Kevin C. Skinner

A hyaluronate based gel for the prevention of postsurgical adhesions : evaluation in two animal species

OBJECTIVE To assess in two animal surgery models, the efficacy of a bioabsorbable gel to prevent postoperative adhesions. DESIGN A randomized, prospective, blinded study using animal abdominal surgery models. SETTING Two animals species with surgical traumas to induce adhesion formation. INTERVENTIONS A chemically modified hyaluronate and carboxymethylcellulose-based gel formulation. MAIN OUTCOME MEASURES The number of animals with no adhesions, mean number of adhesions, and total adhesion score. RESULTS Treatment with the bioabsorbable gel increased the number of animals without any adhesion by 70% in a rat cecal abrasion model and by > 90% in a rabbit sidewall defect-bowel abrasion model when compared with nontreatment control animals. Other outcome measures showed similar efficacy. CONCLUSION The modified hyaluronate-carboxymethylcellulose gel was effective in two animal species after surgery in the abdominal cavity. The gel appears to act as a physical barrier between damaged peritoneal tissue and may be appropriate for human clinical trials in open and laparoscopic surgical procedures.

Paclitaxel-Loaded Crosslinked Hyaluronic Acid Films for the Prevention of Postsurgical Adhesions

AbstractPurpose. Post surgical adhesion formation results in significant morbidity for surgical patients. The purpose of this study was to investigate the use of paclitaxel (PTX) as an inhibitor of adhesion formation in rats and to design and characterize a controlled release film formulation of the drug for application to exposed surgical sites. Methods. The rat cecal side wall abrasion model was used to investigate the anti-adhesion properties of PTX. The drug was administered by either intraperitoneal injection (i.p.), as the cremophor formulation (Taxol®) or by application of carbodiimide crosslinked hyaluronic acid (HA) films containing PTX. The HA films were also characterized by measurements of elasticity, degree of swelling in water and drug release rates. Results. Taxol® administered by i.p. injection at 4 mg/kg on a daily basis for between 3 and 5 days resulted in a significant reduction in adhesion formation. All animals in the control group (n = 10) had some form of adhesion following abrasion whereas the percent of animals without adhesions significantly increased and the mean incidence of adhesion formation decreased in the three Taxol® treated groups. The application of 5% PTX loaded HA films had a similar significant effect in increasing both the % of animals without adhesions and in reducing the mean incidence of adhesions. Conclusions. Paclitaxel is an effective inhibitor of adhesion formation in rats. HA crosslinked with 2 mM water soluble carbodiimide and containing 10% glycerol and 5% PTX are flexible, mucoadhesive, biocompatible controlled release films suitable for application to surgical sites for the prevention of adhesion formation.

Role of transforming growth factor beta-1 in peritonitis-induced adhesions.

Peritonitis is a major cause of intra-abdominal adhesion formation. The overexpression of transforming growth factor beta-l (TGF-Pl), a potent mitogen, chemoattractant, and stimulant for collagen synthesis by fibroblasts, has been linked to tissue fibrosis at various sites throughout the body including peritoneal adhesion formation. Hence we hypothesized that the mechanism(s) involved in peritonitis-induced adhesion formation may be mediated through the upregulation of TGF-β expression. Peritonitis was induced in rats by cecal ligation and puncture, while a control group underwent sham operation. Adhesions were scored and harvested from both groups at 0,6 and 12 hours and at 1,2,4, 7, and 28 days. Tissue expression of TGF-PI mRNA was determined by quantitative reverse transcription-polymerase chain reaction and TGF-β protein was localized by immunohistochemical analysis. Serum and peritoneal fluid TGF-β concentrations were quantified by enzyme-linked immunosorbent assay. Compared with sham operation, peritonitis was associated with a significantly greater incidence of abdominal adhesions and a significant increase in the levels of TGF-β 1 mRNA expression at days 2,4, and 7. Immunostaining intensity of TGF-β in adhesions from the peritonitis group also steadily rose through day 7. In peritoneal fluid, the ratio of active:total TGF-βl was significantly increased in the peritonitis group on days 1, 2, and 4 compared with the sham group. These results suggest that peritonitis is associated with the upregulation of TGF-βl, a mechanism that may exacerbate adhesion formation.

Role of a hyaluronate-based membrane in the prevention of peritonitis-induced adhesions

Adhesions remain a significant postoperative complication of abdominal surgery; however, recent evidence suggests that physical barriers may reduce their incidence. Although these adhesion prevention barriers are efficacious when used under aseptic conditions, little is known about their use in the presence of peritonitis, which is associated with an increased incidence of abdominal adhesions. A sodium hyaluronate and carboxymethylcellulose bioresorbable membrane (HA membrane) has been shown recently to reduce postoperative adhesions in several animal models and in two clinical trials. To investigate the efficacy of HA membrane in the presence of peritonitis, generalized peritonitis was induced in rats by either cecal ligation and puncture (CLP) or cecal ligation (CL) alone. The ceca were resected after 12 hours, and animals were randomly assigned to receive or not receive HA membrane applied to the cecum. At day 7, abdominal adhesions and abscesses were scored. In the presence of peritonitis, HA membrane did not significantly reduce the number or tenacity of adhesions. A trend toward increased abscess formarion was associated with HA membrane in the CL group. Although HA membrane has been shown to reduce the incidence and severity of abdominal adhesions under aseptic conditions, this study demonstrates that it is not efficacious in preventing abdominal adhesions in the presence of peritonitis. The association between HA membrane and abscess formation in the presence of experimental peritonitis requires further investigation.

Differential expression of matrix metalloproteinase and tissue inhibitor of MMP in serosal tissue of intraperitoneal organs and adhesions

Objective To comparatively analyse the expression of matrix metalloproteinase (MMP‐3) and tissue inhibitor of MMP (TIMP‐2) in serosal tissue of intraperitoneal organs and adhesions, as well as peritoneal fluid and serum of subjects with and without adhesions.

The Evaluation of an Injectable Bioresorbable Gel on Adhesion Reduction in Two Animal Models

We have developed an injectable bioresorbable gel Sepragel that acts as a barrier to reduce postsurgical adhesions and can be used in both open and laparoscopic procedures. This study was designed to evaluate the effect of Sepragel on adhesion reduction in a rat sidewall defect model and a rat cecal abrasion model.

An Evaluation of Operator Variability in a Rat Cecal Abrasion Model for the Formation of Abdominal Models

To effectively evaluate adhesion prevention modalities, a consistent and reproducible animal model must be employed. We have developed a model for the formation of abdominal adhesions using a mechanical abrading device to limit variability between surgeons. This study was designed to evaluate surgeon differences in both the formation and evaluation of adhesions in a rat cecal abrasion model.