Postoperative Adhesions: Current Research on Mechanisms, Therapeutics and Preventative Measures.

The onset of postoperative adhesions occurs due to the complex regulations of fibrinolytic activity and deposition of fibrin, biological activities that utilize various pathways, and cell interactions ( Fig. 1 ) [ 17 ]. Of particular interest are the inflammatory response, coagulation cascade and angiogenesis, three mechanisms regularly associated with surgical practice due to their involvement with healing [ 31 – 34 ]. These three are all responsible for the formation of fibrin clots. The excessive deposition of fibrin on injured tissue surfaces, in combination with macrophages and other inflammatory cells that result in these clots are principally responsible for the initial formation of adhesions [ 17 , 35 , 36 ]. Adhesiolysis, which involves fibrinolytic activity is generally meant to break down the formed fibrin clots to prevent them from growing. Physiologically, the enzyme plasmin cleaves the fibrin mesh, dissolving the clots. Plasminogen, the inactive form of plasmin, is activated by both tissue-plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). The t-PAs are slowly released over time by damaged endothelium of the blood vessels, resulting in clots that break down post-healing. t-PA has a much higher activity in the presence of fibrin, with enhanced plasminogen activation upon fibrin binding [ 37 , 38 ]. The u-PAs are recruited immediately to cell membranes via the u-PA receptor (u-PAR) expressed on cell surfaces upon secretion, resulting in promoted plasmin production. This instant recruitment and localization results in a functional distinction between u-PA and t-PA, whereas the former is associated with proteolytic activity while the latter possesses a stronger inclination towards fibrinolytic activity [ 39 ]. Both are inhibited via plasminogen activator inhibitors (PAI) that exhibit delayed releases, preventing activation of plasminogen [ 40 ]. Plasmin and the fibrinolytic system are also linked to matrix metalloproteinase (MMP) activity, which downregulate adhesions formation via degradation of extracellular matrix (ECM) components as seen in Fig. 1 [ 41 ]. When epithelial or mesothelial layers are disrupted during surgery or injury, inflammation, spurred by monocytes and neutrophils, is activated. As bleeding occurs, the coagulation cascade is activated to prevent blood loss as injured cells and blood components result in fibrinogen being converted into fibrin monomers via thrombin-mediated cleavage and removal of N-terminal fibrinopeptides [ 32 , 42 , 43 ]. As the fibrin monomers begin to form mesh networks and aggregate with activated platelets, fibrin clots begin to form which serve as an initial nucleation site to spur adhesions formation. Additionally, the activated platelets, which release cytokines and other factors, function as chemo-attractants for inflammatory cells to initiate healing [ 44 ]. As a result, coagulation upregulates the inflammatory response, further increasing fibrin deposition and the presence of clots. Of note, inflammation activates the coagulation cascade via cytokine induction of tissue factor (TF) expression, explaining the dual upregulation seen in Fig. 1 . When TF expression is prevented, so too is thrombin escalation which would inhibit coagulation [ 45 ]. During inflammation, endothelial cell-to-cell junctions lose their integrity, exposing expressed TF in the adventitial layer [ 46 ]. Inflammation also upregulates the synthesis of TF from endothelial cells and macrophages and encourages platelet activation [ 46 – 48 ]. Importantly, the cytokine IL-6 induces the expression of TF. Beyond IL-6, additional key cytokines such as TNF-α, IL-1, and IL-12 are all pro-inflammatory, indicating they can be potential key markers of adhesions formation [ 49 ]. Thus, the inflammatory response and coagulation cascades upregulate each other, both of which result in fibrin clots [ 46 , 50 ]. An important competing pathway is the protein C anti-coagulation pathway from Fig. 1 which downregulates coagulation via thrombin regulation. When this pathway is triggered by thrombin binding to thrombomodulin, protein C is activated and blocks thrombin catalysis of fibrin formation, downregulating coagulation [ 51 , 52 ]. Intuitively, the inhibition of thrombin would result in a decrease in the inflammatory response due to the shared relation between coagulation and inflammation, however this often fails to regulate adhesions formation due to the inflammatory pathway downregulating the protein C anticoagulation pathway itself despite blocked TF expression [ 51 ]. During wound healing, endothelial cells are stimulated to proliferate and then migrate, allowing for the formation of new blood vessels to begin via angiogenesis. This newly formed vasculature occurs following the degradation of the surrounding ECM from pre-existing vessels, allowing a renewed blood supply into injured tissue to further improve healing [ 53 , 54 ]. This process is regulated by numerous cytokines and growth factors, namely vascular endothelial growth factor (VEGF), a key signaling protein. VEGF is known to influence endothelial cell gene expression, increasing production of proteins such as TF, u-PA, t-PA, PAI-1, and MMPs [ 55 ]. Other key angiogenesis stimulators that have distinct roles in inflammation or coagulation are IL-3, IL-8, macrophages, neutrophils, monocytes, MMP-2, MMP-9, TGF-β, TNF-α, and thrombin [ 55 ]. Key anti-angiogenesis inhibitors are IL-10, IL-12, and TGF-β [ 55 ]. TGF-β is a multifunctional cytokine capable of regulating angiogenesis through modulating endothelial cell proliferation and migration while also upregulating TNF-α and promoting its own expression [ 55 – 57 ]. During inflammation, angiogenesis can be initiated by the fibrinolytic system-led invasion of endothelial cells. With numerous key cytokines and growth factors both promoting and inhibiting angiogenesis, the influence of angiogenesis on adhesions formation has yet to be fully elucidated. Despite this, there are a few key phenomena thought to enhance adhesions formation as listed in Fig. 1 . Following tissue injury, the disruption of vasculature and increased consumption of oxygen by surrounding cells result in a hypoxic environment at the injury site. This results in increased production of VEGF to promote formation of capillaries in the clotting site [ 58 – 60 ]. Additionally, dense capillary network regression results in endothelial apoptotic cells, enhancing scar tissue formation and fibrosis further [ 61 ]. Excessive angiogenesis has been thought to also support scar formation, where pericytes transition into myofibroblasts which further enhance fibrosis [ 62 , 63 ]. Regardless of the unclear impact, the combination of shared cytokines and growth factors between angiogenesis and other pathways, and the current suggestions of how angiogenesis supports adhesions formation has resulted in potential targets that researchers are currently studying to further prevent adhesions through pharmaceuticals. In summary, adhesions formation is defined by a clear imbalance between the deposition of fibrin and subsequent clotting and the fibrinolytic system cleaving fibrin clot buildup. This imbalance has been attributed to numerous factors and pathways, creating a severely complex multidirectional mechanism where they all contribute to adhesions formation. In addition, the importance of each of these factors has yet to be completely realized, further increasing the complexity. This creates the challenge of choosing to pursue one clear biological target, an important reason for why the adhesions problem remains to be solved within the clinic. Postoperative adhesions pathophysiology varies on both tissue type and the relevant timeline. One way of categorizing the adhesions timeline is via the tissue composition. Initially, adhesions are simply a clot of fibrin and platelets, but over time, continued conglomeration of other cell types and tissues create a diverse structure that serves to expand and strengthen adhesions. The initial state, resulting in only membranous adhesions that are generally simple to peel apart by surgeons occurs over approximately the first 3 days post-operation [ 29 ]. This stage is characterized by excessive fibrin deposition with limited fibrinolysis during inflammation and initial coagulation [ 35 , 64 , 65 ]. From 3 to 21 days, vasculature begins to form within the adhesions which strengthens them. This phase is primarily composed of fibroblast cells, collagen III, and capillary vessels [ 66 , 67 ]. This stage can be considered by excessive formation of the ECM and dysregulation of the ECM degradation [ 68 – 71 ]. After 21 days, the adhesions are generally composed of repairing cells; resting fibroblasts, additional endothelial cells, myofibroblasts, macrophages and vein vessels that stiffen the adhesions further [ 72 – 76 ]. The final stage consists of scarring from type 1 collagen fibers and limited numbers of resting fibroblasts and myofibroblasts which can potentially last for years without intervention [ 72 , 73 ]. This last stage also exhibits chronic inflammation inducers, molecules such as reactive oxygen species (ROS) that result in a reoccurring inflammatory response [ 77 ]. Over time, the adhesions become more difficult to operate on, emphasizing the initiative to prevent adhesions from ever forming post-operation. The general distribution of cell types and structure of adhesions follows the above description but with a few differences based on the location of their formation. By far, the most studied and well-known adhesions are peritoneal adhesions that primarily form after abdominal surgeries. These abdominal adhesions have been documented to be a principal cause of small bowel obstruction and other complications such as chronic pain. Within the peritoneum, organs and tissues undergo dynamic movement which is assisted by not only the protection of the peritoneum, but also the frictionless environment it maintains via peritoneal fluid secretion [ 78 ]. The formation of adhesions limits this functionality, binding organs and tissues not only amongst themselves but also the abdominal wall directly. During post-operation wound healing, fibroblasts can undergo apoptosis which results in hypoxic environments, resulting in large amounts of fibroblasts changing phenotypes to myofibroblasts to remodel the injured tissue [ 79 , 80 ]. For peritoneal adhesions to form, these fibroblasts change to an adhesion phenotype which upregulates VEGF production to improve reoxygenation [ 58 ]. This adhesion phenotype is marked by increases in expression of fibronectin, and collage type I and III which is mainly promoted by TGF-β [ 80 , 81 ]. Although less studied than peritoneal adhesions, pericardial adhesions understanding is limited, with literature focusing on consequences rather than prevention. As they form, they can result in immediate life-threatening complications such as ventricular dysfunction, heart compression, and internal hemorrhage [ 82 ]. Pericardial adhesions are thought to be formed by the exposed basal membrane that results from the detachment of mesothelial cells [ 14 ]. This allows fibrin deposition to occur, starting the formation process. Similarly to peritoneal adhesions, the formation of the fibrin clots is the inciting cause for short and long-term adhesions formation. The high incidence of clinical cardiac health issues, such as congenital heart disease where 33% of all operations are reoperations, along with the high percentage of adhesions reoccurrence and increased operation time due to their complexity only serve to increase patient risk further [ 24 , 25 ]. Peritendinous adhesions have a much lower rate of occurrence when compared to peritoneal adhesions, with only a 30–40% incidence rate compared to well over 90% [ 9 , 83 ]. Tendons are covered by a basement membrane epithelium composed of ECM macromolecules around a collagen IV and laminin core [ 84 ]. It is thought that this intact membrane prevents the exposure of fibroblasts to fibrin, preventing adhesions, a possible reason for the lower incidence rate [ 25 ]. Peritendinous adhesions are widely attributed to result in movement limitations due to obstruction and loss of function [ 9 , 85 , 86 ]. The caused obstruction reduces the gliding and range of motion that the tendons are capable of. With inaccurate reporting of uterine adhesions occurrence rates due to asymptomatic patients, undiagnosed cases, and illegal abortion procedures, studies estimate varying rates of formation [ 87 , 88 ]. Incidence rates range from 0% for procedures such as polyp removal to 50% for other resectoscopic procedures, though the true rate of formation remains unknown [ 89 , 90 ]. Adhesions formation in the uterus is primarily caused by trauma and denudation of the endometrium [ 91 ]. Like other models, this exposure of the basement membrane allows for fibrotic tissue deposition. Unique to intrauterine adhesions, the hormone estrogen appears to interact with key growth factor VEGF and TGF-β [ 92 ]. The known roles of VEGF and TGF-β within inflammation and angiogenesis likely link estrogen as another key marker in uterine adhesions formation. Adhesions in the uterus are often associated with chronic pain, amenorrhea and infertility [ 93 , 94 ]. Epidural adhesions are drastically understudied, with true incidence rates varying by procedure. Studies report a 91% incidence for lumbar surgeries, with a 46% incience for patients with Failed Back Surgery Syndrome (FBSS) [ 95 – 98 ]. Epidural adhesions are thought to take months to develop scar tissue, with hematomas being dominant due to increased blood flow in the dural tissue. Besides this, epidural adhesions undergo a similar pathophysiology to peritoneal adhesions. This often results in what is known as the epidural scar, a collection of scar tissue that can form surrounding spinal nerve roots following back surgery [ 99 , 100 ]. Epidural adhesions formation is widely associated with leg and back pain, dural tears, and nerve root injuries [ 101 , 102 ].

The extensive number of potential targets and pathways that are involved with the onset and development of adhesions offer seemingly infinite opportunities to utilize pharmaceuticals to prevent their formation postoperatively. A summary of studied therapeutics to prevent adhesions formation in various models are provided in Table 1 . All these drugs and pharmaceutical agents have been studied to determine their impacts as potential adhesions preventatives. Despite the wide range of effects that have been studied, there are currently no approved therapeutics for use in adhesions prevention, with almost all studied drug classes only showing viability in animal studies thus far with very minimal human trials. Currently, no randomized human clinical trials have demonstrated strong candidacy for any of these drug classes. The interplaying complexity of the various factors in adhesions formation is a likely reason for this, where the reduction of one cellular mediator such as TGF-β is not enough to stop adhesions [ 174 ]. Beyond this, reduction of numerous cellular mediators may result in further cellular damage or limited wound healing, drastically limiting the efficacy of therapeutic usage. Additionally, at the dosage levels where these drugs can be effective, there are associated risks and side-effects since these drugs act on pathways that are a part of the wound healing process of the body and may result in systemic impacts to coagulation and healing. This fails to include the challenges of delivery of these therapeutics. Many applied pharmaceuticals are delivered as fluids (typically in saline) to the operation site, but their controlled distribution and release is drastically decreased. The extended timeline of adhesions formation over several weeks hinders a single therapeutic application during surgery even more. To date, although each strategy attempts to target one key aspect of adhesions pathogenesis, there are no therapeutic strategies that appear to demonstrate substantial safety and efficacy to prevent adhesions. To overcome the shortcomings of therapeutics, physical barriers have been suggested for the prevention of adhesions. The idea behind a physical barrier is the separation of the wound surface and the adjacent surfaces through the placement of a barrier, thereby preventing adhesions from forming between the tissue surfaces. An ideal physical barrier should be biocompatible to prevent triggering an inflammatory response; it should be biodegradable to avoid additional surgeries for barrier removal; the mechanical properties of the barrier should ensure it maintains its integrity throughout the wound healing process and most importantly, the barrier needs to prevent adhesions from forming. Besides the properties, adhesion between the barrier and the targeted tissue site is a desirable property since this would prevent the need to secure the barrier with sutures. With these properties in mind, several natural and synthetic polymers have been used to develop physical barriers to prevent postoperative adhesions, some of which have been approved to be used in surgeries. In the clinical setting, physical barriers are the most common form of treatment to tackle postoperative adhesions. Currently, there are several adhesions barriers available in the market that have been approved for use in Europe and the US, some of which have been tabulated in Table 2 . These barriers are typically made using natural polymers or their derivatives like hyaluronic acid (HA), oxidized regenerated cellulose (ORC), carboxymethylcellulose (CMC), mainly due to their biocompatibility and biodegradability which reduces the possibility of inducing an unwanted foreign body response [ 175 – 177 ]. In addition to natural polymers, several synthetic polymers like poly(lactic acid) (PLA), poly(caprolactone) (PCL), poly(ethylene glycol) (PEG), expanded poly(tetrafluoroethylene) (ePTFE). have been utilized to make adhesions barriers. These products come in different forms although they are mostly either films or hydrogels. Some barriers are also available in the form of solutions. Seprafilm ® and Interceed ® are currently the most widely used film barriers in market to prevent adhesions. Seprafilm ® is a resorbable barrier composed of modified sodium hyaluronate and CMC [ 178 ]. It is a translucent film that turns into a gel within 24–48 h of placement on wet tissue, adhering to the surface, and is then subsequently reabsorbed and excreted by the body within 28 days of placement [ 179 , 180 ]. The primary mechanism of action of Seprafilm ® is as a physical barrier separating the traumatized tissue layer from its surroundings to prevent the formation of adhesions. Following FDA approval in 1996, Seprafilm ® has been extensively studied in preclinical and clinical settings. A meta-analysis of 28 randomized controlled trials (RCTs) conducted by ten Broek et al. on the outcomes of using Seprafilm ® as an adhesions barrier showed that the use of Seprafilm ® in abdominal surgeries reduces the severity of postoperative adhesions and the incidence of small bowel obstructions [ 181 ]. The meta-analysis also concludes that there is a possibility of increased risk of anastomotic leakage with the usage of Seprafilm ® . Several RCTs and meta-analyzes support the conclusion of reduced adhesions incidence and severity when Seprafilm ® has been used in open [ 182 – 187 ] and minimally invasive surgeries [ 188 – 192 ]. However, there is also contradictory evidence that suggests the usage of Seprafilm ® does not reduce the incidence or severity of postoperative adhesions, leading to complications like small bowel obstructions (SBOs), peritonitis, abscesses formation and inflammation [ 193 – 202 ]. In addition to this, there is a significant loss in the tensile properties of Seprafilm ® within 30 min of application due to the swelling of the sodium hyaluronate-CMC network which leads to anastomotic leakages if used in scenarios with bowel anastomosis [ 182 , 193 , 199 , 203 ]. Nevertheless, given the compelling positive evidence, Seprafilm ® has been commonly used as an adhesions prevention barrier in surgeries and is used a benchmark for comparison in adhesions barrier research. Interceed ® is another film-like barrier that has been commonly used in surgeries as a barrier material [ 204 ]. It is a woven sheet made of ORC that turns into a gel layer after 24 h of placement on wet tissue and is absorbed after 4 weeks [ 205 ]. Interceed ® is supposed to be an inert barrier that isolates the afflicted tissue surface from the surrounding tissues; however, ORC has also shown to decrease the inflammatory response of macrophages and increasing fibrinolytic activity through an increase in t-PA, both of which contribute towards the reduction of adhesions [ 206 , 207 ]. Several studies on the efficacy of Interceed ® have shown positive results on its effect on reducing the severity or preventing adhesions. A Cochrane review by Farquhar et al. showed that Interceed ® reduced the incidence of adhesions formation and performed better than Seprafilm ® and Gore-Tex ® [ 208 ]. The woven form factor gives Interceed ® high flexibility, which allows it to be utilized in minimally invasive surgeries. Various studies have shown using Interceed ® reduces the incidence and extent of adhesions in laparoscopic surgeries such as myomectomies, endometriosis surgery, ovarian cystectomy and colorectal surgeries [ 205 , 209 – 216 ]. However, there are also studies that show contradictory results regarding the efficacy of Interceed ® . An RCT conducted by Saravelos et al. on 21 women who underwent electrosurgical treatment for polycystic ovarian syndrome (PCOS) showed no difference between the groups treated with Interceed ® and the control group [ 217 ]. Other studies have shown similar negative results [ 211 , 218 ]. There are also certain drawbacks associated with Interceed ® . Firstly, proper hemostasis must be achieved for Interceed ® to be useful as an adhesions barrier since it is incompatible with blood [ 211 , 219 , 220 ]. Additionally, excess peritoneal fluid also seems to reduce the efficacy of Interceed ® [ 220 ]. Though multiple studies have shown that Interceed ® is safe to use in humans, there have been reports of an inflammatory response and peritoneal inflammatory exudate being produced because of Interceed ® placement on tissue [ 221 – 223 ]. Gore-Tex ® is the tradename for a family of surgical films made of ePTFE such as Preclude ® pericardial membrane [ 224 ]. ePTFE is a hydrophobic, non-biodegradable material without any biological function that purely acts as a physical barrier to separate afflicted tissues. It does not adhere to tissues and must be sutured in place to prevent displacement of the barrier [ 225 ]. Several clinical trials and studies have shown Gore-Tex ® to be effective in the prevention of adhesions in both open and laparoscopic surgeries [ 226 – 230 ]. The main drawbacks with ePTFE films are their non-biodegradability, which necessitates a reoperation for removal after the wound healing period, and the requirements for sutures to ensure that the barrier stays at the target site. Reoperations significantly increase the risk of de novo adhesions formation, creating more adhesions than previously present during the initial surgery, hindering the usage of ePTFE [ 231 ]. Moreover, the long-term stability of ePTFE films in vivo is still unclear [ 228 , 232 ]. Adept ® is a 4% Icodextrin solution that has been approved for use only in laparoscopic procedures [ 233 ]. Adept ® works on the principle of Hydroflotation wherein irrigating the peritoneal cavity causes the organs to float and prevents any contact between them during the wound healing period, in doing so, reduces the chances of adhesive tissues forming between the organs [ 27 , 234 ]. Evidence on the clinical efficacy of Adept ® is conflicting with studies showing both positive and negative outcomes. An RCT involving 402 patients undergoing laparoscopic gynecological surgery conducted by Brown et al. showed that using Adept ® demonstrated clinical success when compared to a Ringer’s Lactate control group [ 235 ]. Clinical success in this study was defined as: “reduction in adhesions of at least three or 30% of sites lysed (whichever is greater) between initial surgery and follow-up laparoscopy”. Another RCT conducted by di Zerega et al. involving 62 women undergoing laparoscopic adnexal surgery shows positive but statistically insignificant improvement on the usage of Adept ® as an adhesions barrier [ 236 ]. On the other hand, Trew et al. evaluated the effects of using Adept ® in 498 women undergoing laparoscopic myomectomy, with the study revealing that there was no evidence on the clinical effects of Adept ® [ 237 ]. Moreover, the usage of Adept ® has been shown to increase the incidence of small bowel obstructions [ 238 ]. In addition to these, there are other barriers that have been utilized in a clinical setting such as SurgiWrap ® , HyaloBarrier ® , Coseal ® , although they have not been as extensively studied as the aforementioned barriers. SurgiWrap ® is a poly( l -lactide-co- d , l -lactide) film that is also marketed as OrthoWrap ® and CardioWrap ® for general, orthopedic and cardiac surgeries although the material composition is the same [ 239 ]. The limited number of studies on the efficacy of SurgiWrap ® show positive effects on its usage as an adhesions barrier although some animal models show contrasting data [ 240 , 241 ]. Hyalobarrier ® is a HA-based injectable hydrogel barrier developed to prevent adhesions in abdominal surgeries [ 242 ]. Since it is a HA-based barrier, it has excellent biocompatibility [ 243 ]. Research on the efficacy of Hyalobarrier ® shows contradictory results with studies showing both positive and negative effects [ 244 – 247 ]. Coseal ® is a PEG-based hydrogel sealant that has also been used as an adhesion barrier [ 248 ]. It has been shown to reduce the severity of pericardial adhesions from cardiac surgeries [ 249 – 252 ]. There are, however, safety issues related to using Coseal ® as an adhesion barrier. Napoleone et al.’s study involving 79 pediatric patients also found complications associated with the significant swelling of the PEG-based hydrogel [ 251 ]. Commercially available physical barriers have been extensively used in surgeries yet, owing to their low efficacy, there is a pressing need for the development of an adhesions barrier that can prevent the formation of adhesions. There is no single agreed-upon strategy that is followed by researchers, giving rise to a wide array of novel adhesions barriers being developed currently, some of which have been tabulated in Table 3 . These barriers can be in different form factors although films, hydrogels and fibers seem to be the most common form factors. Each of these have unique advantages and disadvantages. Film-type barriers are solid sheet-like structures that typically possess better mechanical integrity than hydrogels, cover large surface areas, have good flexibility, low swelling ratios, and offer better control over drug delivery [ 281 – 283 ]. Films can be either in the form of dense or porous continuous structures; or sheets of fibers produced by electrospinning or solution blow-spinning. These techniques produce highly porous fiber mats or films with a wide range of fiber diameters, high surface area, and offer good control over the porosity of the films [ 284 , 285 ]. Additionally, the 3D fibrous morphology of these fiber films mimics the structure of ECM and allows for nutrient exchange, promoting tissue regeneration [ 286 , 287 ]. The tuneable porosity also allows for these fiber films to prevent fibroblast migration while allowing nutrients to pass through, effectively acting as a physical barrier [ 286 , 288 ]. Solution blow-spinning offers an added advantage of being able to spray these fibers directly onto the tissue surface, allowing for excellent tissue conformity [ 289 , 290 ]. Hydrogels are another class of biomaterials that have been utilized as adhesions barriers. The primary characteristics of hydrogels that make them so attractive is their high biocompatibility, biodegradability and swelling ratios [ 291 ]. Hydrogels can also be made to respond to external stimuli such as light, pH, and temperature. Such stimuli-responsive hydrogels have been extensively used in drug delivery systems and as adhesions barriers [ 104 , 291 , 292 ]. Although uncommon, micro and nanoparticles, typically in the form of micro/nanoparticle solutions, have been utilized as adhesions barriers [ 293 – 295 ]. These have been utilized as drug delivery systems owing to their site-specific applicability and tuneable properties [ 296 ]. However, these systems also suffer from issues such as rapid clearance due to their small dimensions. Each material form factor offers its own advantages and disadvantages as a physical barrier to prevent adhesions. Most commercial adhesions barriers are film or hydrogel-based barriers that prevent adhesions by separating the afflicted tissue surface from the surrounding tissues. In theory, this should prevent severe adhesions from forming although this is not the current scenario. These barriers have their own shortcomings like limited efficacy, possibility of inflammatory responses, peritonitis. and studies have been conducted to develop physical barriers that are able to overcome these shortcomings. One such study was conducted by Hinoki et al., who developed PLA nanosheets for the prevention of intestinal adhesions and bacterial propagation [ 299 ]. The nanosheets were synthesized by spin coating PLA solution onto an acetylated HA (AcHA) support layer resulting a composite film. The PLA nanosheet side of the composite film would then be placed on the injured site and subsequently the AcHA layer would be dissolved using saline, depositing a nanosheet of PLA onto the injured site. The adhesions prevention efficacy of PLA nanosheets was tested in a mouse serosal defect model while the effect on bacterial propagation was investigated through irrigation of saline-diluted Escherichia coli in PLA nanosheet or Seprafilm ® covered jejunum. The results show a significant decrease in adhesions intensity of the PLA nanosheet group compared to the no-treatment sham group, although, the Seprafilm ® group also showed a significant decrease in adhesions when compared to the sham group. PLA nanosheets, however, showed excellent anti-bacterial abilities compared to Seprafilm ® , which aggravated intraperitoneal infection, reducing mouse survival. Notably, the survival rate in the Seprafilm ® group was 20% while the PLA nanosheets group had a survival rate between 60 and 70%, showing that the PLA nanosheets had good antibacterial properties and may reduce peritoneal adhesions in the presence of bacterial peritonitis. Additionally, film-like barriers typically must be sutured to be kept at the site of injury, which can cause additional adhesions to form. Developing a film that can stick to tissue surfaces and prevent adhesions from forming is inherently paradoxical since these are two completely opposite phenomena. Hydrogels, on the other hand, can be engineered to gel under physiological conditions, allowing them to be applied onto the injured site while in a viscous liquid form, and completely cover the injured tissue before forming a gel. Li et al. developed a thermosensitive hydrogel based on a combination of Pluronic F127 (AOP127) and oxidized HA (OHA) [ 315 ]. The hydrogel is weak at low temperature owing to the absence of hydrophobic interactions below the low critical solution temperature of AOP127. This allows for the hydrogel to be injected into the body, where the increase in temperature induces hydrophobic interaction, increasing its mechanical strength. Its adhesions prevention efficacy was investigated in a rat sidewall defect-cecum abrasion model. The adhesion scores of the APO127/OHA hydrogel group and normal saline control group were 0.5 and 4.33, respectively, implying that the hydrogel has good adhesions prevention capabilities. The efficacy of film barriers is also dependent upon the establishment of hemostasis at the target tissue site. Cellulose and HA-based barriers have been known to fail in scenarios where establishing hemostasis was not possible. Imbuing the adhesions barrier with hemostatic capabilities is one way to prevent this. Chen et al. developed a sandwich-like scaffold with a sodium CMC/glycerol sponge sandwiched between PLGA/PLA- b -PEG electrospun fiber films capable of effective hemostasis and pericardial adhesions prevention ( Fig. 2 ) [ 341 ]. The sodium CMC/glycerol sponge acts as a hemostatic agent, absorbing excess blood and stopping blood loss while the PLGA/PLA- b -PEG fiber film layer acts as the physical barrier, preventing the formation of adhesions by preventing fibroblast deposition and growth. Despite the advantages, there is still room for improving the efficacy of these barriers in preventing postoperative adhesions. One of the reasons a physical barrier fails to be effective is due its innate biological inertness. There is untapped potential in these materials to be engineered to actively prevent adhesions by interacting with the multiple pathways activated during wound healing. This can be achieved in various ways. Materials can be engineered to prevent the deposition of fibrinogenic molecules and cells onto the surface, effectively creating materials with anti-fouling properties. Materials can also be engineered to actively modulate the pathways involved in wound healing, either through inherent material properties or through the inclusion of therapeutics. Most of these strategies take advantage of the material properties and design drug delivery systems that can simultaneously act as a physical barrier, either preventing tissue connectivity or preventing unwanted surface deposition, and release therapeutic drugs. Researchers employ the first strategy to develop materials that have anti-fouling properties, which can then prevent the deposition of fibrinogenic molecules and cells onto the surface. One of the most common ways of creating an anti-fouling surface is by increasing the hydrophilicity of the material. Surface modification or synthesizing materials using hydrophilic polymers like PEG, and zwitterionic polymers are two commonly used strategies to increase hydrophilicity. The surface of hydrophilic polymers in an aqueous environment is covered by a layer of strongly bound water. This “hydration layer” requires energy to be displaced, thereby preventing the adsorption of protein and cells onto the surface [ 353 , 354 ]. Although both hydrophilic polymers and zwitterionic polymers have anti-fouling properties through the formation of a hydration layer in an aqueous environment, the mechanism of formation of these hydration layers is different between the two. Hydrophilic polymers like polyamines, polysaccharides, PEGs form hydrogen bonds with water, giving rise to the hydration layer on their surfaces while this layer is formed on zwitterionic surfaces through electrostatic interactions [ 355 ]. This implies that the hydration layer formed on the surface of zwitterionic polymers is much stronger, consequently, zwitterionic polymers have better anti-fouling performance [ 356 , 357 ]. Several studies have been undertaken in developing zwitterion-functionalized materials for the prevention of post-operative adhesions [ 300 , 301 , 323 , 325 , 343 , 351 , 352 ]. Yi et al. designed a superlubricated electrospun nanofibrous membrane for preventing peritendinous adhesions ( Fig. 3A , B ) [ 343 ]. PCL and Poly(2-methacryloyloxyethylphosphorylcholine) (PMPC) were dissolved and electrospun together under high relative humidity (65%), creating a layer of bound water on the surface of the fibers, mimicking the “semi-melting” state of the water layer on the surface of ice. The nanofibrous membrane showed excellent adhesions prevention capability in a Rat Achilles Tendon. Zwitterionic polymers have also been used to design a polyzwitterionic lubricant for the prevention of cardiac adhesions by Wang et al. In this work, PMPC was utilized to create a viscous lubricant to prevent cardiac adhesions ( Fig. 3C , D ) [ 351 ]. The lubricant-like nature of the polymer decreased the mechanical stress applied on the heart while being able to prevent adhesions formation. Similarly, a cream-like zwitterionic poly(carboxybetaine acrylamide) (PCBAA) was developed by Zhang et al. for the prevention of peritoneal adhesions [ 352 ]. Both polymers showed excellent adhesions prevention performance, which was attributed to the inhibition of protein adsorption by the zwitterionic polymers. In a similar fashion, PEG and other hydrophilic polymers have been employed to develop physical barriers, utilizing the same principle of protein inhibition as zwitterionic polymers. There is extensive research on PEG-based barriers for adhesions prevention [ 303 , 320 , 322 , 341 , 358 ]. Although not as common as PEG-based materials, hydrophilic polymers have also been utilized to develop physical barriers. Yu et al. developed an ultrasoft hydrogel based on poly( N -acryloyl alaninamide) (PNAAA) [ 317 ]. Physical crosslinks in the form of hydrogen bonds allowed the hydrogel to be injectable. The efficacy of the hydrogel as a barrier was investigated in a rat sidewall defect-cecum abrasion model that was designed for investigating recurrent peritoneal adhesions. The hydrogel was able to significantly reduce the incidence of recurrent adhesions. Using N -(2-hydroxypropyl) methacrylamide (HPMA) and N -acryloyl glycinamide (NAGA) as the monomers, Zhao et al. synthesized an ultra-hydrophilic hydrogel (PNAGA-PHPMA) [ 323 ]. The hydrogel self-assembles through hydrogen-bonding, similar to the PNAAA hydrogel, giving it good injectability. The combination of two hydrophilic monomers significantly increased the hydrophilicity of the hydrogel, greatly reducing protein adsorption. The hydrogel’s in vivo efficacy was confirmed through an investigation in a rat cecum abrasion model where the hydrogel was able to significantly reduce recurrent adhesions. Another strategy for developing adhesions barriers is engineering materials to have a therapeutic effect. One of the ways to prevent adhesions from forming is by targeting the coagulation cascade and inhibit the conversion of fibrinogen to fibrin. The simplest way to achieve this is through hemostasis which prevents the activation of the coagulation cascade. Several polymers like chitosan, alginate, gelatin, ORC, HA. inherently possess hemostatic capabilities and have been used as hemostatic agents [ 359 ]. However, natural polymers have poor mechanical properties and some of these polymers have been shown to induce inflammatory responses. Several studies have been conducted on researching synthetic and natural polymers with hemostatic capabilities to prevent postoperative adhesions formation. Cheng et al. developed a N , O -carboxymethyl chitosan/ORC composite gauze by coating an ORC gauze with N , O -carboxymethyl chitosan [ 314 ]. The addition of N , O -carboxymethyl chitosan imbued the composite gauze with excellent hemostatic functionality. The gauze was also shown to reduce adhesions severity in a rat sidewall trauma-cecum abrasion model. Researchers have also developed materials that target other pathways such as the NF-κB pathway. NF-κB is a transcription factor that has an important role in regulating inflammatory response and influencing macrophage activation [ 360 ]. Xiao et al. proposed a PLA fibrous membrane with a diamond-like carbon (DLC) layer deposited on the surface of the membrane ( Fig. 4 ) [ 342 ]. The DLC coating on PLA displayed ROS-scavenging ability, mitigating M1 macrophage polarization by reducing NF-κB phosphorylation. Additionally, DLC coating delays PLA biodegradation, decreasing the production of lactic acid, inhibiting lactic acid-induced M2 polarization. The capability of the DLC-coated PLA membrane in preventing peritendinous adhesions during tendon repair were investigated in a rat Achilles tendon model wherein the membrane reduced the foreign body response and consequently, the formation of peritendinous adhesions. Similarly, Yao et al. developed a hydrogel patch by combining a PCL fiber layer with a dual dynamic crosslinked hydrogel comprised HA-adipic acid dihydrazide network and a second catechol-based network of protocatechuic aldehyde complexed with Fe 3+ ions, termed PCL@HA-ADH@PA/Fe [ 332 ]. The catechol-Fe 3+ network regulates macrophage polarization through the NF-κB pathway. Additionally, the dual-network hydrogel also exhibits antibacterial activity and self-healing capabilities while the PCL fibrous layer prevents cell penetration. These features allow the hydrogel patch to effectively function as a barrier to prevent peritendinous adhesions while enhancing tissue healing. Materials can also be designed to capture proinflammatory cytokine markers such as IL-1β, IL-6, TNF-α. Given the positive charges of these cytokines, negatively charged materials can be designed to capture these cytokines, decreasing the inflammatory response. One such material was developed by Shin et al. [ 297 ]. They developed a 3D-bioprinted PVA scaffold crosslinked with Na 3 P 3 O 9 as a hernia repair mesh. The negative charge imbued by Na 3 P 3 O 9 allows the scaffold to act as a cytokine trap, modulating the inflammatory response triggered by the placement of the scaffold. RT-PCR analysis showed lower proinflammatory cytokines while the adhesions prevention capabilities were confirmed through a visual inspection. Additionally, disruption of the epithelial or mesothelial layers causes neutrophils to produce factors that exacerbate the inflammatory response. As such, downregulation of neutrophils could alleviate the inflammatory response. This was investigated by Wang et al. through the synthesis of a neutrophil-trapping hydrogel based on poly(2-(methylsulfinyl)ethyl acrylate) (PMeSEA) [ 318 ]. The presence of zwitterionic sulfoxide groups increases the fouling resistance of the hydrogel. In addition to this, the sulfoxide groups can be selectively oxidized by ClO − , preventing the ion from stabilizing neutrophils, thereby inhibiting their formation. The addition of 5-fluorouracil (5-FU) to the hydrogel also allowed the hydrogel to show antitumour activity. The PMeSEA hydrogel could prevent peritoneal adhesions while also presenting antitumour activity through the release of 5-FU. Modulation of wound healing mechanisms locally can lead to a better degree of adhesions prevention. Currently, therapeutic drugs are employed to regulate these mechanisms, of which there is a wide variety. However, regular methods of therapeutic delivery, such as intravenous delivery, have certain drawbacks that prevent these drugs from properly modulating local wound healing mechanisms. Utilizing polymeric materials as drug delivery systems allow for controlled and localized delivery of therapeutic drugs, ensuring a constant supply of drugs throughout the wound healing period. This circumvents the necessity to ensure constant supply through regular means of delivery like intravenous injections, mitigating any adverse systemic effects of the drugs. Historically, hydrogels have been a popular choice for drug delivery systems, owing to their tuneable porosity, drug release kinetics and degradation profiles [ 291 ]. Fibrous mats, either electrospun or blow-spun, have similar properties to hydrogels, and have also been used as drug delivery vehicles [ 361 ]. Given the different pathways involved in the formation of adhesions, several classes of drugs like anticoagulants, anti-inflammatory drugs, hemostatic agents, immunosuppressants, fibrinolytic agents. Physical barriers as drug delivery systems have been extensively studied. Anti-inflammatory drugs decrease the inflammatory response, which is one of the key pathways that lead to adhesions formation. As such, several studies have focused on downregulating the inflammatory response. Lang et at . proposed a carboxymethyl chitosan (CMSC) and Poloxamer 338-based hydrogel loaded with Heparin Sodium (HS). The hydrogel exhibits flowable properties below 20 °C, which then transforms to a physical hydrogel at physiological temperatures. The introduction of CMSC into the hydrogel imbues self-healing capabilities to the hydrogel. This allows the hydrogel to act as a good physical barrier. In addition to this, the controlled release of Heparin Sodium inhibits the inflammatory response. The use of this hydrogel in a rat abdominal wall + cecum abrasion model led to significantly low adhesion scores, confirming its adhesions prevention efficacy. Wang et al. synthesized an anti-inflammatory and ROS-eliminating Tempol + phenylboronic acid pinacol functionalized b-cyclodextrin (TPCD) nanoparticle, which was then loaded into a Poloxamer 407 + Tannic Acid hydrogel [ 334 ]. The localized delivery of TPCD nanoparticles led to an inhibition in inflammatory response and attenuated local oxidative, ultimately leading to reduced epidural adhesions. Additionally, the inclusion of tannic acid improved the tissue adhesion of the hydrogel. The thermosensitivity of Poloxamer 407 also allows for easy handling and better adhesion to tissue without inhibiting spinal cord movement. Anti-inflammatory drugs were also loaded in fiber and film-like materials. Erdi et al. loaded apolipoprotein E mimetic peptide COG133, which is an anti-inflammatory peptide, into a blend of high and low molecular weight poly( d , l -lactide- co -caprolactone) (PLCL) for solution blow-spinning. The blend of high and low molecular weights led to a near-linear degradation profile which allows for controlled release of COG133 rather than a burst release. Nadri et al. reported the development of ibuprofen-loaded PEG/Silk fibrous membranes for the prevention of peritendinous adhesions [ 339 ] where the release of ibuprofen, an NSAID, alleviated the inflammatory response. The anti-inflammatory effects of curcumin, a natural compound found in turmeric, in combination with Celecoxib have been explored by Zhang et al. [ 345 ]. The combined effects of Quercetin, an anti-inflammatory agent, and silver nanoparticles (AgNPs) loaded into a PCL-phosphatidylcholine film were explored by Hosseinpour-Moghadam et al. [ 298 ]. The anti-inflammatory properties of Quercetin and the anti-microbial properties of AgNPs, combined with PCL film acting as a physical barrier, significantly reduced the incidence of adhesions in a rat surgical abrasion model. Prevention or reduction of the inflammatory response can also be achieved through the downregulation of the NF-κB pathway. This strategy was utilized by Wang et al. through a PEG-silicate nanodisks (SNDs) composite hydrogels loaded with dexamethasone ( Fig. 5 ) [ 111 ]. The hydrogel exhibits self-healing properties through a physical network formed by electrostatic interactions between the SNDs, allowing it to maintain a continuous barrier in the presence of pulsating stresses in the pericardial space. Additionally, the continuous of dexamethasone inhibits the NF-κB pathway, preventing the activation of proinflammatory cytokines. This prevented the formation of adhesions in the hydrogel group in a rabbit costal sternotomy model. An NF-κB inhibitor, JSH-23 was loaded into PLA nanofibrous membranes by Wang et al. [ 286 ]. JSH-23 inhibits NF-κB -mediated M1 polarization, decreasing the inflammatory response and consequently, decreasing the severity of adhesions. Bleeding activates the coagulation cascade which in turn results in increased fibrin deposition. Therefore, preventing blood loss through hemostatic agents could lead to a reduction in fibrin formation. As such, several studies have been conducted to explore the effects of loading hemostatic agents into materials. A self-assembling hydrogel using Jelleine-1 (J-1), and adenosine diphosphate (ADP) was proposed by Zhou et al. [ 324 ]. J-1 is an antimicrobial peptide with antimicrobial properties while ADP shows hemostatic activity since it is a platelet-activating factor. Tranexamic acid (TA) is an antifibrinolytic agent that has shown to possess hemostatic properties. Wang et al. loaded an injectable Gelatin-Sodium Alginate gel with TA to improve upon the hemostatic capabilities of gelatin and alginate. The gel, once injected in its sol form onto the target site, was sprayed with a CaCl 2 solution leading to the formation of a crosslinked upper layer that acted as a physical barrier while the sol form of the gel in contact with the tissue ensured good tissue adhesion. The gel also possessed excellent hemostatic performance, confirmed by its efficacy to prevent blood loss in a rat liver injury model and was shown to significantly reduce the formation of peritoneal adhesions. A different approach to prevent adhesions formation by promoting mesothelial cell repair was reported by Wei et al. [ 294 ]. The team synthesized PDA-KGF NPs through in situ self-assembly that can be delivered on the injury site as a solution with HA. The efficacy of the PDA-KGF NPs in HA solution was investigated in a mouse cecum abrasion model. The controlled release of KGF promotes mesothelial regeneration while the addition of HA acts as a physical barrier, separating the injury site from its surrounding tissues, thereby decreasing the severity of adhesions. The addition of PDA has also shown to prolong the bioactivity of KGF, increasing the period of activity of the included therapeutic. Several other therapeutic agents have been utilized by researchers to prevent the formation of adhesions with good efficacy. Overall, the combination of a therapeutic agent with a material that acts as a purely physical barrier or possesses therapeutic properties has shown to be successful in either the reduction of adhesions severity or in the prevention of adhesions formation.

Postoperative adhesions are inevitable complications of surgeries that have serious implications on the health of patients. The formation of adhesions is a result of a complex interplay between several regulatory activities that are part of the body’s wound healing process. Additionally, despite significant advancement, a complete understanding of the mechanisms has yet to be achieved which limits the ability to develop effective treatments. Key gaps in the understanding of how angiogenesis fully contributes to adhesions formation, how certain types of adhesions such as peritendinous adhesions are formed, as well as how the fibrinolytic imbalance occurs via these mechanisms contribute primarily to this issue. Better surgical practices and minimally invasive surgeries have been shown to reduce adhesions formation since they are less stressful on the body, yet the reduction is not to the point where this negates the necessity for additional intervention and is not always effective. In general, the form of treatment can be broadly divided into two classes: therapeutic drugs that modulate parts of the mechanisms that are initiated during wound healing; or a physical barrier that isolates the afflicted tissue and prevents adhesions from forming or if formed on different tissues, prevents them from connecting to form a band of fibrous tissue. The limited understanding of the adhesions formation mechanism as a whole highlights a lack of an ideal target for therapeutics. Additionally, given the complexity of the wound healing process, targeting a particular mechanism is difficult, limiting the efficacy of therapeutic drugs in the prevention of adhesions. On the other hand, physical barriers based on both natural and synthetic polymers have seen varying success since their development, with several of them being developed for use in a surgical setup. These barriers work by preventing fibrous tissue connectivity between the afflicted surface and adjacent tissues. Certain barriers, like Seprafilm ® and Interceed ® , have been extensively used in surgeries to prevent adhesions and have been shown in most cases to reduce the severity of adhesions but these cannot prevent adhesions from forming. In addition to this, their efficacy and consistency in reducing adhesions severity is limited. The inconsistent performance of these clinically approved adhesion barriers has prompted extensive research into new materials. Current research primarily focuses on creating a biocompatible and biodegradable physical barrier that prevents the formation of adhesions by actively preventing the formation of fibrous tissue in the initial stages of wound healing. There are multiple strategies that researchers employ to develop materials with such capability, most of which take advantage of our current level of understanding of the adhesions formation mechanisms. A commonly followed strategy is to develop anti-fouling materials that prevent the deposition of fibrinogenic compounds, protein markers and cells on the surface of the material. Development of an anti-fouling material is achieved through multiple ways, which is typically done by creating a hydrophilic surface by the inclusion of zwitterions like PMPC or PCBAA or highly hydrophilic polymers like PEG, or NAGA. Both strategies have been utilized to create anti-fouling physical barriers with good efficacies found in animal models. Additionally, novel barriers have been designed to exhibit drastically different characteristics, all of which have proven to be moderately effective, creating more questions as to what the ideal barrier characteristics should be. An alternative strategy utilizing physical barriers as drug delivery systems to deliver therapeutics has been gaining popularity. The site-specificity of such targeted drug delivery could circumvent the negative effects of therapeutics such as high required dosages, limited efficacy thereby creating a material that can act as a physical barrier while delivering a therapeutic which modulates a targeted mechanism, preventing adhesions from forming. One possible advantage with such drug delivery systems is their ability to prevent adhesions over a larger area when compared to purely physical barriers, overcoming a major drawback of physical barriers. Another benefit with drug delivery systems is the possibility to include therapeutics to improve tissue repair since some physical barriers are known to block nutrient transport, delaying tissue repair. Significant research has been conducted on developing hydrogels or films as drug delivery vehicles. These materials have shown to have superior efficacy to physical barriers in certain cases however, the possibility of therapeutics having an adverse systemic effect still exists. Overall, the development of a physical barrier that can prevent adhesions has seen significant attention in recent years with many new materials combining ideal material properties with a therapeutic to achieve the optimal barrier. The usage of purely therapeutic approaches has resulted in inconsistent safety and efficacy, and purely physical barriers available on the market exhibit these same inconsistencies. Given the varying degrees of success with each method individually, designing a multi-functional material that combines material design and drug delivery to produce barrier that can synergistically reduce adhesions formation appears to be the better path forward in achieving the ideal adhesions barrier. Ultimately, postoperative adhesions continue to be a defining issue in the clinic and continued research into investigating their development is critical to not only understanding the problem at hand but also to realizing the key qualities that an adhesions preventative must exhibit.

An adhesion is scar tissue that joins two internal body surfaces that are not usually connected. Adhesions develop after surgery, infection, injury (trauma), and appear as fibrotic tissue bridges or as thin sheets that may be vascularised [ 1 ]. Organs or tissues within the body stick to other internal nearby body wall cavity surfaces or adhere to each other, as the body attempts to heal itself. The formation of adhesions can have drastic impacts on patient outcomes and quality of life, often associated with low-risk complications (e.g. chronic pain), life-threatening medical emergencies (e.g. small bowel obstruction, internal hemorrhaging) and life-altering complications (e.g. infertility, paralysis) [ 2 – 6 ]. Although they are widely associated with abdominal surgeries, adhesions are a body-wide complication to consider, having been documented in the pericardium, peritoneum, tendon, uterine, dural, and vitreous base [ 7 – 17 ]. Due to this broad scope, adhesions are extraordinarily common, occurring in over 90% of open gynaecologic and abdominal surgeries [ 18 , 19 ]. In the United States alone, incidence rates were over 95% in 20 million patients, amounting to over $1.3 billion in workload costs annually in 1994, equivalent to over $3 billion in 2024 [ 20 ]. In 2005, it was estimated to cost patients over $2.3 billion, equivalent to $3.8 billion in 2024, in medical costs annually for treatment of postoperative adhesions [ 21 ]. More recently, an economic retrospective analysis showed adhesions-related medical costs estimated to be between $67 and 670 million annually in France alone, revealing the extensive burden adhesions place on both patients and hospitals [ 22 , 23 ]. The adhesions problem, despite the risks it already yields, are further compounded by the limited ability for surgeons to combat them. Traditionally, a surgical procedure called adhesiolysis is performed, involving surgeons opening an afflicted area to sever these fibrotic connections, but this is often limited for treatment of life-threatening issues instead of low-risk complications such as chronic pain [ 21 ]. In addition, this warrants a second operation on a patient and requires inpatient care, further increasing medical costs and labor hours. Despite this, over 350,000 hospitalizations for adhesions procedures occur annually [ 21 ]. However, given their nature to form after tissue trauma, these surgeries often result in the formation of secondary adhesions, requiring an additional procedure to remedy once more. It is reported that almost 80% of procedures are targeting secondary adhesions, indicating an extreme prevalence for reformation [ 21 ]. Additionally, in certain procedures (e.g. cardiac re-entry), adhesions formation serves to increase the difficulty and time required for the operation, further increasing patient risk [ 24 – 26 ]. If these are prevented from forming post-operation, then a large majority of these hospitalizations would be circumvented. As such, many developing clinical treatments focus on the mitigation of primary adhesions. This clinical strategy would serve to prevent nearly all adhesiolysis procedures and drastically reduce reoperation rates, patient and labor costs. Clinically, there are three preventative methods approved by the US Food and Drug Administration for use in adhesions prevention, including two barrier materials in Seprafilm ® and Interceed ® , with a third liquid solution that utilizes Hydroflotation in Adept ® [ 27 ]. Despite three approved methodologies, adhesions continue to remain an issue. Seprafilm ® has limited applicability due to the complex geometries within the body, as the solid film often fails to completely adhere due to brittleness [ 27 ]. Interceed ® has yet to be established as both safe and effective for adhesions prevention, while Adept ® has failed to demonstrate definitive efficacy in human trials [ 27 ]. Beyond materials the usage of laparoscopic rather than open and large incision laparotomic procedures have also been studied. Laparoscopies are minimally invasive procedures utilizing small incisions and thin tubes placed inside the body to limit tissue trauma and contact; however, results have not appeared consistent on the benefits in adhesions prevention [ 28 ]. The inadequacy of current products and surgical methods have resulted in the development of numerous prevention methods for adhesions, including both pharmacological therapeutic methods and barrier materials. Indeed, even multifunctional biomaterials that incorporate therapeutics within a material have been developed to enhance simple barrier properties or targeting of pathological markers [ 29 , 30 ]. This review is aimed towards summarizing the current research ongoing in the field of adhesions understanding and prevention. Due to the complex pathophysiology that governs adhesions formation and the competing molecular pathways, preventing adhesions at a universal level across the body is challenging, with various tissue types and surgical practices involved, such as differences between abdominal surgeries and tendon repair. Although the biological mechanisms are yet to be fully established, here, the studied pathways will be discussed and linked to therapeutics currently being utilized. However, due to this lack of full biological understanding, the use of physical barriers will be summarized to portray the full comprehensive view of adhesions prevention in the current scientific and medical communities.