Prevention strategies of postoperative adhesion in soft tissues by applying biomaterials:Based on the mechanisms of occurrence and development of adhesions

Postoperative adhesion(POA)widely occurs in soft tissues and usually leads to chronic pain,dysfunction of adjacent organs and some acute complications,seriously reducing patients’quality of life and even being life-threatening.Except for adhesiolysis,there are few effective methods to release existing adhesion.However,it requires a second operation and inpatient care and usually triggers recurrent adhesion in a great incidence.Hence,preventing POA formation has been regarded as the most effective clinical strategy.Biomaterials have attracted great attention in preventing POA because they can act as both barriers and drug carriers.Nevertheless,even though much reported research has been demonstrated their efficacy on POA inhibition to a certain extent,thoroughly preventing POA formation is still challenging.Meanwhile,most biomaterials for POA prevention were designed based on limited experiences,not a solid theoretical basis,showing blindness.Hence,we aimed to provide guidance for designing anti-adhesion materials applied in different soft tissues based on the mechanisms of POA occurrence and development.We first classified the postoperative adhesions into four categories according to the different components of diverse adhesion tissues,and named them as“membranous adhesion”,“vascular adhesion”,“adhesive adhesion”and“scarred adhesion”,respectively.Then,the process of the occurrence and development of POA were analyzed,and the main influencing factors in different stages were clarified.Further,we proposed seven strategies for POA prevention by using biomaterials according to these influencing factors.Meanwhile,the relevant practices were summarized according to the corresponding strategies and the future perspectives were analyzed.

Research on Mechanisms of Chinese Medicines in Prevention and Treatment of Postoperative Adhesion

Postoperative adhesion(PA)is currently one of the most unpleasant complications following surgical procedures.Researchers have developed several new strategies to alleviate the formation of PA to a great extent,but so far,no single measure or treatment can meet the expectations and requirements of clinical patients needing complete PA prevention.Chinese medicine(CM)has been widely used for thousands of years based on its remarkable efficacy and indispensable advantages CM treatments are gradually being accepted by modern medicine.Therefore,this review summarizes the formating process of PA and the efficacy and action mechanism of CM treatments,including their pharmacological effects,therapeutic mechanisms and advantages in PA prevention.We aim to improve the understanding of clinicians and researchers on CM prevention in the development of PA and promote the in-depth development and industrialization process of related drugs.

Nanoengineered Shear-Thinning Hydrogel Barrier for Preventing Postoperative Abdominal Adhesions

More than 90%of surgical patients develop postoper-ative adhesions,and the incidence of hospital re-admissions can be as high as 20%.Current adhesion barriers present limited efficacy due to difficulties in application and incompatibility with minimally invasive interventions.To solve thisclinical limitation,we developed an injectable and sprayable shear-thinning hydrogel barrier(STHB)composed of silicate nanoplatelets and poly(ethylene oxide).We optimized this technology to recover mechanical integrity after stress,enabling its delivery though inject-able and sprayable methods.We also demonstrated limited cell adhesion and cytotoxicity to STHB compositions in vitro.The STHB was then tested in a rodent model of peritoneal injury to determine its e cacy preventing the formation of postoperative adhesions.After two weeks,the peritoneal adhesion index was used as a scoring method to determine the formation of postoperative adhesions,and STHB formulations presented superior e cacy compared to a commercially available adhesion barrier.Histological and immunohistochemical examination showed reduced adhesion formation and minimal immune infiltration in STHB formulations.Our technology demonstrated increased e cacy,ease of use in complex anatomies,and compatibility with di erent delivery methods,providing a robust universal platform to prevent postoperative adhesions in a wide range of surgical interventions.

Chinese medicine compound Changtong oral liquid on postoperative intestinal adhesions

AIM: The aim of this study was to observe the effect of a Chinese medicine compound Changtong oral liquid (CT) on tissue plasminogen activity (t-PA), plasminogen activator inhibitor (PAI), TGF-β1 and hydroxyproline (OHP). METHODS: Two sets of animal experiments were performed in the present study. Forty New Zealand rabbits and 48 Sprague-Dawley (SD) rats were assigned randomly to one of the five groups: sham adhesion, adhesion with saline, adhesion with low dosage of the CT, adhesion with middle dosage of the CT and adhesion with high dosage of the CT. t-PA and PAI activity in plasma, OHP and TGF-β1 expression in adhesion were investigated. Analysis of variance was used to test differences among groups. RESULTS: CT treatment increased plasma t-PA activity in rabbits but decreased TGF-β1 activity in rats. The data were expressed from low to high dose respectively as follows: t-PA, 46.1±8.6 μkat/L, 59.6±10.1 μkat/L, 64.0±11.5 μkat/L; TGF-β1 28±7.23%, 31±3.05%, 30±4.04%. There were significant differences compared with saline-treated animals (t-PA 26.4±5.1 μkat/L, TGF-β1 54±5.51%). OHP content in cecum of rabbits from middle and high but not low dose of CT lowered significantly as compared with saline-treated rabbits, 0.3641±0.1373, 0.3348±0.0321, 0.2757±0.0497 mg/g vs 0.4183±0.0883 mg/g of protein, P>0.05, P<0.05, P<0.05 respectively. The rabbit plasma PAI activity and OHP content in abdominal wall had no difference in all groups. CONCLUSION: CT treatment significantly enhanced t-PA activity in rabbits, but decreased TGF-β1 content in rats, OHP content in cecum of rabbits, and failed to affect the activity of PAI and OHP content in abdominal wall in rabbits, compared with saline group. The result suggests that CT could effectively prevent adhesions without interfering wound healina.

Identification of candidate biomarkers correlated with pathogenesis of postoperative peritoneal adhesion by using microarray analysis

BACKGROUND Postoperative peritoneal adhesion(PPA),characterized by abdominal pain,female infertility,and even bowel obstruction after surgery,has always been a major concern.The occurrence and formation of adhesion are from complex biological processes.However,the molecular mechanisms underlying the basis of microarray data profile,followed by peritoneal adhesion formation,are largely unknown.AIM To reveal the underlying pathogenesis of PPA at the molecular level.METHODS The gene expression profile was retrieved from the Gene Expression Omnibus database for our analysis.We identified a panel of key genes and related pathways involved in adhesion formation using bioinformatics analysis methods.We performed quantitative PCR and western blotting in vivo to validate the results preliminarily.RESULTS In total,446 expressed genes were altered in peritoneal adhesion.We found that several hub genes(e.g.,tumor necrosis factor,interleukin 1 beta,interleukin 6,CX-C motif chemokine ligand 1,C-X-C motif chemokine ligand 2)were marked as significant biomarkers.Functional analysis suggested that these genes were enriched in the Toll-like receptor signaling pathway.According to the Kyoto Encyclopedia of Genes and Genomes pathway and published studies,TLR4,myeloid differentiation primary response protein 88(MyD88),and nuclear factor kappa B(NF-κB)played essential roles in Toll-like signaling transduction.Here,we obtained a regulatory evidence chain of TLR4/MyD88/NF-κB/inflammatory cytokines/peritoneal adhesion involved in the pathogenesis of postoperative adhesion.The results of the microarray analysis were verified by the animal experiments.These findings may extend our understanding of the molecular mechanisms of PPA.CONCLUSION The regulatory evidence chain of TLR4/MyD88/NF-κB/inflammatory cytokines/peritoneal adhesion may play key roles in the pathogenesis of PPA.Future studies are required to validate our findings.

Cationic polypeptides in a concept of oppositely charged polypeptides as prevention of postsurgical intraabdominal adhesions

Background: Two differently charged polypeptides, α-poly-L-lysine and poly-L-glutamate, have previously been shown to effectively reduce postoperative intraabdominal adhesions. Though α-poly-L-lysine showed toxicity in doses too close to the lowest therapeutic dose, the aim in the present study was to investigate the possible antiadhesive effect of another four cationic polypeptides. Materials/Methods: 125 mice were studied with a standardized and reproducible adhesion model and given epsilon poly-L-lysine, lactoferrin, lysozyme and polyarginine respectively in a combination with poly-L-glutamate. Epsilon poly-L-lysine was also tested in different concentrations and as single treatment. Results: All four cationic polypeptides above showed a significantly better anti-adhesive effect than the controls receiving saline (p<0.05). Epsilon poly-L-lysine had the best antiadhesive effect of the new substances tested in the experiment. Single treatment with the epsilon poly-L-lysine showed toxic side effects. Discussion: We have shown that epsilon poly-L-lysine, polyarginine, lysozyme and lactoferrin, in descending order, all can reduce postoperative intraabdominal adhesions in mice when combined with poly-L-glutamate. There were side effects of epsilon poly-L-lysine resembling those of α-poly-L-lysine, although less toxic. The antiadhesive effect of epsilon poly-L-lysine did not reach the level of α-poly-L-lysine. Further studies will concentrate on additional investigation, trying to modify the α-poly-L-lysine to lower its toxicity. The less toxic epsilon poly-L-lysine also needs further attention in our research of antiadhesive bioactive polypeptides.

Cytokine orchestration in post-operative peritoneal adhesion formation

Peritoneal adhesions are a near inevitable occurrence after laparotomy and a major cause of both patient and physician misery. To date, clinical attempts at their amelioration have concentrated on manipulating the physical factors that affect their development despite a wealth of experimental data elucidating the molecular mechanisms that underlie their initiation, development and maturation. However, the advent of targeted, specific anti-cytokine agents as directed therapy for inflammatory and neoplastic conditions raises the prospect of a new era for anti-adhesion strategies. To harness this potential will require considerable cross-disciplinary collaboration and that surgeon-scientists propel themselves to the forefront of this emerging fi eld.

Daikenchuto for postoperative adhesive small bowel obstruction:A systematic review and meta-analysis

AIMTo assess the effectiveness of Daikenchuto for patients with postoperative adhesive small bowel obstruction （ASBO）.METHODSA systematic search of PubMed （MEDLINE）, CINAHL, the Cochrane Library and Ichushi Web was conducted, and the reference lists of review articles were hand-searched. The outcomes of interest were the incidence rate of surgery, the length of hospital days and mortality. The quality of the included studies, publication bias and between-study heterogeneity were also assessed.RESULTS Three randomized controlled trials （RCTs） and three retrospective cohort studies were selected for analysis. In the three RCTs, Daikenchuto signifcantly reduced the incidence of surgery （pOR = 0.13; 95%CI： 0.03-0.50）. Similarly, Daikenchuto signifcantly reduced the incidence of surgery （pOR = 0.53; 95%CI： 0.32-0.87） in the three cohort studies. The length of hospital stay and mortality were not measured or described consistently.CONCLUSIONThe present meta-analysis demonstrates that admini-stering Daikenchuto is associated with a lower incidence of surgery for patients with postoperative ASBO in the Japanese population. In order to better generalize these results, additional studies will be needed.

A sandwiched patch toward leakage-free and anti-postoperative tissue adhesion sealing of intestinal injuries

Ideal repair of intestinal injury requires a combination of leakage-free sealing and postoperative antiadhesion.However,neither conventional hand-sewn closures nor existing bioglues/patches can achieve such a combination.To this end,we develop a sandwiched patch composed of an inner adhesive and an outer antiadhesive layer that are topologically linked together through a reinforced interlayer.The inner adhesive layer tightly and instantly adheres to the wound sites via-NHS chemistry;the outer antiadhesive layer can inhibit cell and protein fouling based on the zwitterion structure;and the interlayer enhances the bulk resilience of the patch under excessive deformation.This complementary trilayer patch(TLP)possesses a unique combination of instant wet adhesion,high mechanical strength,and biological inertness.Both rat and pig models demonstrate that the sandwiched TLP can effectively seal intestinal injuries and inhibit undesired postoperative tissue adhesion.The study provides valuable insight into the design of multifunctional bioadhesives to enhance the treatment efficacy of intestinal injuries.

Bottlebrush inspired injectable hydrogel for rapid prevention of postoperative and recurrent adhesion

Postsurgical adhesion is a common clinic disease induced by surgical trauma,accompanying serious subsequent complications.Current non-surgical approaches of drugs treatment and biomaterial barrier administration only show limited prevention effects and couldn’t effectively promote peritoneum repair.Herein,inspired by bottlebrush,a novel self-fused,antifouling,and injectable hydrogel is fabricated by the free-radical polymerization in aqueous solution between the methacrylate hyaluronic acid(HA-GMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)monomer without any chemical crosslinkers,termed as H-HPMA hydrogel.The H-HPMA hydrogel can be tuned to perform excellent self-fused properties and suitable abdominal metabolism time.Intriguingly,the introduction of the ultra-hydrophilic HPMA chains to the H-HPMA hydrogel affords an unprecedented antifouling capability.The HPMA chains establish a dense hydrated layer that rapidly prevents the postsurgical adhesions and recurrent adhesions after adhesiolysis in vivo.The H-HPMA hydrogel can repair the peritoneal wound of the rat model within 5 days.Furthermore,an underlying mechanism study reveals that the H-HPMA hydrogel significantly regulated the mesothelial-to-mesenchymal transition(MMT)process dominated by the TGF-β-Smad2/3 signal pathway.Thus,we developed a simple,effective,and available approach to rapidly promote peritoneum regeneration and prevent peritoneal adhesion and adhesion recurrence after adhesiolysis,offering novel design ideas for developing biomaterials to prevent peritoneal adhesion.