Prevention Of Postoperative Abdominal Adhesions Research Articles

ROS-responsive sprayable hydrogel as ROS scavenger and GATA6+ macrophages trap for the prevention of postoperative abdominal adhesions

Postoperative abdominal adhesions are a common clinical problem after surgery and can cause many serious complications. Current most commonly used antiadhesion products are less effective due to their short residence time and focus primary on barrier function. Herein, we developed a sprayable hydrogel barrier (sHA-ADH/OHA-E) with self-regulated drug release based on ROS levels at the trauma site, to serve as a smart inflammatory microenvironment modulator and GATA6+ macrophages trap for non-adherent recovery from abdominal surgery. Sulfonated hyaluronic acid (HA) conjugates modified with adipic dihydrazide (sHA-ADH), and oxidized HA conjugates grafted with epigallocatechin-3-gallate (EGCG) via ROS-cleavable boronate bonds (OHA-E) were synthesized. sHA-ADH/OHA-E hydrogel was facilely fabricated within 5 s after simply mixing sHA-ADH and OHA-E through forming dynamic covalent acylhydrazones. With good biocompatibility, appropriate mechanical strength, tunable shear-thinning, self-healing, asymmetric adhesion, and reasonable in vivo retention time, sHA-ADH/OHA-E hydrogel meets the requirements of a perfect physical barrier. Intriguingly, sulfonic acid groups endowed the hydrogel with satisfactory anti-fibroblast and macrophage attachment capability, and were demonstrated for the first time to act as polyanion traps to prevent GATA6+ macrophages aggregation. Importantly, EGCG could be intelligently released by ROS triggering to alleviate oxidative stress and promote proinflammatory M1 macrophage polarize to antiinflammatory M2 phenotype. Further, the fibrinolytic system balance was restored to reduce fibrosis. Thanks to the above advantages, the sHA-ADH/OHA-E hydrogel exhibited excellent anti-adhesion effects in a rat sidewall defect–cecum abrasion model and is expected to be a promising and clinically translatable antiadhesion barrier.

Controlled Release of a Therapeutic Peptide in Sprayable Surgical Sealant for Prevention of Postoperative Abdominal Adhesions.

Formation of asymmetric, rigid scar tissue known as surgical adhesions is caused by traumatic disruption of mesothelial-lined surfaces in surgery. A widely adopted prophylactic barrier material (Seprafilm) for the treatment of intra-abdominal adhesions is applied operatively as a pre-dried hydrogel sheet but has reduced translational efficacy due its brittle mechanical properties. Topically administered peritoneal dialysate (Icodextrin) and anti-inflammatory drugs have failed to prevent adhesions due to an uncontrolled release profile. Hence, inclusion of a targeted therapeutic into a solid barrier host matrix with improved mechanical properties could provide dual utility in adhesion prevention and as a surgical sealant. Spray deposition of poly(lactide-co-caprolactone) (PLCL) polymer fibers through solution blow spinning has yielded a tissue-adherent barrier material with previously reported adhesion prevention efficacy due to a surface erosion mechanism that inhibits deposition of inflamed tissue. However, such an approach uniquely presents an avenue for controlled therapeutic release through mechanisms of diffusion and degradation. Such a rate is kinetically tuned via facile blending of "high" molecular weight (HMW) and "low" molecular weight (LMW) PLCL with slow and fast biodegradation rates, respectively. Here, we explore viscoelastic blends of HMW PLCL (70% w/v) and LMW PLCL (30% w/v) as a host matrix for anti-inflammatory drug delivery. In this work, COG133, an apolipoprotein E (ApoE) mimetic peptide with potent anti-inflammatory properties was selected and tested. In vitro studies with PLCL blends presented low (∼30%) and high (∼80%) percent release profiles over a 14-day period based on the nominal molecular weight of the HMW PLCL component. Two independent mouse models of cecal ligation and cecal anastomosis significantly reduced adhesion severity versus Seprafilm, COG133 liquid suspension, and no treatment control. The synergy of physical and chemical methods in a barrier material with proven preclinical studies highlights the value of COG133-loaded PLCL fiber mats in effectively dampening the formation of severe abdominal adhesions.

NFK prevent postoperative abdominal adhesion through downregulating the TGF-β1 signaling pathway.

Postoperative abdominal adhesions (PAAs) represent a frequent condition occurring in more than 90% of patients undergoing abdomen and pelvic surgeries, which can cause chronic abdominal pain, female infertility, and repeated bowel obstruction, requiring repetitive surgical interventions causing morbidity and mortality, as well as high costs. It is therefore of paramount clinical importance and significance to develop practical and reliable strategies for preventing the occurrence of PAAs. In this study, we demonstrated that Nianfukang (NFK, composed of polyethylene glycol 1450 and diclofenac sodium) is highly effective in preventing PAAs, likely by reducing leukocytes and inflammatory factors in the abdominal cavity, and inhibiting intestinal fibrosis in a rat model of PAAs induced by postoperative cecum scraping. We further uncovered that NFK downregulates the expression of TGF-β1, a key factor for adhesion formation, to suppress the TGF-β1/TGF-βRIII/Smad2 signaling pathway, thereby inhibiting the proliferation and migration of fibroblasts and provided evidences for the involvement of the TGF-β1/TGF-βRIII/Smad2 axis in the prevention of PAAs in normal human colon fibroblast CCD-18Co. Our findings support NFK as a potential anti-adhesive product that has the advantages of significant effectiveness, safety profile, and low cost, as well as clear mechanism of action.

Different doses of enoxaparin in the prevention of postoperative abdominal adhesions. Experimental study

BackgroundPostoperative abdominal adhesions (PAAs) are present in more than 90% of patients undergoing abdominal surgery. They are a cause of chronic pain, hospitalizations, multiple surgeries, and infertility in women of reproductive age. The participation of three processes have been recognized: coagulation, fibrinolysis, and inflammation. The usefulness of subcutaneous enoxaparin in their prevention has been established. The objective is to establish the safest and most efficient dose for PAA prevention by testing five different doses of subcutaneous enoxaparin (0.25, 0.5, 1, 1.5, and 2 mg/kg/day) given in one dose/day for seven days. Material and methodsFifty Sprague-Dawley rats were studied, 10 in each group. Adhesions were induced through controlled rubbing of the cecum and suturing of an incision in the terminal ileum. Two independent observers recorded the degree of adhesion formation at 14 days and histologically studied the adhesions. Statistical analysisANOVA compared group averages. The nonparametric Kruskal-Wallis test was used to identify group differences. ResultsThe 0.5 mg/kg/day group had greater formation of adhesions (p < 0.001). There was no significant difference between the 1.5 and 2 mg/kg/day groups, though the latter group had an incidence of 27.2% of bleeding in the abdominal cavity. The degree of adhesions in the histological sections coincided with the macroscopic findings. The interobserver agreement was kappa = 0.88 (very good). ConclusionThe safe and effective dose of subcutaneous enoxaparin to prevent PAA formation was 0.5–1.5 mg/kg/day for seven days.

PCL covered PP meshes plasma-grafted by sulfonated monomer for the prevention of postoperative abdominal adhesions

Abdominal hernia reparation constitutes the second surgical operation in the world with more than 20 million cases per year. However, in more than 50 % of all intra-abdominal operations, postoperative adhesions occur and result in important pain for patients. These adhesions take place after excessive deposition of fibrin between peritoneum and organs within the 7 days after the operation which occurs during the coagulation cascade. For this reason, therapeutic solutions are required to both prevent adhesion and limit the need for a second surgical step. Numerous techniques were described in the past few decades to design biomedical textile implants and, among them, electrospinning shows great interest due to the porous and nanometer diameter range structure of the obtained fibers. In parallel, cold plasma treatment can be used to activate and graft their surface with functional molecules, exhibiting for example antibacterial or anticoagulant properties. This work aims at functionalizing, biodegradable polycaprolactone (PCL) electrospun nanofibers covering polypropylene meshes (PPM) with 2-acrylamido-2-methylpropane sulfonic acid (AMPS) through cold plasma induced graft copolymerization. AMPS was chosen as it contains heparin-like segments, leading potentially to similar anticoagulant effect. First, electrospinning of PCL was optimized by varying process, solution and environmental parameters and allowed to select a solution of 12 % of PCL in formic/acetic acid mixture. The graft-copolymerization of AMPS was then optimized in terms of power and time of plasma treatment, as well as solution concentration, using experimental design, in order to obtain nanofibers rich in SO3H groups at their surface. At each step of the process, the material was thoroughly characterized proving the presence of AMPS onto the surface of the nanofibers. The cytocompatibility and anticoagulant properties, evaluated after sterilization, are promising for an anti-adhesive application of these nanofibrous mats with no release of cytotoxic compound.

Study on Prevention of Postoperative Abdominal Adhesions with PLGA Nanofiber Membrane

Objective: To evaluate the effectiveness of poly (lactic-co-glycolic acid) (PLGA) nanofiber membrane on prevention of postoperative abdominal adhesion. Methods: PLGA nanofiber membrane was prepared by high-voltage electrospinning technique. The effectiveness of the membrane in prevention of postoperative abdominal adhesions was characterized with rat abdominal adhesion models. Results: PLGA nanofiber membrane was prepared successfully by electrospinning technique. Scanning electron microscopy (SEM) observation showed that the average diameter of PLGA fibers was approximately 800 nm, and the membrane had microporous structures. Mechanical tests showed that the tensile strength of PLGA nanofiber membrane was 6.36 ± 0.39 MPa, which was significantly higher than the tensile strength of DIKANG absorbable medical film. The results of in vivo experiments showed that PLGA nanofiber membrane and DIKANG absorbable medical film could both reduce the degree of abdominal adhesions. The histological results showed that there was only a small extent of inflammatory cell infiltration in the PLGA group and the control group. The proliferation of connective tissue was reduced, and so was the degree of adhesion. Conclusion: PLGA nanofiber membrane can significantly reduce the incidence and severity of postoperative adhesions, and bodes well for future clinical applications.

Postoperative abdominal adhesions: pathogenesis and current preventive techniques.

Post-operative abdominal adhesions (PAA) are a condition that occurs in more than 90% of patients undergoing abdomen surgery; they can cause chronic abdominal pain, female infertility and repeated bowel obstruction, requiring repetitive surgical interventions causing morbidity and mortality, as well as high costs. The formation of the PAA is due to an imbalance between the fibrinogenesis and fibrinolysis in favor of the first, associated with tissue hypoxia secondary to aggression of the peritoneum, also due to the own inflammatory response and the increase in the population of adhesion fibroblasts which inhibit the degradation of the extracellular matrix and facilitate mature collagen and supporting connective tissue. The prevention of PAA will decrease secondary complications, as well as hospitalizations, surgeries and consequently, cost containment. The PAA pathophysiologic process allows establishing research strategies in order to prevent them.

Non-invasive monitoring of in vivo degradation of a radiopaque thermoreversible hydrogel and its efficacy in preventing post-operative adhesions.

While a variety of biomaterials have been extensively studied, it is rare to monitor in vivo degradation and medical efficacy of a material after being implanted deeply into the body. Herein, the radiopaque thermoreversible hydrogel developed by us not only holds desirable performance on the prevention of post-operative abdominal adhesions, but also allows non-invasive monitoring of its in vivo degradation with CT imaging in a real-time, quantitative and three-dimensional manner. The methodology based on CT imaging provides important insights into the in vivo fate of the hydrogel after being deeply implanted into mammals for different biomedical applications and significantly reduces the amount of animals sacrificed.

Exogenous pulmonary surfactant prevents the development of intra-abdominal adhesions in rats.

Intra‐abdominal adhesions are major post‐operative complications for which no effective means of prevention is available. We aimed to evaluate the efficacy of exogenous pulmonary surfactant administration in the prevention of post‐operative abdominal adhesions. Rats were randomly assigned to undergo laparotomy (L) or gastroenterostomy (GE) and then treated with surfactant (groups L‐S and GE‐S, respectively). Intra‐abdominal adhesions, collagen fibre content, metalloproteinase (MMP)‐9, expression of growth factors (TGF‐β, KGF and VEGF), type III procollagen (PCIII) and pro‐caspase 3, as well as isolectin B4 and ED1‐positive cells expressing MMP‐9, were evaluated. Groups treated with surfactant (GE‐S and L‐S) exhibited fewer adhesions. A significant reduction in collagen fibre content was observed in GE‐S compared to GE animals (P < 0.001). In situ and gelatin zymography analysis showed higher MMP‐9 expression and activity in the GE‐S group compared to the GE group (P < 0.05). ED1‐positive cell counts were significantly higher in the GE‐S group (P < 0.001) than in the GE group. Virtually all cells positive for ED1 were MMP‐9+. Double‐labelling of MMP‐9 with IB4 showed no significant differences between GE‐S and GE groups. TGF‐β, KGF, PCIII and pro‐caspase‐3 mRNA expression decreased significantly in GE‐S compared to GE animals (P < 0.05). Surfactant administration also reduced apoptosis in the GE‐S group. These findings suggest that surfactant reduces the intra‐abdominal adhesions triggered by laparotomy and gastrointestinal anastomosis, thus preventing fibrosis formation at the peritoneal surfaces. This preclinical study suggests an innovative treatment strategy for intra‐abdominal adhesions with surfactant and to endorse its putative mechanism of action.

The role of aerosolized intraperitoneal heparin and hyaluronic acid in the prevention of postoperative abdominal adhesions

Intraperitoneal adhesions are a common and serious problem following abdominal surgery. Significant research has been performed to investigate the mechanisms involved; however, this has not influenced the incidence; it is still the leading cause of intestinal obstruction, pelvic pain, and infertility in women. The purpose of this study was to evaluate the ability of aerosolized heparin and hyaluronic acid for the prevention of postoperative adhesions. A survival pig model was employed (N = 40). The pigs underwent laparoscopic insertion of polypropylene mesh to create intraperitoneal adhesions. The animals were randomized into four groups: control (n = 10), aerosolized heparin (n = 10), aerosolized hyaluronic acid (n = 10), and aerosolized mixture of both agents (n = 10). After a 2-week recovery period, the animals were killed and intraperitoneal adhesions were assessed. All of the animals in the control group suffered postoperative adhesions (10/10) compared with three in the heparin group, two in the hyaluronic group, and one in the mixed group. The number of adhesions per animal and the severity was higher in the control group compared with the therapeutic groups. The mean number of adhesions in the affected pigs also was higher in the control group compared with the therapeutic groups: 3.3 versus 0.4 in heparin group (range 0-2) versus 0.3 in hyaluronic acid group versus 0.1 in the mixed group (p = 0.002). This study has shown that aerosolised heparin and hyaluronic acid is an effective method to prevent postoperative adhesions whether they were used independently or in synergism. However, the best result was when both agents mixed together compared with the control. A human-based study will be the next step to confirm the success of these agents.

P.O.P.A. Study: Prevention of Postoperative Abdominal Adhesions by Icodextrin 4% Solution After Laparotomy for Adhesive Small Bowel Obstruction. A Prospective Randomized Controlled Trial

BackgroundAdhesive small bowel obstruction (ASBO) is an important cause of hospital admission, is associated with significant morbidity and mortality, and therefore is a substantial burden for healthcare systems worldwide. Icodextrin 4% solution (Adept, Shire Pharmaceuticals, UK) is a high-molecular-weight a-1,4 glucose polymer approved in Europe for use as intraoperative lavage and postoperative instillation to reduce the occurrence of post-surgery intra-abdominal adhesions. The present clinical study aimed to evaluate the safety and effectiveness of icodextrin 4% in decreasing the incidence, extent, and severity of adhesions in patients after abdominal surgery for ASBO. MethodsThe study was a single-center prospective, randomized investigation. The study is designed and conducted in compliance with the principles of Good Clinical Practice regulations. Safety and efficacy of icodextrin 4% in the study group are compared to no anti-adhesion treatment in a parallel control group with blinded evaluation of primary endpoints. Primary endpoints are the evaluation of the therapeutic role of icodextrin 4% in reducing ASBO recurrence incidence and the need of laparotomies for ASBO recurrence, as well as adhesion formation (with evaluation of their incidence, extent, and severity). A sum of 181 patients with ASBO and surgical indication to laparotomy were enrolled and randomized in two groups. Patients were submitted to adhesiolysis with bowel resection if required with or without anastomosis. The first group received traditional treatment (control group), whereas the second group was treated with the addition of icodextrin 4% solution before the abdominal closure. ResultsNinety-one patients were randomized to have icodextrin 4% solution administered intraperitoneally, and 90 patients were randomized to have the traditional treatment. The two study groups were homogeneous regarding their baseline characteristics. The ASBO recurrence rate was 2.19% (2/91) in the icodextrin groups vs 11.11% (10/90) in the control group after a mean follow-up period of 41.4 months (p < 0.05). No differences were found in the need of laparotomies for ASBO recurrence in the studied groups. The adhesion severity score seems lower in the group treated with the addition of icodextrin (p = n.s.). ConclusionsThe data resulting from this RCT showed that the use of icodextrin 4% solution in ASBO is safe and reduces intra-abdominal adhesion formation and the risk of re-obstruction.

Prospective controlled randomized trial on prevention of postoperative abdominal adhesions by Icodextrin 4% solution after laparotomic operation for small bowel obstruction caused by adherences [POPA study: Prevention of Postoperative Adhesions on behalf of the World Society of Emergency Surgery

BackgroundAdhesive small intestine occlusion [ASIO] is an important cause of hospital admission placing a substantial burden on healthcare systems worldwide. Often times, ASIO is associated with significant morbidity and mortality.Icodextrin 4% solution [Adept, Shire Pharmaceuticals, UK] is a high-molecular-weight a-1,4 glucose polymer that is approved in Europe for use as an intra-operative lavage and a post-operative instillate to reduce the occurrence of post-surgery intra-abdominal adhesions.There are no randomized trials on the use of this solution to prevent adhesions after ASIO operation in current medical literature.The current clinical study evaluates the safety and effectiveness of Icodextrin 4% for decreasing the incidence, extent, and severity of adhesions in patients after abdominal surgery for ASIO.DesignThe study project is a prospective, randomized controlled investigation performed in the Department of Transplant, General and Emergency Surgery of St. Orsola-Malpighi University Hospital [Bologna, Italy]. The study is designed and conducted in compliance with the principles of Good Clinical Practice regulations.The study compares the results of Icodextrin 4% against a control group who does not receive anti-adhesion treatment. This randomized study uses a double-blind procedure to evaluate efficacy end points. In other words, designated third party individuals who are unaware of the treatment assigned to the patients to assess adhesion formation.Trial Registration NumberISRCTN22061989Prospective controlled randomized trial on Prevention of Postoperative Abdominal Adhesions by Icodextrin 4% solution after laparotomic operation for small bowel obstruction caused by adherences[POPA study: Prevention of Postoperative Adhesions]

Prevention of Postoperative Abdominal Adhesions by a Novel, Glycerol/Sodium Hyaluronate/Carboxymethylcellulose-Based Bioresorbable Membrane: A Prospective, Randomized, Evaluator-Blinded Multicenter Study

Prevention of Postoperative Abdominal Adhesions by a Novel, Glycerol/Sodium Hyaluronate/Carboxymethylcellulose-Based Bioresorbable Membrane: A Prospective, Randomized, Evaluator-Blinded Multicenter Study

Novel treatment in peritoneal adhesion prevention: Protection by polypeptides

Objective. To evaluate a novel antiadhesive polypeptide complex containing a combination of poly-L-glutamate and poly-L-lysine in order to study its effectiveness and mechanisms in the prevention of postoperative abdominal adhesions in mice. Material and methods. The length of peritoneal adhesions was measured and expressed in percentage of the wound length in a standardized peritoneal injury model and evaluated 7 days and 4 weeks after adhesion induction. The test compound was administered intraperitoneally following surgery. Peritoneal swabs, including the wound area, were stained in order to determine the peritoneal location and clearance of the polypeptides. Electron microscopy was performed to analyze the wound surface and the ultra-structural changes of the phagocytes in cell culture. Moreover, flow cytometry was used to evaluate the effect on macrophage phagocytic function. Results. The poly-L-lysine and poly-L-glutamate combination significantly decreased peritoneal adhesions both at 7 days’ (p<0.001) and 4 weeks’ (p≤0.001) follow-up. From the first day, the compound was found in the wound, after which this was gradually rebuilt, and covered with mesothelial cells. The macrophages phagocytosed the test compound particles, resulting in significant cell growth, and large phagocytic vacuoles. Conclusions. The intraperitoneal administration of poly-L-lysine and poly-L-glutamate resulted in a significant decrease in experimental postoperative peritoneal adhesions.

Prevention of Postoperative Abdominal Adhesions by a Novel, Glycerol/Sodium Hyaluronate/Carboxymethylcellulose-Based Bioresorbable Membrane: A Prospective, Randomized, Evaluator-Blinded Multicenter Study

Postoperative abdominal adhesions are associated with significant morbidity and mortality, placing a substantial burden on healthcare systems worldwide. Development of a bioresorbable membrane containing up to 23 percent glycerol and chemically modified sodium hyaluronate/carboxymethylcellulose offers ease of handling and has been shown to provide significant postoperative adhesion prevention in animals. This study was designed to assess the safety of glycerol hyaluronate/carboxymethylcellulose and to evaluate its efficacy in reducing the incidence, extent, and severity of postoperative adhesion development in surgical patients. Twelve centers enrolled 120 patients with ulcerative colitis or familial polyposis who were scheduled for a restorative proctocolectomy and ileal pouch-anal anastomosis with diverting loop ileostomy. Before surgical closure, patients were randomized to no anti-adhesion treatment (control) or treatment with glycerol hyaluronate/carboxymethylcellulose membrane under the midline incision. At ileostomy closure, laparoscopy was used to evaluate the incidence, extent, and severity of adhesion formation to the midline incision. Data were analyzed using the intent-to-treat population. Treatment with glycerol hyaluronate/carboxymethylcellulose resulted in 19 of 58 patients (33 percent) with no adhesions compared with 6 of 60 adhesion-free patients (10 percent) in the no treatment control group (P = 0.002). The mean extent of postoperative adhesions to the midline incision was significantly lower among patients treated with glycerol hyaluronate/carboxymethylcellulose compared with patients in the control group (P < 0.001). The severity of postoperative adhesions to the midline incision was significantly less with glycerol hyaluronate/carboxymethylcellulose than with control (P < 0.001). Adverse events were similar between treatment and no treatment control groups with the exception of abscess and incisional wound complications were more frequently observed with glycerol hyaluronate/carboxymethylcellulose. Glycerol hyaluronate/carboxymethylcellulose was shown to effectively reduce adhesions to the midline incision and adhesions between the omentum and small bowel after abdominal surgery. Safety profiles for the treatment and no treatment control groups were similar with the exception of more infection complications associated with glycerol hyaluronate/carboxymethylcellulose use. Animal models did not predict these complications.

Prevention of Postoperative Abdominal Adhesions by Tissue Precoating with Polymer Solutions

Polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC) solutions were evaluated in a rat cecal abrasion model to test, the effect of these high-molecular-weight hydrophilic polymer solutions on postoperative adhesion formation when used as tissue precoating solutions. Eleven groups of 5-20 animals each were studied including 25 control animals treated with Ringer's lactate (RL) solution. Animals were reoperated at 2 weeks and adhesions were scored according to a 0-4 grading scale. Tissue coating following cecal abrasion failed to inhibit adhesion formation. However, tissue coating with polymer solutions prior to cecol abrasion significantly reduced the formation of postoperative adhesions. Solutions of 1.5% CMC and 5% of a unique γ-polymerized PVP in RL, exhibited the greatest tissue-protective behavior compared to RL controls ( P < 0.002). Both CMC and γ-PVP solutions warrant further investigation as tissue precoatings to inhibit surgical adhesions.