Prevention of adhesive small bowel obstruction by anti-adhesion barriers: do they really work?

Future progress in adhesion prevention will require a multifaceted translation research strategy that bridges the current gap between mechanistic efficacy and clinical relevance. Standardization of outcome reporting A fundamental step is the standardization of adhesion assessment and outcome reporting. Current (preclinical) studies use heterogeneous definitions of adhesion severity, inconsistent scoring systems, and variable endpoints for adhesion-related complications. This heterogeneity complicates meta-analysis and guideline development. The Peritoneal Adhesion Index (PAI), as recommended by the Bologna Guidelines, offers a standardized framework for quantifying adhesions and may serve as a foundation for systematic assessment (Fig.  4 ) [ 88 ]. Future work should also incorporate standardized, patient-relevant clinical outcomes to comprehensively evaluate barrier effectiveness, including tools such as the clinical adhesion score (CLAS) and the core outcome set developed by the Tripartite Gastrointestinal Recovery SBO Group (Fig.  5 and Table  1 ) [ 101 , 102 ]. Fig. 4 Peritoneal Adhesion Index (PAI). Adapted from “Ten Broek R.P.G., Krielen P, Di Saverio S. et al. Bologna guidelines for diagnosis and management of adhesive small bowel obstruction (ASBO): 2017 update of the evidence-based guidelines from the world society of emergency surgery ASBO working group. World J Emerg Surg. 2018.” Fig. 5 Clinical adhesion score (CLAS). Adapted from “Lier E.J, Van den Beukel B.A.W., Gawria L. et al. Clinical adhesion score (CLAS): development of a novel clinical score for adhesion-related complications in abdominal and pelvic surgery. Surg Endosc. 2020;35(5):2159–2168.” Table 1 A core outcome set for clinical studies of adhesive small bowel obstruction. Adapted from “Tripartite Gastrointestinal Recovery SBO Group. A core outcome set for clinical studies of adhesive small bowel obstruction. Colorectal Dis. 2022;24(10):1204–1210.” Peritoneal Adhesion Index (PAI). Adapted from “Ten Broek R.P.G., Krielen P, Di Saverio S. et al. Bologna guidelines for diagnosis and management of adhesive small bowel obstruction (ASBO): 2017 update of the evidence-based guidelines from the world society of emergency surgery ASBO working group. World J Emerg Surg. 2018.” Clinical adhesion score (CLAS). Adapted from “Lier E.J, Van den Beukel B.A.W., Gawria L. et al. Clinical adhesion score (CLAS): development of a novel clinical score for adhesion-related complications in abdominal and pelvic surgery. Surg Endosc. 2020;35(5):2159–2168.” A core outcome set for clinical studies of adhesive small bowel obstruction. Adapted from “Tripartite Gastrointestinal Recovery SBO Group. A core outcome set for clinical studies of adhesive small bowel obstruction. Colorectal Dis. 2022;24(10):1204–1210.” Patient-centered endpoints and long-term follow-up Future trials should extend beyond surrogate endpoints (e.g., adhesion scores at reoperation) toward patient-centered outcomes that reflect real-world relevance: rates of aSBO readmission, infertility, chronic pain, and quality of life. Large multicenter RCTs with standardized protocols and follow-up beyond 5 years are essential to assess these endpoints. Incorporating health–economic modeling and cost-utility analyses into trial design would clarify the economic implication of barrier use for healthcare systems. Risk-stratified application and precision prevention Rather than pursuing universal prophylaxis, anti-adhesion barriers should be used selectively on the basis of patient and procedural risk. High-risk scenarios include open colorectal resections, extensive oncologic resections (e.g., gynecologic debulking procedures), complex endometriosis surgery, and repeat laparotomies; settings in which adhesion formation and secondary morbidity are most prevalent. Development of risk prediction models by integrating patient factors (e.g., prior surgery, infection, endometriosis, radiation) and procedural variables could support individualized decision-making and optimizing cost-effectiveness and represents an important area for future research [ 103 ]. Integration into minimally invasive and robotic surgery As laparoscopy and robotic surgery continue to expand, the challenge lies in adapting barrier technology for these modalities. Sprayable or hydrogel-based bioresorbable barriers compatible with minimally invasive platforms have shown encouraging results. They can be delivered through narrow trocars, conform to complex or irregular anatomical surfaces, and allow for precise application in confined operative spaces. Future work should focus on delivery systems optimized for deep pelvic spaces, enabling consistent use in advanced gynecologic and colorectal procedures. Next-generation bioactive and hybrid materials Innovation in material science offers promising avenues. Next-generation barriers may combine mechanical separation with biological modulation and thus incorporate antiinflammatory, pro-fibrinolytic or anti-fibrotic agents to actively suppress adhesion pathogenesis. Early phase studies using nanofiber networks and bioresorbable polymer composites have demonstrated biocompatibility and reduced fibrotic response in animal models. Translational research should now focus on scaling these technologies for human trials with emphasis on safety, biodegradability, and feasibility.

Despite experimental and clinical evidence, the translation of anti-adhesion barriers into routine surgical practice remains limited. This gap reflects a multifactorial interplay of economic, regulatory, safety, and technical challenges. Cost-effectiveness remains one of the principal obstacles. Economic modeling has produced variable results, depending on surgical approach and patient risk profile [ 95 , 96 ]. Data from the USA show that barrier use in open colorectal surgery reduces adhesion prevalence from 88.9% to 45.5% and the incidence of aSBO from 8.6% to 6.2%, resulting in an average cost saving of approximately $106 per patient over 4 years. However, in laparoscopic procedures, adhesion rates decreased from 62.3% to 31.8% but overall costs increased by $163 per patient. These analyses consider mainly direct hospital costs, whereas societal costs such as sick leave and quality-adjusted life years remain poorly quantified. For now, selective use in high-risk settings seems the most rational approach [ 94 , 97 ]. Safety considerations remain central to the adoption of anti-adhesion barriers in surgery, particularly given the severe consequences of anastomotic leakage. Early observational studies raised concerns about anastomotic complications when Seprafilm® was applied directly over staple or suture lines [ 98 ]. These findings raised concern regarding impaired anastomotic healing. As a result, current manufacturer recommendations explicitly advise against placement directly over newly created anastomoses. Subsequent analyses did not consistently confirm a significant increase in leak rates [ 98 , 99 ]. A recent meta-analysis across 3456 patients demonstrated that surgical site infection (5.2% versus 4.3%, RR 1.21, 95% CI 0.86–1.70, p  = 0.28), intraabdominal abscess formation (3.6% versus 2.5%, RR 1.46, 95% CI 0.92–2.32, p  = 0.11), and paralytic ileus (4.7% versus 4.8%, RR 0.97, 95% CI 0.68–1.38, p  = 0.87) did not differ significantly between Seprafilm and control groups [ 100 ]. However, anastomotic leaks occurred more frequently when Seprafilm® was placed directly over anastomotic staple or suture line (3.1% versus 1.6%; RR 1.85, 95% CI 1.15–3.00, p  = 0.01), whereas placement away from the staple line did not add any additional infectious or anastomotic risk [ 100 ]. When applied appropriately, available evidence supports its effectiveness in reducing high-grade adhesions and postoperative aSBO. Technical challenges remain substantial, especially for sheet-type barriers that require precise placement on dry hemostatic surfaces. The manipulation and placement of sheet barriers can be technically challenging, particularly in laparoscopy and in deep pelvic procedures where access is limited. The fluid icodextrin barrier might be a viable alternative in these situations. While newer sprayable or hydrogel formulations hold promise of ease of application while remaining in place, cost, lack of safety data, and availability still limit widespread use. Furthermore, adhesion formation is often clinically silent and the absence of immediate observable benefit at surgery provides little positive feedback to the operator, weakening motivation for consistent implementation.

Adhesive small bowel obstruction (aSBO) is a frequent and potentially life-threatening acute complication of adhesions. Readmission rates are 7–8% after open colorectal surgery compared with 2–3% following laparoscopic procedures, thereby showing its clinical relevance and procedure dependence [ 6 – 8 ]. Initial management is typically conservative, including bowel rest, nasogastric decompression, and intravenous fluid resuscitation. This approach succeeds in roughly 70% of uncomplicated cases [ 4 , 5 ]. However, 30% of patients require surgical management, and those presenting with ischemia or strangulation face mortality rates of 3–8% [ 4 ]. Operative mortality ranges from 4% to 7% in large European cohorts [ 1 , 3 ]. Although conservative management remains standard of care, increasing evidence suggests higher recurrence rates compared with surgical intervention [ 6 ]. Recurrence occurs in approximately 20% of patients within 2 years following conservative management versus 13% after surgery [ 6 , 7 ]. Long-term recurrence may reach 40% at 10 years and rises to 30–60% in patients with multiple prior episodes [ 8 – 10 ]. Beyond the clinical burden, the socioeconomic impact is substantial: mean hospital costs per episode are estimated at €2277 ± 265 for conservative cases and significantly higher for surgically treated ones (€16,305 ± 2513) [ 4 ]. Given these findings, a growing number of centers in the Netherlands and Belgium are adopting a more proactive surgical strategy for aSBO. Elective adhesiolysis is considered a viable alternative once the acute episode resolves, particularly in patients with recurrent obstruction or chronic adhesion-related pain. Performed in expert centers and often combined with anti-adhesion barriers, elective adhesiolysis reduces recurrence of aSBO by more than 65% while avoiding the morbidity of emergency surgery [ 37 – 39 ]. The economic burden is likewise substantially reduced in the elective setting. Considering societal costs such as sick leave, and the high prevalence of chronic complaints after an episode of aSBO, this approach is likely to be cost-efficient from a societal perspective [ 40 ]. Chronic postoperative pain is a common but underrecognized consequence of adhesions, affecting 20–40% of patients and impairing quality of life [ 41 , 42 ]. Multiple studies have demonstrated that postoperative adhesions are the primary pathological finding in up to 60% of patients with chronic postoperative abdominal pain and in 45% of those with chronic pelvic pain [ 43 ]. Recent molecular analyses have provided insight into the underlying mechanisms linking adhesions with persistent nociception. Adhesion tissues from patients with chronic pain show increased nerve density and upregulation of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), both key mediators of neural sprouting and sensitization [ 44 , 45 ]. Quantitative analyses have reported a two to four times higher nerve density in adhesions of patients with chronic abdominal pain compared with asymptomatic controls, accompanied by significantly increased NGF gene expression. [ 46 ]. Diagnostic laparoscopy frequently identifies adhesions as the sole abnormal finding when conventional imaging is inconclusive. A meta-analysis reported adhesions as the most likely cause in 57% of such patients [ 43 ]. Evidence for adhesiolysis in chronic pelvic or abdominal pain remains limited, particularly regarding long-term outcomes. Randomized controlled trials (RCT) are scarce. One RCT compared laparoscopic adhesiolysis with an anti-adhesion barrier (Icodextrin 4%) with diagnostic laparoscopy in 50 women. At 6 months, patients in the adhesiolysis group demonstrated significant improvement in VAS scores (median −17.5 versus −1.5; p  = 0.048) and SF-12 physical scores (25.0 versus 6.3; p  = 0.021). In addition, emotional component scores (32.5 versus −5; p  < 0.0074) and EHP-30 emotional well-being scores (32.5 versus −5; p  < 0.0074) were significantly better [ 47 , 48 ]. Follow-up was limited to 6 months and baseline adhesion scores were higher in the treatment group, introducing potential confounding [ 47 ]. Two nonrandomized studies evaluating adhesiolysis with adhesion barriers reported long-term improvement in pain in approximately two-thirds of patients [ 48 , 49 ]. In a study by Van den Beukel et al., operative management (adhesiolysis with barrier) was associated with lower pain interference in daily activities and fewer persistent abdominal symptoms [ 50 ]. Adhesiolysis with an anti-adhesion barrier is safe and can provide meaningful short-term pain relief in selected patients. High-quality RCTs with longer follow-up remain necessary to clarify durability of benefit and investigate patient selection. Peritoneal adhesions are a major cause of secondary infertility, implicated in tubal occlusion, ovarian encapsulation, and distorted pelvic anatomy [ 51 , 52 ]. Globally, an estimated 50–80 million women suffer from infertility and postoperative adhesions represent a preventable contributor [ 53 ]. By restricting organ mobility and disrupting pelvic vascularization, adhesions hinder fimbrial capture of the oocyte, reduce tubal patency and may impair sperm transport, implantation, and uterine contractility. The role of adhesiolysis in fertility restoration remains debated. While in vitro fertilization (IVF) has largely supplanted reconstructive microsurgery with peritubal adhesiolysis, adhesiolysis may avoid complications associated with IVF and be less costly [ 54 – 56 ]. Early studies reported no improvement in conception rates. However, subsequent evidence demonstrated clear benefit in patients with dense adnexal adhesions [ 57 – 59 ]. In a retrospective cohort of 147 infertile women with periadnexal adhesions and unexplained infertility, pregnancy rates reached 32% at 12 months and 45% at 24 months after salpingo-ovariolysis, compared with 11% and 16%, respectively, in untreated women ( p  < 10 –6 ) [ 59 ]. Moreover, in women undergoing tubal surgery, pregnancy rates were inversely correlated with adhesion scores, confirming the link between adhesion severity and reproductive outcomes [ 60 ]. Most of the aforementioned studies, however, have not applied barriers as part of fertility-enhancing surgery. While there is consistent evidence from RCTs that barriers reduce adhesion formation in fertility-enhancing surgery, these trials lack the follow-up to report on pregnancy rates [ 61 , 62 ]. One cohort study reported higher pregnancy rates in follow-up when an adhesion barrier was used in addition to adhesiolysis for fertility surgery [ 63 ]. Although high-quality randomized data remain scarce, these findings suggest that preventing adhesion formation through surgical technique and use of barrier agents may indirectly improve fertility outcomes, particularly in women undergoing myomectomy, endometriosis surgery, or tubal reconstructive procedures.

In colorectal surgery, postoperative adhesion formation remains a major clinical burden, occurring in up to 90% of patients after open procedures and 60% following laparoscopic surgery [ 5 ]. The Bologna Guidelines (2017) therefore emphasize adhesion prevention as a central component of perioperative care, and anti-adhesion barriers have attracted the most extensive clinical evaluation [ 88 ]. Within this field, HA/CMC barriers (Seprafilm®) have accumulated the most consistent evidence. Seprafilm® reduces adhesion formation and the need for reoperation for aSBO by about 50%. A large meta-analysis ( n  = 62,886) evaluated Seprafilm® predominantly during primary abdominal surgery, with focus on elective abdominal and colorectal resections. Seprafilm® was associated with a 55% decrease in postoperative aSBO (odds ratio (OR) 0.45, 95% CI 0.33–0.61, p  < 0.001). Because minimally invasive surgery independently reduces adhesion formation, laparoscopic resections were examined separately. Even in this lower-risk environment, Seprafilm® still significantly reduced postoperative adhesion formation (OR 0.43, 95% CI 0.25–0.75, p  = 0.003) [ 89 ]. A second meta-analysis evaluated Seprafilm during primary abdominal surgery across mixed indications. The pooled RR for postoperative small bowel obstruction was 0.45 (95% CI 0.34–0.60, p  < 0.00001), supporting a clinically meaningful effect [ 90 ]. Comparative data across barrier classes confirm that HA/CMC remains the best-supported option in colorectal surgery. ORC (Interceed®) reduces adhesion incidence (RR 0.51, 95% CI 0.31–0.86) but lacks evidence for preventing aSBO. The Bologna guideline panel did not recommend its use for this indication in general surgery [ 61 , 62 , 88 ]. Icodextrin (Adept®) is a liquid barrier applicable in open and laparoscopic settings. In a RCT of patients undergoing open adhesiolysis for established aSBO, icodextrin 4% significantly reduced aSBO recurrence (RR 0.20, 95% CI 0.04–0.88) [ 91 ]. Polyethylene-glycol-based hydrogels (SprayShield®/SprayGel) reduce adhesion scores in early trials, yet long-term outcomes including obstruction and reoperation rates were not reported [ 92 , 93 ]. An overview is provided in Supplementary Table 1. A cost-effectiveness model estimates that HA/CMC use in open colorectal surgery reduced adhesion incidence from 88.9% to 45.3% and decreased aSBO incidence from 8.6% to 6.2%, resulting in a modest but tangible overall cost reduction over a 4-year period. In laparoscopic surgery, adhesion incidence decreased from 62.3% to 31.8%, but direct hospital costs increased by $162 per patient (incremental cost-effectiveness ratio (ICER) $123)[ 94 ]. Taken together, current evidence supports the targeted use of anti-adhesion barriers in colorectal surgery, particularly HA/CMC. Gynecologic operations carry the highest risk of postoperative adhesions, with rates up to 90% after open myomectomy and 45–65% following repeat caesarean section. Adhesions in this context are clinically significant by contributing to 20–40% of secondary infertility cases and predisposing to chronic pelvic pain, bowel obstruction, and placenta accreta spectrum disorders [ 37 ]. A range of physical and bioresorbable barriers has been evaluated in RCTs across various gynecologic indications, unfortunately without assessing long-term fertility or complication results. In addition, other clinically relevant outcomes such as pain or aSBO are rarely reported, as these outcomes are not routinely included in trial protocols. An overview of the available clinical studies is provided in the Supplementary Material.

The evolution of anti-adhesion barrier technology reflects over half a century of progress in biomaterials science and surgical innovation (Fig.  3 ). The earliest known barrier is the Cargile membrane, a treated bovine peritoneum introduced in the early 1900s. It represents the first systematic attempt to prevent serosal fusion. Despite its innovation, it suffered from poor mechanical stability, rapid absorption, and foreign-body reactions that limited clinical efficacy [ 64 , 65 ]. Fig. 3 Timeline of the development of anti-adhesion barriers Timeline of the development of anti-adhesion barriers By the 1970s the focus shifted toward synthetic and polymeric biomaterials as interest grew in the concept of a biocompatible, temporary physical barrier. The 1980s marked the advent of commercially successful anti-adhesion barriers. Oxidized regenerated cellulose (ORC), such as Interceed® and Surgicel®, provided the first bioresorbable mesh capable of reducing adhesion formation by forming a gel-like layer over traumatized peritoneal surfaces. Their Food and Drug Administration (FDA) approval was a milestone in translating adhesion prevention from experimental to clinical practice [ 66 , 67 ]. However, efficacy was reduced in the presence of blood and manipulation during laparoscopy remained challenging [ 68 – 70 ]. In parallel, expanded polytetrafluoroethylene (ePTFE) (Gore-Tex ®) emerged as a durable, nonabsorbable barrier offering superior short-term adhesion reduction (up to 85% versus 65% for ORC). However, its requirement for surgical removal limited long-term use and adoption [ 71 – 73 ]. Advances in polysaccharide chemistry during the 1990s produced hyaluronic acid/carboxymethylcellulose (HA/CMC) film such as Seprafilm®. These transparent bioresorbable sheets provided uniform coverage and demonstrated reductions in adhesion severity, particularly in colorectal and gynecological surgery. While multiple RCTs confirmed reduced adhesion scores, long-term outcomes remain unclear [ 74 , 75 ]. Other HA-based systems, including Hyalobarrier® and Hyalomatrix®, maintain hydroflotation for approximately 1 week and thereby align with the critical window of peritoneal mesothelial repair. These formulations established HA as the biochemical foundation for multifunctional systems [ 76 ]. The early 2000s saw the introduction of fluid and sprayable barriers aimed at improving usability and coverage. Icodextrin 4% solution (Adept®) provided prolonged hydroflotation and modest reductions in adhesion reformation, while polyethylene glycol (PEG) hydrogels such as SprayShield® and Cosael® allowed for conformable application on complex geometries. These systems improved practicality but did not demonstrate superiority in long-term clinical endpoints [ 77 , 78 ]. While the clinical use of standalone adhesion barriers has remained limited, the long-standing development of implants suitable for intraperitoneal application illustrates that anti-adhesion strategies are neither novel nor uncommon in surgery. The rise of laparoscopic ventral hernia repair created a growing need for meshes that were suitable for intraperitoneal use [ 79 ]. Early experience with intraperitoneal placement of conventional prosthetic meshes, such as polypropylene, was associated with aggressive adhesion formation and serious complications such as the risk of fistulae. These concerns prompted the development of composite meshes incorporating temporary anti-adhesive interfaces on the visceral surface, combined with a prosthetic scaffold to allow for durable hernia repair. The coatings are chemically and functionally comparable to the anti-adhesion barriers listed above. These coating of these meshes are degradable and are resorbed within 3–4 weeks (e.g. Proceed®, Sepramesh®, Parietex®), overlapping with mesothelial regeneration.The widespread use of these integrated barrier technologies provides indirect but compelling evidence that barrier-based strategies are safe and effective in reducing adhesion formation within the abdominal cavity [ 79 – 81 ]. The latest phase in adhesion research has transitioned from passive physical barriers toward bioactive systems that interact with the peritoneal healing environment. The so-called smart barriers are designed not only to separate serosal surfaces, but also to modulate inflammation, fibrinolysis, and mesothelial regeneration. Most contemporary designs combine natural polymers such as HA with synthetic copolymers such as PEG, polycaprolactone (PCL), or polylactic-co-glycolic acid (PLGA) [ 82 ]. A growing number of these materials incorporate bioactive or drug-eluting components to achieve targeted modulation of the peritoneal microenvironment [ 83 ]. By combining mechanical separation with localized biochemical signaling, these constructs represent a conceptual continuum from traditional HA-based films toward fully bio-interactive systems. Emerging “fourth-generation” or smart barriers extend these principles through nanoparticle-mediated delivery systems and gene-silencing systems (e.g., siRNA targeting PAI-1 or TGF-β pathways) [ 84 ]. Some prototypes employ self-healing hydrogels or microneedle-embedded membranes to adapt to tissue movement and enhance drug penetration to prevent adhesion formation and actively restore peritoneal homeostasis [ 85 – 87 ]. Although results from animal and early phase human studies are encouraging, these technologies remain in the translational phase. Challenges persist regarding manufacturing scalability and the standardization of outcome metrics.

Anti-adhesion barriers have a proven capacity to reduce postoperative adhesion formation, yet their translation into clinically meaningful, patient-centered outcomes remains incomplete. Evidence supports their benefit in reducing reoperation for adhesive small bowel obstruction and potential cost-effectiveness in high-risk open colorectal surgery. However, uncertainty persists regarding their effects on fertility, chronic pain, and long-term quality of life. In contemporary surgical practice, anti-adhesion barriers should be viewed as selective adjuncts rather than universal prophylaxis. On the basis of available evidence, application of barriers in patients presenting with adhesion-related complaints and risk-stratified application seems justified. Results of application should be evaluated by standardized outcome reporting and gathering long-term evidence. Continued innovation in biomaterials will be essential to reach the full potential of these technologies. Ultimately, aligning adhesion prevention research with patient-centered outcomes will be the key to closing the gap between scientific promise and clinical adoption.

Peritoneal adhesions are an almost inevitable consequence of abdominal surgery, with up to 93% of patients developing adhesions after laparotomy and 10–20% experiencing adhesion-related morbidity during their lifetime [ 1 , 2 ]. Adhesive small bowel obstruction (aSBO) accounts for approximately 70% of small bowel obstruction (SBO) cases and is a leading cause of emergency admissions [ 3 ]. Adhesions complicate reoperations, increase intraoperative risks, and contribute to infertility and chronic abdominal pain [ 4 , 5 ]. A landmark population-based study by Parker et al. demonstrated that approximately 60% of aSBO episodes occur within 4 years of the index operation, underlining the long-term impact of adhesions [ 6 ]. Recent advances in imaging techniques, such as cinematographic-magnetic resonance imaging (cineMRI), have improved the diagnosis and management of chronic postoperative abdominal pain, thereby demonstrating the relevance of adhesions in patients with chronic abdominal pain and reinforcing their significance as a public health problem rather than merely a surgical inconvenience [ 7 ]. Despite minimally invasive approaches and meticulous surgical technique, adhesion-related morbidity persists. Laparoscopy reduces adhesion formation, partly due to reduced peritoneal trauma and inflammatory response compared with open surgery. Anti-adhesion barriers have been proposed, yet their clinical benefit and adoption remains debated [ 8 , 9 ]. This review evaluates their role in preventing aSBO, including mechanisms, evidence, limitations and future directions .

Peritoneal injury initiates a cascade of inflammation, coagulation, and tissue repair that may culminate in adhesion formation (Fig. 1 ). Surgical, ischemic, or infectious insults disrupt the mesothelial monolayer and expose the underlying extracellular matrix (ECM), triggering leukocyte infiltration, cytokine release, and coagulation, with fibrin deposition[ 10 ]. Integrated molecular mechanisms underlying postoperative adhesion development Normally, fibrin is degraded within 5–7 days through fibrinolysis, restoring the mesothelial layer. When fibrinolysis is impaired, plasmin activator inhibitor 1 (PAI-1) expression increases and suppresses the activity of tissue plasminogen activator (tPA), thereby reducing fibrin clearance. Persistent fibrin networks provide a matrix for fibroblast migration, angiogenesis, and ECM deposition, leading to organization into mature adhesions [ 11 ]. Hypoxia disrupts apoptosis–proliferation balance, promoting fibroblast survival, increasing reactive oxygen species (ROS), and activating profibrotic pathways mediated by transforming growth factor-β (TGF-β) and nuclear factor-κB (NF-κB) [ 12 – 16 ]. Adhesion severity correlates inflammation [ 17 ]. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) enhance inflammation and fibrin formation, while IL-17 and interferon-γ (IFN-γ), sustain this response [ 18 , 19 ]. Innate and adaptive immune cells determine adhesion formation. Neutrophils and macrophages act sequentially and often in opposing directions [ 20 ]. Neutrophils act early, producing ROS and TGF-β, thereby linking inflammation and fibrosis. Experimental reduction of ROS production attenuates adhesion formation [ 21 ]. Macrophages infiltrate later. Active macrophages enhance plasminogen activation and fibrinolysis and contribute to resolution of inflammation, whereas macrophage depletion promotes fibrosis [ 22 ]. The balance between proinflammatory M1 and reparative M2 macrophages is increasingly recognized as a critical determinant of adhesion outcome and remains a focus of ongoing research [ 23 – 25 ]. Resident GATA6 + large peritoneal macrophages rapidly aggregate on exposed fibrin clots, forming a transient cellular barrier. However, in the setting of extensive injury, this response may become dysregulated, leading to exaggerated macrophage aggregation that physically bridges adjacent serosal surfaces and evolves into adhesions [ 26 , 27 ]. Experimental augmentation of resident macrophages reduces adhesions in murine models [ 27 ]. These findings highlight macrophages as both regulators and potential therapeutic targets. Mast cells and T lymphocytes contribute to the later stages of adhesion maturation. Mast cells, which are abundant in the peritoneal cavity, degranulate in response to injury, releasing pro-fibrotic mediators (histamine, tryptase, TGF-β, TNF-α, and vascular endothelial growth factor (VEGF)) [ 28 – 30 ]. Their numbers peak approximately 7 days after injury, coinciding with the onset of the remodeling phase [ 31 ]. CD4 + T secrete cytokines regulating fibroblast activity [ 32 , 33 ]. As inflammation resolves, mesothelial cells undergo mesothelial-to-mesenchymal transition (MMT), losing epithelial characteristics and acquiring a myofibroblast-like phenotype [ 34 ]. This transition is driven by TGF-β, caveolin-1, and YAP-mediated pathways (Yes-associated protein) [ 35 ]. Mesothelial-derived myofibroblasts secrete collagen and fibronectin, contributing to ECM expansion and neovascularization through VEGF release [ 36 ]. Inhibition of MMT in experimental models significantly reduces adhesion formation, proving its central pathogenic role [ 35 ]. Ultimately, these intertwined processes lead to vascularized collagen-rich fibrous bands that fixate adjacent peritoneal surfaces, forming permanent adhesions. Anti-adhesion barriers aim to interrupt this cascade by maintaining temporary separation of the injured peritoneal surfaces during the critical healing window (Fig. 2 ). Solution-based barriers such as icodextrin 4% (Adept ® ) provide hydroflotation, whereas sheet barriers such as hyaluronic acid-carboxymethylcellulose (Seprafilm ® ) and oxidized regenerated cellulose (Interceed ® ) act as localized mechanical separators [ 37 , 38 ]. Future preventive strategies may combine mechanical separation with targeted modulation of early immune responses. Interruption of the postoperative adhesion pathway by barrier application