Effects of Icodextrin Solution (Adept®) on Ovarian Cancer Cell Proliferation in an In Vitro Model.

Background and objective: Anti-adhesion barriers are currently used during ovarian cancer surgery to decrease adhesion-related morbidity. Adept® (4% icodextrin) solution, a liquid anti-adhesion material, has been widely used during gynecologic surgeries, though the risk of this barrier for oncologic surgery is controversial. The aim of this study was to determine the effect of Adept® solution on the proliferation of ovarian cancer cells. Materials and methods: We assessed the dose- and time-dependent effects of icodextrin on the growth and proliferation of OVCAR-3 and A2780 human ovarian tumor cell lines in vitro. Cell growth was determined by cell number counting. Expressions of cell cycle-regulation proteins (cyclin D1 and cyclin B1) were determined using Western blot analysis. Results: Adept® did not significantly increase ovarian cancer cell growth when tested at various concentrations (0, 1, 5, 10, 15, and 20%, equal to 0, 0.04, 0.2, 0.4, 0.6 and 0.8% icodextrin) and different time points (1-3 days) compared to control cells. Moreover, the protein levels of cyclin D1 and B1 were not overexpression-elevated in icodextrin-treated ovarian cancer cells, either with an increasing concentration or with an increasing treated time. These results demonstrated that Adept® does not activate the growth or proliferation of ovarian cancer cells in either a dose- or time-dependent manner. Conclusions: This study supports the use of Adept® solution as a safe anti-adhesion barrier for ovarian cancer surgery, though further in vivo studies are necessary.

Study protocol: a multicenter randomized controlled trial of the multifaceted workload reduction of the anti-adhesion barrier for diverting ileostomy in laparoscopic rectal surgery, YCOG 2005 (ADOBARRIER study).

BACKGROUND: There are few randomized controlled trials on the efficacy of spray-type anti-adhesion material during diverting ileostomy in laparoscopic rectal cancer surgery. PURPOSE: This study will assess whether or not spraying an anti-adhesion material during diverting ileostomy could reduce the surgeon's multifaceted workload in ileostomy closure. METHODS: Patients with laparoscopic or robotic surgery for rectal cancer scheduled for low anterior resection and diverting ileostomy will be enrolled in the ADOBARRIER study (multicenter, single-blind, randomized controlled trial). The target sample size is set at 120 cases, which will be randomly divided into an anti-adhesion material-using group and a non-using group at a ratio of 1:1. The primary endpoint is the multifaceted workload of the surgeon of ileostomy closure using SURG-TLX between groups with and without usage of the anti-adhesion material during diverting ileostomy construction; the secondly endpoint is the operative time, amount of intraoperative blood loss, degree of adhesions, and extent of intra-abdominal adhesions when the ileostomy is closed. CONCLUSIONS: This RCT will evaluate the efficacy and safety of spray-type anti-adhesion material for diverting ileostomy construction. The results of this study are expected to facilitate decision-making regarding the use of anti-adhesion material. TRIAL REGISTRATION: This trial was registered with the Japan Registry of Clinical Trials (jRCT) in October 2020 as jRCTs032200155.

Prevention of Adhesions after Bone Fracture Using a Carboxymethylcellulose and Polyethylene Oxide Composite Gel in Dogs.

The formation of adhesions is a common complication following traumatic injuries and surgical procedures, often resulting in pain, stiffness, and loss of function. This study aimed to evaluate the feasibility and safety of using a composite material comprising of carboxymethylcellulose (CMC), polyethylene oxide (PEO), and calcium chloride, for preventing adhesions between muscle and bone during the healing stage, as well as its effect on the bone healing process. Ten healthy purpose-bred laboratory Beagle dogs were randomly subjected to two consecutive operations with a 6-month interval, alternating between left and right forelimbs. On the left forelimb an osteotomy at the ulna was performed, while on the right forelimb the same procedure was supplemented by the application of the anti-adhesion agent in the osteotomy site prior to closure. Clinical, diagnostic imaging, macroscopic, and histological evaluations were performed at various time points. The results showed no significant differences in surgical site perimeter (p = 0.558), lameness (p = 0.227), and radiographic bone healing (p = 0.379) between the two groups. However, the macroscopic (p = 0.006) and histological assessments revealed significantly lower adhesion scores (p = 0.0049) and better healing (p = 0.0102) in the group that received the anti-adhesion agent. These findings suggest that the CMC/PEO composite material is a safe and potentially effective intervention for preventing post-traumatic and post-surgical adhesions in canine patients without compromising bone healing. Further research is warranted to fully characterize the clinical benefits of this approach.

Investigation of anti-adhesion ability of 8-arm PEGNHS-modified porcine pericardium.

In post-adhesion surgery, there is a clinical need for anti-adhesion membranes specifically designed for the liver, given the limited efficacy of current commercial products. To address this demand, we present a membrane suitable for liver surgery applications, fabricated through the modification of decellularized porcine pericardium with 20 KDa hexaglycerol octa (succinimidyloxyglutaryl) polyoxyethylene (8-arm PEGNHS). We also developed an optimized modification procedure to produce a high-performance anti-adhesion barrier. The modified membrane significantly inhibited fibroblast cell adherence while maintaining minimal levels of inflammation. By optimizing the modification ratio, we successfully controlled post-adhesion formation. Notably, the 8-arm PEG-modified pericardium with a molar ratio of 5 exhibited the ability to effectively prevent post-adhesion formation on the liver compared to both the control and Seprafilm®, with a low adhesion score of 0.5 out of 3.0. Histological analysis further confirmed its potential for easy separation. Furthermore, the membrane demonstrated regenerative capabilities, as evidenced by the proliferation of mesothelial cells on its surface, endowing anti-adhesion properties between the abdominal wall and liver. These findings highlight the membrane's potential as a reliable barrier for repeated liver resection procedures that require the removal of the membrane multiple times.

Encircling tendon repair site with collagen sheet in flexor zone 2: retrospective study.

BACKGROUND: Peritendinous adhesion is the most common complication of tendon repairs in the hand and often requires surgical intervention, resulting in increased labor loss and increased treatment costs. Many agents used to reduce tendon adhesion in animal models, however these agents have not entered clinical use. This study is the first-ever clinical study that evaluates encircling tendon repair site with collagen sheet as an anti-adhesion barrier. METHODS: Between December 2014 and January 2020, 156 patients included in this study, with clean cut isolated flexor digitorum profundus (FDP) tendon injury in flexor tendon zone 2. All tendons repaired with modified double Kessler technique. In 76 patients, tendon repair site encircled with collagen sheet. 80 patients were randomly selected from our clinical records and functional results are compared with Strickland's total active motion grading system. RESULTS: The mean total range of motion was 79% in the control group and 81% in the collagen sheet group, and there was no statistically significant difference between the two groups (Z: - 1.393, p = 0.164). In the control group, very good and good repair according to Strikland classification was 65/80 (81%). In the collagen sheet group, it was 62/76 (82%), respectively. There was statistically significant difference between 5 FDP TAM measurements between collagen sheet and control group (t(35) = 0.29, p = 0.016, p < 0.05). The mean TAM of the 5 FDP tendons in the collagen sheet group: 83.8 (SD: 8.2) in the and 76.1 (SD: 9.5) in the control group. CONCLUSIONS: For the first time in the literature, functional results of Zone 2 flexor tendon repair using collagen sheets in patients with clean cut tendon injuries reported. However, there were no statistical difference about total active motion between control and collagen sheet group, 5th FDS tendon repairs encircled with collagen sheets had better outcomes. Prospective studies in patient groups with high adhesion risk are recommended.

Effect of hyaluronate-based bioresorbable membrane (Seprafilm) on outcomes of abdominal surgery: a meta-analysis and trial sequential analysis of randomised controlled trials.

We aimed to evaluate comparative outcomes of abdominal surgery with and without hyaluronate-based bioresorbable membrane (Seprafilm).We conducted a systematic search of electronic databases and bibliographic reference lists with application of a combination of free text and controlled vocabulary search adapted to thesaurus headings, search operators and limits. Small bowel obstruction, anastomotic leak, surgical site infections, ileus, and severity of adhesions were the evaluated outcome measures. Thirteen randomised controlled trials reporting a total of 3665 patients evaluating outcomes of abdominal surgeries with (n = 1800) or without (n = 1865) use of Seprafilm were identified. Use of Seprafilm was associated with significantly lower risk of small bowel obstruction (RR 0.53, 95% CI 0.38-0.73, P = 0.0001) but significantly higher rate of anastomotic leak (RR 1.85, 95% CI 1.15-3.00 P = 0.01). Moreover, while Seprafilm resulted in significantly more adhesions-free patients (RR 5.57, 95% CI 3.37-9.19, P < 0.0001) compared to no Seprafilm, its use was associated with significantly lower grade 2 (RR 0.57, 95% CI 0.35-0.95, P = 0.003) or 3 (RR 0.31, 95% CI 0.17-0.55, P < 0.0001) adhesions. There was no significant difference in surgical site infection (RR: 1.21, 95 CI 0.86-1.70, P = 0.28), intra-abdominal abscess (RR 1.46, 95 CI 0.92-2.32, P = 0.11) or paralytic ileus (RR 0.97, 95 CI 0.68-1.38, P = 0.87) between two groups. The trial sequential analysis demonstrated that the meta-analysis findings are conclusive. Our meta-analysis demonstrated that Seprafilm reduces the risk of small bowel obstruction and severity of adhesions after abdominal surgery. However, it may increase the risk of anastomotic leak. We recommend use of Seprafilm in any abdominal surgery which does not involve an anastomosis.

A novel thermosensitive poloxamer-hyaluronic acid- kappa-carrageenan-based hydrogel anti-adhesive agent loaded with 5-fluorouracil: A preclinical study in Sprague-Dawley rats.

Although the first-choice treatment for colorectal cancer is cytoreductive surgery combined with chemotherapy, post-surgical peritoneal adhesion and extant malignancy can cause fatal complications. Studies examining hydrogel-based postoperative anti-adhesion treatments are still limited. In this study, several formulations of 5-fluorouracil (5-FU) loaded into hyaluronic acid (HA) and kappa-carrageenan (kCGN)-poloxamer 407 (P407)-based cross-linked hydrogels were prepared and evaluated in vitro and in vivo for their efficacy in preventing adhesion. These hydrogels met a set of desired specifications such as thermosensitive behavior, strong elasticity at body temperature (tan δ < 1.0 at 37 °C), and ability to encapsulate hydrophilic drug and deliver it in a sustained released manner. Our secondary purpose is to provide in situ 5-FU for additional local antitumor effect when the anti-adhesion agent is spread over the tumor site. Over 60% of the total loaded drug was released within 4 h, and about 80% of 5-FU was released after three days. Both the Higuchi and Korsmeyer-Peppas models showed that the mechanism of sustained drug release involved diffusion. The constructed hydrogels were evaluated for in vivo intra-abdominal anti-adhesion barrier efficiency; the HA/kCGN 1%/3% w/v hydrogel formulation showed the best anti-adhesion effect in this preclinical study using Sprague-Dawley rat models.

Dual-functional anti-adhesion barrier prepared using micro-hierarchical structured and neutralized shellac films for drug release.

Micro-hierarchical structured shellac films were prepared using a solution casting method with dodecyltrichloro-immobilized shellac microparticles. We evaluated two opposite surfaces of the shellac films-one a micro-hierarchical structured side and the other a neutralized shellac side using alkali ethanol-for their applications in the medical field. A bending strength test using a tensile strength testing machine and measurement of surface hardness using a scratch hardness tester indicated that the optimal composition of the base films comprised 15% shellac and 10% calcium phosphate as durability promoting agents. Further, dodecyltrichloro-immobilized shellac microparticles were synthesized and spray-deposited on the films. The solubility of shellac increased as the pH of the shellac solution increased. Analyses of cell adhesion, proliferation, and anti-thrombus efficiency were performed using a WST assay, field emission scanning electron microscope, and hemocytometer. The contact angle with the micro-hierarchical structure surface was approximately 150°. The spray-deposited shellac film yielded a lower cell and platelet adhesion rate (20%) than the untreated film. These results indicate that the micro-hierarchical structure has unique properties and that this novel superhydrophobic biodegradable shellac film can be applied as a blood/tissue-compatible, biodegradable material for implantable medical devices that need an anti-adhesion barrier.

Development of a Lidocaine-Loaded Alginate/CMC/PEO Electrospun Nanofiber Film and Application as an Anti-Adhesion Barrier.

Surgery, particularly open surgery, is known to cause tissue/organ adhesion during healing. These adhesions occur through contact between the surgical treatment site and other organ, bone, or abdominal sites. Fibrous bands can form in unnecessary contact areas and cause various complications. Consequently, film- and gel-type anti-adhesion agents have been developed. The development of sustained drug delivery systems is very important for disease treatment and prevention. In this study, the drug release behavior was controlled by crosslinking lidocaine-loaded alginate/carboxymethyl cellulose (CMC)/polyethylene oxide (PEO) nanofiber films prepared by electrospinning. Lidocaine is mainly used as an anesthetic and is known to have anti-adhesion effects. Our results show that drug release is regulated by the crosslinking degree of the lidocaine-loaded alginate/CMC/PEO film. The drug release behavior was confirmed by HPLC, and, as a result, an excellent anti-adhesion barrier was developed that can be applied to treat patients in the medical field.

Biomaterials to Prevent Post-Operative Adhesion.

Surgery is performed to treat various diseases. During the process, the surgical site is healed through self-healing after surgery. Post-operative or tissue adhesion caused by unnecessary contact with the surgical site occurs during the normal healing process. In addition, it has been frequently found in patients who have undergone surgery, and severe adhesion can cause chronic pain and various complications. Therefore, anti-adhesion barriers have been developed using multiple biomaterials to prevent post-operative adhesion. Typically, anti-adhesion barriers are manufactured and sold in numerous forms, such as gels, solutions, and films, but there are no products that can completely prevent post-operative adhesion. These products are generally applied over the surgical site to physically block adhesion to other sites (organs). Many studies have recently been conducted to increase the anti-adhesion effects through various strategies. This article reviews recent research trends in anti-adhesion barriers.

Pharmacokinetic Profile and Anti-Adhesive Effect of Oxaliplatin-PLGA Microparticle-Loaded Hydrogels in Rats for Colorectal Cancer Treatment.

Colorectal cancer (CRC) is one of the most malignant and fatal cancers worldwide. Although cytoreductive surgery combined with chemotherapy is considered a promising therapy, peritoneal adhesion causes further complications after surgery. In this study, oxaliplatin-loaded Poly-(d,l-lactide-co-glycolide) (PLGA) microparticles were prepared using a double emulsion method and loaded into hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based cross-linked (HC) hydrogels. From characterization and evaluation study PLGA microparticles showed smaller particle size with higher entrapment efficiency, approximately 1100.4 ± 257.7 nm and 77.9 ± 2.8%, respectively. In addition, microparticle-loaded hydrogels showed more sustained drug release compared to the unloaded microparticles. Moreover, in an in vivo pharmacokinetic study after intraperitoneal administration in rats, a significant improvement in the bioavailability and the mean residence time of the microparticle-loaded hydrogels was observed. In HC21 hydrogels, AUC0-48h, Cmax, and Tmax were 16012.12 ± 188.75 ng·h/mL, 528.75 ± 144.50 ng/mL, and 1.5 h, respectively. Furthermore, experimental observation revealed that the hydrogel samples effectively protected injured tissues from peritoneal adhesion. Therefore, the results of the current pharmacokinetic study together with our previous report of the in vivo anti-adhesion efficacy of HC hydrogels demonstrated that the PLGA microparticle-loaded hydrogels offer novel therapeutic strategy for CRC treatment.

Oxaliplatin-loaded chemically cross-linked hydrogels for prevention of postoperative abdominal adhesion and colorectal cancer therapy.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer among both men and women worldwide. New therapeutic strategies involving cytoreductive surgery and intra-peritoneal chemotherapy could lead to a definitive cure in some cases. However, postoperative intra-abdominal adhesion can cause further complications. In this study, hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based novel cross-linked hydrogels (HC hydrogels) were synthesized and fully characterized. We demonstrated that varied compositions of HA and CMCNa altered the microstructure, rheology, and degradation behavior of hydrogels. Pre-constructed hydrogels were further loaded with oxaliplatin to prevent intra-abdominal adhesion following chemotherapy. Sustained release of oxaliplatin was observed from hydrogels compared that from solutions, which release drugs through diffusion, following the Higuchi and Korsmeyer-Peppas models. Moreover, low adhesion scores in an in vivo SD rat model demonstrated inhibition of intra-peritoneal adhesion in response to HC hydrogels. Therefore, HC hydrogels offer a novel formulation strategy for providing an intra-abdominal anti-adhesion barrier after cytoreductive surgery and intra-peritoneal chemotherapy for CRC treatment.

Absorptive anti-adhesion barrier for the prevention of bowel obstruction after laparoscopic colorectal cancer surgery.

OBJECTIVES: The protective efficacy of an absorptive adhesion prevention product (SeprafilmⓇ) against bowel obstruction (BO) during open surgery was demonstrated in a large-scale randomized controlled clinical trial in Europe and America. However, the efficacy of Seprafilm against BO in laparoscopic surgery remains uncertain. The objective of this study was to clarify the protective efficacy of Seprafilm against BO after laparoscopic surgery for colorectal cancer. METHODS: From 2009 to 2016, 1328 laparoscopic colorectal resections were performed for colorectal cancer. From 2009, Seprafilm was used for preventing BO in laparoscopic colorectal surgery. The incidence of BO and short-term results were compared between the Seprafilm and non-Seprafilm groups after propensity score matching. RESULTS: Propensity scoring generated 270 matched patients per group for the comparisons between the Seprafilm and non-Seprafilm groups. The two groups showed no significant differences regarding patients' backgrounds. Among all patients, 73.1% (19/26) of BO occurred within 30 days after the surgery. Significantly lower incidences of all grade (2.6% vs. 7.0%; p = 0.016) and grade 2 + 3a (1.5% vs. 5.2%; p = 0.017) BO were observed in the Seprafilm group than in the non-Seprafilm group; no significant difference regarding grade 3b BO (1.1% vs. 1.9%; p = 0.476) was found. A significant difference in BO within 30 days was also noted between the two groups (1.9% vs. 5.2%, p = 0.036). There were no significant differences between the groups regarding anastomotic leakage and deep surgical site infection. CONCLUSIONS: Seprafilm was useful for preventing BO, requiring decompression therapy of the bowel, after laparoscopic colorectal surgery without increasing adverse events.

Injectable pullulan hydrogel for the prevention of postoperative tissue adhesion.

Methods for reducing and preventing postoperative abdominal adhesions have been researched for decades; however, despite these efforts, the formation of postoperative peritoneal adhesions is continuously reported. Adhesions cause serious complications such as postoperative pain, intestinal obstruction, and infertility. Tissue adhesion barriers have been developed as films, membranes, knits, sprays, and hydrogels. Hydrogels have several advantages when used as adhesion barriers, including flexibility, low tissue adhesiveness, biodegradability, and non-toxic degraded products. Furthermore, compared with preformed hydrogels, injectable hydrogels can fill and cover spaces of any shape and do not require a surgical procedure for implantation. In this study, pullulan was modified through reaction with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to introduce carboxyl and phenyl groups as crosslinking sites. The grafting of tyramine on pullulan allows crosslinking branches on pullulan backbone. We successfully fabricated pullulan hydrogel with an enzymatic reaction using horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). The chemical structure of modified pullulan was analyzed with ATR-FTIR and (1)H NMR spectroscopies. Rheological properties were tested by measuring storage modulus with varying H2O2, HRP, polymer solution concentrations and tyramine substitution rates. Cell viability and animal tests were performed. The modified pullulan hydrogel is an invaluable advance in anti-adhesion agents.

Genipin-crosslinked gelatin microspheres as a strategy to prevent postsurgical peritoneal adhesions: In vitro and in vivo characterization.

BACKGROUND: Peritoneal adhesions are a common complication after abdominal surgery. They cause small bowel obstruction, female infertility and chronic abdominal pain. Peritoneal adhesions also hamper uniform drug distribution in the peritoneal cavity, thereby reducing the efficacy of intraperitoneal chemotherapy after cytoreductive surgery. AIM: The goal of this study was to develop a formulation that prevents peritoneal adhesions, evenly distributes in the abdominal cavity, and simultaneously extends residence time and improves local drug concentration. This report describes the formulation and characterization of genipin-crosslinked gelatin microspheres (GP-MS). METHODS AND RESULTS: Spheroid gelatin microspheres were prepared by an emulsification solvent extraction method. A higher degree of crosslinking was obtained by increasing genipin concentration and crosslinking time. The degree of crosslinking allowed to tailor the degradation rate of GP-MS, hence their residence time. GP-MS did not affect cell viability. In vivo experiments showed excellent GP-MS biocompatibility and degradation characteristics. GP-MS were distributed evenly throughout the abdominal cavity. Adhesions were induced in Balb/c mice by application of an abraded peritoneal wall-cecum model. GP-MS-treated mice developed significantly less postsurgical adhesions compared to saline and Hyalobarrier(®) group. Histopathological examination showed a decrease of peritoneal inflammation over time in GP-MS-treated mice with complete recovery of peritoneal wounds post-operative day 14. CONCLUSION: GP-MS are a promising strategy to prevent postoperative peritoneal adhesions and improve efficacy of postoperative intraperitoneal chemotherapy.

Poly(ethylene glycol) dicarboxylate/poly(ethylene oxide) hydrogel film co-crosslinked by electron beam irradiation as an anti-adhesion barrier.

The cross-linked poly(ethylene glycol) dicarboxylate (PEGDC)/poly(ethylene oxide) (PEO) and poly(ethylene glycol) dimethacrylate (PEGDMA)/(PEO) hydrogels were developed for possible biomedical applications such as an anti-adhesion barrier. Various contents of PEGDC/PEO film were irradiated using an electron beam with various beam intensities in order to obtain various degrees of crosslinked hydrogels. The optimum dose (300 kGy) and total crosslinker content of 10% were used to prepare crosslinked hydrogel films with three different compositions (10% PEGDC, 10% PEGDMA, 5% PEGDC-5% PEGDMA). Among them, 10% PEGDC hydrogel film exhibited the highest elongation at break (69.33±6.87%) with high mechanical strength. 10% PEGDC hydrogel film showed the lowest hemolysis activity (6.03±0.01%) and the highest tissue adherence (75.67±1.15 cN). The result also indicated that the carboxyl groups in PEGDC affect the tissue adherence of hydrogel films via H-bonding interactions. In animal studies, 10% PEGDC anti-adhesion hydrogel film degraded within 3 weeks and demonstrated better anti-adhesive effect compared to Guardix-SG®.

Application of nanosheets as an anti-adhesion barrier in partial hepatectomy.

Postoperative adhesion often causes serious adverse effects such as bowl obstruction, chronic abdominal pain, pelvic pain, and infertility. We previously reported that a poly-L-lactic acid (PLLA) nanosheet can efficiently seal a surgical incision without scarring. In this report, we examined whether the PLLA nanosheet can form an effective anti-adhesion barrier in partial hepatectomy accompanied by severe hemorrhaging in rats. To evaluate the anti-adhesive property of the nanosheet, the liver wound surface was covered with TachoComb(®) , a well-known hemostat material used in clinical procedures, and then with the PLLA nanosheet. Dressing the wound surface with TachoComb(®) alone caused severe adhesion with omentum and/or residual parts of the liver. By contrast, combinational usage of TachoComb(®) and the PLLA nanosheet significantly reduced such adhesion, presumably by inhibiting the permeation of oozing blood cells and the infiltration of fibroblastic cells. Moreover, the nanosheet displayed low permeability against serum proteins as well as cells in vitro, supporting the notion that the PLLA nanosheet has anti-adhesive properties in vivo. These results strongly suggested that the PLLA nanosheet is a promising material for reducing unwanted postoperative adhesion.