Postsurgical Adhesion Formation Research Articles

Neutrophil Extracellular Traps: A Crucial Factor in Post-Surgical Abdominal Adhesion Formation.

Post-surgical abdominal adhesions, although poorly understood, are highly prevalent. The molecular processes underlying their formation remain elusive. This review aims to assess the relationship between neutrophil extracellular traps (NETs) and the generation of postoperative peritoneal adhesions and to discuss methods for mitigating peritoneal adhesions. A keyword or medical subject heading (MeSH) search for all original articles and reviews was performed in PubMed and Google Scholar. It included studies assessing peritoneal adhesion reformation after abdominal surgery from 2003 to 2023. After assessing for eligibility, the selected articles were evaluated using the Critical Appraisal Skills Programme checklist for qualitative research. The search yielded 127 full-text articles for assessment of eligibility, of which 7 studies met our criteria and were subjected to a detailed quality review using the Critical Appraisal Skills Programme (CASP) checklist. The selected studies offer a comprehensive analysis of adhesion pathogenesis with a special focus on the role of neutrophil extracellular traps (NETs) in the development of peritoneal adhesions. Current interventional strategies are examined, including the use of mechanical barriers, advances in regenerative medicine, and targeted molecular therapies. In particular, this review emphasizes the potential of NET-targeted interventions as promising strategies to mitigate postoperative adhesion development. Evidence suggests that in addition to their role in innate defense against infections and autoimmune diseases, NETs also play a crucial role in the formation of peritoneal adhesions after surgery. Therefore, therapeutic strategies that target NETs are emerging as significant considerations for researchers. Continued research is vital to fully elucidate the relationship between NETs and post-surgical adhesion formation to develop effective treatments.

Spatial Transcriptomics Reveals Interaction of Injury-Derived Osteopontin with Mesothelial Cells in Serosal Scarring

Abstract Background Abdominal surgeries are often live-saving procedures. However, surgical interventions in the peritoneal cavity can cause the formation of post-surgical adhesions. These irreversible scar bands can trigger severe complications, such as chronic pelvic pain, small bowel obstruction, and infertility in women. Unfortunately, no effective treatment options for adhesion patients exist. On a cellular level, mesothelium-derived mesenchymal myofibroblasts have been identified as key pro-fibrotic players in adhesion formation. Aims Our aim is to study the molecular mechanisms of mesothelial cell recruitment in serosal repair and scarring, and thereby to identify potential targets for specific pharmacological anti-adhesion treatments. Methods We used a mesothelial cell reporter mouse system (Wt1CreERT2xRosa26tdTomato) and experimental injury models to study the differences of mesothelial cell recruitment to sites of adhesion formation in comparison to wound sites healing scar-free. To answer how injury zones affect the accumulation of mesothelial cells, we used untargeted spatial transcriptomics, identifying candidate molecules that were i) upregulated in adhesion formation sites, ii) not highly expressed in scar-free wound sites, and iii) had the potential to interact with mesothelial cells. Results We observed strong spatiotemporal correlation between accumulation of tdTomato+ cells and consecutive scarring. Spatial deconstruction of scar-specific signaling identified the candidate molecule Secreted phosphoprotein 1; an inflammatory zone-specific gene that encodes Osteopontin (OPN). After confirming increased OPN protein levels 7d post-surgery, we investigated its effect on adhesion formation using Spp1-/- mice. Indeed, Spp1-deficient mice showed significantly lower adhesion scores compared to control mice. Mechanistically, recombinant OPN had no chemotactic effect on primary human mesothelial cells, however triggered the upregulation of transcription factors associated with mesothelial-to-mesenchymal transition. Conclusion Together, these findings suggest a pivotal role for OPN in linking inflammation at injury sites with mesothelial cell recruitment in post-surgical serosal scarring. Therefore, OPN represents a potential target for novel pharmacological strategies to specifically inhibit scarring without affecting normal wound repair.

Avastin-Loaded 3D-Printed Alginate Scaffold as an Effective Antiadhesive Barrier to Prevent Postsurgical Adhesion Bands Formation.

Postoperative adhesion can cause complications, such as pain and organ blockage, in the abdominal regions. To address this issue, surgical techniques and antiadhesive treatments are applied. Given the significant role of vascularization in adhesion band formation, Avastin (Ava) that targets vascular endothelial growth factor (VEGF) can be applied to prevent peritoneal adhesion bands. Moreover, Alginate (Alg), a natural polysaccharide, is a promising physical barrier to prevent adhesion bands. Incorporating Ava into Alg hydrogel in a form of 3D-printed scaffold (Alg/Ava) has potential to suppress inflammation and angiogenesis, leading to reduce peritoneal adhesion bands. Following physical, morphological, and biocompatibility evaluations, the efficacy of Alg and Ava alone and their combination in Alg/Ava on the formation of postsurgical adhesions is evaluated. Upon confirming physical stability and sustained release of Ava, the Alg/Ava scaffold effectively diminishes both the extent and strength of adhesion bands. Histopathological examination shows that the reduction in fibrosis and inflammation is responsible for preventing adhesion bands by the Alg/Ava scaffold. Additionally, the cytokine assessment reveals that this is due to the inhibition in the secretion of VEGF and Interleukin 6 suppressing vascularization and inflammatory pathways. This study suggests that a 3D-printed Alg/Ava scaffold has great potential to prevent the postsurgical adhesion bands.

Injectable Multifunctional Composite Hydrogel as a Combination Therapy for Preventing Postsurgical Adhesion.

Postsurgical adhesion (PA) is a common and serious postoperative complication that affects millions of patients worldwide. However, current commercial barrier materials are insufficient to inhibit diverse pathological factors during PA formation, and thus, highly bioactive materials are needed. Here, this work designs an injectable multifunctional composite hydrogel that can serve as a combination therapy for preventing PA. In brief, this work reveals that multiple pathological events, such as chronic inflammatory and fibrotic processes, contribute to adhesion formation in vivo, and such processes can not be attenuated by barrier material (e.g., hydrogel) alone treatments. To solve this limitation, this work designs a composite hydrogel made of the cationic self-assembling peptide KLD2R and TGF-β receptor inhibitor (TGF-βRi)-loaded mesenchymal stem cell-derived nanovesicles (MSC-NVs). The resulting composite hydrogel displays multiple functions, including physical separation of the injured tissue areas, antibacterial effects, and local delivery and sustained release of anti-inflammatory MSC-NVs and antifibrotic TGF-βRi. As a result, this composite hydrogel effectively inhibited local inflammation, fibrosis and adhesion formation in vivo. Moreover, the hydrogel also exhibits good biocompatibility and biodegradability in vivo. Together, the results highlight that this "all-in-one" composite hydrogel strategy may provide insights into designing advanced therapies for many types of tissue injury.

Mesothelial Cell Recruitment Towards Sites of Post-Surgical Adhesion Formation in the Peritoneal Cavity

Abstract Background Abdominal surgeries are often inevitable and live-saving procedures, however, they can be associated with post-surgical complications, such as the formation of irreversible scar bands called peritoneal adhesions. Adhesions in the peritoneal cavity can lead to serious health burden by causing small bowel obstruction, infertility, and chronic pelvic pain. Unfortunately, no effective treatment for adhesion patients exists today. Mesothelial cells and mesothelial cell-derived mesenchymal myofibroblasts have been identified as key players in the pathogenesis of adhesions, and thus represent a novel target for pharmacological interventions. Aims Our aim is to study the molecular mechanisms of mesothelial cell recruitment towards peritoneal adhesion sites, which could serve as potential drug targets to effectively prevent the formation of adhesions. Methods By exploiting genetic lineage tracing and experimental animal surgery, we have established a surgical-transgenic mouse model system that allows us to study mesothelial cell recruitment during processes of scar-free wound healing and wound healing associated with adhesion formation. To identify candidate molecules predominantly required for the recruitment of mesothelial cells towards adhesion sites, we apply an untargeted transcriptomics-based research strategy (spatial transcriptomics, single cell RNA sequencing). Results Histological characterization of our mouse model showed that over seven days post-surgery increasing numbers of mesothelial or mesothelial cell-derived cells accumulate at adhesion sites whereas their numbers stay constant in wounds healing without scar formation. Along with these findings, we have determined candidate molecules potentially triggering mesothelial cell migration towards sites of adhesion formation and will next test their proposed function in vivo and in vitro. Conclusions Mesothelial cells and mesothelial cell-derived mesenchymal myofibroblasts particularly accumulate at sites of adhesion formation. Therapeutic targeting of the recruitment mechanism of these cells might represent a novel strategy to prevent post-surgical adhesion formation in the peritoneal cavity.

Analogical Evaluation of Endoscopic Septoplasty in Posterior Septal Deviation

Background: Deviated Nasal Septum is one of the pronounced causes of Nasal Obstruction. A number of surgeries are being done since decades to alleviate symptoms. Recent advancement with endoscopes has revolutionized the surgical approach towards minimal invasive procedures. Aim: To analyze the post-op hospital stay and complications in headlight vs. endoscopic septoplasty Study design: The study is Cross sectional Randomized Control Trial. Place and duration of study: We conducted this study in ENT Unit I of Jinnah Hospital Lahore from June 2021 to January 2022. The follow up time was 2 months. Methodology: We performed this study on 30 patients who were diagnosed with Posterior Septal deviation. We randomly divided the patients into two groups. Group A was to undergo trans-nasal trans-speculum (TNTS) septoplasty while group B, endoscopic septoplasty. We analyzed the outcomes in the form of incidence of anterior nasal packing, post-op hospital stays and rate of adhesion formation. Results: We concluded that in Group A, nasal packing was required in 14(93.3%) patients, adhesion formation in 2(13.3%) patients and the mean post-operative hospital stay was 2.13±0.352 days while in Group B, only 3(20%) patients needed anterior nasal packing, none developed post-surgical adhesion formation and the mean postop hospital stay was 1.00±0.000 days. Practical implication: This study delineated that endoscopic septoplasty once mastered is far superior to Endonasal Conventional septoplasty and must be adopted in all public and private sectors to improve cost-effectiveness. Conclusion: We concluded that endoscopic septoplasty is far superior to trans-nasal trans-speculum (TNTS) septoplasty when post-op hospital stays and incidence of nasal packing was concerned in posterior septoplasty. However, there was no statistical difference in terms of post-surgical adhesion formation among the two studied groups. Keywords: Endoscopic Septoplasty, Trans-nasal trans-speculum (TNTS) septoplasty, Deviated Nasal Septum

Activating SIRT3 in peritoneal mesothelial cells alleviates postsurgical peritoneal adhesion formation by decreasing oxidative stress and inhibiting the NLRP3 inflammasome

Peritoneal adhesions (PAs) are a serious complication of abdominal surgery and negatively affect the quality of life of millions of people worldwide. However, a clear molecular mechanism and a standard therapeutic strategy for PAs have not been established. Here, we developed a standardized method to mimic the pathological changes in PAs and found that sirtuin 3 (SIRT3) expression was severely decreased in adhesion tissues, which was consistent with our bioinformatics analysis and patient adhesion tissue analysis. Thus, we hypothesized that activating SIRT3 could alleviate postsurgical PAs. Sirt3-deficient (Sirt3−/−) mice exhibited many more PAs after standardized abdominal surgery. Furthermore, compared with wild-type (Sirt3+/+) mice, Sirt3-deficient (Sirt3−/−) mice showed more prominent reactive oxygen species (ROS) accumulation, increased levels of inflammatory factors, and exacerbated mitochondrial damage and fragmentation. In addition, we observed NLRP3 inflammasome activation in the adhesion tissues of Sirt3−/− but, not Sirt3+/+ mice. Furthermore, mesothelial cells sorted from Sirt3−/− mice exhibited impaired mitochondrial bioenergetics and redox homeostasis. Honokiol (HKL), a natural compound found in several species of the genus Magnolia, could activate SIRT3 in vitro. Then, we demonstrated that treatment with HKL could reduce oxidative stress and the levels of inflammatory factors and suppress NLRP3 activation in vivo, reducing the occurrence of postsurgical PAs. In vitro treatment with HKL also restored mitochondrial bioenergetics and promoted mesothelial cell viability under oxidative stress conditions. Taken together, our findings show that the rescue of SIRT3 by HKL may be a new therapeutic strategy to alleviate and block postsurgical PA formation.

Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling

Abstract Objective Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, ask how contamination of gut microbes influences post-surgical adhesion formation. Methods We make use of an experimental mouse model that allows to investigate how wound repair and adhesion formation differs between sterile injury vs. sterile injury in combination with microbial contamination. We use genetic lineage tracing, bulk- and single-cell RNA-Sequencing to identify potential mechanisms of the observed differences. Next, we use two human cohort studies to confirm the target identified by RNA-Sequencing. Finally, the identified targets are experimentally confirmed by going back to the mouse model. Results We show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. Conclusion Bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery.

The Therapeutic Potential of Targeting the Angiotensin Pathway as a Novel Therapeutic Approach to Ameliorating Post-surgical Adhesions.

Post-surgical adhesion is a common complication after abdominal or pelvic surgeries. Despite improvements in surgical techniques or the application of physical barriers, few improvements have been achieved. It causes bowel obstruction, pelvic pain, and infertility in women and has an adverse effect on the quality of life. Renin-Angiotensin System (RAS) is traditionally considered a blood pressure regulator. However, recent studies have indicated that the RAS plays a vital role in other processes, including oxidative stress, fibrosis, proliferation, inflammation, and wound healing. Angiotensin II (Ang II) is the main upstream effector of the RAS that can bind to the AT1 receptor (ATIR). A growing body of evidence has revealed that targeting Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II type 1 Receptor Blockers (ARBs), and Direct Renin Inhibitors (DRIs) can prevent post-surgical adhesions. Here we provide an overview of the therapeutic effect of RAS antagonists for adhesion. PubMed, EMBASE, and the Cochrane library were reviewed to identify potential agents targeting the RAS system as a potential approach for post-surgical adhesion. Available evidence suggests the involvement of the RAS signaling pathway in inflammation, proliferation, and fibrosis pathways as well as in post-surgical adhesions. Several FDA-approved drugs are used for targeting the RAS system, and some of them are being tested in different models to reduce fibrosis and improve adhesion after surgery, including telmisartan, valsartan, and enalapril. Identification of the pathological causes of post-surgical adhesion and the potential role of targeting the Renin-Angiotensin System may help to prevent this problem. Based on the pathological function of RAS signaling after surgeries, the administration of ARBs may be considered a novel and efficient approach to prevent postsurgical adhesions. Pre-clinical and clinical studies should be carried out to have better information on the clinical significance of this therapy against post-surgical adhesion formation.

Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling

Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, we show that contamination of gut microbes increases post-surgical adhesion formation. Using genetic lineage tracing we show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. In conclusion, bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery.

Effects of Oral Zafirlukast, Sildenafil, or Pirfenidone on the Formation of Postsurgical Intra-Abdominal Adhesions in an Experimental Rat Model

Introduction: Intra-abdominal adhesions’ main etiology is surgical procedures that commonly require reintervention. Oral treatments with sildenafil, zafirlukast, and pirfenidone have yielded decreased severity of fibrotic phenomena secondary to the introduction of foreign material. This study aimed to evaluate the efficacy of oral zafirlukast, sildenafil, or pirfenidone treatment on reducing or preventing intra-abdominal adhesions in an experimental rat model. Methods: Four groups, each of 10 male Wistar rats weighing 250–300 g, were used. A midline laparotomy was used to excise an area of 1.5 × 1.5 cm and reconstructed with polypropylene mesh fixed to the abdominal wall. After 12 h, oral doses of zafirlukast (1.25 mg/kg, group B), sildenafil (15 mg/kg, group C), or pirfenidone (500 mg/kg, group D) were given every day for 8 days. The control group, A, received no treatment. At day 9, animals were reoperated. The implant was resected after ethically approved euthanasia, and specimens were fixed in 10% formaldehyde for histopathology. Results: Control group A yielded adhesions with greater fibrovascular density and neighboring organ involvement than the other groups (p = 0.001), as well as intense inflammatory infiltrates and numerous granulomas (p = 0.04). Adhesions in group C had less fibrovascular density (p = 0.03) with decreased serosal injuries (p = 0.001) and less organ involvement. Group D had reduced adhesions without organ involvement (p < 0.01) and less inflammatory infiltrates, collagen fibers, and foreign body granulomas than group B or C (p < 0.01). Conclusions: Oral administration of these agents did not prevent adhesions but ameliorated them. Oral pirfenidone offered the best performance and could be recommended for human use.

Role of Substance P–Dependent Chemotactic Signaling in Postoperative Adhesion Formation

Postoperative adhesions are a potentially life-threatening complication of abdominal surgery. We previously showed that substance P (SP), acting through the neurokinin-1 receptor (NK-1R), is an important early mediator of adhesiogenesis through its regulation of the tissue plasminogen activator/plasminogen activator inhibitor-1 (PAI-1) fibrinolytic system. SP also mediates neurogenic inflammation by recruiting inflammatory leukocytes, such as neutrophils and macrophages. Our objective was to determine the role of SP-dependent chemotactic recruitment of these inflammatory cells through the CXCR2 in postsurgical adhesion formation. A mouse cecal cauterization model was used to generate intra-abdominal adhesions. Protein and mRNA levels of the chemokines CXCL1 and CXCL2 and their receptor CXCR2 were measured at 3 h and 6 h after surgery in peritoneal tissue and in peritoneal lavages in response to antagonists for the SP receptor and CXCR2, and in IFN-γ knockout mice. Postsurgical adhesion formation was inhibited by both an antagonist to NK-1R and an antagonist to CXCR2. Expression levels of neutrophil chemokines and CXCR2 in peritoneal tissue peaked 3-6 h after surgery and partially depended on SP and IFN-γ, one of its downstream mediators. An NK-1R antagonist inhibited SP-mediated increases in the expression of the PAI-1 inhibitory component of the fibrinolytic system, but the CXCR2 antagonist had no effect. Postsurgical adhesiogenesis involves upregulation of chemokine signaling that is partially SP- and IFN-γ-dependent. However, the adhesiogenic properties of chemokine signaling are not mediated through the inhibition of fibrinolysis with PAI-1, as was previously shown for SP.

What is your diagnosis? Peritoneal fluid from a dog.

What is your diagnosis? Peritoneal fluid from a dog.

Post-Operative Adhesions: A Comprehensive Review of Mechanisms

Post-surgical adhesions are common in almost all surgical areas and are associated with significant rates of morbidity, mortality, and increased healthcare costs, especially when a patient requires repeat operative interventions. Many groups have studied the mechanisms driving post-surgical adhesion formation. Despite continued advancements, we are yet to identify a prevailing mechanism. It is highly likely that post-operative adhesions have a multifactorial etiology. This complex pathophysiology, coupled with our incomplete understanding of the underlying pathways, has resulted in therapeutic options that have failed to demonstrate safety and efficacy on a consistent basis. The translation of findings from basic and preclinical research into robust clinical trials has also remained elusive. Herein, we present and contextualize the latest findings surrounding mechanisms that have been implicated in post-surgical adhesion formation.

Structural and Functional Equivalency Between Lyopreserved and Cryopreserved Chorions with Viable Cells.

Objective: Clinical studies have demonstrated that the use of cryopreserved amnion or trophoblast (TR)-free chorion, containing viable cells, in the treatment of chronic wounds results in high rate of wound closure. Recently, a new lyopreservation method has been developed for preservation of amnion that also retains the endogenous viable cells. The objective of this study was to use this method for lyopreservation of TR-free chorionic membrane (viable lyopreserved chorionic membrane [VLCM]) and compare it with the viable cryopreserved chorionic membrane (VCCM). A second objective was to investigate the immunogenicity of chorion, an important question that has not been fully addressed.Approach: Chorion immunogenicity was tested in vitro in a mixed lymphocyte reaction and lipopolysaccharide (LPS) challenge assay, and in vivo in a mouse subcutaneous pocket implantation model. VLCM tissue structure was assessed histologically, growth factor content by multiplex assay, and cell viability by LIVE/DEAD cell fluorescent staining. Inhibition of tumor necrosis factor α secretion by LPS-activated THP-1 cells and endothelial cell tubule formation assays were performed to evaluate the anti-inflammatory and proangiogenic properties, respectively. An in vivo rabbit abdominal adhesion model was used to evaluate the antifibrotic properties.Results: Chorionic membrane without trophoblast (CM) was shown to be nonimmunogenic. Tissue architecture, growth factors, and cell viability of fresh CM were maintained in VLCM and VCCM. In vitro studies showed that anti-inflammatory and angiogenic properties were retained in VLCM. Furthermore, VLCM prevents formation of postsurgical adhesions in a rabbit abdominal surgical adhesion model.Innovation: Characterization of structural and functional properties of VLCM is reported for the first time.Conclusion: Similar to VCCM, VLCM retains native components of fresh CM, including collagen-rich extracellular matrix, growth factors, and viable cells. In vitro and in vivo models demonstrate that VLCM is anti-inflammatory, proangiogenic and antifibrotic. Results of this study support the structural and functional equivalency between VLCM and VCCM.

The Effect of Daikenchuto, Japanese Herbal Medicine, on Adhesion Formation Induced by Cecum Cauterization and Cecum Abrasion in Mice.

Daikenchuto (DKT) has been widely used for the treatment of postsurgical ileus in Japan. However, its effect on postsurgical adhesion formation has been obscure. In this study, the effect of DKT on postsurgical adhesion formation induced by cecum cauterization or cecum abrasion in mice was investigated. First, the expression of adhesion-related molecules in damaged ceca was investigated by quantitative (q)RT-PCR. During 24 h after surgery, mRNA expressions of interferon-γ (IFN-γ), plasminogen activator inhibitor-1 (PAI-1), interleukin-17 (IL-17), and Substance P (SP) in cauterized ceca and those of PAI-1 and IL-17 in abraded ceca were significantly up-regulated. Next, the effect of DKT on adhesion formation macroscopically evaluated with adhesion scoring standards. DKT (22.5-67.5 mg/d) was administered orally for 7 d during the perioperative period, and DKT did not reduce adhesion scores in either the cauterization model (control : DKT 67.5 mg/d, 4.8 ± 0.2 : 4.8 ± 0.2) or in the abrasion model (control : DKT 67.5 mg/d, 4.9 ± 0.1 : 4.5 ± 0.3). Histologically, collagen deposition and leukocyte accumulation were found at the adhesion areas of control mice in both models, and DKT supplementation did not alleviate them. Last, effect of DKT on expression of proadhesion moleculs was evaluated. DKT also failed to down-regulate mRNA expression levels of them in damaged ceca of both models. In conclusion, PAI-1 and IL-17 may be key molecules of postsurgical adhesion formation. Collagen deposition and leukocytes accumulation are histological characteristic feature of post-surgical adhesion formation. DKT may not have any preventive effect on postsurgical adhesion formation in mice.

Spilt bile and gallstones effect during laparoscopic cholecystectomy: an experimental study for adhesion formation

Laparoscopic cholecystectomy (LC) is recognized as the standard treatment for symptomatic gallstone disease. In comparison with open techniques, LC results in a higher rate of iatrogenic biliary tract damage and spillage of bile and stones. The present study was designed to compare intraperitoneal adhesion formation following LC due to the bile and stone spillage. In this randomized experimental study, 15 dogs were randomly allocated to three groups. Each group contained five dogs. The control group underwent LC, while in the group of bile and stone spillage (BS), 5 cc of a mixture of dog bile and a sterile ground human gallstone was placed in the bed of the gallbladder following LC. The bile spillage (B) group underwent LC, followed by adding 5 cc of the bile in the bed of the gallbladder. Postsurgical adhesion formation was measured, using Nair and Zuhlke classifications for inflammation, fibrosis, and neovascularization. Adhesion formation was noted in one dog from the control and B groups, whereas all animals in group 2 were found to develop high-grade adhesion. Bile cultures were negative for the control group and group B with adhesion. Based on the findings, bile spillage, as well as gallbladder stone spillage, is related to a significant increase in adhesion formation after LC. Therefore, it is necessary to avoid the bile and stone spillage.

Pharmacological Mobilization and Recruitment of Endogenous Stem Cells Prevents Postsurgical Intra-Abdominal Adhesion in Rats

Background: Postsurgical adhesions are a very common complication causing various symptoms from pain to bowel obstruction. We have developed a stem cell mobilizing strategy that enables long-term liver and kidney allograft survival without sustained immunosuppression in animals using a combination of AMD3100 and low-dose FK506 (AF). Serendipitously we have noted a subjective decrease in adhesion formation in animals with AF combination treatment. The purpose of this study was to evaluate the effect of a new stem cell mobilizing strategy on preventing postsurgical adhesion formation in rats. Methods: Abdominal adhesions were induced by creating suture knots on the parietal peritoneum in Lewis rats. Animals were divided randomly into four experimental groups and received subcutaneous injections of saline, single drug or AF combination every other day for 10 days. On postoperative day 14, animals were euthanized and the severity of adhesions were evaluated and scored blindly by five individual surgeons. Results: Most animals treated with saline or single drug exhibited severe peritoneal adhesions around sites of suture knots. AF combination significantly reduced the formation of peritoneal adhesions, 64% animals (7/11) showed few or mild adhesion and no animal showed severe peritoneal adhesions. Searching for mechanisms, we found AF treatment dramatically increased SDF-1 expressing cells, HGF expressing Ym1 M2 macrophages and CD133 stem cells in the injury sites of peritoneal surface at day 5 post-operation. Conclusion: Pharmacological mobilization and recruitment of endogenous stem cells using AF combination significantly reduced postsurgical intra-abdominal adhesions in rats. These findings suggest a novel therapeutic approach to preventing postsurgical adhesions in patients undergoing abdominal or pelvic surgery. Funding Statement: This work was supported by a start-up fund from the surgical department at Johns Hopkins University. Declaration of Interests: None of the authors has a financial interest in any of the products, or drugs mentioned in this manuscript. Ethics Approval Statement: Animals were maintained in a pathogen-free facility of Johns Hopkins University School of Medicine and all animal experiments were performed in accordance with the United States National Institutes of Health (NIH) guidance. All animal protocols were reviewed and approved by the Johns Hopkins University Animal Care and Use Committee.

Pharmacological HIF-inhibition attenuates postoperative adhesion formation

Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5′-Hydroxymethyl-2′-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions. Pretreatment or single intraperitoneal lavage with YC-1 significantly reduced postoperative adhesion formation without prompting systemic adverse effects. Expression analyses of cytokines in peritoneal tissue and fluid and in vitro assays applying macrophages and peritoneal fibroblasts indicated that this effect was cooperatively mediated by various putatively HIF-1α-dependent mechanisms, comprising attenuated pro-inflammatory activation of macrophages, impaired recruitment and activation of peritoneal fibroblasts, mitigated epithelial-mesenchymal-transition (EMT), as well as enhanced fibrinolysis and impaired angiogenesis. Thus, this study identifies prevention of postsurgical peritoneal adhesions as a novel and promising field for the application of HIF inhibitors in clinical practice.

In situ cross-linking carbodiimide-modified chitosan hydrogel for postoperative adhesion prevention in a rat model

BackgroundPostoperative intra-abdominal adhesion often causes many complications. Chitosan fluid has been used in clinic to prevent intra-abdominal adhesion. However, fluid can be easily diluted and cannot stay on the wound site. As hydrogel is able to form stable physical barrier to separate injured tissues, we developed a chitosan hydrogel for better prevention of intra-abdominal adhesion in this study. MethodsWe synthesized a carbodiimide-derivatized chitosan gelatin (cd-CS-gelatin) hydrogel and investigated its rheological properties. A rat model was used to compare the anti-adhesion effect of chitosan hydrogel and fluid. The wounds were created with damage of the underlying muscle of the abdominal wall and the serosal layer of the cecum. They were coated with chitosan fluid or cd-CS-gelatin hydrogel. At day 14 after surgery, the animals were euthanized and intra-abdominal adhesion was assessed. ResultsThe cd-CS-gelatin hydrogel solidified within 3min after the mixing of the reagents. The cecum-abdomen adhesion occurred in all rats without anti-adhesion treatment. The application of cd-CS-gelatin significantly reduced the adhesion rate from 100% to 50%, compared the chitosan fluid only to 88%. The decrease of adhesion breaking strength also manifested that cd-CS-gelatin was more effective than chitosan fluid to reduce postsurgical intra-abdominal adhesion formation. ConclusionsChitosan hydrogel is more effective than chitosan fluid to prevent postoperative cecum-abdomen adhesion. It indicates that hydrogel could be a more promising state than liquid to prevent postoperative intra-abdominal adhesion.