the Hi-Tex Endo-IPÒ mesh showed the best macroscopic results for all investigated parameters at both time points. In view of adhesion reduction, the polyurethane coating seems to effectively prevent ingrowth of visceral structures and thus formation of adhesions. Hi-Tex Endo-IPÒ consists of a non-woven, non-porous material, yet the strength of incorporation of this material was significantly higher than all other materials. This is remarkable since the presence of large pores is generally considered to be necessary for adequate ingrowth [16, 17]. This seems to indicate that this material shows superior properties for intraperitoneal mesh placement. However, the microscopic examination of the implanted Hi-Tex Endo-IPÒ meshes elucidates the extensive ingrowth. The mesh seemed to be fixed or even integrated into the abdominal wall with extensive collagenous and fibrotic infiltration throughout the mesh structure as a whole. Although the extensive ingrowth seems beneficial in terms of recurrence risk, an inflammatory and fibrotic reaction of this extent could give rise to other complications after mesh implantation. Formation of a fibrotic dense scar plate of this extent can lead to a rigid mesh, limiting abdominal wall movement and possibly causing chronic pain in the longterm [18–20]. Theoretically, the collagen content in these, otherwise, healthy rats might be of far better quality than in hernia patients, possibly leading to less favourable results.
However, the coating does seem effective in preventing adhesions to the mesh. Potentially, changing the underlying mesh structure to one with a more favourable host response may lead to a better mesh product. Although the PhysiomeshÒ seemed to provide comparable improvement in adhesion prevention to the Hi-Tex Endo-IPÒ after 90 days, the properties necessary for hernia repair are below average. First of all, the ingrowth of the PhysiomeshÒ was up to ten times lower than that of all other meshes. Since adequate ingrowth and high tensile strength is one of the necessities for effective hernia repair, this lack of abdominal wall integration could be detrimental for the risk of recurrence [21, 22]. We hypothesized that the reason for this lack of tissue integration is the application of an anti-adhesive coatings on both sides of the mesh. Barrier coatings are considered to prevent ingrowth of visceral organs into the mesh and thus prevent adhesions, the application of such a barrier between the mesh and the abdominal wall could in theory lead to a reduced ingrowth into the abdominal wall [9, 13]. Furthermore, since the barrier acts through separation of the mesh material and the abdominal wall, the effect of large pores in a mesh is non-existent [8]. This is supported by histological samples where we see a clear separation between the encapsulated mesh and the abdominal wall, without any signs of abdominal wall ingrowth. Another important risk factor for hernia recurrence after PhysiomeshÒ implantation is the significant loss of craniocaudal mesh size after 90 days. Although the loss in total mesh size was minimal and not significant to control groups, there was a significantly higher reduction in mesh length of up to 30 %. This reduction in size can cause considerable problems when attempting to repair abdominal wall hernias as sufficient overlap of healthy tissue is more difficult to achieve [23, 24]. Furthermore, mesh shrinkage is thought to be associated with increased risk of postoperative pain, although the results on this topic seem to be inconclusive [23, 25]. We believe this mesh shrinkage is due to the extensive fibrotic bridging between the mesh fibres for which the fragmented coating seemed responsible. This combined with the active inflammatory process towards the coating fragments, could lead to contraction of the fibrotic capsule resulting in loss in mesh size. This specific reaction to the small parts of the coating minimizes the effect of large pores through formation of a continuous fibrotic capsule. Potentially this could, subsequently, lead to an extensive scar plate, as seen in the Hi-Tex Endo-IPÒ, with risk of postoperative pain and loss of abdominal wall flexibility [18, 20]. Unfortunately, the OmyraÒ mesh showed inadequate performance on all tested parameters. Although the quality of adhesions was significantly lower than that in ParieteneÒ group at both time points, adhesions were considerably more abundant in numbers than in the other experimental meshes.
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Adding to this, the significant loss of surface area, we believe the effectiveness of this material as an intraperitoneal mesh cannot be proven in this model. Most likely, this lack of effective adhesion prevention is due to the design of the mesh and absence of a tissue separating material. Some studies suggest that even though a material itself can be antiadhesive, the absence of a separating barrier can lead to adhesion formation, possibly due to adhesion formation to the abdominal wall through the mesh pores [26]. Interestingly, most adhesions seem to occur in the region of the cut edges. This phenomenon has previously been described by Schreinemacher et al. [12]. Cutting of the meshes seems to expose underlying mesh fibres and interrupt the coating, leading to bare mesh materials exposed to visceral organs. Manufacturers of all three meshes used in this study claim that they can reduce the amount of adhesions after placement in the intraperitoneal position. However, very few data supporting this claim have been published in the past years. Since the wide range of both mesh materials and animal models makes definitive statements on new meshes very difficult to interpret, we think it is important to test them in a validated model with a validated control group, to gain consistent results on new meshes [27]. Since the prevention of recurrent hernia and adhesion is equally important, we added the shrinkage and ingrowth as additional parameters as described in our previous research [6, 7, 12]. There were some limitations to the present study, warranting further clinical and preclinical research to provide definitive results on presented materials. First of all, this research was performed in an experimental rat model, without any predisposing collagen disease or hernia defect. It is suggested that the presence of an abdominal wall defect has influence on wound healing [28]. The absence of such a defect in our model could possibly influence our results. However, current International Endo hernia Society guidelines advise on reconstruction of the linea alba to improve abdominal wall function [29]. This leads to the assumption that an experimental intraperitoneal mesh model without a defect is adequate for mesh testing. Furthermore, a rat model does not allow for evaluation of postoperative pain and quality of life after mesh implantation. Although this research shows clear differences between meshes implanted, the true impact of the severe inflammatory reaction elicited by the Hi-Tex Endo-IPÒ and the foreign body reaction to the fragmented PhysiomeshÒ coating cannot be evaluated in this model.
Conclusion Although clear distinctions could be made between the meshes used in this study, none of the investigated meshes
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showed superior results in all aspects necessary for hernia repair. Regarding macroscopic results, the Hi-Tex EndoIPÒ clearly showed superior characteristics when compared to all other meshes. However, the extensive foreign body reaction should be taken into account and care should be taken when implanting this mesh in humans. Perhaps modification of the mesh to a large pore construct could improve outcome. For adhesion prevention, PhysiomeshÒ also seemed to give superior results. However, the lack of adequate ingrowth and major loss in mesh length might lead to an increased risk for hernia recurrence, warranting extensive fixation of these meshes to use them effectively. Furthermore, the extensive fibrotic response to the coating material might lead to discomfort and pain on the long-term. More clinical and preclinical studies are thus required to find the ideal intraperitoneal mesh and to test new meshes introduced on the market. Acknowledgments We would like to thank B. Braun and Sto¨pler BV for providing two of the meshes required for this research. Furthermore, we would like to thank S. Hartmans for her assistance to this project. Disclosure Two of the meshes were kindly provided by B. Braun (OmyraÒ mesh) and Sto¨pler BV (Hi-Tex Endo-IPÒ). Authors R.R.M. Vogels, K.W.Y. van Barneveld, M.H.F. Schreinemacher, J.W.A.M. Bosmans, G. Beets, M.J.J. Gijbels, and N.D. Bouvy declare no conflict of interest and have no financial ties.
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