Nature-derived five-star general fighting postoperative abdominal adhesion

Nature-derived five-star general fighting postoperative abdominal adhesion | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Nature-derived five-star general fighting postoperative abdominal adhesion Lin Jin, Xiaolin Pan, Congling Ren, Xing Chen, Xiaoli Liu, Zhe Yang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3469145/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Postoperative adhesion of abdominal is one of major surgical complications, mainly due to inflammation in the wound tissue causing adhesion between the wound tissue and the tissue. These adhesions not only cause the loss of functional parts, but also seriously affect the postoperative rehabilitation. Recently, researchers have developed various types of hydrogels as barriers to prevent adhesion through physical and mechanical isolation. However, the swelling of hydrogel may lead to the new inflammation and generate excessive reactive oxygen species (ROS), inducing the tissue adhesion again. Herein, we designed a Nature-derived five-star general fighting postoperative abdominal adhesion, which possesses a five-star function of anti-swelling, ROS clearance, inflammation inhibition, anti-bacterial and anti-adhesion. Thus, the swelling rate of the prepared nanofiber hydrogel system is confined to 1.21 times, the antibacterial efficiency is 96%, and the adhesion inhibition efficiency is 99%. Combined with its excellent performance, we believe that the prepared anti-swelling, ROS scavenging and antibacterial composite hydrogel system will provide a new strategy for clinical postoperative adhesion inhibition. Nanofiber hydrogel ROS scavenging abdominal adhesion Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Introduction Pathological adhesion formation often occurs after abdominal surgeries, [ 1 – 6 ] and the probability of occurrence is up to 93%.[ 7 , 8 ] There are three main reasons for adhesion, (1) the organ surfaces of postoperative wound sites coalesce with other tissues, or the walls of these sites surrounding cavityhese adhesion, (2) abdominal bacterial infections on the wound sits, (3) postoperative inflammation. [ 9 – 13 ] Despite the improvements of surgical techniques, like minimal or non-invasive surgery, the postoperative abdominal adhesions still threaten the health of people's lives.[ 14 – 18 ] For example, 64% patients of abdominal surgery suffered from a problem related to adhesions within 10 years, or requiring further intra-abdominal surgery treatment.[ 19 , 20 ] However, the re-operations to remove adhesions significantly prolong time-consuming and increase enormous economic burden on healthcare for patients.[ 21 – 23 ] Therefore, eliminating the formation of postoperative adhesions is crucial in the field of clinical surgery. During early adhesion formation process, injured organ surface remains undisclosed and epithelial monolayer destroyed, which imposed to other non-injured organ surface and adjacent surface, and then formed adhesion. [ 24 – 28 ] In addition, inflammation and bacterial infection also support the formation of adhesion. [ 29 , 30 ] Therefore, during early adhesion formation, appropriate treatments is tare vital to prevent adhesions. Recent years, various of barriers have been developed to reduce and prevent surgical adhesions,[ 31 – 36 ] mainly including nanofibers and hydrogel,[ 37 – 43 ] such as super-lubricated electrospun nanofibers,[ 6 ] hierarchical structured nanofibers,[ 9 ] catechol-functionalized oxime hydrogel.[ 7 ] However, these barriers are limited by intrinsic performance limitations, and unable fully meet the complex internal environment's demand to prevent postoperative adhesions. Herein, we developed nanofiber CS-HA-DA/PDA NPs coated emodin composite hydrogel system (NFs-H@PE) ( Fig. 1 A ) for effective prevention of postoperative adhesion through nanofibrous hydrogel as barrier and release of PDA NPs and emodin ( Fig. 1 B ) . The synthesized biological macromolecules hydrogel embedded nanofibers demonstrated excellent biocompatibility, anti-swelling property. Additionally, after loading PDA NPs coated emodin, this system provided better ROS scavenging ability and antibacterial properties. Such nanofiber hydrogel system as barrier achieved injury surface covered without introduce inflammation because anti-swelling, meanwhile, rapid outward permeation of PDA NPs and sustained release of emodin provided an excellent microenvironment for anti-inflammatory and anti-bacterial properties. The obtained system synergistic effect effectively prevents the formation of postoperative adhesions., And we believed that this nanofiber hydrogel composite system might provide a potential candidate for preventing postoperative adhesions in practical clinical application. Experimental section Materials Chitosan was purchased from Haidebei Bio Technology Co. (Shandong Jinan), DA and HA were obtained from Maidelin Bio Technology Co. (Shanhai). Other chemicals were purchased from Guangzhou Chemical Guangzhou Chemical Co. and were used as obtained without further purification. Kunming mice were purchased and cultured in the Center for Experimental Animals at Affiliated Hospital of Hebei Engineering University Health Science Center. The protocol for animal experiments was approved by the Animal Experimentation Ethics Committee of Hebei Engineering University. Synthesis of the NFs-H: CS-HA-DA was synthesized using EDC, NHS under 8h reaction, the mass ratio is 1:1:1, and very step goes through dialysis (8000 DA) and freeze-drying. The PLLA nanofibers were prepared through our previous method.[44] And then, the PLLA nanofibers were dispersed in aqueous solution, subsequently, CS-HA-DA (30 mg/mL) was added into the nanofibers aqueous solution and was became a uniform dispersion through ultrasound, PDA NPs coating emodin also added into above composite solution, finally, ammonium persulfate aqueous solution (0.02g/mL) was added into composite solution to form NFs-H for animal experiments. Characterization of NFs-H: The NMR and FTIR were used characterized for NFs-H. The morphology of PLLA nanofibers and NFs-H were tested using SEM image. DA NPs were characterized by SEM and TEM images, and the pore size distribution and BET surface of PDA NPs were tested using nitrogen adsorption-desorption isotherm. Results and discussion Fabrication of nanofibers CS-HA-DA hydrogel The desired anti adhesive material should meet the complex requirements, such as excellent biocompatibility, anti-swelling performance. The hydrogel with excellent biocompatibility required the synthesis of biomaterials. The triblock derivative was synthesized using chitosan, hyaluronic acid and dopamine through reaction of amine bonds (Fig. 2 A). As shown in the NMR spectrum (Fig. 2 B), the chemical shift (1H) of DA at 2.5, 2.75 and 7.0, which demonstrated that CS and DA grafted onto the chain of hyaluronic acid. In addition, the FTIR spectrum (Fig. 2 C) of CS, HA-CS and HA-CS-DA, also noted that the CS characteristic peaks (1420 cm − 1 , 1650 cm − 1 ) were observed after HA grafted CS, moreover, the DA characteristic peaks were seen after HA-CS grafted DA. These results indicated that the triblock graft derivative was successfully synthesized. Preparation and characterization of PDA coating emodin NPs To scavenge ROS, we synthesized PDA NPs with high yield via a classical Stöber method, to provide antibacterial activity, the emodin was coated on the surface of PDA NPs. The PDA NPs were characterized by TEM and SEM images, as shown in Fig. 3 A, B, the obtained PDA NPs had a uniform diameter distribution, with an average diameter of 130.0 ± 5 nm (Fig. 3 C), small pores on the surface of PDA NPs, and the average pore size was 10 nm (Fig. 3 D). Moreover, the surface area of PDA NPs was 32.8 m 2 /g (Fig. 3 E), which provided much more area for emodin coating. The FTIR spectrum was characterized for PDA NPs coating emodin, as shown in Fig. 3 F, the characteristic peaks of emodin were observed, which suggested that the emodin coated PDA NPs were successfully prepared. Scavenging ROS property of PDA NPs in vitro Scavenging ROS efficiency of PDA NPs (in vitro) was evaluated by hydroxyl radicals (HO·) and superoxide radicals (O 2 · ), the results were as shown in Fig. 4 , which indicated that the prepared PDA NPs had a gradually increasing scavenging capability of HO· produced by H 2 O 2 (10 mM) with PDA NPs concentration increase, when the concentration reached 50 µg/mL, the remaining of HO· was only 10% (Fig. 4 B). In addition, O 2 · scavenging efficiency of PDA NPs was assessed by nitro blue tetrazolium (NBT) assay (Fig. 4 A), the results indicated that the O 2 · scavenging efficiency of PDA NPs has a suitable concentration (100µg/mL). Antibacterial efficiency of PDA NPs coated emodin and NFs@H-PE Postoperative wounds are often accompanied by Staphylococcus aureus, and scratching increases the risk of bacterial infection. Using hydrogel barrier to control bacterial growth may benefit wound and reduce the risk of complications. Chitosan, the main component of hydrogel, has been reported to have good antibacterial properties. Furthermore, emodin had an excellent antibacterial performance. We examined the antibacterial properties of different hydrogels using a classical plate coating method. Relative to the control group, the number of colonies of bacteria co-incubated with the emodin coated PDA NPs and composite hydrogel was significantly reduced (Fig. 4 B). The absorbance of the bacterial suspension after hydrogel treatment also revealed more than 96% clearance efficiency of each group of hydrogels against S. aureus (Fig. 4 C). These results indicate that composite hydrogels could effectively kill bacteria to reduce the chance of bacterial infection in wound sites. As suitable barrier to prevent the formation of adhesion, the ability to suppress deformation and inhibit swelling is very important for the practical application. The PLLA nanofibers were dispersed in hydrogel, to limit deformation and anti-swelling through these nanofibers. The prepared PLLA nanofibers with smooth surface showed well porous structure (Fig. 5 A). The CS-HA-PDA hydrogel formatted after crossing (Fig. 5 D), and the morphology of hydrogel displayed a very loose structure, the pore size was up to 100–200 µm (Fig. 5 B). In contrast, after nanofibers embedded into hydrogel (Fig. 5 E), the morphology became compact, the pore size in hydrogel also was much smaller compared to that with nanofibers embedded ( Fig. 5 C ) . In addition, the NFs-H also demonstrated excellent adhesive properties, 50 mL aqueous water in centrifuge tube could be lift it up through the adhesive interface (as shown in Fig. 5 F and Fig. S1 ), meanwhile, this adhesion kept well in water ( Fig. S2). Furthermore, the NFs-H on the skin tissue (Fig. 5 G) and plastic surface (Fig. 5 H) in air/ DI water also demonstrated stable adhesion performance. To evaluate swelling property, the swelling deformation was tested, as shown in Fig. 6 A, during 24 h period, NFs-H showed much lower swelling rate compared to CS-HA-PDA hydrogel, only was 1.21 folds (Fig. 6 B), in contrast, CS-HA-PDA hydrogel was up to 3.5 folds. The results may be attributed to the nanofibers in the hydrogel inhibiting further swelling of hydrogel through hydrogen bonding between nanofibers and hydrogel. Cytocompatibility of NFs-H and NFs-H@P To verify the cytocompatibility of NFs-H@P hydrogel, we evaluated the cytotoxicity of hydrogel with PDA NPs loading on vascular endothelial cells using MMT assay, TCPs and NFs-H were set as control groups. The results indicated that PDA NPs have no significant effect on cell viability at concentrations below 2 mg/mL. When the concentration is increased to 2 mg/mL (Fig. 7 A), there is only a slight decrease in cell viability. Moreover, the fluorescent image of NFs-H@PE also demonstrated that the cells in composite hydrogel excellent bioactivity, and displayed cellular extension, good contact between cells and NFs-H loading PDA NPs as NFs-H (Fig. 7 B). These results indicated that the NFs-H@EP hydrogel loaded with PDA NPs has good biocompatibility and should be safe in vivo for anti-adhesion application. In vivo anti adhesion Evaluation of preventing abdominal adhesions of NFs-H@EP hydrogels in rats To evaluate the in vivo antiadhesion efficiency of the NFs-H@PE hydrogel, rat abdominal adhesion model was established, which was achieved by scraping the abdominal wall surface until errhysis. The CS-HA-DA hydrogel was also tested in the rats and set as control group. Another group of rats only treated using the saline solution was treated the blank model group. As previous reported, a new adhesion formation usually needs 5–7 days after treated abdominal surgery, and the formation of irreversible adhesions takes 7 to 14 days. Therefore, the adhesions and residues of NFs-H@EP hydrogel were evaluated after surgery 14days. As shown in Fig. 8 A, tissue adhesions were still clear observed in the blank Model group with a score of 4.8 ± 0.2, whereas a thin-film adhesion was observed in HA-CS-DA hydrogel groups with scores of 3.7 ± 0.1. No obvious adhesion was observed in the NFs-H@EP group, the score was only 0.42 ± 0.1. Furthermore, the injury sites had no symptoms of inflammation after the NFs-H@EP hydrogel treated. These results indicated that the NFs-H@EP hydrogel enabled adhesion on the wet tissue surface and covered the wound completely and prevent the formation of peritoneal adhesions. H&E staining and Masson's trichrome staining were performed to assess recovery of the cecum and abdominal wall on day 14 ( Fig. 8 B, C), respectively. The staining results supported the scores obtained from the observational evaluation. After 14 days surgery, the blank Model group displayed obvious adhesion, the nanofibrous HA-CS-DA (NFs-H) hydrogel group showed notable decrease in adhesions with inflammatory cells infiltrating the mesothelial layers of the cecum and abdominal wall. NFs-H@EP hydrogel lacked adhesion ability to protect the injured area, thereby limiting their ability to prevent adhesion formation completely. For the NFs-H@EP hydrogel group, adhesions and inflammatory cell infiltration could hardly be observed between the injured cecum and the abdominal wall, with complete degradation of the gels and complete healing of the injured surface. Taken together, results of the macroscopic observation and pathological evaluation. The tested immunofluorescence results showed that the NFs-H@PE improved the prognosis of adhesion formation by promoting healing of the mesothelial cell layer. Moreover, the NFs-H@PE hydrogel have superior tissue retention properties and a favorable effect against postoperative adhesion formation. The satisfactory antiadhesion effect of the NFs-H@EP formulations could also be attributed to inhibition of the production of typical inflammatory cytokines (mainly PDA NPs) such as tumor necrosis factor TNF-α (Fig. 9 A) and IL-6 (Fig. 9 B), which are mainly involved in the induction of imbalances in local inflammation and tissue fibrosis. In addition, the results of VEGF ((Fig. 9 C) indicated that the generation of new blood vessels also shows that the tissue after inflammation is suppressed exhibits good tissue regeneration performance. In addition, the HE staining of various organs ( Fig. S3 ) indicated that NFs-H@PE has no negative impact on every tissue. Antiadhesion mechanism The potential mechanism for the excellent antiadhesion performance of NFs-H@EP is shown in Fig. 10 . Generally, it is approved that the formation of tissue adhesion mainly involves interstitial fibrosis and inflammation activation. During the process of fibrosis, the adhesion of fibroblasts to the surface of the material is the key factor. ROS as inflammation inducing factors play a key role in production of inflammation activation. Therefore, PDA NPs in the NFs-H@EP hydrogel provided ROS scavenging capability[ 32 ], and then the composite hydrogel sysytem inhibited the formation of inflammation. On another hand, emodin on the surface could provide microenvironment for antibacterial activity. Furthermore, excellent anti-swelling property of NFs-H@EP hydrogel as physical barrier to prevent adhesion, also reduced inflammation caused by material swelling. Conclusion In summary, we developed a novel anti swelling nanofibers hydrogel loading PDA NPs and emodin and achieved ROS scavenging and anti-bacterial. As excellent physical barrier, NFs-H@PE hydrogel excellent anti adhesion, could meet the complex requirements of preventing postoperative adhesions in clinical application. Furthermore, the PDA NPs in the NFs-H through ROS scavenging to provide inhibition for inflammatory cells, achieving an effective anti-inflammatory effect and greatly facilitating rapid wound sites without adhesion. Thus, we believe that our newly prepared and multifunctional anti adhesion system has great potential in the field of inhibition of postoperative adhesion. Statistical Analysis All results are presented as the mean ± standard deviation. Comparison between the groups was assessed through a one-way analysis of ANOVA. Statistical significance was considered as P < 0.05. Declarations Conflict of Interest The authors declare no competing financial interest. Contributions L. J. designed and conducted experiments, wrote the main manuscript. C. R. assisted fabrication of hydrogels and data analysis. X.W. assisted data collection and analysis, and fabrication of nanofibers co-wrote the main manuscript. X.W. assisted antimicrobial experiments and data analysis, and reviewed the manuscript. X. C. reviewed the manuscript. X. L. data analysis. T. W. assisted the chemical test. G. L. provided advice on experimental design, and reviewed the manuscript. Z. Y. reviewed and revised manuscript L. supervised the entire project, acquired funding to support the research, X. Z. reviewed and approved the final manuscript. Acknowledgments This research was supported by the National Natural Science Foundation of China (52273018). Funding This work was supported by National Natural Science Foundation of China, No. 52273018. Availability of Data and Materials All relevant data generated and analyzed during this study, which include experimental, spectroscopic, electron microscopic, and antibacterial data, are included in this article. References L. M. Stapleton, A.N. Steele, H. Wang, H. L. 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Wang, R. Q. Mao, X. Y. Liang, H. R. Wang, Z. Y. Lin, J. X. Li, S. L. Li, J. P. Jiang, T.S. Zhang, Y. F. Ma, Y. Liu, C.C.Han, Y. Liu, Bioact. Mater. 2022, 12, 16-29. Additional Declarations No competing interests reported. Supplementary Files SI.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3469145","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":246747239,"identity":"4d18ac9b-5162-4814-8895-41fa86574f6c","order_by":0,"name":"Lin Jin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIie2QMQuCUBDHTwJbXtqoEPUVnouT0Fc5CZwKGh2DQIcKv0pj41Vgy2t/Q4Mu7Y4ulTY09mxreD84Dh7/H3f3ADSaP8RYg0EIwOz++lhgHHRSoFVG7jaf8UJE3SZRUwGXc98tk5M63ksHROUBGBfkx2gS2OkGFYtZSKEA5l5WkUR2A0dc9wqFcQoTYJagXKJzB+4sOiogw2SJ/PyDMpQzExB/UZpP7jlIEVPe4mXCK+sEpnY/q6r6EYztdKdQVu/2/Dywr/GWiTKh0Wg0mhdSZEz5nnwrfQAAAABJRU5ErkJggg==","orcid":"","institution":"Affiliated Hospital of Hebei Engineering University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Jin","suffix":""},{"id":246747240,"identity":"61a424a3-1299-47f8-a5fb-7c0ada86730b","order_by":1,"name":"Xiaolin Pan","email":"","orcid":"","institution":"International Joint Research Laboratory for Biomedical Nanomaterials of Henan, Zhoukou Normal University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaolin","middleName":"","lastName":"Pan","suffix":""},{"id":246747241,"identity":"91cb4356-89b5-4ec5-818e-9b696e416faa","order_by":2,"name":"Congling Ren","email":"","orcid":"","institution":"International Joint Research Laboratory for Biomedical Nanomaterials of Henan, Zhoukou Normal University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Congling","middleName":"","lastName":"Ren","suffix":""},{"id":246747242,"identity":"91637ab2-85c0-4931-b653-b58af70dee6b","order_by":3,"name":"Xing Chen","email":"","orcid":"","institution":"Harvard University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xing","middleName":"","lastName":"Chen","suffix":""},{"id":246747243,"identity":"33f42aec-2819-4a7f-aba4-4063b3964e24","order_by":4,"name":"Xiaoli Liu","email":"","orcid":"","institution":"Affiliated Hospital of Hebei Engineering University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoli","middleName":"","lastName":"Liu","suffix":""},{"id":246747244,"identity":"bf05ac1f-23b0-43d3-9663-107d548907e9","order_by":5,"name":"Zhe Yang","email":"","orcid":"","institution":"Xi’an Jiaotong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhe","middleName":"","lastName":"Yang","suffix":""},{"id":246747245,"identity":"face1f60-f17a-49da-a6cb-5c3cd66e6103","order_by":6,"name":"Taoxia Wang","email":"","orcid":"","institution":"Affiliated Hospital of Hebei Engineering University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Taoxia","middleName":"","lastName":"Wang","suffix":""},{"id":246747246,"identity":"0384ff0b-2248-41cf-81bf-f724e40df8c4","order_by":7,"name":"Guiying Li","email":"","orcid":"","institution":"Affiliated Hospital of Hebei Engineering University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guiying","middleName":"","lastName":"Li","suffix":""},{"id":246747247,"identity":"a6f55639-a365-412b-92b8-7d5b32bd2afd","order_by":8,"name":"Xingcai Zhang","email":"","orcid":"","institution":"Harvard University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xingcai","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2023-10-20 09:59:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3469145/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3469145/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":46178736,"identity":"587719c6-2fba-429c-8404-5c3ae23befc2","added_by":"auto","created_at":"2023-11-09 19:08:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":524347,"visible":true,"origin":"","legend":"\u003cp\u003eIllustration of NFs-H@PE hydrogel formation (B), the schematic diagram of anti-adhesion of NFs-H@PE hydrogel (C).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/af28c73e736ea11ac998d68b.png"},{"id":46177961,"identity":"74e482bc-7a63-4e6b-be80-e2ff0264c7b1","added_by":"auto","created_at":"2023-11-09 19:00:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":918061,"visible":true,"origin":"","legend":"\u003cp\u003eThe synthesize of triblock macromolecule (HA-CS-DA) (A), the FTIR spectrum of HA-CS-DA, HA-CS (B), and HA (A), H1NMR of HA-CS-DA and HA-CS (C).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/9f676448282603a28b3e9d31.png"},{"id":46177964,"identity":"48f863a4-7dfe-4d1c-bc96-4d4ba6f1fb86","added_by":"auto","created_at":"2023-11-09 19:00:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":738017,"visible":true,"origin":"","legend":"\u003cp\u003eCharacterization of PDA NPs, SEM (A), TEM (B), diameter distribution (C), surface area (D), pore size distribution (E). FTIR spectrum of PDA NPs emodin, and PDA NPs before and after coating emodin (F).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/b53598040b3017d8eb04cb29.png"},{"id":46178737,"identity":"b9667ed5-3819-4a1d-9d48-7a53fb056b2c","added_by":"auto","created_at":"2023-11-09 19:08:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":559946,"visible":true,"origin":"","legend":"\u003cp\u003eThe ROS scavenging capability of various PDA NPs concentrations (A). Antibacterial efficiency of PDA NPs coated emodin and NFs-H@PE. (B) Photo images and (C) antibacterial efficiency of various samples. The antibacterial efficiency of NFs-H@PE calculated by the absorbance of the bacterial solution.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/b64de54d65e684c74814ad3e.png"},{"id":46177963,"identity":"79f9facb-f20d-4f73-88d5-c8b38c322cce","added_by":"auto","created_at":"2023-11-09 19:00:00","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":871253,"visible":true,"origin":"","legend":"\u003cp\u003eThe SEM images of NFs (A), CS-HA-PDA hydrogel (B) and NFs-H (C). The CS-HA-PDA hydrogel before and after crossing (D), NFs-H before and after crossing (E). The adhesion stress (F), and the adhesion to skin tissue (G) and plastic surfaces (H) in air and water of NFs-H.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/b8c9ee0b2863224b68f06dd6.png"},{"id":46177968,"identity":"07de9170-05ee-4949-ae28-9ec64c23ddfa","added_by":"auto","created_at":"2023-11-09 19:00:01","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":766970,"visible":true,"origin":"","legend":"\u003cp\u003eThe swelling evaluation of CS-HA-PDA hydrogel (set as control group) and NFs-H. (A) The swelling photo images (A) on various time points. The swelling rate (B) of CS-HA-PDA hydrogel and NFs-H after 0 and 24 h.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/cf31fa3221bfbd104ec67d57.png"},{"id":46178739,"identity":"8ab41ee6-9430-4ad4-aafb-27888a6a09f5","added_by":"auto","created_at":"2023-11-09 19:08:01","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1967594,"visible":true,"origin":"","legend":"\u003cp\u003eThe biocompatibility evaluation of NFs-H@P and NFs-H. (A) Fluorescent images and proliferation (B) of vascular endothelial cells cultured on TCPs, in the NFs, NFs-H@P-1MG, and NFs-H@P-2mg. The bars were 10 μm.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/560c03e211f10929bac3c33f.png"},{"id":46177967,"identity":"6ef4f98f-d406-4a69-9783-bab0ed885596","added_by":"auto","created_at":"2023-11-09 19:00:01","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":1946297,"visible":true,"origin":"","legend":"\u003cp\u003eThe evaluation of NFs-H@PE in vivo anti-tissue adhesion properties. Photos (A), adhesion score (B), HE staining (C) and (D) Masson's trichrome staining of control, NFs-H, and NFs-H@PE.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/8b97701a565887bd9f2d4aac.png"},{"id":46177966,"identity":"39fc238d-6a04-4d25-8962-8a8b726679ea","added_by":"auto","created_at":"2023-11-09 19:00:01","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":1110840,"visible":true,"origin":"","legend":"\u003cp\u003eThe immunofluorescence staining of NFs-H@PE in vivo anti-tissue adhesion properties and angiogenesis performance. IL-6, TNF-α and VEGF. The bar was 100 μm.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/ae403bb9354c877689e086ad.png"},{"id":46179443,"identity":"3e64f06d-d864-4734-9144-23b87cecf515","added_by":"auto","created_at":"2023-11-09 19:16:01","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":541452,"visible":true,"origin":"","legend":"\u003cp\u003eThe diagram of NFs-H@PE hydrogel anti adhesion mechanism.\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/a056c553da4d7bf65e5baa6c.png"},{"id":46267118,"identity":"c9093d98-b850-4fa4-bb12-e52a269c31be","added_by":"auto","created_at":"2023-11-11 09:22:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8284485,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/93b87bc5-4aec-4925-822e-2e267e84bae3.pdf"},{"id":46178738,"identity":"3122aa42-ec42-46bf-b287-3502afecb726","added_by":"auto","created_at":"2023-11-09 19:08:01","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1532234,"visible":true,"origin":"","legend":"","description":"","filename":"SI.docx","url":"https://assets-eu.researchsquare.com/files/rs-3469145/v1/07fb660bd6077f0657cd9af4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Nature-derived five-star general fighting postoperative abdominal adhesion","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePathological adhesion formation often occurs after abdominal surgeries, [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and the probability of occurrence is up to 93%.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] There are three main reasons for adhesion, (1) the organ surfaces of postoperative wound sites coalesce with other tissues, or the walls of these sites surrounding cavityhese adhesion, (2) abdominal bacterial infections on the wound sits, (3) postoperative inflammation. [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Despite the improvements of surgical techniques, like minimal or non-invasive surgery, the postoperative abdominal adhesions still threaten the health of people's lives.[\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] For example, 64% patients of abdominal surgery suffered from a problem related to adhesions within 10 years, or requiring further intra-abdominal surgery treatment.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] However, the re-operations to remove adhesions significantly prolong time-consuming and increase enormous economic burden on healthcare for patients.[\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Therefore, eliminating the formation of postoperative adhesions is crucial in the field of clinical surgery.\u003c/p\u003e \u003cp\u003eDuring early adhesion formation process, injured organ surface remains undisclosed and epithelial monolayer destroyed, which imposed to other non-injured organ surface and adjacent surface, and then formed adhesion. [\u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] In addition, inflammation and bacterial infection also support the formation of adhesion. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Therefore, during early adhesion formation, appropriate treatments is tare vital to prevent adhesions. Recent years, various of barriers have been developed to reduce and prevent surgical adhesions,[\u003cspan additionalcitationids=\"CR32 CR33 CR34 CR35\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] mainly including nanofibers and hydrogel,[\u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] such as super-lubricated electrospun nanofibers,[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] hierarchical structured nanofibers,[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] catechol-functionalized oxime hydrogel.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] However, these barriers are limited by intrinsic performance limitations, and unable fully meet the complex internal environment's demand to prevent postoperative adhesions.\u003c/p\u003e \u003cp\u003eHerein, we developed nanofiber CS-HA-DA/PDA NPs coated emodin composite hydrogel system (NFs-H@PE) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA\u003cb\u003e)\u003c/b\u003e for effective prevention of postoperative adhesion through nanofibrous hydrogel as barrier and release of PDA NPs and emodin \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB\u003cb\u003e)\u003c/b\u003e. The synthesized biological macromolecules hydrogel embedded nanofibers demonstrated excellent biocompatibility, anti-swelling property. Additionally, after loading PDA NPs coated emodin, this system provided better ROS scavenging ability and antibacterial properties. Such nanofiber hydrogel system as barrier achieved injury surface covered without introduce inflammation because anti-swelling, meanwhile, rapid outward permeation of PDA NPs and sustained release of emodin provided an excellent microenvironment for anti-inflammatory and anti-bacterial properties. The obtained system synergistic effect effectively prevents the formation of postoperative adhesions., And we believed that this nanofiber hydrogel composite system might provide a potential candidate for preventing postoperative adhesions in practical clinical application.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Experimental section","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMaterials\u003c/h2\u003e \u003cp\u003eChitosan was purchased from Haidebei Bio Technology Co. (Shandong Jinan), DA and HA were obtained from Maidelin Bio Technology Co. (Shanhai). Other chemicals were purchased from Guangzhou Chemical Guangzhou Chemical Co. and were used as obtained without further purification. Kunming mice were purchased and cultured in the Center for Experimental Animals at Affiliated Hospital of Hebei Engineering University Health Science Center. The protocol for animal experiments was approved by the Animal Experimentation Ethics Committee of Hebei Engineering University.\u003c/p\u003e \u003cp\u003eSynthesis of the NFs-H: CS-HA-DA was synthesized using EDC, NHS under 8h reaction, the mass ratio is 1:1:1, and very step goes through dialysis (8000 DA) and freeze-drying. The PLLA nanofibers were prepared through our previous method.[44] And then, the PLLA nanofibers were dispersed in aqueous solution, subsequently, CS-HA-DA (30 mg/mL) was added into the nanofibers aqueous solution and was became a uniform dispersion through ultrasound, PDA NPs coating emodin also added into above composite solution, finally, ammonium persulfate aqueous solution (0.02g/mL) was added into composite solution to form NFs-H for animal experiments.\u003c/p\u003e \u003cp\u003eCharacterization of NFs-H: The NMR and FTIR were used characterized for NFs-H. The morphology of PLLA nanofibers and NFs-H were tested using SEM image. DA NPs were characterized by SEM and TEM images, and the pore size distribution and BET surface of PDA NPs were tested using nitrogen adsorption-desorption isotherm.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results and discussion","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eFabrication of nanofibers CS-HA-DA hydrogel\u003c/h2\u003e\n\u003cp\u003eThe desired anti adhesive material should meet the complex requirements, such as excellent biocompatibility, anti-swelling performance. The hydrogel with excellent biocompatibility required the synthesis of biomaterials. The triblock derivative was synthesized using chitosan, hyaluronic acid and dopamine through reaction of amine bonds (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). As shown in the NMR spectrum (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB), the chemical shift (1H) of DA at 2.5, 2.75 and 7.0, which demonstrated that CS and DA grafted onto the chain of hyaluronic acid. In addition, the FTIR spectrum (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC) of CS, HA-CS and HA-CS-DA, also noted that the CS characteristic peaks (1420 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, 1650 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) were observed after HA grafted CS, moreover, the DA characteristic peaks were seen after HA-CS grafted DA. These results indicated that the triblock graft derivative was successfully synthesized.\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n\u003ch2\u003ePreparation and characterization of PDA coating emodin NPs\u003c/h2\u003e\n\u003cp\u003eTo scavenge ROS, we synthesized PDA NPs with high yield via a classical St\u0026ouml;ber method, to provide antibacterial activity, the emodin was coated on the surface of PDA NPs. The PDA NPs were characterized by TEM and SEM images, as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA, B, the obtained PDA NPs had a uniform diameter distribution, with an average diameter of 130.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5 nm (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC), small pores on the surface of PDA NPs, and the average pore size was 10 nm (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eD). Moreover, the surface area of PDA NPs was 32.8 m\u003csup\u003e2\u003c/sup\u003e/g (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eE), which provided much more area for emodin coating. The FTIR spectrum was characterized for PDA NPs coating emodin, as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eF, the characteristic peaks of emodin were observed, which suggested that the emodin coated PDA NPs were successfully prepared.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\n\u003ch2\u003eScavenging ROS property of PDA NPs in vitro\u003c/h2\u003e\n\u003cp\u003eScavenging ROS efficiency of PDA NPs (in vitro) was evaluated by hydroxyl radicals (HO\u0026middot;) and superoxide radicals (O\u003csub\u003e2\u003c/sub\u003e\u0026middot; ), the results were as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, which indicated that the prepared PDA NPs had a gradually increasing scavenging capability of HO\u0026middot; produced by H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (10 mM) with PDA NPs concentration increase, when the concentration reached 50 \u0026micro;g/mL, the remaining of HO\u0026middot; was only 10% (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB). In addition, O\u003csub\u003e2\u003c/sub\u003e\u0026middot; scavenging efficiency of PDA NPs was assessed by nitro blue tetrazolium (NBT) assay (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA), the results indicated that the O\u003csub\u003e2\u003c/sub\u003e\u0026middot; scavenging efficiency of PDA NPs has a suitable concentration (100\u0026micro;g/mL).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\n\u003ch2\u003eAntibacterial efficiency of PDA NPs coated emodin and NFs@H-PE\u003c/h2\u003e\n\u003cp\u003ePostoperative wounds are often accompanied by Staphylococcus aureus, and scratching increases the risk of bacterial infection. Using hydrogel barrier to control bacterial growth may benefit wound and reduce the risk of complications. Chitosan, the main component of hydrogel, has been reported to have good antibacterial properties. Furthermore, emodin had an excellent antibacterial performance. We examined the antibacterial properties of different hydrogels using a classical plate coating method. Relative to the control group, the number of colonies of bacteria co-incubated with the emodin coated PDA NPs and composite hydrogel was significantly reduced (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB). The absorbance of the bacterial suspension after hydrogel treatment also revealed more than 96% clearance efficiency of each group of hydrogels against S. aureus (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eC). These results indicate that composite hydrogels could effectively kill bacteria to reduce the chance of bacterial infection in wound sites.\u003c/p\u003e\n\u003cp\u003eAs suitable barrier to prevent the formation of adhesion, the ability to suppress deformation and inhibit swelling is very important for the practical application. The PLLA nanofibers were dispersed in hydrogel, to limit deformation and anti-swelling through these nanofibers. The prepared PLLA nanofibers with smooth surface showed well porous structure (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eA). The CS-HA-PDA hydrogel formatted after crossing (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eD), and the morphology of hydrogel displayed a very loose structure, the pore size was up to 100\u0026ndash;200 \u0026micro;m (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eB). In contrast, after nanofibers embedded into hydrogel (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eE), the morphology became compact, the pore size in hydrogel also was much smaller compared to that with nanofibers embedded \u003cstrong\u003e(\u003c/strong\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eC\u003cstrong\u003e)\u003c/strong\u003e. In addition, the NFs-H also demonstrated excellent adhesive properties, 50 mL aqueous water in centrifuge tube could be lift it up through the adhesive interface (as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eF \u003cstrong\u003eand Fig. \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/strong\u003e), meanwhile, this adhesion kept well in water (\u003cstrong\u003eFig. S2).\u003c/strong\u003e Furthermore, the NFs-H on the skin tissue (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eG) and plastic surface (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eH) in air/ DI water also demonstrated stable adhesion performance.\u003c/p\u003e\n\u003cp\u003eTo evaluate swelling property, the swelling deformation was tested, as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eA, during 24 h period, NFs-H showed much lower swelling rate compared to CS-HA-PDA hydrogel, only was 1.21 folds (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eB), in contrast, CS-HA-PDA hydrogel was up to 3.5 folds. The results may be attributed to the nanofibers in the hydrogel inhibiting further swelling of hydrogel through hydrogen bonding between nanofibers and hydrogel.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n\u003ch2\u003eCytocompatibility of NFs-H and NFs-H@P\u003c/h2\u003e\n\u003cp\u003eTo verify the cytocompatibility of NFs-H@P hydrogel, we evaluated the cytotoxicity of hydrogel with PDA NPs loading on vascular endothelial cells using MMT assay, TCPs and NFs-H were set as control groups. The results indicated that PDA NPs have no significant effect on cell viability at concentrations below 2 mg/mL. When the concentration is increased to 2 mg/mL (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eA), there is only a slight decrease in cell viability. Moreover, the fluorescent image of NFs-H@PE also demonstrated that the cells in composite hydrogel excellent bioactivity, and displayed cellular extension, good contact between cells and NFs-H loading PDA NPs as NFs-H (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eB). These results indicated that the NFs-H@EP hydrogel loaded with PDA NPs has good biocompatibility and should be safe in vivo for anti-adhesion application.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eIn vivo anti adhesion\u003c/h2\u003e\n\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\n\u003ch2\u003eEvaluation of preventing abdominal adhesions of NFs-H@EP hydrogels in rats\u003c/h2\u003e\n\u003cp\u003eTo evaluate the in vivo antiadhesion efficiency of the NFs-H@PE hydrogel, rat abdominal adhesion model was established, which was achieved by scraping the abdominal wall surface until errhysis. The CS-HA-DA hydrogel was also tested in the rats and set as control group. Another group of rats only treated using the saline solution was treated the blank model group.\u003c/p\u003e\n\u003cp\u003eAs previous reported, a new adhesion formation usually needs 5\u0026ndash;7 days after treated abdominal surgery, and the formation of irreversible adhesions takes 7 to 14 days. Therefore, the adhesions and residues of NFs-H@EP hydrogel were evaluated after surgery 14days. As shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003eA, tissue adhesions were still clear observed in the blank Model group with a score of 4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2, whereas a thin-film adhesion was observed in HA-CS-DA hydrogel groups with scores of 3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1. No obvious adhesion was observed in the NFs-H@EP group, the score was only 0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1. Furthermore, the injury sites had no symptoms of inflammation after the NFs-H@EP hydrogel treated. These results indicated that the NFs-H@EP hydrogel enabled adhesion on the wet tissue surface and covered the wound completely and prevent the formation of peritoneal adhesions.\u003c/p\u003e\n\u003cp\u003eH\u0026amp;E staining and Masson's trichrome staining were performed to assess recovery of the cecum and abdominal wall on day 14 \u003cstrong\u003e(\u003c/strong\u003eFig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003eB, C), respectively. The staining results supported the scores obtained from the observational evaluation. After 14 days surgery, the blank Model group displayed obvious adhesion, the nanofibrous HA-CS-DA (NFs-H) hydrogel group showed notable decrease in adhesions with inflammatory cells infiltrating the mesothelial layers of the cecum and abdominal wall. NFs-H@EP hydrogel lacked adhesion ability to protect the injured area, thereby limiting their ability to prevent adhesion formation completely. For the NFs-H@EP hydrogel group, adhesions and inflammatory cell infiltration could hardly be observed between the injured cecum and the abdominal wall, with complete degradation of the gels and complete healing of the injured surface. Taken together, results of the macroscopic observation and pathological evaluation.\u003c/p\u003e\n\u003cp\u003eThe tested immunofluorescence results showed that the NFs-H@PE improved the prognosis of adhesion formation by promoting healing of the mesothelial cell layer. Moreover, the NFs-H@PE hydrogel have superior tissue retention properties and a favorable effect against postoperative adhesion formation. The satisfactory antiadhesion effect of the NFs-H@EP formulations could also be attributed to inhibition of the production of typical inflammatory cytokines (mainly PDA NPs) such as tumor necrosis factor TNF-\u0026alpha; (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003eA) and IL-6 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003eB), which are mainly involved in the induction of imbalances in local inflammation and tissue fibrosis. In addition, the results of VEGF ((Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003eC) indicated that the generation of new blood vessels also shows that the tissue after inflammation is suppressed exhibits good tissue regeneration performance. In addition, the HE staining of various organs (\u003cstrong\u003eFig. S3\u003c/strong\u003e) indicated that NFs-H@PE has no negative impact on every tissue.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eAntiadhesion mechanism\u003c/h2\u003e\n\u003cp\u003eThe potential mechanism for the excellent antiadhesion performance of NFs-H@EP is shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e10\u003c/span\u003e. Generally, it is approved that the formation of tissue adhesion mainly involves interstitial fibrosis and inflammation activation. During the process of fibrosis, the adhesion of fibroblasts to the surface of the material is the key factor. ROS as inflammation inducing factors play a key role in production of inflammation activation.\u003c/p\u003e\n\u003cp\u003eTherefore, PDA NPs in the NFs-H@EP hydrogel provided ROS scavenging capability[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e], and then the composite hydrogel sysytem inhibited the formation of inflammation. On another hand, emodin on the surface could provide microenvironment for antibacterial activity. Furthermore, excellent anti-swelling property of NFs-H@EP hydrogel as physical barrier to prevent adhesion, also reduced inflammation caused by material swelling.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we developed a novel anti swelling nanofibers hydrogel loading PDA NPs and emodin and achieved ROS scavenging and anti-bacterial. As excellent physical barrier, NFs-H@PE hydrogel excellent anti adhesion, could meet the complex requirements of preventing postoperative adhesions in clinical application. Furthermore, the PDA NPs in the NFs-H through ROS scavenging to provide inhibition for inflammatory cells, achieving an effective anti-inflammatory effect and greatly facilitating rapid wound sites without adhesion. Thus, we believe that our newly prepared and multifunctional anti adhesion system has great potential in the field of inhibition of postoperative adhesion.\u003c/p\u003e "},{"header":"Statistical Analysis","content":"\u003cp\u003eAll results are presented as the mean \u0026plusmn; standard deviation. Comparison between the groups was assessed through a one-way analysis of ANOVA. Statistical significance was considered as \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL. J. designed and conducted experiments, wrote the main manuscript. C. R. assisted fabrication of hydrogels and data analysis. X.W. assisted data collection and analysis, and fabrication of nanofibers co-wrote the main manuscript. X.W. assisted antimicrobial experiments and data analysis, and reviewed the manuscript. X. C. reviewed the manuscript. X. L. data analysis. T. W. assisted the chemical test. G. L. provided advice on experimental design, and reviewed the manuscript. Z. Y. reviewed and revised manuscript L. supervised the entire project, acquired funding to support the research, X. Z. reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the National Natural Science Foundation of China (52273018).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Natural Science Foundation of China, No. 52273018.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant data generated and analyzed during this study, which include experimental, spectroscopic, electron microscopic, and antibacterial data, are included in this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eL. M. Stapleton, A.N. Steele, H. Wang, H. L. Hernadez, A. C. Yue, M. J. Paulsen, A. A.A. Smith, G. A. Roth, A. D. Thakore, H. J. Lucian, K. P. Totherow, S. W. Baker, Y. 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Mater.\u003c/em\u003e 2022, 12, 16-29.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Nanofiber, hydrogel, ROS scavenging, abdominal adhesion","lastPublishedDoi":"10.21203/rs.3.rs-3469145/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3469145/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePostoperative adhesion of abdominal is one of major surgical complications, mainly due to inflammation in the wound tissue causing adhesion between the wound tissue and the tissue. These adhesions not only cause the loss of functional parts, but also seriously affect the postoperative rehabilitation. Recently, researchers have developed various types of hydrogels as barriers to prevent adhesion through physical and mechanical isolation. However, the swelling of hydrogel may lead to the new inflammation and generate excessive reactive oxygen species (ROS), inducing the tissue adhesion again. Herein, we designed a Nature-derived five-star general fighting postoperative abdominal adhesion, which possesses a five-star function of anti-swelling, ROS clearance, inflammation inhibition, anti-bacterial and anti-adhesion. Thus, the swelling rate of the prepared nanofiber hydrogel system is confined to 1.21 times, the antibacterial efficiency is 96%, and the adhesion inhibition efficiency is 99%. Combined with its excellent performance, we believe that the prepared anti-swelling, ROS scavenging and antibacterial composite hydrogel system will provide a new strategy for clinical postoperative adhesion inhibition.\u003c/p\u003e","manuscriptTitle":"Nature-derived five-star general fighting postoperative abdominal adhesion","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-09 18:59:56","doi":"10.21203/rs.3.rs-3469145/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"56e9f0e0-193d-423d-acca-c69f59c49d0a","owner":[],"postedDate":"November 9th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-11-11T09:14:18+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-09 18:59:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3469145","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3469145","identity":"rs-3469145","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}