Postoperative abdominal adhesions are the irreversible vascularized fibrous bridges formed between the abdominal wall, omentum and internal organs because of natural wound healing [1]. They are common and serious clinical problems that can occur in up to 93% of abdominal/pelvic surgery patients [[2], [3], [4]]. Consequently, adhesions can lead to many serious complications such as severe abdominal pain, intestinal obstruction, secondary infertility, and even death [5,6], which not only significantly reduces patient's life quality, but also brings extra troubles to surgeons and healthcare providers [7]. A second operation (adhesiolysis) is the only effective treatment to release adhesion, but approximately 80% of patients have been reported to suffer from more severe recurrent adhesions and additional medical risks [5,8]. Therefore, effective treatment procedures that can prevent adhesions formation is emergently demanded.

The widely investigated clinical strategies to prevent postoperative adhesions mainly include improving surgical skills, drug treatments, and using biological barriers [9]. Recently, barrier materials (e.g., polymer solutions, solid films, and hydrogels) that can separate the damaged tissue-surface from surrounding tissues/organs, are considered to be more effective adjuncts in adhesion prevention [[10], [11], [12]]. However, these commercially available physical barriers have been reported to have different deficiencies, although they remain the mainstream anti-adhesion treatments clinically. Icodextrin liquid barrier (Adept®) has been documented to play a vital role in reducing adhesions following routine general surgery [8,13]. However, Adept® is absorbed quickly in vivo and has various adverse effects in some clinical cases, such as extravasation, small-bowel obstruction, postoperative peritonitis and intestinal perforation, displaying limited anti-adhesion effect [8,[14], [15], [16]]. Oxidized regenerated cellulose film (Interceed®) and Seprafilm® composed of hyaluronic acid and carboxymethyl cellulose are two of the most common solid anti-adhesion products. In practice, these films do not guarantee the complete cover of irregular wounds [17,18]. Worsely, Seprafilm® can aggressively adhere to any moisture surface, making it less maneuverable in surgical procedures [19]. Although several animal and clinical trials have found that they can reduce the severity and extent of adhesions, these films do not completely eliminate adhesions formation [[20], [21], [22], [23]]. Consequently, numerous efforts have been devoted to exploiting injectable hydrogels as anti-adhesion barriers. Sodium hyaluronate gel, the most widely used clinically, can complete coverage the irregular wounds and is suitable for laparoscopic surgery. Disappointingly, it suffers from fast degradation time, low mechanical strength, and poor adherence to the target organs [24], resulting in inability to function at the critical stage of adhesion formation. Thus, it can be seen that the existing commercial products have unsatisfactory effects on preventing adhesion. We assumed the crucial reason may be that these products merely function as physical barriers and have no pharmacological effects, but little attention has focused on their capacity to also intelligently regulate the pathological signals of adhesion development.

According to reports, postoperative adhesion formation is a multiple complex cascade involving inflammatory reaction, oxidative stress and fibrin deposition, which further disrupts the balance between fibrin production and degradation, leading to the occurrence of adhesions [9,25]. Particularly, the acute inflammatory response associated with excessive reactive oxygen species (ROS) production after surgery is a trigger and catalyst of the adhesions formation cascade [25]. In addition, one latest research demonstrated that excessive aggregation of GATA6+ macrophages via scavenger receptors (MSRs) is also an accomplice to adhesion formation, and this aggregation can be blocked by using polyanionic ligands [26]. Recently, many types of inflammation modulation sprayable hydrogels have been developed for postsurgical microenvironment regulation and tissue repair [[27], [28], [29], [30], [31]], showing great potential in biomedical applications and providing inspiring ideas for adhesion prevention. Some studies have attempted to confer antiinflammatory or antioxidative functions on hydrogels to improve barriers performances for better anti-adhesion effect [32,33], however, little research has focused on smart ROS scavenging, and the simultaneous regulation of inflammatory microenvironment and GATA6+ macrophages aggregation. Therefore, rational design of functionalized hydrogel barriers to intelligently intervene in the key stage of postoperative wound healing according to the pathophysiological of adhesion is challenging but crucial for adhesion prevention.

To overcome the current defects, we engineered a ROS-responsive asymmetric-adhesive spray hydrogel barrier (sHA-ADH/OHA-E), which served as a smart inflammatory microenvironment regulator and GATA6+ macrophages trap to achieve postoperative adhesion-free wound healing. To achieve high biocompatibility and reasonable degradation performances, hyaluronic acid (HA), an immunologically inert and biodegradable natural component [34], was selected as a hydrogel precursor skeleton material. First, epigallocatechin-3-gallate (EGCG), a polyphenolic compound with antiinflammation and antioxidation activity [35,36], was covalently grafted onto phenylboronic acid (PBA)-modified oxidized hyaluronic acid (OHA-3APBA) via a ROS-sensitive boronate bond to synthesize OHA-E conjugate. Meanwhile, another HA conjugate sHA-ADH co-modified with sulfonic acid groups and adipic dihydrazide (ADH) was synthesized. Next, sHA-ADH/OHA-E hydrogel can be fabricated within 5 s after simple mixing of OHA-E and sHA-ADH through forming dynamic covalent acylhydrazone bonds (Scheme 1A).

In vitro and in vivo experiments demonstrated that sHA-ADH/OHA-E has the following advantages and working mechanisms for adhesions prevention (Scheme 1B): (1) Intelligently release EGCG according to ROS levels in wound microenvironment to alleviate oxidative stress and promote M2 phenotype macrophage polarization, and the fibrinolytic system balance was further restored to reduce fibrosis. Meanwhile, the negatively charged sulfonic acid groups made the hydrogel resistant to fibrin deposition, fibroblast and macrophage attachment. More importantly, we demonstrated for the first time that the sulfonic acid group modification endowed the hydrogel as a polyanion trap to neutralize scavenger receptors and then impeded uncontrolled aggregation of GATA6+ macrophages. As a result, sHA-ADH/OHA-E hydrogel fundamentally prevented the occurrence of adhesions by regulating the key steps of the pathological cascade of adhesion formation. (2) Fast gelation, regulable shear-thinning, rapid self-healing and enough mechanical strength, to promise convenient application, uniform spraying and withstand pressure and shear stress of abdominal microenvironment, showing great potential to adapt to various abdominal/pelvic tissues. (3) Asymmetric and satisfactory tissue adhesion, to avoid undesired adhesion with surrounding normal tissues, and guarantee reasonable local retention for at least 14 days, which covers the critical stages of wound healing. Collectively, sHA-ADH/OHA-E acted as an ideal physical barrier and perfect trauma microenvironment regulator to enable adhesion-free wound healing. We believe this hydrogel represents a promising anti-adhesion barrier and provides a clinically translatable design concept to effectively prevent postoperative adhesions.