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  • 8/18/2019 Early and Late Postoperative Inflammatory and Collagen

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    O RI G I N A L A RT I CL E

    Early and late postoperative inflammatory and collagendeposition responses in three different meshes: an experimental

    study in rats

    C. G. Pereira-lucena   • R. Artigiani Neto   •

    D. T. de Rezende   • G. de J. Lopes-Filho   •

    D. Matos   • M. M. Linhares

    Received: 12 January 2013 / Accepted: 12 December 2013 / Published online: 27 December 2013

     Springer-Verlag France 2013

    Abstract

    Purpose   Although meshes reduce abdominal herniarecurrence, they increase the risk of inflammatory com-

    plications. This study aimed to compare the early and late

    postoperative inflammation and collagen deposition

    responses induced by three meshes.

     Methods   Rats were allocated into three groups. In group

    I, a polypropylene (PP) mesh was implanted in the

    abdominal wall. In groups II and III, PP ?  polyglactin

    (PP  ?  PG) and PP ?   titanium (PP ?  TI) meshes were

    employed, respectively. On the seventh (7th) postoperative

    day, collagen deposition and inflammation were evaluated,

    and immunohistochemistry was performed on abdominal

    wall biopsies. These data were compared with those

    obtained on the fortieth (40th) postoperative day in a pre-

    vious study.

     Results   The early inflammatory responses were the same

    in all groups. With time, it decreased in group I

    ( p  =  0.047) and increased in group II ( p  =  0.003). Group I

    exhibited early elevated VEGF ( p\ 0.001), COX2

    ( p\ 0.001), and collagen ( p  =  0.023) levels, and group II

    exhibited the most severe inflammatory tissue response. On

    the 40th postoperative day, the VEGF ( p\ 0.001) and

    collagen ( p\ 0.005) were reduced as compared with the

    7th postoperative day in all groups.Conclusions   Belatedly, the inflammatory reaction

    decreased in PP mesh group and increased in PP  ?  PG

    mesh group. The PP mesh induced early great elevations in

    VEGF, COX2 and collagen levels, whereas the PP  ?  PG

    mesh caused severe tissue inflammation with small eleva-

    tion in these levels. PP  ?  TI mesh induced inflammatory

    response levels between the others. In conclusion, the

    inflammatory response depends on the mesh density and

    also the mesh material with clinical implications.

    Keywords   Hernia    Mesh     Inflammatory response  

    Collagen     VEGF    COX2.INFLAMMATORY

    Introduction

    Cytokines are synthesized by injured tissue to modulate the

    inflammatory cascade during the initial phase of repair in the

    abdominal wall [1]. Cytokines are fundamental to cell pro-

    liferation, the extracellular matrix, and collagen synthesis [2].

    Meshes were developed due to the high rate of recur-

    rence after hernia surgery with primary sutures, and mesh

    application in abdominal wall repairs has reduced the

    recurrence indexes from over 50 % to approximately 10 %,

    particularly in ventral hernias [3]. Although meshes are the

    most commonly used biomaterials in medical practice,

    with approximately 1.5 million implants used per year [4],

    numerous questions remain about the host inflammatory

    response induced by mesh implants [3–10]. Despite the

    frequent use of mesh implants, there remains no consensus

    regarding their classification and nomenclature [11].

    Polypropylene (PP) is the most commonly material

    used to manufacture meshes, but other absorbable and

    C. G. Pereira-lucena    R. Artigiani Neto  

    D. T. de Rezende    G. de J. Lopes-Filho    D. Matos  

    M. M. Linhares

    Pós-Graduação em Ciência Cirúrgica Interdisciplinar,

    Universidade Federal de São Paulo, Rua Napoleão de Barros,

    610-Vila Clementino, São Paulo, SP CEP 04024-002, Brazil

    C. G. Pereira-lucena (&)

    Rua Volney Loureiro Tavares, No. 27-bairro Inácio Barbosa,

    Aracaju, SE CEP 49040-670, Brazil

    e-mail: [email protected]

     1 3

    Hernia (2014) 18:563–570

    DOI 10.1007/s10029-013-1206-4

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    non-absorbable materials are also used [11,   12]. Theo-

    retically, the increased diameter of the pores and the

    reduction in the density of meshes could minimize

    inflammation and, therefore, the complications related

    to this implant [8]. However, several studies have

    reported conflicting results, including reports of the

    reduction of early complications and reports of a pos-

    sible increase in recurrences [13–18]. Unexpectedcomplications, such as the reduced sperm mobility in

    response to lightweight mesh implanted in the inguinal

    region [17] and mechanical failure with fracture of a

    lightweight mesh in the surgical repair of a recurrent

    median ventral hernia [18], have been reported.

    Klinge et al. [11] evaluated the indications for explant-

    ing mesh implants in 1,000 cases. Infection was the main

    reason for removing small pore PP meshes, which were

    prevalent in the reviewed data. Hernia recurrence was the

    main reason for explanting large-pore meshes [11].

    Pascual et al. [19] observed that an intense inflammatory

    reaction was related to the presence of absorbable material;additional characteristics include low expression of growth

    factors, worse collagen deposition, and worse mesh inte-

    gration in host tissue [19].

    Some authors have studied mesh modified with a coat-

    ing film or the use of various substances, including those

    from hormonal sources, like aldosterone. Although these

    authors shared the goals of reducing the formation of 

    adhesions or modulating the inflammatory process, e.g., the

    action of mast cells, foreign body reactions, or fibrosis [12,

    20–22], their results are varied.

    In a previous study, we assessed the serum, inflam-

    matory response, and collagen deposition in rats on the

    40th postoperative day after mesh implantation, includ-

    ing conventional PP, lightweight PP  ?   polyglactin

    (PG  ?   PG), and lightweight PP  ?  titanium (PP  ?  TI).

    Serum cytokines were similar in all groups. The heavy-

    weight PP mesh belatedly induced the least inflammation

    and improved collagen deposition. The PP  ?   PG mesh

    was correlated with the most intense tissue inflammatory

    response and low, irregular, and heterogeneous collagen

    deposition. The PP  ?   TI mesh led to an intermediate

    result [23].

    The above results prompted further questions. The

    results appear contradictory with respect to whether

    collagen deposition depends on an inflammatory reac-

    tion. PP mesh belatedly induces a subdued inflammatory

    reaction but leads to greater collagen deposition, which

    is in direct contrast with the results observed for the

    PP  ?   PG mesh. Would it be possible to demonstrate a

    more intense early tissue inflammatory response with PP

    mesh? Could the kind of inflammatory reaction induced

    by the PP  ?   PG mesh be the key factor for the belated

    inhibition of collagen deposition? Could the differences

    be due to pro-inflammatory molecules present in the

    host tissue, especially growth factors related to collagen

    deposition that were not detected in the blood of 

    animals?

    This study aimed to compare the early (7th postopera-

    tive day) and late (40th postoperative day) inflammatory

    tissue response (histological changes and immunohisto-

    chemistry for inflammatory substances) and collagenmorphology in response to conventional PP, lightweight

    PP  ?  PG, and lightweight PP  ?  TI meshes.

    Methods

    This research was an experimental study in which it was

    employed an acute wound model, not a hernia model.

    Thirty male adult Wistar rats weighing 250–300 g were

    randomly allocated into groups I, II and III. Each group

    comprised 10 animals. An intraperitoneal injection of 10 %

    ketamine hydrochloride and 2 % xylazine solution wasapplied for anesthesia.

    After a 4-cm longitudinal incision was made along the

    animal’s flank, a fragment of the anterior abdominal

    musculature measuring 2 cm2 (2.0  9  1.0 cm) was

    removed. The mesh was positioned to replace the defect

    that had been produced and was fixed by six PP 3-0

    switches sutures. In group I, the mesh was made of 

    heavyweight monofilament PP and had small pores (In-

    tracorp, Venkuri, Brazil). In group II, the mesh contained

    large pores and was made of lightweight PP and an

    absorbable material, PG (VyproII, Ethicon, USA). In

    group III, a large-pore lightweight mesh made of PP and a

    nonabsorbable material, TI, was used (Timesh, GfE,

    Germany).

    Group I, the group in which the animals were implanted

    with the most commonly used type of mesh [11], was

    considered the control group.

    On the 7th postoperative day, the rats were killed by

    means of a lethal dose of ketamine. A fragment was

    removed from the central region of the prosthesis as far as

    possible from the mesh stitches. The tissue sample was sent

    for a histological inflammatory response analysis, includ-

    ing hematoxylin-eosin, Masson trichrome, and picrosirius

    (under polarized light to assess collagen deposition), and

    the immunohistochemical analysis of Vascular Endothelial

    Growth Factor (VEGF-Dbs rabbit polyclonal antibody,

    Santa Cruz Biotechnology, Inc.) and Cyclooxygenase 2

    (COX2-rabbit polyclonal antibody, Spring Cold Spring

    Harbor Laboratory, USA).

    To objectively evaluate the tissue reaction and expres-

    sion of VEGF and COX2, numeric scales were employed

    [23–25], and the scoring scales are presented in Tables  1,

    2.

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    Pixels corresponding to collagen were counted on amicrocomputer after image capture using Image Tool

    software, version 3.0, according to the following steps:

    •   gray scale conversion;

    •   automatic threshold;

    •   image inversion for better viewing;

    •   automatic collagen pixels count by the computer

    program.

    These data were compared with previously obtained

    data from our group using the same methodology on the

    40th postoperative day [23].

    For the statistical analyses of the histological and

    immunohistochemistry scores, the nonparametric Kruskal–

    Wallis test was used. For the morphometric analysis of the

    collagen and the inflammatory score, a sum ANOVA was

    used. To compare early and late postoperative results, the

    Mann–Whitney (tissue response, VEGF, and COX2) and

    student’s t (tissue response score sum and collagen) tests

    were employed. Statistical calculations were performedusing the Statistical Package for the Social Sciences

    (SPSS) 19.0 for Windows, R-Program 2.11.1.

    Results

    In this research, we studied some aspects of the host

    response resulting from the implantation of three different

    meshes (PP, PP and PP  ?  PG  ?  TI) in the abdominal wall

    on early (7th PO) and late postoperative period (40th PO).

    The obtained results are described below:

    •   Tissue inflammatory response: The early sum score of 

    histologic inflammation was quantitatively similar in all

    groups ( p  =   0.509). But, compared with the 7th post-

    operative day, the scores on the 40th postoperative day

    were decreased in group I (PP) ( p  =  0.047) and

    increased in group II (PP  ?  PG) ( p  =  0.003). In group

    III (PP  ?  TI), the early and late inflammatory responses

    were the same ( p  =  0.341). The results of the analyses

    and the inflammatory parameters are shown in Fig.  1.

    •   Immunohistochemical expression of pro-inflammatory

    substances: Group I exhibited early elevated expression

    ofVEGF( p\ 0.001) and COX2 ( p\0.001), and groupII exhibited the lowest levels. On the 40th postoperative

    day, VEGF decreased ( p\ 0.001) in all groups, and

    reductions in COX2 were observed only in group I

    ( p  =  0.011). These data are presented in Figs. 2, 3 and 4.

    •   Collagen deposition: On the 7th postoperative day,

    group I exhibited the best collagen deposition

    ( p  =  0.023), while group II exhibited the worst. When

    we compared the early and late samples, collagen

    deposition decreased over time in all groups, but the

    reduction was more intense and organized in group I.

    Figures 5,  6  and 7  demonstrate this comparison.

    Table 1   Numeric scales to value tissue inflammatory response in

    groups I (PP), II (PP ?  PG) and (PP  ? TI)

    Points Legend

    A: Cell layers at the margins of the granulomas

    1 1–4 layers

    2 5–9 layers

    3 10–30 layers4   [30 layers

    B: Inflammatory reaction in the host tissue

    1 Non-dense, mature fibrous tissue

    2 Immature fibrous tissue with fibroblasts and little collagen

    3 Dense granular tissue with fibroblasts and many

    inflammatory cells

    4 Mass of inflammatory cells with disorganized connective

    tissue

    C: Inflammatory response on the mesh surface

    1 Fibroblasts without macrophages or foreign body cells

    2 Isolated foci of macrophages or foreign body cells

    3 One layer of macrophages and foreign body cells4 Multiple layers of macrophages and foreign body cells

    D: Tissue maturation

    1 Dense, mature interstitial tissue, similar to normal connective

    or adipose tissue

    2 Interstitial tissue with blood vessels, fibroblasts, and a few

    macrophages

    3 Interstitial tissue with giant inflammatory cells but with

    permeating connective tissue

    4 Mass of inflammatory cells without permeating connective

    tissue

    Table 2   Numeric scales to value VEGF and COX2 imunohistochemistry expression in groups I (PP), II (PP ?  PG) and (PP  ?  TI)

    VEGF COX2

    % cells Score Intensity Score % cells Score Intensity Score

    0–25 1 Weak 1 0–25 1 Weak 1

    26–50 2 Moderate 2 26–50 2 Moderate 2

    51–75 3 Strong 3 51–100 3 Strong 3

    76–100 4

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    Discussion

    The main reason for the subject and the design of this

    research was our need to continue investigating the ques-

    tions raised in our previous study, in which conventional

    PP mesh placement unexpectedly and belatedly resulted in

    less tissue inflammation and increased late collagen depo-

    sition compared with PP  ?  PG and PP  ?  TI meshes.

    The first phase of the healing process of the abdominal

    wall (hemostasis  ?  inflammation) is indispensable for the

    deposition of collagen and scar formation [2]. We won-

    dered whether an early intense reaction, with the release of 

    pro-inflammatory cytokines, particularly growth factors,

    could result in later collagen deposition resulting from PP

    mesh.

    We were also interested in exploring the effects of mesh

    coated with an absorbable material on maintaining a for-

    eign body-type inflammation, with granulomas formation

    and reduced growth factors expression, potentially resulted

    in less collagen deposition. Thus, we asked whether thepore size, mesh density, or type of material affected the

    intensity and characteristics of the inflammatory response.

    Previous research demonstrated that PP can induce a fast

    inflammatory reaction, especially in the early phase after

    surgery [26]. Some authors have noted that PP mesh causes

    an elevated short-term inflammatory reaction, resulting in

    more discomfort for patients. However, in the long term,

    various kinds of meshes exhibit similar behavior, and

    higher rates of hernia recurrence have been reported with

    lightweight mesh [6,   9,   11,   13,   14,   27]. Other studies,

    however, have reported no differences in the inflammatory

    response between various materials and have reported that

    the mesh density is the most important factor affecting the

    inflammatory response [5–8]. These diverse results could

    be explained by the heterogeneity in the study designs and

    the parameters studied.

    In this research study, the results of the histological

    analysis of inflammatory process were similar between the

    groups on the 7th postoperative day. However, when we

    compared the early and late postoperative periods, we

    observed that, although there was no accentuation of the

    Fig. 1   Boxplot graph that demonstrates the sum

    (S  =  A  ? B  ?  C  ?   D) of the items related to inflammatory tissue

    reaction on 7th and 40th postoperative days (PO) in groups I, II and

    III, where A is the layer of cells on granulomas, B is the inflammatoryreaction in host tissue, C is the inflammatory response on the surface

    of the mesh, D is the tissue maturation

    Fig. 2   Boxplot graph that demonstrates VEGF imunohistochemistry

    expression on 7th and 40th postoperative days (PO) in groups I (PP),

    II (PP  ?  PG) and III (PP  ?  TI)

    Fig. 3   Boxplot graph that demonstrates COX2 imunohistochemistry

    expression on 7th and 40th postoperative days (PO) in groups I (PP),

    II (PP  ?  PG) and III (PP  ?  TI)

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    inflammatory response over time in group III (PP  ?  TI), a

    significant increase in the inflammatory response was

    observed belatedly in group II (PP  ?  PG) ( p  =  0.003), as

    shown in Figs. 1,   2,   3. These results suggest that the

    absorbable material may be the key determinant in the

    intensity of the inflammatory process in meshes made of 

    PG, similar to the results of Pascual et al. [19]. However,

    the late inflammatory response in group I (PP) was smaller

    than the early response ( p  =   0.047), supporting the idea

    that this material induced a rapid inflammatory reaction.

    VEGF expression has been used previously to evaluate

    the healing process after abdominal wall hernia surgery.

    Some authors have reported increased expression of this

    cytokine in response to PP meshes and lower expression in

    response to meshes containing biodegradable material(e.g., PG) [19]. Our results corroborate the findings

    described above. In group I (PP), the average VEGF

    immunohistochemistry score was elevated on the 7th

    postoperative day with respect to the other groups

    ( p\ 0.001), and all animals in this group, except one,

    exhibited the maximum assessment scores. Group III

    (PP  ?  TI) exhibited intermediate scores, whereas group II

    (PP  ?  PG) exhibited the lowest scores.

    With respect to the late inflammatory response, all

    groups exhibited reductions in the late VEGF score com-

    pared with the earlier score. These results are compatible

    with the results obtained by Di Vita et al. [26] in their studyof serum VEGF levels in humans. The authors observed

    higher cytokine levels during the early postoperative period

    in patients undergoing surgical repair of hernias of the

    abdominal wall, which could explain the rapidity of the PP-

    receiving host response. We believe that new researches

    could clarify this response and other questions, including

    the COX2 involvement in the tissue inflammatory response

    caused by mesh use and abdominal wall healing.

    Fig. 4   Photomicrography (9100). Immunohistochemical analysis of COX2 (narrows) in groups I (PP), II (PP  ?  PG) and III (PP  ?  TI) on the

    7th postoperative day. Observe mesh filaments (stars)

    Fig. 5   Boxplot graph that demonstrates the score of the collagen

    representative pixels on 7th and 40th postoperative days (PO) on

    groups I (PP), II (PP ?  PG) and III (PP  ?  TI)

    Fig. 6   Photomicrgraphy (940). Picrosirius demonstrates collagen deposition (narrows) on the 7th postoperative day in groups I (PP), II

    (PP  ?  PG) and III (PP  ?   TI). Observe mesh filaments (stars)

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    Conflicting findings about collagen deposition in mesh

    implants have been reported. Although some authors state

    that there is increased collagen deposition in heavyweight

    meshes, others claim the opposite [11,   26]. A recentlypublished study reports that PP meshes can result in a

    higher density of collagen in the host scar tissue [ 28]. In the

    current study, collagen reduction was observed in all

    groups when we compared the evolution of the morphology

    of collagen between the 7th and the 40th postoperative

    days. However, on the 40th postoperative day, the collagen

    deposition remained more intense and more organized in

    response to PP mesh than for the other meshes (Fig.  6).

    This amendment is consistent with some authors’

    descriptions [2]. Vaz et al. [29] studied collagen deposition

    in Wistar rats after PP mesh implantation. The authors’

    results demonstrated that, on the 30th postoperative day,type III collagen (immature) was replaced by type I col-

    lagen (mature) [2,   29]. Thus, in this study, we chose the

    40th postoperative day as the endpoint of the late evalua-

    tion. Moreover, 40 days in a rat’s life correspond to 3 years

    and 3 months in humans, which is sufficient time for the

    scar remodeling process [30]. This experimental design

    minimizes the differences between the host response after

    mesh implantation in rats and humans but cannot avoid

    them completely. To evaluate tissue inflammation induced

    by mesh implants over time, serial biopsies of the

    abdominal wall would be necessary, which would be eth-

    ically unacceptable. After experimental studies in animals,

    new studies in humans could use other methods to analyze

    abdominal wall healing, including computer tomography or

    magnetic resonance.

    Group II, which was characterized in the histological

    studies by an intense inflammatory process, exhibited poorexpression of VEGF, which is a well-established important

    inflammatory marker; this observation reinforces the

    hypothesis that each mesh type induces a different reaction.

    The observation that the mesh that induced lower VEGF

    expression also induced less collagen deposition strength-

    ens the probable relationship between this growth factor

    and collagen. Our results strengthen the conclusions of 

    Pascual et al. [6], who reported that a material that stim-

    ulates a foreign body-type reaction would, with the mini-

    mal release of VEGF, result in a frail and disabled scar in

    terms of collagen deposition. Further studies may shed

    light on this topic.To synthesize the basic characteristics exhibited by the

    mesh studied in this research, we have observed the

    following:

    •   The conventional mesh, made of heavyweight PP with

    small pores, exhibited an intense initial tissue inflam-

    matory reaction, strong expression of VEGF and

    COX2, and increased collagen deposition. Over time,

    there was a reduction in the inflammatory response, the

    levels of VEGF and COX2, expression, and collagen

    deposition. On the 40th postoperative day, collagen

    fibers were grouped into organized bundles, and thismesh exhibited the greatest collagen deposition among

    the meshes studied.

    •   The lightweight mesh made of large pores consisting of 

    PP  ?  PG exhibited an intense initial inflammatory

    reaction, predominantly of the foreign body type, with

    the presence of abundant granulomas and giant cells.

    Characteristically, faint VEGF and COX2 expression

    and an erratic deposition of collagen were observed.

    This reaction can be perpetuated, becomes even more

    pronounced over time, and is likely related to the

    presence of an absorbable material in the implant.

    •   The large pores and lightweight mesh made of PP andcovered with TI resulted in an intermediate histolog-

    ically defined inflammatory response, intermediate

    VEGF and COX2 expression, and intermediate colla-

    gen deposition with respect to the other groups.

    Although this mesh contains a an inert material that

    is used in orthopedic and endovascular prosthesis, it led

    to an early inflammatory reaction similar to other

    meshes and long-term inflammation that was more

    severe than that induced by the PP mesh.

    Fig. 7   Photomicrography (9400): Picrosirius demonstrates collagen

    deposition (arrows) on 7th and 40th postoperative days (PO) in

    groups I (PP), II (PP  ?   PG) and III (PP  ?  TI). Note the organized

    collagen deposition in group I and irregular collagen deposition in

    group II

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    Therefore, we conclude the following:

    •   Although the early inflammatory response was the

    same in all groups, the late inflammatory response was

    elevated in the PP  ?  PG mesh group and decreased in

    the PP mesh group.

    •   On the 7th postoperative day, the greatest COX2

    expression occurred in PP mesh. However, on the 40thpostoperative day, it decreased in the PP mesh group

    but not in the PP  ?  PG and PP  ?  TI mesh groups.

    •   The mesh that resulted in the highest early VEGF

    expression (PP) resulted in better collagen deposition,

    whereas the mesh that resulted in the lowest VEGF

    expression (PP  ?   PG) resulted in the worse collagen

    deposition.

    •   The mesh density, pore diameter, and material can

    influence the host inflammatory response resulting from

    its implantation in the abdominal wall, with clinical

    implications for wall rigidity, foreign body reaction,

    abscesses, and infection.

    Acknowledgments   This research was funded by Fundação de

    Amparo à  Pesquisa do Estado de São Paulo (FAPESP) and the Co-

    ordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior

    (CAPES).

    Conflict of interest   The authors declare no conflict of interest.

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    C o p y r i g h t o f H e r n i a i s t h e p r o p e r t y o f S p r i n g e r S c i e n c e & B u s i n e s s M e d i a B . V . a n d i t s    

    c o n t e n t m a y n o t b e c o p i e d o r e m a i l e d t o m u l t i p l e s i t e s o r p o s t e d t o a l i s t s e r v w i t h o u t t h e      

    c o p y r i g h t h o l d e r ' s e x p r e s s w r i t t e n p e r m i s s i o n . H o w e v e r , u s e r s m a y p r i n t , d o w n l o a d , o r e m a i l    

    a r t i c l e s f o r i n d i v i d u a l u s e .