Antibacterial Biopolymer Gel Coating on Meshes Used for Abdominal Hernia Repair Promotes Effective Wound Repair in the Presence of Infection.

Prosthetic mesh infection is a devastating complication of abdominal hernia repair which impairs natural healing in the implant area, leading to increased rates of patient morbidity, mortality, and prolonged hospitalization. This preclinical study was designed to assess the effects on abdominal wall tissue repair of coating meshes with a chlorhexidine or rifampicin-carboxymethylcellulose biopolymer gel in a Staphylococcus aureus (S. aureus) infection model. Partial abdominal wall defects were created in New Zealand white rabbits (n = 20). Four study groups were established according to whether the meshes were coated or not with each of the antibacterial gels. Three groups were inoculated with S. aureus and finally repaired with lightweight polypropylene mesh. Fourteen days after surgery, implanted meshes were recovered for analysis of the gene and protein expression of collagens, macrophage phenotypes, and mRNA expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Compared to uncoated meshes, those coated with either biopolymer gel showed higher collagen 1/3 messenger RNA and collagen I protein expression, relatively increased VEGF mRNA expression, a significantly reduced macrophage response, and lower relative amounts of MMPs mRNAs. Our findings suggest that following mesh implant these coatings may help improving abdominal wall tissue repair in the presence of infection.

Polymer Hernia Repair Materials: Adapting to Patient Needs and Surgical Techniques.

Biomaterials and their applications are perhaps among the most dynamic areas of research within the field of biomedicine. Any advance in this topic translates to an improved quality of life for recipient patients. One application of a biomaterial is the repair of an abdominal wall defect whether congenital or acquired. In the great majority of cases requiring surgery, the defect takes the form of a hernia. Over the past few years, biomaterials designed with this purpose in mind have been gradually evolving in parallel with new developments in the different surgical techniques. In consequence, the classic polymer prosthetic materials have been the starting point for structural modifications or new prototypes that have always strived to accommodate patients' needs. This evolving process has pursued both improvements in the wound repair process depending on the implant interface in the host and in the material's mechanical properties at the repair site. This last factor is important considering that this site-the abdominal wall-is a dynamic structure subjected to considerable mechanical demands. This review aims to provide a narrative overview of the different biomaterials that have been gradually introduced over the years, along with their modifications as new surgical techniques have unfolded.

Therapeutic Implications of TGFß in Cancer Treatment: A Systematic Review.

Transforming growth factor ß (TGFß) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of this factor, or the deregulation of its signaling cascade, can lead to different pathologies, including cancer. A great variety of therapeutic strategies targeting TGFß, or the members included in its signaling pathway, are currently being researched in cancer treatment. However, the dual role of TGFß, as a tumor suppressor or a tumor-promoter, together with its crosstalk with other signaling pathways, has hampered the development of safe and effective treatments aimed at halting the cancer progression. This systematic literature review aims to provide insight into the different approaches available to regulate TGFß and/or the molecules involved in its synthesis, activation, or signaling, as a cancer treatment. The therapeutic strategies most commonly investigated include antisense oligonucleotides, which prevent TGFß synthesis, to molecules that block the interaction between TGFß and its signaling receptors, together with inhibitors of the TGFß signaling cascade-effectors. The effectiveness and possible complications of the different potential therapies available are also discussed.

Chitosan hydrogels functionalized with either unfractionated heparin or bemiparin improve diabetic wound healing.

Diabetes mellitus causes severe impairment in the cutaneous wound healing process, which has led to extensive research striving to establish new treatments. In this work, we describe the effects of chitosan hydrogels functionalized with either unfractionated heparin or bemiparin (a low molecular weight heparin, LMWH) as topical treatments in an experimental diabetic wound healing model. Although wound morphometry showed similar values at the end of the study, microscopic analyses revealed impaired healing in diabetic animals in terms of inflammation and tissue formation. However, both types of loaded hydrogels accelerated inflammation resolution and improved the epithelialization process, while showing a neodermal thickness similar to that of nondiabetic animals. Immunohistochemistry analyses revealed an intermediate response in macrophage evolution between diabetic and nondiabetic controls in the treated groups, as well as enhanced collagenization and myofibroblast progression patterns. However, these changes were not accompanied by differences among groups in collagen I, III and TGF-ß1 gene expression. Functionalized hydrogels improved diabetes-associated impaired wound healing, thus promoting the progression of the process and inducing the formation of high-quality cicatricial tissue. Although the beneficial healing effect observed after topical treatment with chitosan hydrogels loaded with bemiparin or unfractionated heparin was similar, the chitosan hydrogel loaded with bemiparin is the preferred choice as it exhibited high-quality tissue in the neoformed dermal tissue.

Evaluation of synthetic reticular hybrid meshes designed for intraperitoneal abdominal wall repair: Preclinical and in vitro behavior.

INTRODUCTION: Reticular hybrid meshes represent an alternative material for intraperitoneal repair of abdominal hernias. These consist of a reticular mesh coated or interwoven/knitted with inert materials. This study assesses the performance of two reticular polypropylene-containing hybrid meshes, TiMESH (coated with titanium) and DynaMesh (interwoven with polyvinylidene fluoride), in vitro, as well as their efficiency in adhesion prevention and tissue incorporation in an intraperitoneal model. METHODS: The mesothelialization capacity of TiMESH and DynaMesh was evaluated in vitro and compared to that of Surgipro (reticular bare polypropylene) and Preclude (laminar expanded polytetrafluoroethylene). Mesh fragments were placed on the intact parietal peritoneum of New Zealand white rabbits (n = 24), and laparoscopy performed 7 days post-surgery. Fourteen days post-implantation, adhesions were evaluated and host tissue incorporation, macrophage response, collagen expression (immunohistochemistry/RT-PCR) and neoperitoneum formation assessed. Adhesions and omental tissue were also examined. RESULTS: Mesh pores in reticular meshes were devoid of cells in the in vitro study. TiMESH, DynaMesh and Surgipro showed similar adhesion rates at 7/14 days and optimal tissue integration, with significant differences in comparison to Preclude. The greatest presence of macrophages was observed for TiMESH and was significant versus that for Preclude. Hybrid meshes revealed significantly higher collagen 1 mRNA expression in implants, with no differences in the levels of collagen 3. Omental samples from animals with a reticular mesh showed significantly greater collagen 1 mRNA levels. CONCLUSIONS: The reticular structure of a mesh limits the formation of a continuous mesothelial monolayer in vitro, regardless of its composition. The presence of titanium as a coating or polyvinylidene fluoride interwoven with polypropylene in a reticular structure did not prevent adhesions. The hybrid meshes showed proper integration and an increase in the mRNA Col 1 levels in the implant area compared to Surgipro or Preclude.

Pre-clinical assay of the tissue integration and mechanical adhesion of several types of cyanoacrylate adhesives in the fixation of lightweight polypropylene meshes for abdominal hernia repair.

INTRODUCTION: Lightweight (LW) polypropylene (PP) meshes better adapt to host tissue, causing less fibrosis and inflammatory responses than high-density meshes. Mesh fixation using tissue adhesives (TA) that replace conventional sutures may improve the process of hernia repair and tissue trauma. This preclinical study compares the behavior of different cyanoacrylate-based adhesives in the fixation of LW-PP meshes for hernia repair. METHODS: Partial abdominal wall defects were repaired using LW-PP Optilene meshes in New Zealand rabbits. The following groups were established according to the mesh fixation method: Suture (control), Glubran 2 (n-butyl), Ifabond (n-hexyl), SafetySeal (n-butyl) and Evobond (n-octyl). At 14, 90 and 180 days after surgery, the recovered implants were examined to assess the host tissue integration, the macrophage response and the biomechanical strength. RESULTS: All the groups showed optimal host tissue incorporation regardless of the fixation procedure. Significantly increased levels of collagen 1 and collagen 3 gene expression (p<0.001) were observed at 14 days compared to the medium- and long-term durations, where the Suture and Glubran groups showed the highest expression of collagen 1. All the adhesives increased the macrophage reaction (p<0.001) compared to sutures at all implant times. Maximal macrophage response was observed in the short-term Glubran group (p<0.01) compared to the rest of the groups. Although SafetySeal and Evobond did not reach the biomechanical resistance of sutures at 14 days, all the adhesives did reach this level in the medium- to long-term periods, providing significantly higher resistance (p<0.05). CONCLUSIONS: All the cyanoacrylates, despite inducing a significantly increased macrophage response versus sutures, showed optimal host tissue integration and long-term mechanical behavior; thus, they might be good choices for LW-PP mesh hernia repairs.

Involvement of transforming growth factor-ß3 and betaglycan in the cytoarchitecture of postoperative omental adhesions.

BACKGROUND: Adhesions commonly appear in patients after abdominal surgery, with considerable individual variation in adhesion composition and severity of the repair process. Here, we address the influence of transforming growth factor (TGF)-ß3 and betaglycan in this response, in relation to TGF-ß1, in an adhesiogenic rabbit model. MATERIALS AND METHODS: Omental adhesions were recovered 3, 7, 14, and 90 d after the implantation of a polypropylene mesh on the parietal peritoneum in New Zealand White rabbits. Omentum from nonoperated animals served as control. Tissue specimens were examined for TGF-ß3 and TGF-ß1 (Western blotting, reverse transcription-polymerase chain reaction), and TGF-ß1:TGF-ß3 messenger RNA and protein expression ratios were analyzed. Immunohistochemical detection of TGF-ß3 and betaglycan was performed. RESULTS: Injury to the omentum led to mobilization of TGF-ß3 and betaglycan-expressing cells from milky spots. Fibrous zones in adhesions were simultaneous to the presence of TGF-ß1 and the membrane-bound form of betaglycan (7-d adhesions), whereas soluble betaglycan appeared in TGF-ß1-positive areas showing limited fibrosis (3-d adhesions). The elevated expression of TGF-ß3 concurrent with the presence of membrane-bound form of betaglycan was observed in zones of adipose regeneration (14-d adhesions), whereas zones of fibrous consistency were negative for TGF-ß3. CONCLUSIONS: Milky spots on the omentum contain inflammatory/immune cells positive for TGF-ß3, TGF-ß1, and betaglycan, playing a role in the damaged omentum repair. Our observations support the contribution of TGF-ß3 to tissue repair through adipose tissue regeneration and the profibrotic role of TGF-ß1 and suggest that these effects on the local wound repair response could be driven by the expression of betaglycan in its soluble or membrane-bound form.

Postimplant intraperitoneal behavior of collagen-based meshes followed by laparoscopy.

BACKGROUND: When repairing an abdominal wall defect, sometimes a prosthetic mesh needs to be placed directly on the parietal peritoneum. Although the standard mesh for this purpose is the laminar implant expanded polytetrafluoroethylene (PTFE), it is gradually being replaced by the laminar collagen-based meshes. This study was designed to assess the intraperitoneal behavior of three of these biomeshes, mainly in terms of their susceptibility to adhesion formation. METHODS: Two 3-cm × 3-cm fragments of prosthetic material were placed on the parietal peritoneum in male New Zealand White rabbits in the following combinations: PTFE and CollaMend(®), PTFE and Permacol(®), or PTFE and Surgisis(®). The meshes were fixed at the four corners with individual 4/0 polypropylene sutures. Adhesion formation was quantified by sequential laparoscopy and image analysis performed at 3, 7, 14, and 90 days postimplant. All animals were killed at 90 days and the mesh specimens were subjected to microscopy and immunohistochemistry. RESULTS: Intensely vascularized adhesions to all the implants were observed, although Surgisis showed the lowest percentage of adhesions at each follow-up time. Adhesions had stabilized by 7-14 days. The PTFE meshes were enveloped by a layer of macrophages and connective tissue, bounded by a monolayer of mesothelial cells. Permacol and CollaMend showed similar histological behavior, including cell ingrowth through their fenestrations with no signs of degradation detected at 90 days. In contrast, the Surgisis mesh at 90 days was practically replaced with neoformed tissue. CONCLUSIONS: No difference in susceptibility to adhesion formation was noted in the crosslinked collagen meshes compared to PTFE meshes. The noncrosslinked collagen mesh Surgisis showed the best behavior in that it induced fewer adhesions. Ninety days after implant, a more intense macrophage response was observed in CollaMend and Permacol than in PTFE or Surgisis.

Active matrix metalloproteinase-2 upregulation in the abdominal skin of patients with direct inguinal hernia.

BACKGROUND: Prior studies suggest impaired collagen metabolism involving the whole abdominal wall including the skin in patients with abdominal hernia. We compared expression patterns of matrix metalloproteinase-2 (MMP-2) and its modulators membrane type-1-matrix metalloproteinase (MT-1 MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the skin of patients with and without primary inguinal hernia. MATERIALS AND METHODS: Skin biopsy specimens from abdominal wall incisions were obtained during surgery from patients with direct inguinal hernia, indirect inguinal hernia or without hernia (controls). MMP-2, MT-1 MMP and TIMP-2 expression were determined using immunocytochemistry and immunoblotting in intact tissue and in cultured fibroblasts isolated from the biopsies. The degradation activity of MMP-2 was semiquantitatively determined using zymography. RESULTS: Significantly greater active MMP-2 expression was observed in skin fibroblasts obtained from patients with direct hernia compared with controls. MT1-MMP expression was directly correlated with MMP-2 expression with most intense staining produced in patients with direct or indirect inguinal hernia. TIMP-2, was maximally expressed in the control group, with significantly diminished expression levels recorded in the hernia groups. CONCLUSIONS: Our findings indicate active MMP-2 upregulation in the abdominal skin of patients with direct inguinal hernia. This metalloproteinase plays a role in matrix degradation, weakening the abdominal wall. Skin disorders and previously described transversalis fascia defects in these patients could point to a systemic collagen metabolism abnormality as a risk factor for direct hernia.

Peritoneal adhesion formation and reformation tracked by sequential laparoscopy: optimizing the time point for adhesiolysis.

BACKGROUND: In a high proportion of patients, operatively lysed adhesions reform. Using a rabbit adhesiogenesis model, this study assessed the efficacy of adhesiolysis and examined how this relates to the tissue composition of adhesions at the time of lysis. METHODS: Polypropylene meshes (5 x 3.5 cm) were implanted on the parietal peritoneum of New Zealand white rabbits. Some animals were killed 3, 7, 14, and 90 days postimplantation to obtain adhesion tissue. Adhesion formation/reformation was monitored by sequential laparoscopy in other animals kept for 90 days and in a separate experimental group subjected to adhesiolysis at 3 days postimplantation. Immune and inflammatory response markers were determined by immunohistochemical, Western blotting, and real-time reverse transcriptase polymerase chain reaction procedures in adhesion tissue; areas occupied by adhesions were quantified in meshes. RESULTS: In animals undergoing adhesiolysis, mesh areas covered by adhesions were significantly decreased at each follow-up time and affected areas became mesothelialized. Increased transforming growth factor (TGF)-beta1 expression was detected in adhesions at 3 days. Greatest TGF-beta1 and vascular endothelial growth factor (VEGF) protein expressions were observed at 7 days, whereas genetic overexpression was noted at 14 days. Active inflammatory cells peaked at the 7-day time point. CONCLUSION: Adhesions formed at 3 days; at this critical time, an adhesiolysis was effective in preventing reformation of future adhesions. TGF-beta1 gene and protein expression were increased in 3-day adhesions with respect to the omentum. Levels of active TGF-beta1 and VEGF were increased at 7 days, along with the inflammatory response at this time point related to tissue remodeling, which led to stabilization of adhesions.

Characterizing omental adhesions by culturing cells isolated from a novel in vivo adhesion model.

Although it has been established that postoperative adhesions in the peritoneal cavity are the consequence of injury to the peritoneum, there is much controversy over the nature of the cells giving rise to this neotissue. Here, we establish a novel adhesiogenic model in the rabbit to analyze the phenotype and proliferation in vitro of cells comprising adhesion tissue seven days postsurgery. Adhesion-free omentum tissue was used as control. Cells derived from adhesions and from the control omentum were subcultured and characterized through immunofluorescence and Western blotting procedures to determine markers of cell differentiation and pluripotential, and viability and proliferation assays. Our findings indicate the existence of a mesenchymal population in the omentum revealed by markers of pluripotent cells with high angiogenic capacity. This population seems to be responsible for the adhesions formed in response to mesothelial damage. Depending on the local environment, mesenchymal cells are capable of in vivo differentiation towards at least two different cell phenotypes rendering two types of adhesions with clearly differentiated characteristics. One type of adhesion shows a highly vascularized adipose morphology containing cells differentiating into a vascular lineage. The other adhesions are fibrous with large amounts of collagen and comprised mainly of myofibroblasts conferring less compliance to this tissue.

Early tissue incorporation and collagen deposition in lightweight polypropylene meshes: bioassay in an experimental model of ventral hernia.

BACKGROUND: This study was designed to assess the early host tissue incorporation of several polypropylene lightweight (PP-LW) meshes used to repair abdominal wall defects and to correlate collagen deposition with the biomechanical response shown by PP-LW versus polypropylene heavyweight (PP-HW) meshes. METHODS: Ventral hernial defects (7 x 5 cm) were created in the anterior abdominal wall of New Zealand rabbits and repaired by fixing PP-LW mesh of different pore sizes or a low porosity HW mesh to the edges of the defect. Rabbits were killed 14 days after implant, and specimens were taken from the central mesh area to examine collagen deposition by light microscopy, real time reverse transcription polymerase chain reaction, immunohistochemistry, and Western blotting. The biomechanical resistance of the biomaterials was also assessed. RESULTS: All the materials showed excellent incorporation in host tissue. Relative amounts of collagen III mRNA were considerably higher than collagen I mRNA. Higher collagen I and III mRNA levels were noted for pore sizes equal to or greater than 3.45 +/- 0.19 mm(2) (Ultrapro/Optilene Elastic. These two meshes showed significantly higher levels of collagen III than Parietene and Surgipro with smaller pores. Biomechanical resistance values for Optilene were significantly higher than those recorded for Surgipro and Parietene. CONCLUSIONS: (a) LW meshes of pore size larger than 3 mm(2) induced the genetic overexpression of collagen types I and III; (b) the larger pore-sized LW meshes induced more collagen type III deposition and its faster conversion to collagen I; (c) Optilene, the most porous LW mesh examined, showed the greatest tensile strength 14 days after implant.

Postimplant behavior of lightweight polypropylene meshes in an experimental model of abdominal hernia.

BACKGROUND: Over the years, reticular prostheses have undergone changes in their structure and composition to give rise to today's partially absorbable lightweight meshes. This study was designed to assess the biological and biomechanical behavior of these prostheses to establish whether they offer any advantages over nonabsorbable lightweight polypropylene prostheses. MATERIALS AND METHODS: 7 x 5 cm defects were created in the anterior abdominal wall of New Zealand White rabbits and repaired by securing different prostheses to the edges of the defect with a running 4/0 polypropylene suture. The lightweight biomaterials compared were two nonabsorbable meshes: Parietene and Optilene elastic, and two partially absorbable prostheses: Vypro II and Ultrapro. At 14 and 90 days postimplant, tissue/prosthesis specimens were subjected to histological, immunohistochemical, shrinkage, and biomechanical analyses. RESULTS: Adhesion formation on the peritoneum-facing surface of the meshes was significantly less extensive in the meshes with absorbable components at 90 days postimplant. The newly formed tissue around the prosthetic filaments was comprised of collagen fibers, fibroblasts, blood vessels, and macrophages. The partially absorbable meshes showed higher macrophage proportions (due to remnants of absorbable material and their structure) than the nonabsorbable meshes at 90 days, although differences were not significant. At 90 days postimplant, similar tensile strengths were recorded for all the implants. CONCLUSIONS: All the prosthetic materials induced good host tissue ingrowth, with no significant differences in tensile strength observed. Our findings suggest that partially absorbable lightweight prostheses could offer advantages over nonabsorbable lightweight meshes since less foreign material persists in the recipient, improving abdominal wall compliance.

[Real-time monitoring of the peritoneal behavior of composite prostheses by sequential laparoscopy: applicability in ventral hernia repair]. / Seguimiento del comportamiento peritoneal de diferentes biomateriales empleando laparoscopia secuencial. Aplicabilidad en la reparación de hernias ventrales.

INTRODUCTION: Despite the advantages offered by meshes, their use in abdominal wall repair can promote adhesions and damage the intra-abdominal viscera. This study was designed to assess the behavior at the peritoneal interface of several composite prostheses using sequential laparoscopy to monitor the real-time adhesion formation process. MATERIALS AND METHODS: Three composite prostheses, Parietex Composite (n=8), Sepramesh (n=8) and PL-PU 99 (n=8), were used to repair 7 x 5 cm defects created in the abdominal wall of 24 New Zealand white rabbits. The area occupied by adhesions at 3, 7 and 14 days after prosthesis placement was established by tracing the adhesions onto a polyethylene template, using images obtained from sequential laparoscopy, and subjecting it to image analysis. At 14 days, the animals were sacrificed and specimens of the prostheses plus adjacent host tissue were obtained for histological and morphometric tests. RESULTS: Adhesion formation was laparoscopically observed to stabilize between 7 and 14 days post-implant, with no increase in adhesions produced at 14 days. The Parietex and PL-PU99 meshes showed significantly lower proportions of adhesions (0.55 +/- 0.06% and 0.27 +/- 0.20% respectively) than Sepramesh (18.55 +/- 1.96%). All three composites induced similar host tissue ingrowth and mesothelialization of the peritoneal prosthetic surface. CONCLUSIONS: a) The three prostheses tested showed optimal behavior at the peritoneal interface; b) the critical period when most adhesions form is the first week after implant; c) these biomaterials are suitable for use in laparoscopic ventral hernia repair.

Peritoneal effects of prosthetic meshes used to repair abdominal wall defects: monitoring adhesions by sequential laparoscopy.

BACKGROUND: The prosthetic materials currently used to repair abdominal wall defects sometimes have to be placed in contact with the visceral peritoneum. This interface is often a site of complications such as intestinal obstruction or fistulas due to adhesions. The aim of this study was to follow the process of adhesion formation in several prosthetic materials by sequential laparoscopy. MATERIAL AND METHODS: Defects (7 x 5 cm) were created in the abdominal wall of 30 New Zealand White rabbits and repaired using Surgipro polypropylene mesh (PP), Ultrapro monocryl-prolene mesh (UP), Dual Mesh expanded polytetrafluoroethylene (ePTFE), Composix (PP-ePTFE), Parietex Composite (polyester with collagen-polyethylene glycol-glycerol coating [PO-gl]), or PL-PU99 (PP-polyurethane) patches fixed to the edges of the defect by running polypropylene suture. Adhesions to the implants were laparoscopically determined at 3, 7, and 14 days after surgery. RESULTS: Percentage adhesion scores were significantly lower for ePTFE, PP-ePTFE, PO-gl, and PP-PU, compared to PP or UP. No differences were observed in adhesion scores recorded at 3, 7, and 14 days postimplant. Reticular prostheses were infiltrated by disorganized scar tissue with fibers concentric to the mesh filaments. In contrast, ePTFE implants were encapsulated by organized tissue, with fibers running parallel to the surface of biomaterial. All three composites achieved good recipient tissue integration and a homogeneous, organized, and well-vascularized neoperitoneum. CONCLUSION: At 14 days postimplant, laminar prostheses and composites showed similar results in terms of adhesion formation and integration within host tissue. Our findings suggest that both the composite prostheses and the laminar ePTFE performed very well in terms of reduced adhesion formation at the peritoneal interface.