Gynecologic postoperative anti-adhesion barriers: From biomaterials to barrier development

Definition Three-Dimensional Alkoxyamine-terminated Pluronic F127 Carboxymethyl Cellulose Carboxymethyl Cellulose (low-viscosity grade) Carboxymethyl Chitosan Collagen Cesarian Section Dichloromethane N,N-Dimethylformamide Dimethyl Sulfoxide Extracellular Matrix Electrohydrodynamic atomization Fibroblast Growth Factor 1 Glycosaminoglycans Gelatin Methacryloyl Glycidyl-Methacrylate-modified Hyaluronic Acid Gynecologic postoperative adhesions Hyaluronic Acid Interleukin Mitomycin C Melt ElectroWriting Mononuclear Phagocyte System Methylprednisolone Mesenchymal Stem Cell Near-Field Electrospinning Nitric Oxide Non-Steroidal Anti-Inflammatory Drugs Oxidized Hyaluronic Acid Oxidized Regenerated Cellulose Polycaprolactone Polyethylene Glycol Polyethylene Terephthalate Polyglycolic Acid Prostaglandins Polylactic Acid Poly(lactic-co-glycolic acid) Polymethyl Methacrylate Polymorphonuclear Neutrophils Postoperative Adhesions Polypropylene Sodium Alginate Silicon Dioxide Human intestinal epithelial cell line TC-7 Transforming Growth Factor Transglutaminase Tumor Necrosis Factor Thermoplastic Polyurethane Tissue Plasminogen Activator Urokinase-type Plasminogen Activator Vancomycin Vascular Endothelial Growth Factor Vascular Endothelial Growth Factor A Working Distance (nozzle–collector spacing in electro-/melt-writing) Expanded Polytetrafluoroethylene

Abbas Fazel Anvari-Yazdi: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Project administration, Methodology, Investigation, Conceptualization. Daniel J. MacPhee: Writing – review & editing, Supervision, Funding acquisition. Ildiko Badea: Writing – review & editing, Supervision, Funding acquisition. Xiongbiao Chen: Writing – review & editing, Supervision, Funding acquisition.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The support from the Natural Sciences and Engineering Research Council (NSERC) of Canada (Funding Numbers: RGPIN 06,369–2019 and 2020–05315 ) and the University of Saskatchewan’s Devolved Scholarship to the present work is acknowledged. Ethics statement NA Data availability No additional data is available. Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this manuscript, the authors used ChatGPT (GPT4o), Grammarly, and ProWritingAid for editing, grammar check, and clarity. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Effectively managing peritoneal adhesions requires a deep understanding of the numerous factors contributing to their formation and the intricate biological processes involved. Key among these are inflammation, coagulation, and fibrinolysis. The formation of adhesions is marked by the dense deposition of new collagen and the aggregation of immune-inflammatory cells at the adhesion site. Different cell types, such as neutrophils, macrophages, and mesothelial cells, exhibit varying activity cycles—with neutrophils being the first responders to mesothelial damage [ 41 ]. These cells interact and cooperate after tissue trauma, collectively driving adhesion formation [ 42 ]. Therefore, understanding the unique roles of each cell type, their interactions, and the timing of interventions that promote mesothelial healing and restore fibrinolytic balance is crucial for developing effective anti-adhesion strategies. The peritoneum, the largest serous membrane in the body, is lined with a monolayer of elongated, flattened, and squamous-like mesothelial cells of approximately 25 µm thickness, which serves as a critical protective barrier in the abdominal cavity [ 43 ]. The basement membrane, stroma, capillaries, and lymphoid tissue are located underneath the mesothelial layer ( Fig. 1 B). The peritoneum is a two-way, semi-permeable membrane with a strong absorption capacity [ 44 ]. In 1863, Von Recklinghausen described the presence of ‘stomata’—small cavities located at the junctions between two or more mesothelial cells. These stomata, typically 3–12 μm in diameter, are most often found in regions with cuboidal mesothelial cells [ 45 ]. Von Recklinghausen theorized that these openings allow fluid and particulate matter to move in and out of the serous cavities. The stomata provide direct access to the underlying sub-mesothelial lymphatic system, allowing for the rapid removal of fluid. Mesothelial cells continuously secrete peritoneal fluid, which is released into the abdominal cavity and then reabsorbed by the peritoneum stomata [ 46 ]. This process facilitates the constant exchange of growth factors, nutrients, and cytokines between the peritoneal fluid and blood. Additionally, a small amount of peritoneal fluid is always present in the abdominal cavity to ensure lubrication [ 47 ]. The mesothelial cells produce glycosaminoglycans (GAGs) and hyaluronic acid (HA), forming a lubricating layer that helps prevent internal adhesions by maintaining a smooth surface on the abdominal cavity's inner layer ( Fig. 1 B) [ 48 ]. Hyaluronan, which increases in response to injury, is incorporated into a hyaluronan-rich pericellular matrix ( Fig. 1 B) [ 49 ]. Additionally, hyaluronan may help protect serosal membranes from the formation of adhesions [ 50 , 51 ]. Hyaluronan is not obtained from the bloodstream but is produced locally [ 48 ]. This natural liquid barrier reduces friction and minimizes the risk of adhesions forming between tissues and organs during scar formation. Adhesion formation begins when two injured peritoneal surfaces come into contact, initiating both the coagulation and inflammation processes [ 52 ]. Mesothelial cells, which are metabolically active, play a significant role in this response. Following peritoneal injury, the release of signaling molecules such as histamine increases vascular permeability, allowing immune cells—mainly neutrophils and macrophages—to migrate to the wound site ( Fig. 1 C 1 ) [ 53 ]. Simultaneously, fibrinogen from the plasma is released into the area. Thrombinogen is converted to thrombin, aggregating platelets and transforming fibrinogen into fibrin, forming a provisional fibrin matrix. The elevated secretion of cytokines from the inflammatory response may inhibit tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) enzyme activity, resulting in a reduced tPA/PAI ratio and impaired fibrinolytic function ( Fig. 1 C 1 ). Both uPA and tPA are essential in regulating fibrinolysis to break down fibrin in blood clots for normal tissue healing [ 54 ]. The early stages of adhesion formation involve the fibrin matrix serving as a temporary bridge between two injured peritoneal surfaces. This matrix acts as a scaffold for additional immune cells and fibroblasts, contributing to the healing process and the potential development of adhesions ( Fig. 1 D) [ 55 , 56 ]. Over the first few days, this matrix becomes infiltrated by various immune cells, including polymorphonuclear leukocytes (PMNs), macrophages, eosinophils, and erythrocytes ( Fig. 1 C 2 ). The clot formed from this process is initially unorganized but begins to undergo structural changes as fibroblasts and macrophages take over. By day four, macrophages become the predominant cell type, and fibroblasts begin forming a syncytium with them, gradually replacing the fibrin strands with collagen fibers ( Fig. 1 C 2 ) [ 57 , 58 ]. As adhesion formation progresses, fibroblasts synthesize collagen, creating a more stable fibrous structure [ 55 ]. By day seven, adhesions primarily consist of collagen fibers and fibroblasts, interspersed with small vascular channels lined with endothelial cells ( Fig. 1 C 2 ) [ 59 ]. These adhesions mature over the following weeks to months into fibrous bands containing connective tissue, blood vessels, and mesothelial cells. Collagen fibrils dominate the tissue structure, while immune cells such as macrophages and lymphocytes gradually decrease, though they may persist for some time [ 57 , 59 ]. Several factors influence the persistence and organization of adhesions. The presence of a fibrinous exudate is crucial for adhesion formation. Intraperitoneal structures, which are highly mobile, do not form permanent adhesions unless they are held in continuous, close contact until fibroblast invasion and collagen deposition occur, typically around the third postoperative day [ 60 ]. If natural fibrinolytic processes absorb the fibrin matrix, the adhesion dissolves. However, if the fibrin bridge contains cellular elements like erythrocytes, leukocytes, and platelets, it is more likely to become organized into a permanent fibrous adhesion [ 55 , 61 ]. Intraperitoneal adhesions are a significant clinical challenge, especially after surgical procedures involving tissue dissection, cutting, or coagulation. Their formation is closely tied to the impact of the injury on the mesothelium and the interplay of blood products, immune responses, and fibrin persistence. Any damage to peritoneal tissue facilitates adhesion development, highlighting the importance of careful tissue handling and surgical settings and adhesion barriers to minimize the risk of postoperative adhesions.

Anti-adhesion barriers and biomaterials are at a pivotal point where customization, innovation, and targeted approaches are essential for advancing surgical outcomes. Beyond simply preventing post-surgical adhesions, there is a growing recognition of the need for more sophisticated and patient-specific solutions. Diagnosing and identifying adhesions prior to surgery, such as through adhesionlysis, can guide the selection of materials and techniques best suited for each patient, rather than relying on generic, "one-size-fits-all" barriers. Film and gel barriers both have merits and demerits. To ensure proper treatment, it is necessary to identify and fully cover the injured area precisely. Despite the challenges posed by the complex geometries of the abdominal cavity, it is difficult to apply physical barriers. On the other hand, gel barriers possess specific advantages that physical films do not have. However, despite their advantages, gel barriers have a notable disadvantage—there is a higher risk of gel migration to areas that were not intended, especially after the abdominal closure. Additionally, bowel movements can push the gels out of place, and they fail to provide sufficient coverage to the injured area within the critical seven-day healing window. Surgeons must manually apply the barriers by graspers, which increases the risk of additional tissue trauma, and their use in laparoscopic surgery procedures is limited due to the range of movement and access to the pelvic cavity. This approach can significantly improve surgical outcomes by personalizing the thickness, flexibility, and adherence properties of barriers to match the specific type of surgery. Furthermore, an important area of research lies in improving the shelf life of adhesion barriers, which would allow for more extended storage without compromising the efficacy of bioactive components, such as proteins. In this regard, dry barrier films offer distinct advantages over gel-based barriers, as they are better suited to maintaining stability and bioactivity over extended periods, making them a more favorable choice in many clinical applications. Developing self-healing bioadhesion barriers marks an innovative leap forward in the field. By creating materials that can repair themselves after damage or rupture due to abdominal closure or bowel movement, we can significantly reduce complications and the need for additional interventions. This is particularly valuable in abdominal surgeries where tissues are under mechanical stress, leading to potential rupture or failure of standard barriers. Advancing current FDA-approved anti-adhesion barriers like INTERCEED™, Seprafilm®, and SurgiWrap® with pharmaceutical cues offers another promising avenue. By incorporating active pharmaceutical ingredients locally, these materials can prevent adhesions and modulate the local biological environment to enhance healing, reduce inflammation, and minimize adverse effects. This type of multifunctional material design could revolutionize post-operative care, reducing the rate of adhesion recurrence and improving patient recovery times. Caesarean section adhesions, specifically, represent an often overlooked but serious complication, with implications for future pregnancies [ 235 ]. Scar tissue from C-sections can form internal and external niches, increasing the risk of uterine rupture in subsequent pregnancies, which poses risks to both the mother and baby [ 236 , 237 ]. Developing specialized bandages and films that support myometrial tissue reconstruction is a crucial need. This could significantly reduce these risks, ensuring safer deliveries and healthier outcomes for mothers and infants. Moreover, microneedle Janus patches are promising for drug delivery applications due to their ability to adhere effectively to damaged tissue without suturing. Their capacity to provide sustained drug release makes them particularly valuable in postoperative settings, where minimizing invasive procedures and ensuring prolonged therapeutic effects are key objectives. Janus patches and hydrogels are the next generation of barriers. In the case of endometriosis, a condition that affects a significant proportion of women, the need for specific adhesion barriers coupled with pharmaceutical interventions is vital [ 3 ]. Current research focuses predominantly on surgical injuries like myomectomy and adhesiolysis, while the unique challenges posed by endometriosis-related adhesions require additional attention. These adhesions, often painful and recurrent, necessitate a more integrated approach that includes surgical barriers and pharmaceutical strategies to modulate the disease process and alleviate symptoms. Looking forward, the future of adhesion barriers lies in creating multifunctional, bioactive materials that go beyond simple physical barriers to actively contribute to healing processes, tissue regeneration, and even diagnostic capabilities. The convergence of biomaterial science, pharmaceuticals, and advanced imaging technologies holds the potential to dramatically improve outcomes in various surgical settings, reducing complications, enhancing recovery, and improving quality of life for millions of patients globally. Implementing this method has significantly reduced the risk of negative laparoscopies and inadvertent enterotomies, showcasing promising results. On the downside, one drawback of this technique is the restricted pool of radiologists who possess the necessary experience in this particular area. Integrating artificial intelligence (AI) into computer-aided detection systems is expected to lead to improved usage and accuracy, thereby benefiting a wide range of applications. Microneedle Janus patches represent promising candidates for drug delivery applications due to their ability to adhere effectively to damaged tissue without suturing. Their capacity to provide sustained drug release makes them particularly valuable in postoperative settings, where minimizing invasive procedures and ensuring prolonged therapeutic effects are key objectives. Janus patches and hydrogels are the next generation of barriers.

A critical design criterion for postoperative anti-adhesion biomaterials is ensuring safe exertion and stability at the implantation site during healing, followed by predictable degradation to avoid retention or inflammatory complications [ 79 , 93 ]. Control of biodegradation kinetics is accordingly essential to maintain function and safety throughout the healing timeline. These barriers—typically thin films, gels, or membranes—are placed within the peritoneal cavity to prevent fibrous tissue bridges between adjacent organs during the healing process. They are most often composed of biodegradable polymers, which are designed to remain in place and then break down into non-toxic byproducts that are efficiently cleared from the body without the need for surgical retrieval. The clearance mechanisms of biomaterials are critically dependent on molecular weight, chemical composition, and degradation kinetics. Improper clearance of residual polymer fragments may elicit foreign‑body reactions, tissue encapsulation, and even organ accumulation, potentially disrupting physiological function. Conversely, optimally engineered materials are designed to degrade into biologically benign metabolites and be eliminated via natural pathways such as renal excretion [ 98 , 99 ]. Following degradation in the peritoneal cavity, polymer fragments may be eliminated via four primary pathways: (a) Renal (urinary) excretion, (b) Hepatic and biliary clearance, (c) Respiratory exhalation as CO₂, and (d) Lymphatic transport (as an intermediate step) [ 79 ]. (a) Renal Elimination is predominant for hydrophilic degradation products under a certain size threshold (∼30–40 kDa). These fragments can freely pass through the glomerular filtration barrier and be eliminated in urine. For example, Seprafilm®, composed of hyaluronic acid and carboxymethyl cellulose, degrades into oligosaccharides and water-soluble fragments and is primarily cleared through the kidneys within approximately 28 days. Similarly, polyethylene glycol chains under ∼40 kDa are effectively excreted renally, and only low-molecular-weight HA fragments (<12 kDa) are known to be filtered by the kidneys in physiological conditions [ [100] , [101] , [102] ]. (b) Hepatic and Biliary Excretion becomes important for larger or more hydrophobic fragments. These may be taken up by the mononuclear phagocyte system (MPS), including Kupffer cells and liver sinusoidal endothelial cells, then excreted into bile and ultimately the feces. For instance, high-molecular-weight hyaluronic acid (HA) is predominantly sequestered and cleared by liver-resident phagocytic and endothelial cells without significant metabolic degradation. A similar shift from renal to hepatic clearance is observed for large PEG chains (>50 kDa), which tend to accumulate in the liver. However, polymers up to ∼200 kDa may still undergo dual clearance, involving both renal filtration and hepatic uptake, depending on their degradation state and solubility [ 101 , 103 ]. (c) Respiratory Elimination is particularly relevant for aliphatic polyesters, such as PLA and PLGA. These degrade into lactic acid and glycolic acid, which are metabolized via the tricarboxylic acid (TCA) cycle and ultimately exhaled as carbon dioxide and water. This metabolic route provides a nearly complete elimination pathway that mimics physiological energy metabolism. Other polymers, such as oxidized cellulose (which degrades to glucose acids) and natural biopolymers like collagen or gelatin (which break down to amino acids), similarly follow metabolic clearance routes, either being reused in biosynthetic pathways or oxidized for energy [ 79 , 104 ]. (d) Lymphatic Transport plays a critical intermediary role for high-molecular-weight or slowly absorbed polymers, especially those administered intraperitoneally. The peritoneum is equipped with lymphatic stomata that can take up macromolecules and direct them toward the thoracic duct and bloodstream. A notable example is Icodextrin (Adept®), a starch-derived polymer too large for direct absorption into capillaries. It is absorbed via the lymphatics and subsequently broken down enzymatically in the circulation, after which the resulting oligosaccharides are excreted renally [ 105 ]. Renal Elimination is predominant for hydrophilic degradation products under a certain size threshold (∼30–40 kDa). These fragments can freely pass through the glomerular filtration barrier and be eliminated in urine. For example, Seprafilm®, composed of hyaluronic acid and carboxymethyl cellulose, degrades into oligosaccharides and water-soluble fragments and is primarily cleared through the kidneys within approximately 28 days. Similarly, polyethylene glycol chains under ∼40 kDa are effectively excreted renally, and only low-molecular-weight HA fragments (<12 kDa) are known to be filtered by the kidneys in physiological conditions [ [100] , [101] , [102] ]. Hepatic and Biliary Excretion becomes important for larger or more hydrophobic fragments. These may be taken up by the mononuclear phagocyte system (MPS), including Kupffer cells and liver sinusoidal endothelial cells, then excreted into bile and ultimately the feces. For instance, high-molecular-weight hyaluronic acid (HA) is predominantly sequestered and cleared by liver-resident phagocytic and endothelial cells without significant metabolic degradation. A similar shift from renal to hepatic clearance is observed for large PEG chains (>50 kDa), which tend to accumulate in the liver. However, polymers up to ∼200 kDa may still undergo dual clearance, involving both renal filtration and hepatic uptake, depending on their degradation state and solubility [ 101 , 103 ]. Respiratory Elimination is particularly relevant for aliphatic polyesters, such as PLA and PLGA. These degrade into lactic acid and glycolic acid, which are metabolized via the tricarboxylic acid (TCA) cycle and ultimately exhaled as carbon dioxide and water. This metabolic route provides a nearly complete elimination pathway that mimics physiological energy metabolism. Other polymers, such as oxidized cellulose (which degrades to glucose acids) and natural biopolymers like collagen or gelatin (which break down to amino acids), similarly follow metabolic clearance routes, either being reused in biosynthetic pathways or oxidized for energy [ 79 , 104 ]. Lymphatic Transport plays a critical intermediary role for high-molecular-weight or slowly absorbed polymers, especially those administered intraperitoneally. The peritoneum is equipped with lymphatic stomata that can take up macromolecules and direct them toward the thoracic duct and bloodstream. A notable example is Icodextrin (Adept®), a starch-derived polymer too large for direct absorption into capillaries. It is absorbed via the lymphatics and subsequently broken down enzymatically in the circulation, after which the resulting oligosaccharides are excreted renally [ 105 ]. This multi-route elimination framework provides a rational basis for the safe design of anti-adhesion barriers. An effective barrier must maintain its mechanical or biological function during the peak risk period of adhesion formation (typically the first 5–7 days post-surgery), followed by timely degradation and safe elimination. Advances in polymer chemistry—such as molecular weight tuning, incorporation of enzyme-cleavable linkages, or adjusting hydrophilicity—further enable developers to fine-tune degradation rates and clearance profiles for optimized patient safety. A comparative summary of representative materials and their major clearance routes is provided in Table 3 . Table 3 Representative Anti-Adhesion Materials and Their Primary Physiological Elimination Routes. Table 3: Material/Example Primary Elimination Pathway Notes Seprafilm® (HA/CMC) Renal (urinary) Cleared within 28 days via urine Low-MW HA (<12 kDa) Renal (urinary) Only fragments <12 kDa filtered PEG (50 kDa) Hepatic & renal Taken up by Kupffer cells; biliary and renal excretion PLA/PLGA Respiratory (CO₂) & renal Lactic acid → CO₂; glycolic acid → urine or CO₂ Oxidized Cellulose Respiratory (CO₂) & renal Metabolized into glucose acid intermediates Collagen/Gelatin Respiratory or reutilization Amino acids reused or oxidized to CO₂ Icodextrin (Adept®) Lymphatic → renal Lymphatic uptake, enzymatic breakdown, then renal excretion Representative Anti-Adhesion Materials and Their Primary Physiological Elimination Routes.

Over the past decades, various natural and synthetic polymers with biocompatible and biodegradable properties have been developed and used as physical barriers to inhibit tissue adhesion following surgery ( Fig. 2 ). The major classes include natural and synthetic biopolymers. Fig. 2 Bio-Polymers Classification for Postoperative Adhesion (GPOA) Management. This diagram categorizes biomaterials into natural and synthetic polymers, further subdivided into biodegradable and non-biodegradable types. Natural Polymers: These include phospholipids (e.g., triglycerides, cholesterol), polyphenols (e.g., lignin, tannic acid, humic acid), polysaccharides (e.g., hyaluronic acid, alginate, cellulose, chitosan), and proteins (e.g., collagen, gelatin, silk). Natural polymers are highly biocompatible but may exhibit variability in mechanical properties and production consistency. Synthetic Polymers: These materials offer enhanced versatility, with the ability to tailor biodegradability and mechanical characteristics. Biodegradable synthetic polymers such as polylactic acid (PLA), polycaprolactone (PCL), and polyglycolic acid (PGA) are commonly employed in GPOA applications for their controlled degradation and mechanical strength. Non-biodegradable polymers like polyethylene terephthalate (PET), polytetrafluoroethylene (ePTFE), and polymethyl methacrylate (PMMA) provide permanent structural support where long-term functionality is required. This classification highlights the wide range of natural and synthetic materials explored for managing postoperative adhesions, emphasizing their respective properties and potential applications in the medical field. Fig. 2: Bio-Polymers Classification for Postoperative Adhesion (GPOA) Management. This diagram categorizes biomaterials into natural and synthetic polymers, further subdivided into biodegradable and non-biodegradable types. Natural Polymers: These include phospholipids (e.g., triglycerides, cholesterol), polyphenols (e.g., lignin, tannic acid, humic acid), polysaccharides (e.g., hyaluronic acid, alginate, cellulose, chitosan), and proteins (e.g., collagen, gelatin, silk). Natural polymers are highly biocompatible but may exhibit variability in mechanical properties and production consistency. Synthetic Polymers: These materials offer enhanced versatility, with the ability to tailor biodegradability and mechanical characteristics. Biodegradable synthetic polymers such as polylactic acid (PLA), polycaprolactone (PCL), and polyglycolic acid (PGA) are commonly employed in GPOA applications for their controlled degradation and mechanical strength. Non-biodegradable polymers like polyethylene terephthalate (PET), polytetrafluoroethylene (ePTFE), and polymethyl methacrylate (PMMA) provide permanent structural support where long-term functionality is required. This classification highlights the wide range of natural and synthetic materials explored for managing postoperative adhesions, emphasizing their respective properties and potential applications in the medical field. Natural biopolymers encompass a wide array of materials, including proteins and extracellular matrix (ECM)-derived substances like collagen, gelatin, fibrin, silk fibroin , and decellularized ECM, all of which hold significant potential in various biomedical applications. These biomaterials inherently mimic the composition of native tissue and often contain ligands that promote cell attachment and healing. Collagen and fibrin, for instance, are integral to the body’s wound repair processes and have been used in gels or sponge forms to encourage regenerative healing while minimizing scarring [ 62 ]​. Gelatin (denatured collagen) offers low antigenicity and has been formulated into bioresorbable films and sealants [ 63 ]​. Silk fibroin, a fibrous protein from silkworm cocoons, provides exceptional mechanical strength and slow degradability, making it useful for load-bearing scaffolds such as uterine wall patches. Decellularized matrices (e.g., uterine or placental dECM) carry native growth factors and structural proteins, which can enhance biocompatibility and tissue-specific regeneration​ [ 64 ]. Natural polymers generally excel in biocompatibility and bioactivity, but their mechanical properties can be inferior to synthetic materials and may require crosslinking or blending to achieve the desired strength​. Polysaccharides are carbohydrate-based polymers like cellulose, chitosan, as well as alginate, and are another important category. Cellulose derivatives (such as oxidized regenerated cellulose and carboxymethyl cellulose) have been successfully used in commercial adhesion barriers, where their hydrophilicity and gel-forming ability create a protective film over injured surfaces​ [ 65 ]. Chitosan , a sugar polymer from chitin, offers inherent antimicrobial properties and has been formulated into anti-adhesive membranes and porous scaffolds; its cationic nature can promote mucoadhesion and hemostasis at wound sites​ [ 66 ]. Alginate , derived from algae, is a mild gelling polysaccharide that is biocompatible and easily loaded with drugs or cells [ [67] , [68] , [69] , [70] ]. ​In uterine tissue engineering, alginate hydrogels have been used to deliver stem cells and growth factors, although alginate can elicit inflammation unless highly purified [ 71 ]​. Polysaccharide materials are attractive due to their tunable viscosity and generally low toxicity. Still, they often require chemical modification (e.g., cross-linking) to improve their stability and cell-interacting properties for long-term tissue support. Synthetic biodegradable polymers include polyesters and other lab-synthesized polymers such as poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and polyethylene glycol (PEG) . PLGA and related polyesters are widely used in biomedical devices and are FDA-approved; they degrade by hydrolysis into metabolizable by-products (lactic and glycolic acid) and can be engineered into fibers, meshes, or foams with high porosity [ [67] , [68] , [69] ]​. For adhesion prevention, PLGA and PLA films have been applied as resorbable barriers that physically separate tissues and gradually disappear after fulfilling their function [ 72 ]​. In uterine repair, PLGA scaffolds provide initial mechanical support and have been shown to maintain a high porosity conducive to cell infiltration​ [ 73 ]. PCL is another polyester with a slower degradation rate and greater flexibility; PCL electrospun scaffolds can be fabricated with nano- to microscale fibers that mimic the uterine muscle layer architecture​ [ 74 ]. PEG , unlike the polyesters, is a biologically inert, hydrophilic polymer; it does not degrade in vivo by itself but is often used in crosslinked form as a hydrogel (e.g. PEG-based hydrogels like Coseal™) or as a component in copolymers. PEG gels are used as sprayable or injectable adhesion barriers that conform to tissue shapes and then resorb, and as cell-laden hydrogels in regenerative medicine​ [ 75 ]. Synthetic degradable polymers offer the advantage of tailorable mechanical properties and degradation kinetics, allowing customization for specific applications. However, care must be taken to ensure their degradation products and processing solvents do not induce inflammation that could counteract the anti-adhesion or pro-regenerative goals​ [ 76 ]. Non-degradable polymers are traditional non-resorbable plastics like expanded polytetrafluoroethylene (ePTFE) and polypropylene (PP) that represent another class, historically used in surgical implants and meshes. ePTFE is chemically inert and biologically stable; as mentioned, it has been used as a physical barrier to block adhesions (e.g., in abdominal or cardiac surgery) and successfully reduces initial scar formation​ [ 77 ]. Polypropylene meshes are commonly employed for hernia repairs and pelvic organ prolapse support due to their high tensile strength and durability. In adhesion prevention, however, polypropylene and other non-degradable implants can incite foreign body reactions and fibrotic responses over time. If placed in direct contact with peritoneal organs, an unmodified PP mesh will almost invariably become encapsulated by dense adhesions. To mitigate this, composite mesh products have been developed where an adhesive layer (often collagen or absorbable polymer) is bonded to polypropylene to act as a temporary barrier. In general, permanent polymers are not ideal for intra-abdominal adhesion prevention unless they can be removed. Any remaining material that remains indefinitely may trigger chronic inflammation or serve as a nidus for new adhesions once the initial barrier function has ceased​ [ 78 ]. Consequently, their role in modern adhesion management is limited. However, they remain essential in scenarios where long-term mechanical reinforcement is needed (e.g. structural support in uterine prolapse surgery), with appropriate precautions or coatings to minimize adhesiogenic contact. To facilitate direct comparison across material classes, Table 1 presents a concise matrix outlining the key advantages, limitations, degradation behavior, and clinical translation status of the most widely used biomaterials in anti-adhesion applications. While natural polymers offer strong biocompatibility and rapid resorption, synthetic polymers provide tunable longevity but may generate acidic by-products. Composite systems aim to balance these traits, whereas emerging bio-inspired materials introduce new functionalities such as self-healing and intrinsic immunomodulation. This comparative overview supports material selection strategies tailored to specific gynecologic surgical contexts. Table 1 Comparative matrix of major biomaterial classes for anti-adhesion barriers [ 39 , 79 ]. Table 1: Biomaterial Class Key Examples Pros Cons Degradation Profile Clinical Readiness Natural polymers Hyaluronic acid, Alginate, Chitosan, Collagen - Biocompatible- Pro-healing - Low immunogenicity - Weak mechanical strength - Rapid degradation - Batch variability Days to 2 weeks (enzymatic, hydrolytic) Several FDA-approved (e.g., Seprafilm®, Hyalobarrier®) Synthetic polymers PLA, PLGA, PCL, PEG - Tunable mechanics- Scalable & reproducible - Slow, controlled resorption - Acidic degradation by-products (PLA/PLGA) - Hydrophobicity may hinder integration Weeks to >12 months (hydrolytic, passive) Many approved (e.g., SprayGel®); others in clinical trials Composite systems HA–CMC, PEG–silk, PLA–ORC, ZnO–GelMA Janus patch - Combine strengths of components - Enable multi-functionality (e.g., ROS-scavenging + shielding) - Better control over barrier lifespan - Complex fabrication - Regulatory challenges - Long-term safety less studied Tunable: days to months depending on the matrix Some are in clinical trials; most are pre-clinical Emerging bio-inspired systems Supramolecular hydrogels, polyphenol-rich cryogels, host–guest networks - Self-healing - Injectable - Intrinsic bioactivity (anti-inflammatory, antimicrobial) - Novelty limits clinical data - Expensive - Challenging scale-up Often rapid clearance (<1 week); low acidity Mostly pre-clinical or in vitro proof-of-concept Comparative matrix of major biomaterial classes for anti-adhesion barriers [ 39 , 79 ]. To provide a side-by-side view of how base polymers are transformed into clinically relevant barriers, Table 2 catalogs the most-studied raw materials, the chemical or processing steps used to convert them, their final barrier formats, and the key degradation and inflammatory profiles that determine their suitability for gynecologic surgery. This comparative snapshot underscores why seemingly similar polymers—e.g., fast-resorbing hyaluronic acid versus slowly hydrolyzing PCL—must be matched to the desired barrier-life window and tissue environment. Table 2 Snapshot representative raw polymers, conversion strategies, and final anti-adhesion barrier applications in gynecologic surgery. Table 2: Raw polymer Typical conversion / processed format Final Form Representative gynecologic (or translational) barrier use Main degradation & inflammatory notes Ref. Hyaluronic acid (HA) Carbodiimide- or aldehyde-cross-linked sheet (HA/CMC film) or in-situ hydrogel Film, hydrogel Seprafilm® sheet placed over uterine or pelvic serosa after myomectomy Hyaluronidase cleavage → N-acetyl-glucosamine → renal; generally non-acidic, low inflammation [ [80] , [81] , [82] , [83] ] Alginate Ca²⁺-gelled spray / photo-cross-linked hydrogel Film, Sponge, Gel Alginate-HA gel coating uterine incision at C-section (rat) Hydrolysis → uronic acids → fecal + renal; high-G alginate may recruit macrophages [ [84] , [85] , [86] ] Carboxymethyl chitosan (CMCS) CMCS + oxidised regenerated cellulose composite gauze Film, Sponge Barrier packed around ovaries & uterus in rabbit pelvic surgery Lysozyme depolymerisation → glucosamine; transient M2-skewed macrophage response [ 79 , 87 ] Collagen / Gelatin TGase-cross-linked COL/CMCS/CMCL membrane Film, Gel, Sponge Film sutured onto uterine horn defect (rat) Protease digestion → amino acids; very low antigenicity [ 88 ] Silk fibroin Electrospun PEG/Silk core-sheath nanofibre loaded with ibuprofen Patch laid on pelvic peritoneum to curb inflammation & adhesions Protease-mediated β-sheet erosion; mild macrophage infiltration [ 89 , 90 ] Polycaprolactone (PCL) Super-hydrophobic electrospun PCL / beeswax sheet Mesh, Film Physical spacer isolating uterus from bowel Very slow hydrolysis (18–24 mo) → ε-caprolactone → β-oxidation; minimal acidity [ 91 , 92 ] Polyethylene glycol (PEG) Multi-arm PEG spray-gel (e.g., SprayGel™ / Coseal®) Gel Laparoscopic myomectomy—spray coats uterine incision Hydrolysis → PEG fragments (2–20 kDa) → renal; osmotic diuresis if excess [ 79 , [93] , [94] , [95] , [96] ] Polyphenols (lignin / tannic acid) Metal–phenolic dynamic network in Janus patch Film Conceptual uterine Janus barrier with ROS-scavenging inner face Enzymatic oxidation → phenolic acids → urine; ROS neutralization dampens TNF-α [ 40 , 97 ] Snapshot representative raw polymers, conversion strategies, and final anti-adhesion barrier applications in gynecologic surgery.

Gynecologic postoperative adhesions (GPOA) represent a significant complication following surgical procedures, particularly after abdominal or pelvic surgeries. Several factors can contribute to post-surgical peritoneal trauma, such as the trauma caused by surgical incisions, friction from gauze, damage from sutures, reduced blood flow (ischemia), tissue desiccation, exposure to gases during laparoscopic surgery, intense surgical light, or damage caused by surgical instruments [ 1 ]. Acute endometriosis and other sources of peritoneal irritation can also result in the development of adhesions [ 2 , 3 ]. Gynecologic surgeries account for some of the highest adhesion-related morbidity: adhesions develop in up to 90 % of women after open myomectomy and extensive endometriosis excision, 45–65 % after repeat caesarean section, and 20–30 % after operative hysteroscopy. These adhesions jeopardize reproductive capacity (estimated 20–40 % of secondary infertility cases) and may precipitate life-threatening complications such as bowel obstruction or placenta accreta spectrum disorders. Consequently, designing barriers that conform to the dynamic, hormone-responsive uterine environment is a distinct materials-science challenge, separate from bowel-oriented barriers [ [4] , [5] , [6] , [7] , [8] , [9] ]. From a clinical perspective, GPOA differs significantly from those arising in other types of surgeries. While adhesions can occur after any abdominal operation, GPOA is uniquely associated with reproductive structures such as the uterus, fallopian tubes, and ovaries. These adhesions often cause infertility by obstructing gamete transport or distorting pelvic anatomy [ 10 ]. Unlike colorectal or general surgical adhesions—which more commonly lead to mechanical complications like bowel obstruction—GPOA frequently affects hormonal cycles, fertility, and obstetric outcomes, including placenta accreta spectrum and ectopic pregnancy [ [11] , [12] , [13] ]. Therefore, the clinical imperative to prevent adhesions is particularly high in gynecology, not only to reduce pain and reoperation rates but to preserve fertility and prevent high-risk pregnancies. The multifactorial aetiology of peritoneal adhesions is not entirely understood, though significant progress has been made in identifying the key factors involved [ 14 ]. Following trauma to the peritoneum, the release of histamine increases vascular permeability, resulting in the production of inflammatory exudates, including cytokines, neuropeptides, and cell adhesion molecules, as well as the formation of a myofibroblast and fibrin matrix. Fig. 1 A schematically illustrates the role of fibroblasts and fibrin in adhesion formation. The body’s healing response in the peritoneal cavity involves a delicate balance between the regeneration of mesothelial cells and the formation of scar tissue (fibrosis) [ 1 ]. The fibrin matrix plays a crucial role in the early stages of healing, and when the rate of fibrin production matches its degradation at the surgical site, normal wound healing occurs. Once this balance is disrupted, the process may lead to adhesion formation [ 15 ]. Fig. 1 Mechanisms and progression of postoperative adhesion formation in the uterus and peritoneal cavity. (A) Schematic representation of uterine injury and the cascade of events leading to adhesion formation, highlighting the central role of thrombin in fibrin clot formation, platelet activation, and inflammation. Under pathological conditions such as surgery or infection, impaired fibrinolysis leads to persistent fibrin deposition and extracellular matrix production by fibroblasts. (B) Structural anatomy of the peritoneum showing the mesothelial layer (∼25 µm thick) composed of squamous-like cells and stomata. This surface, enriched with glycosaminoglycans and hyaluronan, normally facilitates fluid exchange and prevents adhesion by reducing friction. (C 1 and C 2 ) Healing pathogenesis after peritoneal trauma, where increased vascular permeability leads to fibrin exudate formation. In non-ischemic conditions, fibrinolysis clears this matrix, allowing mesothelial repair. However, under ischemia, fibrin persists, becomes infiltrated by fibroblasts, and transitions into fibrous adhesions. (D) Early adhesion formation is depicted as fibrin matrix deposition between injured peritoneal surfaces. If not resolved, this provisional matrix matures into permanent adhesions through fibroblast proliferation, collagen deposition, and potential attachment to adjacent pelvic organs. Fig. 1: Mechanisms and progression of postoperative adhesion formation in the uterus and peritoneal cavity. (A) Schematic representation of uterine injury and the cascade of events leading to adhesion formation, highlighting the central role of thrombin in fibrin clot formation, platelet activation, and inflammation. Under pathological conditions such as surgery or infection, impaired fibrinolysis leads to persistent fibrin deposition and extracellular matrix production by fibroblasts. (B) Structural anatomy of the peritoneum showing the mesothelial layer (∼25 µm thick) composed of squamous-like cells and stomata. This surface, enriched with glycosaminoglycans and hyaluronan, normally facilitates fluid exchange and prevents adhesion by reducing friction. (C 1 and C 2 ) Healing pathogenesis after peritoneal trauma, where increased vascular permeability leads to fibrin exudate formation. In non-ischemic conditions, fibrinolysis clears this matrix, allowing mesothelial repair. However, under ischemia, fibrin persists, becomes infiltrated by fibroblasts, and transitions into fibrous adhesions. (D) Early adhesion formation is depicted as fibrin matrix deposition between injured peritoneal surfaces. If not resolved, this provisional matrix matures into permanent adhesions through fibroblast proliferation, collagen deposition, and potential attachment to adjacent pelvic organs. Adhesion bonding can be formed between the operated organs, intestines, fallopian tubes, omentum, and/or abdominal wall; essentially, between any two surfaces within the abdominal cavity as part of the healing process [ 16 ]. Three different types of postoperative adhesion formations have been reported: (i) adhesions occurring at the surgical site, (ii) reformation of adhesions (those that form again after the removal of previous adhesions), and (iii) de novo adhesions (adhesions forming at nonsurgical sites) [ 17 , 18 ]. These types of adhesions can severely affect pelvic organ function, and in gynecology, directly threaten fertility, pregnancy outcome, and sexual health, leading to serious complications such as bowel obstruction, impaired organ function, infertility, dyspareunia (painful or difficult sexual intercourse), and chronic pelvic pain, all of which contribute to increased long-term morbidity [ 19 ]. Adhesions can also complicate future surgeries, often leading to patients being readmitted for adhesiolysis within five to ten years [ 8 ]. This procedure increases mortality risk and imposes a significant financial burden on patients and the healthcare system [ 20 ]. The risk of developing these adhesions is a common concern after abdominal surgeries, making preventive measures a key part of post-operative care. Postoperative adhesions can be reduced through various preventative approaches. For years, the main options have been two strategies: using adhesion barriers and employing minimally invasive surgical methods, such as laparoscopy [ 8 , 21 , 22 ]. Laparoscopic surgeries are favoured over traditional open procedures (laparotomies) because their smaller incisions lead to a 50 % reduction in adhesion formation, along with less postoperative pain and fewer complications [ 4 , 23 , 24 ]. This minimally invasive approach also offers faster recovery and reduced adhesion-related morbidity. However, despite these advantages, there are still challenges with laparoscopy, particularly related to the use of CO 2 pneumoperitoneum [ 16 ]. CO 2 , which is used to inflate the abdomen during laparoscopy, plays a critical role in facilitating the procedure. However, research shows that using cold, dry CO 2 can negatively affect the peritoneal lining, contributing to adhesion formation [ 25 ]. Prolonged exposure to this unconditioned gas increases the risk of peritoneal adhesions, especially in longer surgeries. To counteract this, studies suggest that using a warmed, humidified gas mixture of CO 2 can significantly reduce these adverse effects, resulting in less postoperative pain, lower rates of peritoneal adhesions, and faster recovery times [ 26 ]. Adding small amounts of N 2 O and O 2 to the CO 2 mixture has also shown promise in preventing peritoneal hypoxia, further reducing adhesion risk [ 27 ]. In addition to these surgical and gas-related considerations, adhesion barrier films remain a critical component in the overall strategy to prevent adhesions. Barrier films act as physical separators, preventing tissues from sticking together during healing. When combined with surgical techniques guided by Halstedian principles—such as gentle tissue handling, meticulous hemostasis, and avoiding foreign body contamination—barrier films provide a robust defense against the formation of adhesions [ 28 ]. A variety of adhesion barriers are available today to prevent adhesion formation. Films such as oxidized regenerated cellulose (e.g., INTERCEED ™) and hyaluronic acid/carboxymethylcellulose (e.g., Seprafilm ™) were the first FDA-approved products and continue to be widely used due to their efficacy in separating tissues during the healing phase [ [29] , [30] , [31] , [32] , [33] ]. These pioneering products laid the foundation for the development of more advanced barriers. Beyond Seprafilm™ and INTERCEED™, numerous other options have entered the market, offering improved versatility and adaptability to various surgical environments. These include bioresorbable materials like polylactic acid (PLA), polyglycolic acid (PGA), and polycaprolactone (PCL), which are designed to be gradually absorbed by the body, eliminating the need for surgical removal. Gels and liquids, such as hyaluronic acid-based and polyethylene oxide/carboxymethylcellulose solutions, provide another layer of protection, particularly in cases where films may be difficult to apply [ 18 , 34 , 35 ]. These materials coat tissues and create a temporary barrier, preventing adhesion formation while dissolving naturally over time. By leveraging a combination of these advanced materials—whether in film, gel, or liquid form—surgeons can tailor their approach to adhesion prevention based on the surgical context and patient needs. Integrating these diverse anti-adhesion products with modern techniques like laparoscopy, conditioned CO 2 , and meticulous surgical handling has proven to be one of the most effective strategies for minimizing postoperative adhesions, improving patient outcomes, and reducing the risk of long-term complications. Over the past decade, significant progress has been made in developing anti-adhesion barriers for many tissues. To provide a specific example, the research has involved the innovative application of nanoengineering and the development of hierarchically structured fibrous scaffolds as a means of addressing the complex problem of post-injury scarring and tendon adhesion, with a particular emphasis on understanding the underlying molecular processes. Electrospun drug-eluting micro/nanofibres are developed to create ECM-mimetic topographies while providing programmed, multi-phase release of anti-fibrotic payloads, thereby unifying physical shielding with chemotherapeutic regulation of myofibroblast activity [ 36 ]. Expanding upon the aforementioned concept, there is a critical need for precise tailoring of fiber orientation, stiffness properties, and drug-release kinetics, specifically optimized to align with the unique biological characteristics of tendon sheaths.This research underscores the significant advantages offered by composite membranes capable of simultaneously providing a protective barrier function and facilitating controlled, on-demand release of therapeutic biofactors [ 37 ]. Parallel advances in nanomedicine have demonstrated that scar-formation pathways can be ‘nano-managed’: Pan et al. summarised how mesoporous silica nanoparticles, nanofibres and nanogroove substrates modulate reactive oxygen species (ROS) levels, macrophage phenotype and collagen alignment to drive scar-less dermal and internal healing [ 38 ]. Experimentally, micro-/nano-environment dual-modulated membranes embedding siRNA-loaded GelMA nanogels achieved MMP-triggered, site-specific gene silencing of ERK-2 and significantly reduced peritendinous adhesion in vivo [ 39 ]. Most recently, a drug-free Janus patch that couples a ZnO-tannic-acid hydrogel layer (inner) with a PLLA fibrous layer (outer) provided a one-two punch of ROS scavenging / anti-bacterial action and physical isolation, yielding superior biomechanical and histological outcomes after tendon repair [ 40 ]. Collectively, these studies illuminate three design principles that guide the present work: [ 1 ] anisotropic or Janus architectures that decouple tendon-side bioactivity from sheath-side anti-adhesion; [ 2 ] stimulus-responsive delivery (oxidative, enzymatic, or mechanical) rather than bolus release; and [ 3 ] integration of intrinsic anti-oxidative and anti-microbial motifs to obviate high-dose pharmacologics. Guided by these principles, this review offers a current state of post-operative adhesion barriers, with a primary focus on their functional capacity to prevent adhesions, particularly within the complex anatomical structures of the female reproductive system. Recent advancements in anti-adhesion barrier technology are highlighted, including strategies for managing peritoneal adhesions, biomaterial selection and elimination, fabrication techniques, future development, and overall perspectives.

The development of effective anti-adhesion barriers and tissue scaffolds hinges on material composition and fabrication technique, each playing a critical role in determining the functional performance of the biomaterial. A successful anti-adhesion barrier must balance biocompatibility with controlled degradation rates and essential physical properties such as mechanical strength, flexibility, wettability, and optimal thickness. These characteristics ensure that the barrier remains intact and functional throughout the critical 7–10 day postoperative healing window, thereby minimizing adhesion formation without introducing new complications [ 19 ]. Additionally, practical considerations such as ease of application during surgery and selective tissue adhesion or non-adhesiveness are crucial for clinical usability [ 106 ]. Equally important, the fabrication method significantly affects the structural and functional attributes of the biomaterial. Architectural features—including pore size, porosity, surface texture, and degradation kinetics—must be tailored to the intended application [ 107 ]. A conformal film or hydrogel uniformly covering injured tissue surfaces is ideal for anti-adhesion purposes [ 108 ]. In contrast, a three-dimensional porous scaffold is preferred for uterine repair or regeneration to facilitate cellular infiltration, tissue integration, and neovascularization [ 109 ]. Together, these design principles ensure that the biomaterial effectively supports healing while minimizing the risk of adverse tissue responses or adhesion formation. Recent advances in biomaterial fabrication techniques, particularly electrospinning and bioprinting, have significantly improved the precision and versatility of anti-adhesion barrier design. These technologies enable the creation of customized porous architectures with tunable fiber morphology, porosity, and degradation profiles, offering better control over the molecular weight distribution and clearance kinetics of the materials. Research has shown that by electrospinning, scaffolds can be engineered by adjusting polymer composition and process parameters to fine-tune biodegradation behavior and match therapeutic timelines [ 110 ]. Such precise control is essential in anti-adhesion applications, where maintaining barrier integrity during the critical healing window, followed by safe and complete degradation, is crucial. Furthermore, integrating conventional and advanced fabrication methods (e.g., blending casting with electrospinning or crosslinking strategies) helps overcome the limitations of individual techniques, paving the way for next-generation barriers with improved mechanical and biological performance. In line with this, dynamic/covalent dual-crosslinked hyaluronic acid hydrogels were reported with enhanced structural integrity and controlled degradation, which mirror the temporary yet predictable breakdown profile desired in peritoneal barrier systems [ 111 ]. Electrospun nanofibrous scaffolds have been explored as anti-adhesion barriers due to their structural similarity to the extracellular matrix (ECM), which supports cell attachment and proliferation [ 112 , 113 ]. These scaffolds can be engineered to release bioactive agents, such as anti-inflammatory drugs or growth factors, providing localized and controlled therapeutic effects [ 114 , 115 ]. This capability is particularly beneficial in preventing adhesions by modulating the inflammatory response and promoting proper tissue healing [ 116 ]. Building on this foundation, recent advancements in electrohydrodynamic atomization (EHDA) techniques—such as core–sheath fibers, triaxial, and Janus electrospinning—have further expanded the functional capabilities of electrospun barriers, enabling precise control over drug delivery, surface properties, and multi-functional integration [ 117 ]. Core–sheath fibers and triaxial electrospinning allow the fabrication of core–shell and multilayer nanofibers with precisely controlled drug release kinetics. In wound healing, such architectures have been used to deliver antibiotics and growth factors in a sustained manner, minimizing burst release, and while maintaining therapeutic levels over extended periods. This strategy or principle can be adapted to anti-adhesion materials by encapsulating anti-inflammatory or anti-fibrotic agents (e.g., mitomycin C, siRNAs) within a protected core, surrounded by a degradable outer shell that controls release at the surgical site [ 118 ]. Janus (side-by-side) electrospinning enables the creation of fibers with spatially distinct functional domains, allowing for tailored interactions with surrounding tissues. For instance, one side may offer anti-adhesive properties while the other delivers antibacterial or regenerative agents. In wound healing, tri-layer Janus fibers incorporating berberine and aloin have demonstrated two-phase drug release and synergistic effects on infection control and tissue repair [ 119 , 120 ]. Applied to post-surgical settings, this compartmentalization strategy could support a bioactive, tissue-facing surface to modulate inflammation and healing, while maintaining a non-adhesive, organ-facing surface—thus combining therapeutic delivery with physical separation [ 121 ]. This builds upon the broader concept of multifunctional scaffolds, previously discussed, by enabling simultaneous control over drug kinetics and surface behavior within a single fibrous structure [ 120 , 122 ]. Electrospraying can be used to deposit Janus particles, thereby supporting the creation of multifunctional materials; for example, research combining PCL-ciprofloxacin with TPU-ZnO has resulted in a bifunctional coating with antibacterial and UV-protective capabilities [ 119 ]. This method could be adapted for spray-on anti-adhesion coatings with directionally tailored drug presentation. In addition, green electrospinning approaches, such as water-based or melt electrospinning, have been developed to eliminate the use of toxic organic solvents. These solvent-free processes are particularly suitable for producing intrauterine or peritoneal barrier materials that require high biocompatibility and regulatory safety [ 123 ]. Collectively, these EHDA-derived fabrication strategies allow control over fiber structure, surface function, and release kinetics. Their application in anti-adhesion barrier development represents a promising direction for combining physical separation with biological modulation of healing—a crucial dual function in the prevention of postoperative adhesions in gynecologic surgery. Recent advancements in electrospinning techniques have enabled the fabrication of architecturally complex nanofibers that support multifunctionality in anti-adhesion applications. For instance, Dong et al. developed core–sheath nanofibers with asymmetrical distributions of soluble (PVP) and insoluble (EC) polymers, enabling spatial control over drug release and minimizing initial burst effects—an approach that could be translated into anti-adhesion barriers to ensure prolonged anti-inflammatory activity at the surgical site [ 124 ]. Similarly, Yu et al. demonstrated Janus nanofibers fabricated via side-by-side electrospinning, allowing independent release of two therapeutic agents (ciprofloxacin and ferulic acid) with distinct kinetics, offering combined antibacterial and antioxidant effects [ 125 ]. This spatial separation is particularly valuable in post-operative adhesion prevention, where both infection and oxidative stress contribute to aberrant healing. Complementing these findings, Zhao et al. engineered Janus nanofibers with dual-sided functionalities using PCL and gelatin; one side promoted tissue integration while the other minimized fibroblast attachment, showcasing a biomaterial platform capable of simultaneously supporting wound healing and preventing unwanted tissue adhesion [ 126 ]. These strategies underline the promise of advanced electrohydrodynamic atomization techniques for tailoring anti-adhesion scaffolds with directional, stimulus-responsive, and compartmentalized functions. Electrospinning can be used to produce either blended fiberssingle-core and or core–sheath fibersmulti-core (coaxial) fibers, depending on the study design and objectives. Blended fibersSingle-core fibers consist of one polymer solution, while multi-core fibers can include multiple layers or phases, allowing for more complex structures and functions [ 127 ]. Blended fibers: Blended fibers comprise a homogeneous polymer matrix and are commonly used to create barrier membranes that physically separate tissues during the healing process ( Fig. 3 A). In gynecological procedures, these fibers have been utilized to deliver anti-adhesive agents directly to the surgical site, reducing the incidence of adhesion formation. The release kinetics of incorporated therapeutics can be tailored by modifying polymer properties such as molecular weight and hydrophilicity. Fig. 3 Schematic working principle of blended fibers electrospinning (A), blended TPU anti adhesion barrier (A1), and PCL coated with beewax anti adhesion barrier (A2). Schematic of co-axial electrospinning (B), GelMA/SA-Van@PCL patch (B1), and (PEG)/silk fibroin nanofibrous membrane (B2). All figures adapted with permission [ 89 , 128 , 129 , 132 ]. Fig. 3: Schematic working principle of blended fibers electrospinning (A), blended TPU anti adhesion barrier (A1), and PCL coated with beewax anti adhesion barrier (A2). Schematic of co-axial electrospinning (B), GelMA/SA-Van@PCL patch (B1), and (PEG)/silk fibroin nanofibrous membrane (B2). All figures adapted with permission [ 89 , 128 , 129 , 132 ]. For instance, researchers fabricated thermoplastic polyurethane (TPU) nanofibers using electrospinning to prevent postsurgical abdominal adhesions. The study demonstrated that TPU nanofibers effectively reduced adhesion formation in a rat cecal abrasion model, attributed to their biodegradability and antibacterial properties [ 128 ]. They found that 8 % and 10 % TPU also inhibited inter-visceral adhesions ( Fig. 3 A1). Super-hydrophobic electrospun membranes were similarly prepared from poly(ε-caprolactone) and beeswax [ 129 ]. These membranes served as physical barriers to isolate wound sites, thereby preventing adhesion formation ( Fig. 3 A2). The study highlighted their potential to reduce postoperative adhesions due to their biocompatibility and mechanical strength. Core–sheath fibers: Core–sheath electrospun fibersare fabricated using a coaxial spinneret, resulting in a core-sheath fibers structure. This design enables the encapsulation of bioactive compounds within the core, while the shell controls their release profile ( Fig. 3 B) [ 130 ]. Among electrospun membranes, multi-core-sheath electrospun fibers have gained attention due to their core-shell architecture, which allows for the encapsulation of therapeutic agents in the core. At the same time, the shell regulates their release profile. This design is particularly beneficial in gynecological and abdominal surgeries, where sustained and controlled drug delivery is crucial for preventing adhesion formation over extended periods. Additionally, core-sheath electrospinning enables combination therapies, where multiple drugs can be incorporated with different release rates, targeting various aspects of inflammation, fibroblast proliferation, and tissue healing [ 131 ]. A recent study developed a bilayered composite patch using coaxial 3D printing and electrospinning to address abdominal tissue repair and adhesion prevention [ 132 ]. The patch consisted of an antibacterial layer (GelMA/SA-Van@PCL) incorporating gelatin methacryloyl (GelMA), sodium alginate (SA), and vancomycin (Van), aimed at promoting tissue regeneration while preventing infection ( Fig. 3 B1). The anti-adhesive layer (PCL-SiO₂), created via electrospinning and electrostatic spray deposition of hydrophobic silicon dioxide (SiO₂), provided long-term adhesion prevention by reducing protein adsorption and cell attachment. The composite patch exhibited excellent mechanical properties, with tensile strength exceeding 17.66 N/cm, making it suitable for abdominal tissue reinforcement. Moreover, the sustained release of vancomycin over 240 h ensured effective bacterial inhibition, preventing infection-related complications. Animal studies confirmed the reduction of postoperative adhesions, demonstrating that the bilayered structure effectively prevents adhesion formation while supporting tissue regeneration. Another study focused on core-sheath electrospun ibuprofen-loaded polyethylene glycol (PEG)/silk fibroin nanofibrous membranes for peritoneal adhesion prevention​ ( Fig. 3 B2) [ 89 ]. The study aimed to combine anti-adhesion and anti-inflammatory effects in a single membrane by utilizing a core-shell structure, where ibuprofen was encapsulated in the PEG core and surrounded by a silk fibroin shell. The in vitro characterization demonstrated optimized surface wettability, porosity (78 %), and degradation behavior, which supported gradual membrane disintegration over 60 days. Mechanical testing confirmed that the membrane possessed sufficient tensile strength and elongation to be applied as an anti-adhesion barrier. Drug release studies showed a dual-phase release profile, where 42 % of the ibuprofen was released within the first 4 h, followed by a sustained release over 14 days, ensuring long-term inflammation control [ 89 ]. In vivo evaluations demonstrated that the ibuprofen-loaded PEG/silk membrane significantly reduced peritoneal adhesions in a rat model, with histological analyses confirming lower inflammation scores compared to untreated controls [ 89 ]. Additionally, adhesion scoring systems indicated a significant reduction in adhesion severity, confirming the efficacy of the electrospun membrane as a physical and bioactive barrier. The study concluded that the core-sheath electrospun membrane successfully combined mechanical, biological, and pharmacological functionalities, making it a promising candidate for preventing peritoneal adhesions following abdominal or gynecological surgeries [ 89 ]​. Comparing these approaches, the bilayered composite patch focused on abdominal tissue repair, integrating antibacterial and anti-adhesive functionalities into a single construct, whereas the ibuprofen-loaded PEG/silk fibroin membrane aimed at combining physical barrier properties with sustained anti-inflammatory effects. Both approaches emphasized the importance of material selection, drug release control, and surface modification in enhancing the clinical performance of anti-adhesion membranes. Electrospinning's versatility in producing nanofibrous scaffolds with tunable properties makes it a promising approach for developing effective anti-adhesion barriers in gynecological and abdominal surgeries. Electrospun barriers can be customized to meet specific clinical needs by selecting appropriate polymers and fabrication parameters, potentially improving patient outcomes by minimizing postoperative adhesion-related complications. Melt electrowriting (MEW) and electrospinning are fiber fabrication techniques with distinct advantages for biomedical applications. MEW involves the extrusion of a molten polymer through a nozzle under an electric field, allowing precise control over fiber deposition and microstructure ( Fig. 4 ) [ 133 ]. This precise architecture is particularly beneficial in anti-adhesion barrier applications, where fiber alignment and pore structure influence cell attachment, tissue integration, and degradation rates. MEW's solvent-free nature prevents cytotoxicity issues and enhances the biocompatibility of fabricated membranes compared to solution electrospinning, which often requires solvent evaporation [ 134 ]. Fig. 4 (A) Schematic representation of melt electrospinning technique, (B) SEM images of ciprofloxacin-loaded fiber mats prepared using melt electrospinning, demonstrating uniform fiber morphology and controlled drug incorporation. (C) SEM images of PCL meshes loaded with daunorubicin, highlighting differences in fiber structure and surface characteristics at varying drug concentrations. The release profile indicates a controlled and sustained release of daunorubicin, confirming the potential of melt electrospun fibers for localized drug delivery applications, and (D) Evaluation of peritoneal scaffolds fabricated using melt electrowriting (MEW) and their biological impact on peritoneal mesothelial cells and adhesion prevention. All figures reproduced with permission [ [137] , [138] , [139] ]. Fig. 4: (A) Schematic representation of melt electrospinning technique, (B) SEM images of ciprofloxacin-loaded fiber mats prepared using melt electrospinning, demonstrating uniform fiber morphology and controlled drug incorporation. (C) SEM images of PCL meshes loaded with daunorubicin, highlighting differences in fiber structure and surface characteristics at varying drug concentrations. The release profile indicates a controlled and sustained release of daunorubicin, confirming the potential of melt electrospun fibers for localized drug delivery applications, and (D) Evaluation of peritoneal scaffolds fabricated using melt electrowriting (MEW) and their biological impact on peritoneal mesothelial cells and adhesion prevention. All figures reproduced with permission [ [137] , [138] , [139] ]. Melt electrospinning and its variations, including near-field electrospinning (NFES), have emerged as promising techniques for designing anti-adhesion barrier membranes. Melt electrospinning: Utilizes a heated polymer melt without solvents, making it ideal for biomedical applications requiring biocompatibility and controlled degradation. The process generates highly stable and tunable porous membranes that can serve as physical barriers to prevent post-surgical adhesions. The controlled fiber deposition (Work Distance (WD) = 10–15 cm) allows for the creation of membranes with tailored pore sizes, influencing their mechanical stability and degradation behavior in vivo ( Fig. 4 A) [ 135 ]. Near-field electrospinning (NFES): Enables the precise placement of fibers onto a collector at a short working distance (WD ≤1 cm), enhancing control over fiber morphology and spatial arrangement ( Fig. 4 B) [271]. This technique facilitates the fabrication of anti-adhesion barriers with defined patterns that can influence cellular interactions and prevent fibroblast infiltration, a key factor in adhesion formation [ 136 ]. Melt electrospinning has gained significant attention for its potential in drug delivery and biomedical applications. More recent findings highlight the ability of precise fiber deposition to facilitate sustained bioactive release, making it a promising approach for controlled drug delivery. Investigations into ciprofloxacin-loaded melt electrospun PCL+PEG mats have demonstrated their effectiveness in controlled drug release, reinforcing the relevance of melt electrospinning in wound healing and anti-adhesion applications ( Fig. 4 B) [ 137 ]. Similarly, recent research on PCL meshes loaded with daunorubicin has demonstrated that melt electrospinning enables localized drug delivery for cancer therapy [ 138 ]. The solvent-free fabrication process preserves drug stability, while the slow-release profile enhances therapeutic efficacy and reduces systemic toxicity. Additionally, PCL’s extended degradation time supports gradual drug diffusion, making it ideal for long-term localized treatments ( Fig. 4 C) [ 138 ]. Recent advancements in biomaterial engineering have explored innovative strategies for preventing postoperative peritoneal adhesions while promoting peritoneal repair. A notable study investigated the application of melt MEW to fabricate PCL scaffolds with microfibers arranged at varying angles (30°, 60°, and 90°) to assess their influence on mesothelial cell behavior and adhesion prevention [ 139 ]. The results demonstrated that scaffolds with 30° fiber crossings provided an optimal environment for mesothelial cell proliferation and guided migration, effectively mimicking the natural peritoneal structure. In vivo experiments further confirmed that these scaffolds acted as effective physical barriers, reducing macrophage infiltration and inflammatory responses at the injury site, significantly lowering the risk of adhesion formation. Cell tracking studies also revealed that mesothelial cells actively contributed to peritoneal regeneration when seeded onto the scaffold, highlighting the scaffold’s dual function in adhesion prevention and tissue repair. These findings underscore the potential of MEW-printed scaffolds as a promising approach for clinical translation in post-surgical peritoneal adhesion management. The growing interest in melt electrowriting and direct-write electrospinning has also led to the development of 3D fiber architectures with enhanced mechanical properties and controlled degradation, essential for long-term stability [ 140 ]. These advancements establish melt electrospinning as a versatile technique for next-generation anti-adhesion barriers, biofunctional scaffolds, and sustained-release drug delivery systems [ 141 , 142 ]. Conventional anti-adhesion barriers—like oxidized cellulose sheets, hyaluronic acid gels, or electrospun mats—are used to separate tissues during healing physically. However, these methods have limitations, including suboptimal fit, rapid degradation, or insufficient bioactivity, often resulting in high adhesion recurrence rates [ 143 ]. Recent advances in 3D-Bioprinting offer new strategies to fabricate anti-adhesion barriers with improved precision and functionality. 3D-Bioprinting enables the creation of patient-tailored barrier membranes and scaffolds that not only mechanically prevent tissue adhesion but can also incorporate cells or bioactive cues to promote regeneration​ [ 144 , 145 ]. 3D-Bioprinting of scaffolds involves the precise layer-by-layer deposition of biomaterials to construct structures with a 3D architecture, designed for applications in tissue engineering and regenerative medicine. Unlike traditional methods, 3D printing allows for exceptional control over the structural and architectural properties of the scaffold [ 146 ]. This control makes it possible to engineer scaffolds with specific porosities and complex geometries that closely mimic natural tissues and organs. Additionally, this technology supports the incorporation of living cells during the fabrication process, creating biologically functional scaffolds [ 147 ]. 3D-Bioprinting technologies are categorized into several techniques, including inkjet, laser-assisted, acoustic, extrusion, and stereolithography, each with unique principles and applications [ 68 , 69 ]. These techniques have unique strengths regarding resolution, material compatibility, and application, offering diverse options for regenerative medicine engineers and researchers. Among them, extrusion-based printing extrudes biomaterial solutions as continuous strands or fibers onto a printing stage. It offers precise control over filament deposition, enabling the fabrication of complex, multilayered structures with tunable porosity and mechanical properties. This technique is widely utilized in tissue engineering and regenerative medicine because it accommodates a broad range of biomaterials, including hydrogels, cell-laden bioinks, and composite formulations, while maintaining biocompatibility and structural integrity [ 68 , 69 , 148 ]. The material is stored in a syringe and driven through a nozzle using mechanical forces such as pressurized neutral gas, a piston, or a screw, resulting in the formation of a scaffold [ 149 ]. This technique is advantageous for creating robust, multilayered structures and is ideal for tissue engineering ( Fig. 5 ). Fig. 5 Bio-ink preparation, leading 3D Bioprinting technologies (Inkjet, Laser-assisted, Acoustic, Extrusion, and Stereolithography), and post-treatments of Bioprinting. Fig. 5: Bio-ink preparation, leading 3D Bioprinting technologies (Inkjet, Laser-assisted, Acoustic, Extrusion, and Stereolithography), and post-treatments of Bioprinting.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Efforts to develop anti-adhesion barriers have spanned over a century, evolving from the early attempts utilizing a variety of biological and inert materials to the recent anti-adhesion barriers integrated with multiple strategies for improved performance. In the early 1900s, Cargile membrane, from the bovine peritoneum, was used to prevent adhesions in various surgical contexts (e.g. peritoneal cavity), while demonstrating some limitations, like the membrane’s foreign body reaction and tendency to disintegrate or become absorbed, undermining its efficacy in this context [ 150 , 151 ]. Later in the 1970s, researchers started to develop methods and products to inhibit and manage adhesions; one of the common ways to do so was to use barriers constructed from natural and synthetic polymers. The most common and favourable types of barriers are films, gels, and solutions, respectively. As shown in Fig. 6 , in 1982, the first commercial and FDA-approved physical barrier was introduced to the market was INTERCEED® (oxidized regenerated cellulose (ORC), Johnson & Johnson), followed by GoreTex® (expanded polytetrafluoroethylene, ePTFE), Seprafilm™ (sodium hyaluronate (HA) and carboxymethylcellulose (CMC), Genzyme), and SURGICEL™ (ORC, Johnson & Johnson) [ [152] , [153] , [154] , [155] , [156] ]. The INTERCEED® and SURGICEL™ are barrier films made of ORC, a biodegradable polymer derived from plant sources [ 157 ]. It is chemically modified to enhance its properties, reducing tissue adhesion and promoting healing. The barrier is applied directly over tissues prone to adhesion formation, such as in pelvic or abdominal surgeries [ 158 ]. When placed between tissues, it absorbs fluids and forms a gel-like substance that prevents adjacent tissues from adhering to each other during the critical healing period. Over time, the barrier film is absorbed by the body and excreted. Numerous clinical studies have shown that INTERCEED® and SURGICEL™ significantly reduce the incidence of post-surgical adhesions, particularly in gynecological surgeries [ [159] , [160] , [161] ]. Gore-Tex® is a non-degradable ePTFE that is physically adjacent to prevent adhesion. The main limitation of ePTFE is that the second surgery to remove the membrane causes a cost burden for patients and increases the risk of surgery. Surgeons and scientists have a controversy on the removal of the ePTFE. Still, based on studies, Gore-Tex® reduced the adhesion up to 85 % compared to INTERCEED® with 65 %, and only one patient had a postoperative infection, for which the second surgery was not necessary. Their finding suggested that the Gore-Tex® can probably be left in place with no severe side effects [ 162 , 163 ]. In a Cochrane study, they found that Gore-Tex® may be superior to INTERCEED® in preventing adhesion formation, but sutures are required at the incision site and later removal [ 164 ]. Another noteworthy invention is FzioMed’s Oxiplex® technology, a synthetic absorbable biomaterial designed for various surgical applications, including peritoneal surgeries. Oxiplex® gel is a viscoelastic gel composed of polyethylene oxide and carboxymethylcellulose stabilized by calcium chloride, offering significant versatility in adhesion prevention and tissue regeneration [ 165 ]. Table 4 summarizes the key design parameters, fabrication methods, degradation profiles, and clinically reported outcomes for representative gynecologic anti-adhesion barriers. Fig. 6 Comprehensive timeline of Peritoneal Anti-Adhesion Barriers Development. Fig. 6: Table 4 Representative anti-adhesion barriers used in gynecologic surgery, detailing their composition, fabrication technique, degradation/barrier duration, key biocompatibility or performance metrics (e.g., adhesion-score reduction, pregnancy outcomes), and typical clinical or experimental application scenarios. Abbreviations: ORC = oxidized regenerated cellulose; HA = hyaluronic acid; CMC = carboxymethylcellulose; PEG = polyethylene glycol; HP = heparin–poloxamer; E2 = 17β-estradiol; KGF = keratinocyte growth factor. Table 4: # Barrier / Product (status) Form & fabrication technique Core composition Degradation / barrier duration Key performance characteristics* Typical gynecologic application scenario Ref. 1 Interceed® (ORC sheet) (clinical) Woven fabric cut to size; sterile oxidation of regenerated cellulose Oxidized regenerated cellulose Gelates in situ; enzymatic resorption ≈ 14 d; cleared within 4 wk 60 % pts adhesion-free vs 12 % control at 2nd-look lap. after laparoscopic myomectomy ↑ pregnancy rate vs untreated controls in laparoscopy cohort Covering uterine serosa or adnexa after open / laparoscopic myomectomy, endometriosis excision [ 174 , 175 ] 2 Seprafilm® (HA/CMC film) (clinical) Solvent-cast cross-linked HA–CMC sheet Sodium hyaluronate + carboxymethyl-cellulose Hydrates ≤ 48 h fully degraded ≈ 7 d Multicenter RCT: ↓ incidence, severity, & area of adhesions post-myomectomy (46 % uterus/adnexa adhesion-free vs 10 % control) Open myomectomy, extensive endometriosis surgery; laid over raw peritoneal or uterine surfaces [ 33 ] 3 Hyalobarrier® Gel (clinical) Syringe-delivered auto-cross-linked HA hydrogel High-MW hyaluronic acid Persists 5–7 d; enzymatically cleared ≤ 30 d Pilot RCT: ↓ moderate–severe adhesions; trend toward higher clinical pregnancy (33 % vs 15 %) after laparoscopy Intra-uterine instillation after hysteroscopic adhesiolysis; peritoneal coating after lap. myomectomy [ 176 , 177 ] 4 SprayGel™ / Coseal® (PEG hydrogel) (clinical pilot) Biphasic spray forms in-situ PEG hydrogel (cationic–anionic cross-linking) Multi-arm PEG & trilysine / dextran aldehyde Intact barrier ≈ 5–7 d; hydrolytic clearance in urine 7–10 d Prospective pilot: ↓ total adhesion score after laparoscopic or open myomectomy; no device-related complications Laparoscopic myomectomy or adhesiolysis, where spray access is advantageous [ 178 , 179 ] 5 ADEPT® (4 % Icodextrin solution) (clinical) Iso-osmolar starch solution instilled as hydro-flotation fluid α−1,4-linked glucose polymer (14–18 kDa) Cavity residence ≈ 72–96 h; enzymatic α-amylase cleavage → oligosaccharides, renal clearance 402-pt double-blind RCT: 15 % sites with adhesions vs 44 % for Ringer’s at 2nd-look lap. after laparoscopic adhesiolysis; no ↑ complications End-of-case peritoneal instillation after extensive laparoscopic adhesiolysis / endometriosis [ 180 ] 6 E2-HP Thermosensitive Hydrogel (pre-clinical) Injectable heparin-poloxamer solution → gels at 37 °C 17β-estradiol-loaded HP copolymer Gel persists ≈ 3 d; gradual in-situ erosion Rat intra-uterine adhesion (IUA) model: ↑ endometrial thickness, ↓ fibrosis, restored gland number; functional recovery noted Adjuvant to hysteroscopic adhesiolysis in severe IUA (future translation) [ 181 ] 7 KGF-loaded HP Hydrogel (pre-clinical) Same poloxamer in-situ gel method Keratinocyte growth factor + heparin-modified poloxamer Matches 5–7 d regeneration window Mouse IUA model: ↑ angiogenesis & implantation rate; minimal inflammation reported Experimental regenerative therapy for thin endometrium / severe adhesions [ 182 ] Comprehensive timeline of Peritoneal Anti-Adhesion Barriers Development. Representative anti-adhesion barriers used in gynecologic surgery, detailing their composition, fabrication technique, degradation/barrier duration, key biocompatibility or performance metrics (e.g., adhesion-score reduction, pregnancy outcomes), and typical clinical or experimental application scenarios. Abbreviations: ORC = oxidized regenerated cellulose; HA = hyaluronic acid; CMC = carboxymethylcellulose; PEG = polyethylene glycol; HP = heparin–poloxamer; E2 = 17β-estradiol; KGF = keratinocyte growth factor. To avoid future complications, placing a suitable barrier on the injury site is recommended, which can be safely degraded within weeks. However, the utilization of barriers in clinical practice has been restricted due to limitations in preparation and application, insufficient flexibility, complex methods for securing the product, the requirement for complete hemostasis, and incompatibility with laparoscopic and laparotomy surgeries [ 166 ]. Another notable innovation is the development of recombinant fibrous protein biomaterials. The use of synthetic biology enables scientists to engineer microorganisms and harness their ability to produce recombinant collagens, elastin, and silk proteins [ 167 ]. These biomaterials offer excellent biocompatibility and can be tailored for anti-adhesion barriers, where they provide structural support and promote tissue regeneration while reducing variability and improving scalability compared to natural counterparts [ 168 ]​. Targeted drug delivery systems using lipid-based materials have shown promise in preventing infection and promoting tissue repair at surgical sites [ 169 ]. Alongside these advancements, antibacterial biomaterials are gaining attention for their potential to prevent infections, a major complication in surgeries, particularly when placing anti-adhesion barriers at the surgical site [ 170 ]. Bioelectronic materials are another exciting innovation, incorporating electronic properties into biomaterials for tissue regeneration and healing. These materials can interface with the body’s natural systems, potentially delivering electrical stimulation to promote healing [ 171 ]. Additionally, programmable biomaterials that respond to environmental cues, such as changes in pH or temperature, are emerging [ 172 ]. These materials can be used for controlled drug delivery or tailored to degrade at specific rates in different biological environments [ 173 ]​. Researchers have extensively investigated biodegradable polymers for use in anti-adhesion barriers, exploring various compositions while maintaining a common objective: effectively minimizing post-surgical adhesions. Despite differences in material formulations, these studies have consistently demonstrated promising outcomes in reducing tissue adhesion. Recent breakthroughs in biomaterials, particularly in developing advanced anti-adhesion barriers, have significantly expanded the scope of this research. These innovations go beyond the capabilities of conventional polymer blends, incorporating novel fabrication techniques, bioactive components, and tailored degradation profiles to enhance biocompatibility and therapeutic efficacy. As a result, modern anti-adhesion barriers are evolving into multifunctional platforms with applications extending beyond traditional adhesion prevention, paving the way for more sophisticated and targeted biomedical interventions. Among the comprehensive searches on adhesion barriers, the most common FDA-approved biomaterials used for barriers are HA, CMC, PEG, PLA, PEO, PCL, collagen, gelatin, alginate, and chitosan, which we discussed earlier in Section 3 . Recent breakthroughs in biomaterials, with a focus on anti-adhesion barriers, have advanced this research area. These advancements surpass the applications of traditional polymer blends. Developing triblock copolymers, like PLA–PEU–PLA (a combination of polylactic acid and polyether urethane), is a noteworthy advancement. Research into these biodegradable membranes has centered on the prevention of adhesion. In vivo studies using a rat model have demonstrated that the membrane begins a degradation process after two weeks, with complete degradation observed within ten weeks, yielding promising preliminary data regarding its degradation profile and mechanical properties [ 183 ]. The degradation rate of these membranes is specifically designed to retain their anti-adhesion effects while facilitating controlled tissue healing over time [ 183 ]. Additionally, many biomaterials have been synthesized to enhance the efficacy of barrier films. Researchers developed a hydrogel film from alginate and a photo-crosslinkable HA derivative: glycidyl methacrylate functionalized hyaluronic acid (GMHA) [ 84 ]. Urea was incorporated to improve the porosity of the film, which also led to its malleability. The open pores enhanced the permeability of nutrients and minimized hypoxia of the injured peritoneum. This polysaccharide film could effectively prevent adhesion and was statistically comparable with Seprafilm® ( Fig. 7 A). Fig. 7 Innovations and development of anti-adhesion barrier films. (A) photo-crosslinkable HA derivative: glycidyl methacrylate functionalized hyaluronic acid (GMHA), (B) , O-carboxymethyl chitosan (N, OCS) and oxidized regenerated cellulose (ORC), (C) carboxymethyl chitosan (CMCS), carboxymethyl cellulose (CMCL), and collagen (COL) crosslinked using transglutaminase (TGase), (D) PCL/chitosan film, and (E) electrospun alginate/CMC/PEO nanofiber films. All figures reproduced with permission [ 84 , 184 – 187 ]. Fig. 7: Innovations and development of anti-adhesion barrier films. (A) photo-crosslinkable HA derivative: glycidyl methacrylate functionalized hyaluronic acid (GMHA), (B) , O-carboxymethyl chitosan (N, OCS) and oxidized regenerated cellulose (ORC), (C) carboxymethyl chitosan (CMCS), carboxymethyl cellulose (CMCL), and collagen (COL) crosslinked using transglutaminase (TGase), (D) PCL/chitosan film, and (E) electrospun alginate/CMC/PEO nanofiber films. All figures reproduced with permission [ 84 , 184 – 187 ]. In another study, researchers focused on a composite gauze made from N, O-carboxymethyl chitosan (N, O—CS) and oxidized regenerated cellulose (ORC) to prevent tissue adhesions. This material showed excellent biodegradability, antimicrobial properties, and hemostatic efficacy, which were tested on rabbit models. The gauze effectively prevented peritoneal adhesions and displayed strong antimicrobial functionality against S. aureus and Escherichia coli. The interaction between the N, O—CS, and ORC enhanced the barrier's durability while maintaining biocompatibility ( Fig. 7 B). Furthermore, in vitro and in vivo experiments confirmed that the composite gauze was non-toxic and promoted effective wound healing without significant inflammation​ [ 184 ]. Another study developed a composite anti-adhesion membrane made from carboxymethyl chitosan (CMCS), carboxymethyl cellulose (CMCL), and collagen (COL), crosslinked using transglutaminase (TGase) [ 185 ]. By varying the ratios of CMCS, CMCL, and COL, they found that TGase crosslinking significantly enhanced the membrane's mechanical properties, cytocompatibility, and biodegradability. The 25/25/50 CMCS/CMCL/COL membrane crosslinked with TGase significantly reduced peritoneal adhesion scores from ∼3.0 to 90 % HSF cell viability, demonstrating excellent biodegradability, mechanical integrity, and biocompatibility for postoperative adhesion prevention ( Fig. 7 C). The addition of collagen improved the biocompatibility and healing properties. At the same time, TGase crosslinking ensured the membrane was durable yet biodegradable, preventing early degradation​ [ 185 ]. They utilized CMCS as a base material for anti-adhesion barriers, emphasizing their biocompatibility and biodegradability. The key distinction lies in adding collagen and TGase for crosslinking, which improved mechanical stability and reduced rapid degradation. Collagen provided additional benefits, such as promoting cell adhesion and wound healing, while TGase facilitated stable yet reversible crosslinking under physiological conditions. In contrast, incorporating ORC enhances antimicrobial and hemostatic functions, which are crucial for infection control in surgical environments. Both methods effectively reduced postoperative adhesions while addressing specific functional needs [ 184 , 185 ]. The wettability of the barrier films is the most critical function in biomaterial selection and scaffold design. Due to biomaterials' solubility in diverse solvent groups, their toxicity and functional groups can improve or deteriorate wettability. These functional groups also play a crucial role in synthetic and natural biomaterial blending and antibacterial behavior. Researchers developed an electrospun PCL/chitosan film for an anti-adhesion barrier [ 186 ]. Due to PCL's low surface wettability, the chitosan coating's efficiency is limited. To solve this problem, they dissolved the PCL in dichloromethane (DCM), N, N-Dimethylformamide (DMF), and acetic acid (AC) and post-treated the PCL with O 2 plasma to improve the hydrophilicity of PCL ( Fig. 7 D). The anti-adhesive effects of lidocaine within electrospun alginate/CMC/PEO nanofiber films were explored in another study, and the results are displayed in Fig. 7 E. A 9 % (w/v) lidocaine-loaded alginate/CMC/PEO electrospun nanofiber film crosslinked with CaCl₂ demonstrated controlled drug release based on crosslinking density. At 1 % CaCl₂, ∼70 % of lidocaine was released within 1 hour, indicating burst release, while 3 % and 5 % CaCl₂ films showed <50 % release at 1 hour and sustained release up to 7 h [ 187 ]. Regarding cell viability, no toxicity was found for the NIH/3T3 fibroblast cell line; however, the 9 % alginate/CMC/PEO (2:2:1) nanofiber film showed uniform fiber distribution without beads and less cell attachment on the hydrophobic electrospun film [ 187 ]. Various drugs are typically used to prevent post-surgical adhesions, often integrated into functionalized biomaterials like hydrogels or films for controlled, localized release. Non-steroidal anti-inflammatory drugs are commonly included to reduce inflammation, a significant factor in adhesion formation. When incorporated into hydrogels, these drugs provide a prolonged local anti-inflammatory effect [ 188 ]. Potent anti-inflammatory corticosteroids like dexamethasone and hydrocortisone can inhibit the inflammatory response, preventing fibroblast proliferation and reducing the risk of fibrous tissue adhesions when delivered via hydrogels or films [ 188 , 189 ]. Heparin is another drug that helps to prevent adhesions by inhibiting blood clotting and fibrin formation and can be incorporated into barrier materials to address the initial stages of adhesion development [ 190 ]. Drugs such as mitomycin C and pirfenidone directly inhibit fibroblast activity and collagen deposition, both crucial in adhesion formation [ 191 , 192 ]. These agents are particularly favored when minimizing the fibrotic process is a primary concern. Specific inhibitors of growth factors like transforming growth factor-beta (TGF-β) can also prevent excessive tissue growth that leads to adhesions [ 193 ]. TGF-β inhibitors are incorporated into functionalized biomaterials to modulate healing without inducing fibrosis [ 77 ]. Table 5 outlines the drug classifications and their mechanisms for preventing local adhesion development. Table 5 Overview of Drug Classes Preferred for Preventing Post-Surgical Adhesions, Their Mechanisms of Action, and Applications in Biomaterials. Table 5: Drug Class Examples Mechanism of Action Application in Biomaterials Ref. Anti-inflammatory agents Ibuprofen, Celecoxib Reduce inflammation, which helps to prevent excessive tissue adhesion Integrated into hydrogels for prolonged local anti-inflammatory effects. [ 188 , 194 ] Corticosteroids Dexamethasone, Hydrocortisone Suppress the immune response and reduce fibroblast proliferation Delivered via hydrogels or films for localized, prolonged action. [ 189 , 195 ] Anticoagulants Heparin Prevent blood clotting and fibrin formation, reducing the risk of adhesion formation Incorporated into barrier materials to inhibit initial adhesion stages. [ 196 , 197 ] Anti-fibrotic agents Mitomycin C, Pirfenidone Inhibit fibroblast activity and collagen deposition, directly reducing the fibrotic process Used in hydrogels or films to reduce fibroblast activity locally. [ [198] , [199] , [200] ] Growth factor inhibitors TGF-β inhibitors Inhibit growth factors involved in tissue overgrowth and adhesion formation Used to modulate the healing process and prevent excessive tissue growth. [ 201 , 202 ] Overview of Drug Classes Preferred for Preventing Post-Surgical Adhesions, Their Mechanisms of Action, and Applications in Biomaterials. Anti-inflammatory agents like ibuprofen, celecoxib, and naproxen (NSAIDs) play a key role in reducing inflammation, a natural defense mechanism triggered by tissue damage, injury, or infection. Following surgery, there is an increase in blood flow at the site of the injury, an increase in vascular permeability, and migration of immune cells [ 188 ]. Prostaglandins (PGs), nitric oxide (NO), and cytokines like interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF) are released by activated inflammatory cells (neutrophils, eosinophils, mononuclear phagocytes, and macrophages) present at the site [ 203 ]. One specific requirement for signaling in the body is the presence of a certain amount of the free radical NO, especially for functions like thermoregulation, vasodilation, and neuromodulation [ 203 ]. On the other hand, anticoagulants, like hirudin, heparin, DMSO, and thrombolytic protein from cobra venom, prevent blood clot formation by inhibiting thrombin and other coagulation factors. Unfractionated and low-molecular-weight heparin, along with hirudin and warfarin, have been studied for their potential anti-adhesion properties [ [204] , [205] , [206] , [207] , [208] ]. However, results are inconclusive, indicating the need for further research into their efficacy in preventing surgical adhesions. Fibrinolytic agents , like N-acetyl-l-cysteine and streptokinase, dissolve blood clots by activating plasminogen, which breaks down fibrin. These agents have shown anti-adhesive effects, but their use can lead to complications like excessive bleeding or severe hypotension. While promising, fibrinolytic agents require careful consideration due to these risks [ [209] , [210] , [211] ]. According to a study by Liu et al., the antitumor antibiotic Mitomycin C (MC) has been found to have anti-adhesion effects by crosslinking DNA and inhibiting cell proliferation. When MC is applied topically, it inhibits fibroblast proliferation and collagen formation, which are key factors in scar tissue and adhesion development. This makes MC useful in preventing post-operative adhesions in abdominal or pelvic surgeries. Reducing fibroblast activity helps minimize the risk of excessive tissue formation, leading to adhesion. However, its use is not without risks. MC can cause significant side effects, including local tissue toxicity, delayed wound healing, and even cell necrosis at the application site. Therefore, while MC shows promise for preventing adhesions, its clinical application must be carefully managed to balance its benefits with its potential adverse effects [ [198] , [199] , [200] ]. Growth factors like vascular endothelial growth factor (VEGF) has been shown to effectively regenerate scarred peritoneum by stimulating angiogenesis [ 212 ]. In addition to these benefits, they are also biocompatible, which can greatly contribute to the healing process of wounds. This is achieved through the delivery of an aqueous environment that helps reduce friction forces and prevents the formation of sticky layers of tissue caused by exudate [ 213 ]. The combined application of VEGF and other growth factors, delivered via nanotechnologies or mRNA therapies, has shown promising results in preclinical models, enhancing wound closure and reducing scar formation. This makes VEGF and its associated signaling pathways a vital area of study for regenerative medicine and the development of anti-adhesion therapies [ 214 , 215 ]. While witnessing these advancements is encouraging, it is important to acknowledge the difficulty of preventing adhesions after surgery, including intraperitoneal and intrauterine adhesions. It is crucial to continue exploring new surgical techniques and materials to improve patient outcomes. A cutting-edge field involves self-healing polymers, which can autonomously repair minor damage. These materials are being designed to extend the lifespan of barriers used in surgical applications, minimizing the need for replacements [ 216 ]. Anti-adhesion barriers with self-healing properties preserve their structural integrity for extended durations, minimizing the chance of post-operative adhesions reforming [ 217 ]. A dual dynamically crosslinked hydrogel was developed using alkoxyamine-terminated Pluronic F127 (AOP127) and oxidized hyaluronic acid (OHA) to prevent postoperative adhesions [ 218 ]. The hydrogel forms through covalent oxime bonding and hydrophobic interactions, providing self-fixation, thermosensitivity, and enhanced mechanical stability. It has low viscosity, thus is easily injectable at room temperature and gels at body temperature (37 °C) with a high storage modulus (∼3000 Pa). The hydrogel adheres well to tissue (∼4.6 kPa), prevents fibroblast and blood cell adhesion, and exhibits low hemolysis (∼3 %), ensuring biocompatibility. A rat model of peritoneal adhesion significantly reduced adhesion formation, promoted tissue healing, and fully degraded within 14 days [ 218 ]. These properties make it a promising clinical anti-adhesion barrier ( Fig. 8 A1-A5) [ 218 ]. Fig. 8 (A1) AOP127/OHA hydrogel prevents postoperative adhesions through dual dynamic crosslinking via oxime bonds and physical associations, forming a stable physical barrier, (A2 and A3). (A4) showing adhesion on synthetic materials and (A5) rat tissues. (B1) Schematic illustrations of the synergistic action of AM-BNMs components to prevent adhesions and promote uterine tissue and abdominal wall regeneration, (B2) Photographs of AM-BNMs patch and injectable AM-BNMs, (B3) Macroscopical adhesiveness test at 300 s on rat uterine surface, (B4) Complete degradation time of different absorbable anti-adhesion barriers ( n = 3), (B5) Water contact angles of AM-BNMs showed good hydrophilia, AND (B6) Adhesive interface between AM-BNMs and tissues. SEM image showed the topology of the external surface of the rat uterus (Left). White arrow: micrometer-scale grooves. Cross-sectional SEM images and local magnification of AM-BNMs adhered to the uterus (Right). All figures reproduced with permission [ 218 , 219 ]. Fig. 8: (A1) AOP127/OHA hydrogel prevents postoperative adhesions through dual dynamic crosslinking via oxime bonds and physical associations, forming a stable physical barrier, (A2 and A3). (A4) showing adhesion on synthetic materials and (A5) rat tissues. (B1) Schematic illustrations of the synergistic action of AM-BNMs components to prevent adhesions and promote uterine tissue and abdominal wall regeneration, (B2) Photographs of AM-BNMs patch and injectable AM-BNMs, (B3) Macroscopical adhesiveness test at 300 s on rat uterine surface, (B4) Complete degradation time of different absorbable anti-adhesion barriers ( n = 3), (B5) Water contact angles of AM-BNMs showed good hydrophilia, AND (B6) Adhesive interface between AM-BNMs and tissues. SEM image showed the topology of the external surface of the rat uterus (Left). White arrow: micrometer-scale grooves. Cross-sectional SEM images and local magnification of AM-BNMs adhered to the uterus (Right). All figures reproduced with permission [ 218 , 219 ]. Another study developed biomimetic nanostructural anti-adhesion materials (AM-BNMs) derived from the human amniotic membrane (AM) for postoperative self-healing and adhesion prevention [ 219 ]. AM-BNMs consist of AM-derived ECM nanofibers enriched with mesenchymal stem cell (MSC)-secretome, which promotes wound healing, angiogenesis, and tissue regeneration. The material adapts to complex anatomical surfaces, prevents direct tissue contact, and gradually degrades within ∼14 days, ensuring sustained release of regenerative factors (VEGF, angiogenin, miR-302a-3p). In a rat caesarean section (CS) model, AM-BNMs significantly reduced adhesion formation, improved uterine wound healing, and demonstrated strong hemostatic properties [ 219 ]. Compared to commercial barriers (Interceed™), AM-BNMs provided better adhesion prevention, enhanced tissue recovery, and superior biocompatibility. These findings highlight AM-BNMs as a promising self-healing anti-adhesion barrier for surgical applications ( Fig. 8 B1–B6) [ 219 ]. Recent developments in the field of biomaterials have introduced microneedle patches designed for internal applications, such as the pelvic cavity, with dual functionalities for drug delivery and serving as anti-adhesion barriers [ 220 ]. A prime example is the development of Janus adhesive microneedle patches, which consist of a dual-layer system [ 221 ]. The Janus microneedle patch is a sophisticated biomaterial device that refers to structures with two distinct surfaces or layers with different properties, optimized for multiple functions. These patches have an adhesive inner layer offering sustained drug release over several days, and an outer layer that prevents tissue adhesion. This design has shown significant potential in treating intrauterine adhesions, offering both barrier properties and promoting tissue regeneration, while preventing post-surgical adhesions. The microneedles can efficiently penetrate tissues to deliver bioactive molecules, promote vascularization, and healing [ 221 ]. Additionally, core–shell microneedle patches have been developed, with a similar approach for controlled drug delivery. These patches can be used for sustained release of bioactive compounds like mangiferin and mesenchymal stromal cell (MSC)-derived exosomes. Such systems promote angiogenesis and reduce inflammation over extended periods, making them effective for internal applications requiring prolonged therapeutic effects [ 222 ]. These patches are engineered to have: An adhesive inner layer: This layer, loaded with bioactive molecules such as exosomes, enables the microneedles to penetrate and adhere to tissue effectively. Exosomes promote angiogenesis (formation of new blood vessels) and tissue regeneration, which are critical in preventing adhesions and promoting healing [ 223 ]. An outer anti-adhesion layer: This layer acts as a physical barrier to prevent tissues from sticking together post-surgery, which is particularly important for reducing postoperative complications like intrauterine adhesions. The anti-adhesion surface is designed to have low cell and protein adhesion properties, ensuring it does not interfere with the healing tissue. An adhesive inner layer: This layer, loaded with bioactive molecules such as exosomes, enables the microneedles to penetrate and adhere to tissue effectively. Exosomes promote angiogenesis (formation of new blood vessels) and tissue regeneration, which are critical in preventing adhesions and promoting healing [ 223 ]. An outer anti-adhesion layer: This layer acts as a physical barrier to prevent tissues from sticking together post-surgery, which is particularly important for reducing postoperative complications like intrauterine adhesions. The anti-adhesion surface is designed to have low cell and protein adhesion properties, ensuring it does not interfere with the healing tissue. The sustained drug-release capability is one of the core advantages of this technology. For example, in rat models, Janus patches could release up to 80 % of loaded exosomes over seven days, effectively promoting endometrial healing. This type of patch provides a stable barrier, delivering therapeutic agents over time, thus facilitating both tissue regeneration and long-term adhesion prevention [ 221 ]. Beyond intrauterine applications, the Janus microneedle concept has been explored for other medical uses such as skin regeneration, where similar dual-layer designs offer controlled drug delivery combined with surface properties optimized for tissue healing. The multi-functional design of Janus microneedles makes them a promising innovation in minimally invasive surgeries and other biomedical applications [ 224 ]. These innovations are part of a broader movement in biomaterials science to prevent adhesions and actively promote tissue regeneration and healing, addressing some of the long-standing limitations of older technologies. Open myomectomy: In a multicenter randomized clinical trial, 61 women undergoing open myomectomy were randomized to receive a hydrophilic absorbable film (PREVADH™) on the uterine incision versus Ringer’s solution. On second-look laparoscopy (54 patients, 10–20 weeks later), only 43 % of the PREVADH™ group had uterine adhesions versus 92 % of controls ( p = 0.001). The treated ovaries also had significantly lower adhesion scores. No adverse events were reported. In summary, PREVADH™ film significantly reduced adhesion incidence and severity after laparotomic myomectomy [ 225 ] . Laparoscopic myomectomy: In another case series study, sprayable dextrin hydrogel (AdSpray™) was applied to the myomectomy site during laparoscopy. All 24 patients later underwent caesarean delivery with repeat laparoscopy. Only 4 of 24 (16.7 %) had any adhesions at the uterine incision. AdSpray (a commercially available carboxymethyl-dextrin spray) was easily applied after myoma removal. The low adhesion rate (and absence of adverse effects) suggests that laparoscopic spraying of AdSpray™ markedly reduces postoperative adhesion formation [ 226 ]. Hyaluronic acid gel vs. ovarian suspension: In a double-blind, randomized trial, 50 women with bilateral endometriomas underwent laparoscopic cystectomy. Each patient was randomized so that one ovary received an auto-crosslinked HA gel (HYAcorp Endogel) applied to the denuded ovarian surfaces intraoperatively. The other side was sutured to the abdominal wall for suspension. At the 3-month ultrasound follow-up, the HA-treated ovaries showed minimal adhesions in 80.5 % compared to only 35.5 % of the suspended ovaries ( p < 0.001), and ovarian mobility was significantly better in the HA group. This study shows that HA gel is more effective than suspension for preventing postsurgical ovarian adhesions [ 227 ]. 4DryField® starch powder: In another randomized clinical trial, 50 women underwent 2-stage laparoscopic resection of deep endometriosis with the application of 4DryField®pH (a modified polysaccharide powder that forms a gel) versus no barrier. Second-look laparoscopy revealed a dramatic reduction in adhesions: the mean total adhesion score was 2.2 with 4DryField® versus 14.2 in controls ( p = 0.004), an 85 % reduction. The average number of adhesion sites per patient also decreased by 53 % (1.1 vs 2.3, p = 0.004). Thus, 4DryField® spray-gel significantly lowered the severity and extent of adhesions after endometriosis surgery [ 228 ]. Seprafilm®: Scientists conducted a large, multicenter randomized clinical trial involving ∼753 women undergoing primary caesarean sections to receive Seprafilm® (HA-carboxymethylcellulose sheet) or no barrier. About 80 from each arm returned for repeat caesarean. Adhesions at the next surgery were virtually identical: 75.6 % of Seprafilm® patients versus 75.9 % of controls had any adhesions ( p = 0.99), and the median adhesion score was 2 in both groups ( p = 0.65) [ 229 ]. In other words, prophylactic Seprafilm® did not reduce postoperative adhesions in this trial. There were no safety differences between groups [ 229 ]. Oxidized cellulose: In a U.S. cohort study, 262 women undergoing primary caesarean sections were reviewed. An ORC adhesion barrier (commercial absorbable mesh) monitored. Of the 112 women who later had a repeat caesarean, 74 % of the ORC group had no adhesions at the second surgery versus only 22 % of the no-barrier group ( p = 0.011). Severe adhesions (grades 2–3) were significantly less common with ORC (11 % vs 64 %, p = 0.012). This retrospective study suggests ORC membrane substantially reduced caesarean adhesions, though it was not randomized [ 230 ]. In a randomized clinical trial, researchers explored the effectiveness of hyaluronic acid gel in comparison to an intrauterine device (IUD) involving 89 infertile women diagnosed with intrauterine adhesions (IUA), where the participants were assigned to receive either autocrosslinked HA gel alone or a Lippes-loop IUD alone following hysteroscopic adhesiolysis. At second-look hysteroscopy 1–2 months later, the HA gel group had a significantly higher rate of adhesion prevention and greater improvement in adhesion scores than the IUD group. The authors concluded that HA group was superior to an inert IUD in preventing IUA recurrence. Pregnancy rates were slightly higher in the HA group, however not statistically significant [ 231 ]. Hyaluronic–CMC gel after Dilation and Curettage: A study performed in 2021 focused on 68 women who experienced first-trimester pregnancy loss and underwent the medical procedure known as vacuum aspiration. Patients were randomized to intrauterine instillation of an alginate–carboxymethylcellulose–hyaluronic acid gel (ACH gel) or no gel. On hysteroscopy 8–12 weeks later (62 patients), only 5/62 (8.1 %) in the gel group had new adhesions versus 12/62 (19.4 %) in controls ( p = 0.04). The severity of adhesions was low in both groups. This single-blind randomized clinical trial indicates that intrauterine HA/CMC gel application after uterine curettage significantly reduced adhesion incidence [ 232 ]. 4DryField starch powder: In a study, 40 women underwent repeat gynecologic surgery (often for severe endometriosis) with planned adhesiolysis. 17 patients received 4DryField pH powder (sprayed and gelled in situ) on raw ovarian/pelvic surfaces, while 23 had no barrier. At second-look laparoscopy, the 4DryField group showed significantly lower adhesion extent and severity than the no-barrier group, which had worsened adhesions. This suggests 4DryField powder (hemostatic starch) can markedly reduce adnexal adhesion recurrence (Outcomes were adhesion scores; pregnancy was not assessed) [ 233 ]. Oxidized cellulose: In a controlled trial, women with bilateral ovarian cysts had one ovary covered with ORC film (Interceed) at cystectomy and the other left unprotected (Keckstein et al. 1996). On second-look laparoscopy (17 patients), 76 % of ORC-treated ovaries were adhesion-free versus only 35 % of untreated ovaries ( P < 0.05). The mean area of ovarian adhesion was significantly smaller with ORC. This randomized clinical trial demonstrates that an ORC barrier at ovarian cystectomy can dramatically reduce postoperative ovarian adhesions [ 234 ].