The Therapeutic Potential of Targeting Key Signaling Pathways as a Novel Approach to Ameliorating Post-Surgical Adhesions.

BACKGROUND: Peritoneal adhesions (PA) are a common complication of abdominal operations. A growing body of evidence shows that inhibition of inflammation and fibrosis at sites of peritoneal damaging could prevent the development of intra-abdominal adhesions. METHODS: A search of PubMed, Medline, CINAHL and Embase databases was performed using the keywords 'postsurgical adhesion', 'post-operative adhesion', 'peritoneal adhesion', 'surgery-induced adhesion' and 'abdominal adhesion'. Studies detailing the use of pharmacological and non-pharmacological agents for peritoneal adhesion prevention were identified, and their bibliographies were thoroughly reviewed to identify further related articles. RESULTS: Several signaling pathways, such as tumor necrosis factor-alpha, tissue plasminogen activator, and type 1 plasminogen activator inhibitor, macrophages, fibroblasts, and mesothelial cells play a key part in the development of plasminogen activator. Several therapeutic approaches based on anti-PA drug barriers and traditional herbal medicines have been developed to prevent and treat adhesion formation. In recent years, the most promising method to prevent PA is treatment using biomaterial-based barriers. CONCLUSION: In this review, we provide an overview of the pathophysiology of adhesion formation and various agents targeting different pathways, including chemical agents, herbal agents, physical barriers, and clinical trials concerning this matter.

Prevention of Post-Operative Adhesions: A Comprehensive Review of Present and Emerging Strategies.

Post-operative adhesions affect patients undergoing all types of surgeries. They are associated with serious complications, including higher risk of morbidity and mortality. Given increased hospitalization, longer operative times, and longer length of hospital stay, post-surgical adhesions also pose a great financial burden. Although our knowledge of some of the underlying mechanisms driving adhesion formation has significantly improved over the past two decades, literature has yet to fully explain the pathogenesis and etiology of post-surgical adhesions. As a result, finding an ideal preventative strategy and leveraging appropriate tissue engineering strategies has proven to be difficult. Different products have been developed and enjoyed various levels of success along the translational tissue engineering research spectrum, but their clinical translation has been limited. Herein, we comprehensively review the agents and products that have been developed to mitigate post-operative adhesion formation. We also assess emerging strategies that aid in facilitating precision and personalized medicine to improve outcomes for patients and our healthcare system.

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.

Small bowel obstruction due to a congenital adhesion: a rare case report.

The exact incidence of small bowel obstruction (SBO) due to congenital adhesions remains unclear. Herein, we report a 59-year-old male who appeared in the emergency department with diffuse abdominal pain associated with vomiting. The patient reported no previous medical or surgical history. Clinical examination revealed a soft, distended abdomen and diffuse tenderness. Computed tomography indicated a close loop obstruction. A congenital band extending from mesentery to ileum and causing an internal hernia was identified via a midline incision. The band was ligated and divided. There is no difference in the clinical presentation, and the initial work-up of SBO on account of congenital adhesions was compared to other bowel obstruction causes. Surgical exploration is crucial for the diagnosis and treatment of congenital adhesions. Although laparotomy is considered the cornerstone of surgical management, laparoscopy has emerged as a feasible and safe alternative for the diagnosis and treatment of these congenital bands.

Post-Surgical Peritoneal Scarring and Key Molecular Mechanisms.

Post-surgical adhesions are internal scar tissue and a major health and economic burden. Adhesions affect and involve the peritoneal lining of the abdominal cavity, which consists of a continuous mesothelial covering of the cavity wall and majority of internal organs. Our understanding of the full pathophysiology of adhesion formation is limited by the fact that the mechanisms regulating normal serosal repair and regeneration of the mesothelial layer are still being elucidated. Emerging evidence suggests that mesothelial cells do not simply form a passive barrier but perform a wide range of important regulatory functions including maintaining a healthy peritoneal homeostasis as well as orchestrating events leading to normal repair or pathological outcomes following injury. Here, we summarise recent advances in our understanding of serosal repair and adhesion formation with an emphasis on molecular mechanisms and novel gene expression signatures associated with these processes. We discuss changes in mesothelial biomolecular marker expression during peritoneal development, which may help, in part, to explain findings in adults from lineage tracing studies using experimental adhesion models. Lastly, we highlight examples of where local tissue specialisation may determine a particular response of peritoneal cells to injury.

Sterile Injury Repair and Adhesion Formation at Serosal Surfaces.

Most multicellular organisms have a major body cavity containing vital organs. This cavity is lined by a mucosa-like serosal surface and filled with serous fluid which suspends many immune cells. Injuries affecting the major body cavity are potentially life-threatening. Here we summarize evidence that unique damage detection and repair mechanisms have evolved to ensure immediate and swift repair of injuries at serosal surfaces. Furthermore, thousands of patients undergo surgery within the abdominal and thoracic cavities each day. While these surgeries are potentially lifesaving, some patients will suffer complications due to inappropriate scar formation when wound healing at serosal surfaces defects. These scars called adhesions cause profound challenges for health care systems and patients. Therefore, reviewing the mechanisms of wound repair at serosal surfaces is of clinical importance. Serosal surfaces will be introduced with a short embryological and microanatomical perspective followed by a discussion of the mechanisms of damage recognition and initiation of sterile inflammation at serosal surfaces. Distinct immune cells populations are free floating within the coelomic (peritoneal) cavity and contribute towards damage recognition and initiation of wound repair. We will highlight the emerging role of resident cavity GATA6+ macrophages in repairing serosal injuries and compare serosal (mesothelial) injuries with injuries to the blood vessel walls. This allows to draw some parallels such as the critical role of the mesothelium in regulating fibrin deposition and how peritoneal macrophages can aggregate in a platelet-like fashion in response to sterile injury. Then, we discuss how serosal wound healing can go wrong, causing adhesions. The current pathogenetic understanding of and potential future therapeutic avenues against adhesions are discussed.

Transabdominal ultrasound: Can it be used to detect and quantify adhesions/reported pain, following Caesarean section?

BACKGROUND: Caesarean section is common in the UK with post-procedural adhesions causing life-long clinical symptoms and impacting future pregnancies. This study's aim was to explore associations between these surgical adhesions, via transabdominal ultrasound findings, and perceived symptoms. METHOD: Females demonstrating 1-3 transverse, lower-segment Caesareans were included. Visceral slide transabdominal ultrasound elicited positive adhesions (<1 cm movement) and negative adhesions (>1 cm movement). Scar tissue quality was assessed by the Patient and Observer Scar Assessment Scale (POSAS) and Numerical rating scales (NRS) described pain symptoms. The relationship between adhesions was explored using Fisher's exact test and multiple regression analysis. RESULTS: Twenty-two subjects (mean-age 35) were recruited; twenty participants (91%) had undergone 1 Caesarean, one each of the remainder had undergone 2 and 3 Caesareans respectively. Increased Visceral slide (>1 cm) was seen as predictive of increased scar pain (R2 = 0.76 (95% CI 0.12-0.28), P < 0.001). CONCLUSION: Caesarean adhesion scans showed significant associations with pain symptomology. Comprehensive adhesion assessment needs to be developed to improve long term outcomes of adhesions. Transabdominal Ultrasound can be considered a useful, quick and non-deleterious alternative diagnostic tool to Laparoscopy, therefore preventing further adhesion formation.

A first-in-human, randomized, controlled, subject- and reviewer-blinded multicenter study of Actamax™ Adhesion Barrier.

PURPOSE: Post-surgical adhesions remain a significant concern following abdominopelvic surgery. This study was to assess safety, manageability and explore preliminary efficacy of applying a degradable hydrogel adhesion barrier to areas of surgical trauma following gynecologic laparoscopic abdominopelvic surgery. METHODS: This first-in-human, prospective, randomized, multicenter, subject- and reviewer-blinded clinical study was conducted in 78 premenopausal women (18-46 years) wishing to maintain fertility and undergoing gynecologic laparoscopic abdominopelvic surgery with planned clinically indicated second-look laparoscopy (SLL) at 4-12 weeks. The first two patients of each surgeon received hydrogel, up to 30 mL sprayed over all sites of surgical trauma, and were assessed for safety and application only (n = 12). Subsequent subjects (n = 66) were randomized 1:1 to receive either hydrogel (Treatment, n = 35) or not (Control, n = 31); 63 completed the SLL. RESULTS: No adverse event was assessed as serious, or possibly device related. None was severe or fatal. Adverse events were reported for 17 treated subjects (17/47, 36.2%) and 13 Controls (13/31, 41.9%). For 95.7% of treated subjects, surgeons found the device "easy" or "very easy" to use; in 54.5%, some residual material was evident at SLL. For 63 randomized subjects who completed the SLL, adjusted between-group difference in the change from baseline adhesion score demonstrated a 41.4% reduction for Treatment compared with Controls (p = 0.017), with a 49.5% reduction (p = 0.008) among myomectomy subjects (n = 34). CONCLUSION: Spray application of a degradable hydrogel adhesion barrier during gynecologic laparoscopic abdominopelvic surgery was performed easily and safely, without evidence of clinically significant adverse outcomes. Data suggest the hydrogel was effective in reducing postoperative adhesion development, particularly following myomectomy.

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions.

Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial-to-mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post-surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT-PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor-beta (TGF-ß) pathway. The severity of adhesions and MMT-related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT-related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF-ß resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents.

A European survey on awareness of post-surgical adhesions among gynaecological surgeons.

The present survey was conducted among gynaecological surgeons from several European countries to assess the actual knowledge and practice related to post-surgical adhesions and measures for reduction. From September 1, 2012 to February 6, 2013, gynaecological surgeons were invited to answer an 18-item online questionnaire accessible through the ESGE website. This questionnaire contained eight questions on care settings and surgical practice and ten questions on adhesion formation and adhesion reduction. Four hundred fourteen surgeons participated; 70.8 % agreed that adhesions are a source of major morbidity. About half of them declared that adhesions represented an important part of their daily medical and surgical work. About two thirds informed their patients about the risk of adhesion. Most cited causes of adhesions were abdominal infections and extensive tissue trauma, and endometriosis and myomectomy surgery. Fewer surgeons expected adhesion formation after laparoscopy (18.9 %) than after laparotomy (40.8 %); 60 % knew the surgical techniques recommended to reduce adhesions; only 44.3 % used adhesion-reduction agents on a regular basis. This survey gives a broad picture of adhesion awareness amongst European gynaecological surgeons, mainly from Germany and the UK. The participants had a good knowledge of factors causing adhesions. Knowledge of surgical techniques recommended and use of anti-adhesion agents developed to reduce adhesions need to be improved.