Comparison of the effect of Everolimus, Prednisolone, and a combination of both on experimentally induced peritoneal adhesions in rats.

Postoperative intra-abdominal adhesions represent a significant post-surgical problem. Its complications can cause a considerable clinical and cost burden. Herein, our study aimed to investigate the effect of Everolimus on peritoneal adhesion formation after inducing adhesions in rats. In this experimental study, adhesion bands were induced by intraperitoneal injection of 3 ml of 10% sterile talc solution in 64 male albino rats. The first group served as the control group. The second one received oral Prednisolone (1 mg/kg/day), the third received Everolimus (0.1 mg/kg/day), and group four received both drugs with similar dosages for four consecutive weeks. The formation of adhesion bands was qualitatively graded according to the Nair classification. The rats in the control group had extensive adhesions between the abdominal wall and the organs. Regarding substantial adhesion formation, 50% (8/16) of animals in the control group had substantial adhesions, while this rate in the groups receiving Prednisolone, Everolimus, and combination treatment was 31%, 31%, and 31%, respectively. Also, 68.75% (5/11) of the Prednisolone recipients had insubstantial adhesions, the same as Everolimus recipients, while in the combination group, 66.66% (10/15) rats had insubstantial adhesions. Everolimus demonstrated satisfactory results in reducing the rates of induced peritoneal adhesion in an experimental model, similar to Prednisolone and superior to a combination regime.

Inhibition of chemokine receptor CXCR2 attenuates postoperative peritoneal adhesion formation.

BACKGROUND: Postoperative peritoneal adhesions remain a problem after general and gynecological surgery. METHODS: Hematoxylin and eosin and Masson's trichrome staining of ischemic buttons were performed 6, 12, 24 hours, and 7 days after button induction. Scanning electron microscopy, ribonucleic acid sequencing, quantitative real-time polymerase chain reaction, immunohistochemical staining, and flow cytometry were used to elucidate the pathophysiology of postoperative peritoneal adhesions. RESULTS: The results showed that thickening of the peritoneum and abscission of mesothelial cells and collagen fibers increased significantly on the surface of the "button" in the control groups at 24 hours postoperatively. Scanning electron microscopy revealed a large number of granulocytes on the button surface in the control group at 24 hours. Ribonucleic acid sequencing and quantitative real-time polymerase chain reaction also revealed that CXCR2 expression was significantly upregulated. In addition, danirixin, a CXCR2 inhibitor, reduced abdominal adhesion in the injured area by inhibiting the infiltration of inflammatory cells and collagen production. Immunohistochemical staining showed decreased expression of CXCR2 in the adhesion area 7 days after surgery in the treatment group. Flow cytometry showed a significantly decreased neutrophil ratio in the treatment group compared with that in the control group 24 hours after the operation. CONCLUSIONS: Inflammation plays an important role in the early stages of postoperative peritoneal adhesion formation, whereas collagen fibers and angiogenesis play important roles in the late stages. The CXCL2-CXCL3-CXCR2 signaling axis is an important link in the mechanism of postoperative peritoneal adhesion formation, and the application of CXCR2 inhibitors can alleviate the formation of postoperative peritoneal adhesions.

Mechanisms and Therapeutic Approaches for Peritoneal Adhesions: A Comprehensive Review.

Peritoneal adhesions are responsible for several and sometimes severe clinical phenotypes remaining a major problem for many patients today. Adhesions are formed within the peritoneal cavity as a result of surgery, inflammation, or injury and can cause a range of clinical symptoms, including abdominal pain, small bowel obstruction, infertility, and other complications. The incidence of peritoneal adhesions remains high as it is estimated that more than 50% of patients who undergo abdominal surgery will develop adhesions. Although advancements in surgical techniques and perioperative management have been developed, the risk of adhesion formation cannot be eliminated, and thus, the development of effective prevention strategies and treatments remains a priority in the field of surgery. In this review, we summarize the cellular and molecular mechanisms involved in the peritoneal adhesions, but also the experimental therapy approaches that have been investigated toward a solution to their possible clinical phenotypes.

The preventive effect of omega-3 fish oil on peritoneal adhesion formation.

INTRODUCTION: Postoperative peritoneal adhesions formed after abdominal surgery still continue to exist as an unresolved health problem. AIM: The aim of the present study is to examine whether omega -3 fish oil has a preventive effect on postoperative peritoneal adhesions. METHODS: Twenty-one female Wistar-Albino rats were separated into 3 groups (sham, control, and experimental group), each consisting of 7 rats. In sham group, only laparotomy was performed. Both in control and experimental group rats; the right parietal peritoneum and cecum were traumatized to form petechiae. Following this procedure, unlike the control group, the abdomen was irrigated with omega-3 fish oil in the experimental group. Rats were re-explored on the 14th postoperative day and adhesions were scored. Tissue samples and blood samples were taken for histopathological and biochemical analysis. RESULTS: None of the omega-3 fish oil given rats developed macroscopically postoperative peritoneal adhesion (P=0.005). Omega-3 fish oil formed an anti-adhesive lipid barrier on injured tissue surfaces. Microscopic evaluation revealed diffuse inflammation with excessive connective tissue and fibroblastic activity in control group rats while foreign body reactions were common in omega-3 given rats. The mean amount of hydroxyproline in samples from injured tissues was significantly lower in omega-3 given rats than in control rats. (P=0.004). CONCLUSION: Intraperitoneal application of omega-3 fish oil prevents postoperative peritoneal adhesions by forming an anti-adhesive lipid barrier on injured tissue surfaces. However, further studies are needed to determine whether this adipose layer is permanent or will be resorbed over time.

The preventive effect of omega-3 fish oil on the formation of peritoneal adhesions.

<br><b>Introduction:</b> Postoperative peritoneal adhesions that form after abdominal surgery still continue to exist as an unresolved health problem.</br> <br><b>Aim:</b> The aim of the study is to examine whether omega-3 fish oil has a preventive effect on postoperative peritoneal adhesions.</br> <br><b>Material and methods:</b> Twenty-one female Wistar albino rats were separated into 3 groups (sham, control and experimental), each consisting of 7 rats. In the sham group, only laparotomy was performed. In both the control and experimental group rats, the right parietal peritoneum and cecum were traumatised to form petechiae. Following this procedure, the abdomen was irrigated with omega-3 fish oil in the experimental group. The rats were re-explored on the 14^th postoperative day and any adhesions were scored. Tissue samples and blood samples were taken for histopathological and biochemical analysis.</br> <br><b>Results:</b> None of the rats that were administered omega-3 fish oil developed macroscopic postoperative peritoneal adhesions (P = 0.005). The omega-3 fish oil formed an anti-adhesive lipid barrier on the injured tissue surfaces. Microscopic evaluation revealed diffuse inflammation with excessive connective tissue and fibroblastic activity in the control group rats, while foreign body reactions were common in the omega-3 rats. The mean amount of hydroxyproline in samples from injured tissues was significantly lower in the omega-3 rats than in the control rats (P = 0.004).</br> <br><b>Conclusion:</b> Intraperitoneal application of omega-3 fish oil prevents postoperative peritoneal adhesions by forming an anti-adhesive lipid barrier on injured tissue surfaces. However, further studies are needed to determine whether this adipose layer is permanent or will be resorbed over time.</br>.

Comparison of Oral Sirolimus, Prednisolone, and Combination of Both in Experimentally Induced Peritoneal Adhesion.

INTRODUCTION: Peritoneal adhesion formation is a challenging postoperative complication. We aim to evaluate the effect of orally administered sirolimus, prednisolone, and their combination to prevent this entity. METHODS: Eighty female albino underwent intraperitoneal injection of 3 mL of 10% sterile talc solution to induce peritoneal adhesion, and were subsequently and randomly divided into four groups (each n = 20); including a control group; 1 mg/kg oral prednisolone daily in the morning; 0.1 mg/kg oral sirolimus daily; and a combination group which received both drugs, with the same dosage. On the 29th day, abdominal cavities were explored, and classification was done based on Nair classification. RESULTS: All rats were healthy on the 29th day, in which exploration was performed. The rats in the control group had extensive intra-abdominal adhesions, while 17 (85%) rats in the control group had substantial adhesion; however, the prednisolone, sirolimus, and combination group had lesser adhesion formation. Also, 14 (70%) rats of prednisolone group, 13 (65%) of sirolimus group, and 16 (80%) of combination group had insubstantial adhesion. The decrease in the grade of peritoneal adhesion bands was highly significant in the combination group (P > 0.001). CONCLUSIONS: The combination of sirolimus and prednisolone was effective for preventing peritoneal adhesions in rats.

Immunoregulation by type I interferons in the peritoneal cavity.

The peritoneal cavity, a fluid-containing potential space surrounding the abdominal and pelvic organs, is home to a rich network of immune cells that maintain tissue homeostasis and provide protection against infection. However, under pathological conditions such as peritonitis, endometriosis, and peritoneal carcinomatosis, the peritoneal immune system can become dysregulated, resulting in nonresolving inflammation and disease progression. An enhanced understanding of the factors that regulate peritoneal immune cells under both homeostatic conditions and in disease contexts is therefore required to identify new treatment strategies for these often life-limiting peritoneal pathologies. Type I interferons (T1IFNs) are a family of cytokines with broad immunoregulatory functions, which provide defense against viruses, bacteria, and cancer. There have been numerous reports of immunoregulation by T1IFNs within the peritoneal cavity, which can contribute to both the resolution or propagation of peritoneal disease states, depending on the specifics of the disease setting and local environment. In this review, we provide an overview of the major immune cell populations that reside in the peritoneal cavity (or infiltrate it under inflammatory conditions) and highlight their contribution to the initiation, progression, or resolution of peritoneal diseases. Additionally, we will discuss the role of T1IFNs in the regulation of peritoneal immune cells, and summarize the results of laboratory studies and clinical trials which have investigated T1IFNs in peritonitis/sepsis, endometriosis, and peritoneal carcinomatosis.

Nintedanib, a multitarget tyrosine kinase inhibitor, suppresses postoperative peritoneal adhesion formation in a rat model.

BACKGROUND: Nintedanib is an antifibrotic agent approved by the United States Food and Drug Administration for the treatment of lung fibrosis. This study aimed to evaluate the efficacy of nintedanib for the prevention of postoperative peritoneal adhesion formation in a rat model. METHODS: Eighteen female Sprague-Dawley rats underwent peritoneal ischemic button creation to induce peritoneal adhesion formation and were randomly allocated to receive 1 mL saline, 50 mg/kg nintedanib, or 100 mg/kg nintedanib by gavage once daily for 7 days. Peritoneal adhesion evaluation and histological and immunochemical examinations were performed on postoperative day 7. Twelve additional Sprague-Dawley rats underwent ileal resection and anastomosis and were randomized to receive saline or 100 mg/kg nintedanib by gavage once daily for 7 days. Anastomotic bursting pressure was assessed on postoperative day 7. RESULTS: All rats survived until death 7 days after surgery without complications. Peritoneal adhesion incidence, quality, and tenacity were lower in both nintedanib groups than in the saline group (P < .01), but no differences were found between the 2 nintedanib groups (P > .05). Histological and immunochemical results demonstrated less inflammation, fibrosis, collagen, and cell proliferation and fewer myofibroblasts in the ischemic buttons treated with 50 mg/kg or 100 mg/kg nintedanib than in those treated with saline (P < .01), but no difference was found between the 2 nintedanib groups (P > .05). Anastomotic bursting pressures were not significantly different between the saline and nintedanib groups (P > .05). CONCLUSION: Nintedanib is effective for the prevention of postoperative peritoneal adhesion formation in a rat model.

Salvia miltiorrhiza hydroalcoholic extract inhibits postoperative peritoneal adhesions in rats.

BACKGROUND: One of the most prevalent postoperative complications is believed to be intra-abdominal peritoneal adhesions, which is followed by several complications. Several adhesion prevention products have been examined, yet none of them were found to be completely effective. The current research is conducted to evaluate the beneficial effects of Salvia miltiorrhiza hydroalcoholic extract in inhibiting postoperative peritoneal adhesions in rats. METHODS: Forty rats were randomly classified into five equal groups (n = 8): 1) the normal group did not undergo surgical operations, 2) the control group in which the adhesion was induced, and which did not receive any treatment, 3) distilled water group that received distilled water, and 4,5) treatment groups treated with 1 and 5% of Salvia miltiorrhiza hydroalcoholic extract. The rats were euthanized 14 days following the surgery and the macroscopic score, the microscopic score of granulomatous inflammation and granulation tissue formation, IHC markers (vimentin, CD31, IL-1ß, COX-2, and iNOS), and oxidative stress biomarkers (MDA, GPx, CAT, and TAC) were assessed in the experimental groups of the study. RESULTS: The difference between the control group and other groups for the adhesions macroscopic score, microscopic score, IHC markers, and oxidative stress biomarkers was significant (p < 0.05). Distilled water had no protective effect on the formation of peritoneal adhesions. Salvia miltiorrhiza treatment in two different doses significantly reduced macroscopic and microscopic scores, MDA concentration, Vimentin, IL-1ß, COX-2, and iNOS compared to the control group (p < 0.05). The levels of GPx, CAT, and TAC in the treatment groups increased significantly compared with the control group (p < 0.05). Our findings revealed that a higher dose of Salvia miltiorrhiza was more effective in reducing peritoneal adhesions, proinflammatory and mesenchymal cell markers, and oxidative stress. CONCLUSIONS: Salvia miltiorrhiza extract, owing to its strong antioxidant and anti-inflammatory properties, could effectively reduce peritoneal adhesions. Therefore, Salvia miltiorrhiza is recommended to be used as an effective anti-peritoneal post-operative adhesive agent.

Postoperative peritoneal adhesion: an update on physiopathology and novel traditional herbal and modern medical therapeutics.

Postoperative peritoneal adhesion (PPA) is a serious clinical condition that affects the high percentage of patients after abdominal surgery. In this review, we have tried to focus on pathophysiology and different underlying signal pathways of adhesion formation based on recent progress in the molecular and cellular mechanisms. Also, the strategies, developed based on traditional herbal and modern medicines, to prevent and treat the PPA via regulation of the molecular mechanisms were investigated. The search engines such as Google Scholar, PubMed, Scopus, and Science Direct have been used to evaluate the current literature related to the pathogenesis of adhesion formation and novel products. Recently, different mechanisms have been defined for adhesion formation, mainly categorized in fibrin formation and adhesion fibroblast function, inflammation, and angiogenesis. Therefore, the suppression of these mechanisms via traditional and modern medicine has been suggested in several studies. While different strategies with encouraging findings have been developed, most of the studies showed contradictory results and were performed on animals. The herbal products have been introduced as safe and effective agent which can be considered in future preclinical and clinical studies. Although a wide range of therapeutics based on traditional and modern medicines have been suggested, there is no agreement in the efficacy of these methods to prevent or treat adhesion formation after surgeries. Further basic and clinical researches are still needed to propose the efficiency of recommended strategies for prevention and treatment of PPA.

Fouling-resistant zwitterionic polymers for complete prevention of postoperative adhesion.

Postoperative adhesions are most common issues for almost any types of abdominal and pelvic surgery, leading to adverse consequences. Pharmacological treatments and physical barrier devices are two main approaches to address postoperative adhesions but can only alleviate or reduce adhesions to some extent. There is an urgent need for a reliable approach to completely prevent postoperative adhesions and to significantly improve the clinical outcomes, which, however, is unmet with current technologies. Here we report that by applying a viscous, cream-like yet injectable zwitterionic polymer solution to the traumatized surface, postoperative adhesion was completely and reliably prevented in three clinically relevant but increasingly challenging models in rats. The success rate of full prevention is over 93% among 42 animals tested, which is a major leap in antiadhesion performance. Clinically used Interceed film can hardly prevent the adhesion in any of these models. Unlike current antiadhesion materials serving solely as physical barriers, the "nonfouling" zwitterionic polymer functioned as a protective layer for antiadhesion applications with the inherent benefit of resisting protein/cell adhesions. The nonfouling nature of the polymer prevented the absorption of fibronectins and fibroblasts, which contribute to the initial and late-stage development of the adhesion, respectively. This is the key working mechanism that differentiated our "complete prevention" approach from current underperforming antiadhesion materials. This work implies a safe, effective, and convenient way to fully prevent postoperative adhesions suffered by current surgical patients.

The novel mechanism of valproate to prevent peritoneal adhesion formation.

PURPOSE: A novel pharmacological mechanism of valproate was analyzed using a hamster model of adhesion. METHODS: Valproate or placebo was administered just after cecal injury and adhesion severity scores and histological were analyzed. RESULTS: The adhesion severity scores in the placebo- and valproate-treated groups were 2.67 ± 0.42 and 1.0 ± 0.37, respectively, with a significant difference between the groups. A significant increase in mast cell numbers was observed in the placebo-treated group vs. the sham-operated group; however, the mast cell number in the adhesive lesion was significantly lower in the valproate-treated group than in the placebo-treated group. The number of cells positive for chymase, an enzyme in mast cells, in the adhesive lesion was significantly higher in the placebo-treated group, but its increase was attenuated significantly by treatment with valproate. The myeloperoxidase gene expression level in the cecum was significantly higher in the placebo-treated group than in the sham-operated group, but there was no significant difference in the myeloperoxidase gene expression level between the sham-operated and valproate-treated groups in. In an in vitro experiment, valproate inhibited purified human and hamster chymases dose-dependently. CONCLUSION: The chymase inhibitory effect of valproate may contribute to prevent adhesion formation after abdominal injury.

Sodium aescinate significantly suppress postoperative peritoneal adhesion by inhibiting the RhoA/ROCK signaling pathway.

BACKGROUND: Although mechanical barriers and modern surgical techniques have been developed to prevent postoperative adhesion formation, high incidence of adhesions still represents an important challenge in abdominal surgery. So far, there has been no available therapeutic drug in clinical practice. PURPOSE: In this study, we explored the efficacy of sodium aescinate (AESS) treatment against postoperative peritoneal adhesions, the potential molecular mechanism was also investigated. STUDY DESIGN AND METHODS: Sixty male Sprague-Dawley rats were randomly divided into 6 groups for the study: the blank, vehicle, positive control and three AESS administration groups (0.5, 1 and 2 mg/kg/d, intravenous administration for 7 days). Adhesions were induced by discretely ligating peritoneal sidewall. An IL-1ß-induced HMrSV5 cell model was also performed to explore possible functional mechanism. RESULTS: The results indicated that the incidence and severity of peritoneal adhesions were significantly lower in the AESS-treated groups than that in the vehicle and positive control group. AESS-treated groups showed that the secretion, activity, and expression of tPA in rat peritoneum were notably increased. The FIB levels in rat plasma were decreased. The immunohistochemical staining analysis demonstrated that collagen I and α-SMA deposition were significantly attenuated in AESS-treated peritoneal tissues. Besides, we found that AESS treatment reduced the protein levels of p-MYPT1. To further explore the mechanisms of AESS, both activator and inhibitors of RhoA/ROCK pathway were employed in this study. It was found that AESS-induced up-regulation of tPA was reversed by activator of ROCK, but the effects of ROCK inhibitors were consistent with AESS. CONCLUSION: Taken together, the findings of in vivo and in vitro experiments proved that AESS could significantly suppress postoperative peritoneal adhesion formation through inhibiting the RhoA/ROCK signaling pathway. Our researches provide important pharmacological basis for AESS development as a potential therapeutic agent on peritoneal adhesions.

Randomized clinical trial of the effect of intraoperative humidified carbon dioxide insufflation in open laparotomy for colorectal resection.

BACKGROUND: Animal studies have shown that peritoneal injury can be minimized by insufflating the abdominal cavity with warm humidified carbon dioxide gas. METHODS: A single-blind RCT was performed at a tertiary colorectal unit. Inclusion criteria were patient aged 18 years and over undergoing open elective surgery. The intervention group received warmed (37°C), humidified (98 per cent relative humidity) carbon dioxide (WHCO2  group). Multiple markers of peritoneal inflammation and oxidative damage were used to compare groups, including cytokines and chemokines, apoptosis, the 3-chlorotyrosine/native tyrosine ratio, and light microscopy on peritoneal biopsies at the start (T0 ) and end (Tend ) of the operation. Postoperative clinical outcomes were compared between the groups. RESULTS: Of 40 patients enrolled, 20 in the WHCO2 group and 19 in the control group were available for analysis. A significant log(Tend /T0 ) difference between control and WHCO2 groups was documented for interleukin (IL) 2 (5·3 versus 2·8 respectively; P = 0·028) and IL-4 (3·5 versus 2·0; P = 0·041), whereas apoptosis assays documented no significant change in caspase activity, and similar apoptosis rates were documented along the peritoneal edge in both groups. The 3-chlorotyrosine/tyrosine ratio had increased at Tend by 1·1-fold in the WHCO2 group and by 3·1-fold in the control group. Under light microscopy, peritoneum was visible in 11 of 19 samples from the control group and in 19 of 20 samples from the WHCO2 group (P = 0·006). The only difference in clinical outcomes between intervention and control groups was the number of days to passage of flatus (2·5 versus 5·0 days respectively; P = 0·008). CONCLUSION: The use of warmed, humidified carbon dioxide appears to reduce some markers related to peritoneal oxidative damage during laparotomy. No difference was observed in clinical outcomes, but the study was underpowered for analysis of surgical results. Registration number: NCT02975947 ( www.ClinicalTrials.gov/).

ANTECEDENTES: Los estudios en animales han demostrado que la lesión peritoneal se puede minimizar insuflando gas de dióxido de carbono caliente y humidificado (warm, humidified carbon dioxide gas,WHCO2(g) ) en la cavidad abdominal. El objetivo de este ensayo fue investigar los marcadores de inflamación peritoneal y de daño oxidativo en pacientes sometidos a cirugía colorrectal y abdominal tratados dióxido de carbono calentado humidificado en comparación con controles. El objetivo secundario fue evaluar los resultados clínicos perioperatorios. MÉTODOS: Se llevó a cabo un ensayo aleatorizado, controlado y simple ciego en una unidad colorrectal terciaria. Se incluyeron pacientes de > 18 años de edad sometidos operaciones electivas por vía abierta. El grupo de intervención recibió CO2(g) calentado (37°C) y humidificado (98% humedad relativa). Para la comparación de los grupos, se determinaron múltiples marcadores de inflamación peritoneal y daño oxidativo, incluyendo citocinas y quimiocinas, apoptosis (actividad Caspasas -3 y -7 y DeadEndTM TUNEl sistema fluorométrico), la tasa 3-clorotirosina/tirosina nativa (HPLC-MS) y microscopía electrónica de biopsias peritoneales al inicio (T0 ) y al término (Tfinal ) de la operación. Los resultados clínicos postoperatorios se compararon entre los grupos. RESULTADOS: De los 40 pacientes incluidos en el estudio, se dispuso de datos para el análisis en 20 pacientes asignados al grupo de CO2 y en 19 asignados al grupo control. Se observó una diferencia significativa Log(Tend/T0) entre los grupos respecto a IL-2 (grupo control: 5,34, grupo CO2: 2,78, P = 0,028) y IL-4 (grupo control: 3,53, grupo CO2: 2,00, P = 0,04), en tanto que los análisis relativos a la apoptosis no pusieron de manifiesto cambios significativos en la actividad de la caspasa, y se observaron tasas de apoptosis similares a lo largo del borde peritoneal en ambos grupos. La tasa 3-clorotirosina/tirosina nativa aumentó en 1,05 veces en el grupo del CO2 y en 3,1 veces en el grupo control. Por microscopía óptica el peritoneo era visible en el 57,9% de los sujetos del grupo control y en el 95% de los que recibieron tratamiento con WHCO2(g) (P = 0,006). La única diferencia en los resultados clínicos entre los grupos de intervención y control fue el número de días para el paso de gases (2,5 en el grupo de CO2 versus 5,0 días en el grupo control, P = 0,008). CONCLUSIÓN: El uso de WHCO2(g) parece disminuir algunos de los marcadores relacionados con el daño peritoneal por estrés oxidativo durante la laparotomía. Aunque no se observaron diferencias en los resultados clínicos, el estudio no tenía la suficiente potencia para analizar los resultados quirúrgicos.

The effect of Punica granatum L. flower extract on post-surgical peritoneal adhesions in a rat model.

OBJECTIVE: Peritoneal adhesions may develop after every abdominopelvic surgery. Many agents and technical modifications have been investigated to minimize adhesions. Punica granatum (pomegranate) flower has some anti-inflammatory and antioxidative effects that would reduce the formation of peritoneal adhesions. In the present study, the effects of different doses of oral Punica granatum flower extract on postoperative peritoneal adhesions were evaluated in a rat model. STUDY DESIGN: Thirty-two female Wistar rats were divided into four groups: one control group (CG) and three experimental groups, treated with 100 (EG100), 200 (EG200), and 400 (EG400) mg/kg/day Punica granatum extract orally for eight days. Induction of peritoneal adhesions was done in all groups using the same method. Two weeks after the first surgery, all rats re-operated and adhesions were evaluated via both macroscopic and microscopic changes. RESULTS: We observed that rats in the control group had statistically higher adhesion area and more severe adhesions when compared to all experimental groups. Besides, those in the EG-400 group had a significantly lower rate of foreign body reaction in serosal layer when compared to the other three study groups. Other microscopic findings were comparable between the four groups. CONCLUSION: Administration of the oral Punica granatum flower extract was associated with a decreased quantity and quality of the adhesions in the animal model of rat in this study. This therapy might be an effective and safe strategy to reduce intraperitoneal adhesion after abdominal surgeries in animal models.

Experimental fortification of intestinal anastomoses with nanofibrous materials in a large animal model.

Anastomotic leakage is a severe complication in gastrointestinal surgery. It is often a reason for reoperation together with intestinal passage blockage due to formation of peritoneal adhesions. Different materials as local prevention of these complications have been studied, none of which are nowadays routinely used in clinical practice. Nanofabrics created proved to promote healing with their structure similar to extracellular matrix. We decided to study their impact on anastomotic healing and formation of peritoneal adhesions. We performed an experiment on 24 piglets. We constructed 3 hand sutured end-to-end anastomoses on the small intestine of each pig. We covered the anastomoses with a sheet of polycaprolactone nanomaterial in the first experimental group, with a sheet of copolymer of polylactic acid with polycaprolactone in the second one and no fortifying material was used in the Control group. The animals were sacrificed after 3 weeks of observation. Clinical, biochemical and macroscopic signs of anastomotic leakage or intestinal obstruction were monitored, the quality of the scar tissue was assessed histologically, and a newly developed scoring system was employed to evaluate the presence of adhesions. The material is easy to manipulate with. There was no mortality or major morbidity in our groups. No statistical difference was found inbetween the groups in the matter of level of peritoneal adhesions or the quality of the anastomoses. We created a new adhesion scoring system. The material appears to be safe however needs to be studied further to prove its' positive effects.

Prevention of Peritoneal Adhesions by Non-Thermal Dielectric Barrier Discharge Plasma Treatment on Mouse Model: A Proof of Concept Study.

Purposes: Formation of peritoneal adhesions is a common consequence of abdominopelvic surgeries and remarkably increases the mortality and morbidity. Moreover, peritoneal adhesions linked to chronic abdominopelvic pain and infertility in women. Various attempts for prevention of peritoneal adhesions were reported. However, these methods either remain insufficient to prevent formation of peritoneal adhesions or carry some practical limitations and thus, there is a need for novel techniques that could effectively decrease the formation of peritoneal adhesions. The aim of the present prospective, randomized, controlled, and single blinded study was to evaluate the effect of non-thermal atmospheric plasma (NTAP) treatment on prevention of peritoneal adhesions. Materials and Methods: Sixteen male CD-1 mice were randomly divided into two groups: control and plasma. Excisional and abrasion adhesion models were generated on the peritoneal side wall and cecum, respectively. Ten days after creating adhesion models, mice were sacrificed and adhesion formations were evaluated macroscopically using Knightly's and Linsky's grading systems to assess the intensity and extent of adhesions, respectively. Zühlke's grading system was used for microscopic assessment of adhesions. Results: The mean scores for peritoneum and cecum in control group according to Knightly's grading system were determined as 3.3 and 2.6, respectively. In NTAP-treated group, Knightly's score was determined as 1.6 and 0.5 for peritoneum and cecum, respectively. NTAP treatment reduced Linsky's score from 3.8 to 1.3 and 2.1 to 1.1 on peritoneum and cecum. Finally, in microscopic evaluation, NTAP treatment reduced Zühlke's score from 3.4 to 1.5 and 2.6 to 1.3 for peritoneum and cecum, respectively. Conclusions: The results of the present proof of concept study suggest that NTAP could be a novel method to reduce and/or prevent the formation of peritoneal adhesions after abdominopelvic surgeries.

Preperitoneal Fat Grafting Inhibits the Formation of Intra-abdominal Adhesions in Mice.

BACKGROUND: Adhesion formation contributes to postoperative complications in abdominal and gynaecological surgery. Thus far, the prevention and treatment strategies have focused on mechanical barriers in solid and liquid form, but these methods are not in routine use. As autologous fat grafting has become popular in treatment of hypertrophic scars because of its immunomodulatory effects, we postulated that fat grafting could also prevent peritoneal adhesion through similar mechanisms. METHODS: This was a control versus intervention study to evaluate the effect of fat grafting in the prevention on peritoneal adhesion formation. An experimental mouse model for moderate and extensive peritoneal adhesions was used (n = 4-6 mice/group). Adhesions were induced mechanically, and a free epididymal fat graft from wild type or CAG-DsRed mice was injected preperitoneally immediately after adhesion induction. PET/CT imaging and scaling of the adhesions were performed, and samples were taken for further analysis at 7 and 30 days postoperation. Macrophage phenotyping was further performed from peritoneal lavage samples, and the expression of inflammatory cytokines and mesothelial layer recovery were analysed from peritoneal tissue samples. RESULTS: Fat grafting significantly inhibited the formation of adhesions. PET/CT results did not show prolonged inflammation in any of the groups. While the expression of anti-inflammatory and anti-fibrotic IL-10 was significantly increased in the peritoneum of the fat graft-treated group at 7 days, tissue-resident and repairing M2 macrophages could no longer be detected in the fat graft at this time point. The percentage of the continuous, healed peritoneum as shown by Keratin 8 staining was greater in the fat graft-treated group after 7 days. CONCLUSIONS: Fat grafting can inhibit the formation of peritoneal adhesions in mice. Our results suggest that fat grafting promotes the peritoneal healing process in a paracrine manner thereby enabling rapid regeneration of the peritoneal mesothelial cell layer.

The effect of Allium sativum in experimental peritoneal adhesion model in rats.

PURPOSE: To evaluate the effect of garlic on formation of postoperative adhesions in rats. METHODS: Twenty-four Sprague dawley rats were divided into three groups. In Group 1 (sham), laparotomy was performed and stitched up. In Group 2 (control), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and 2 cc of saline was intraperitoneally administered to each rat. In Group 3 (experimental), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered a sterile Allium sativum derivative. The rats in all groups were re-laparotomized on postoperative day 7; samples were obtained from the peritoneal tissue surrounding the cecum. RESULTS: In Group 3, there was a statistically significant difference in terms of inflammation, lymph node size, and free oxygen radicals; these parameters tended to increase. In terms of fibrosis evaluated using H&E and MT, there was no significant difference between groups 2 and 3. CONCLUSIONS: No positive outcomes indicating that Allium sativum reduces intra-abdominal adhesions were obtained. However, it caused severe inflammation in the tissue. Additionally, in immunohistochemical analyses conducted to detect oxidative stress, allium sativum increased the production of free oxygen radicals in the tissue.

Adhesion reformation and the limited translational value of experiments with adhesion barriers: A systematic review and meta-analysis of animal models.

Today, 40-66% of elective procedures in general surgery are reoperations. During reoperations, the need for adhesiolysis results in increased operative time and a more complicated convalescence. In pre-clinical evaluation, adhesion barriers are tested for their efficacy in preventing 'de novo' adhesion formation, However, it is unknown to which extent barriers are tested for prevention of adhesion reformation. The aim of this systematic review and meta-analysis is to assess the efficacy of commercially available adhesion barriers and laparoscopic adhesiolysis in preventing adhesion reformation in animal models. Pubmed and EMBASE were searched for studies which assessed peritoneal adhesion reformation after a standardized peritoneal injury (in the absence of an intra-peritoneal mesh), and reported the incidence of adhesions, or an adhesion score as outcome. Ninety-three studies were included. No study met the criteria for low risk of bias. None of the commercially available adhesion barriers significantly reduced the incidence of adhesion reformation. Three commercially available adhesion barriers reduced the adhesion score of reformed adhesions, namely Seprafilm (SMD 1.38[95% CI]; p < 0.01), PEG (SMD 2.08[95% CI]; p < 0.01) and Icodextrin (SMD 1.85[95% CI]; p < 0.01). There was no difference between laparoscopic or open adhesiolysis with regard to the incidence of adhesion reformation (RR 1.14[95% CI]; p ≥ 0.05) or the adhesion score (SMD 0.92[95% CI]; p ≥ 0.05). Neither currently commercially available adhesion barriers, nor laparoscopic adhesiolysis without using an adhesion barrier, reduces the incidence of adhesion reformation in animal models. The methodological quality of animal studies is poor.