A hydrogel for adhesion prevention: characterization and efficacy study in a rabbit uterus model

Abstract

Objective

Postoperative peritoneal adhesions following gynaecological surgery remain a clinically relevant problem. One approach to prevent adhesion formation is to apply physical barriers such as hydrogels.

Study design

A physically crosslinked polyvinyl alcohol and carboxymethylcellulose (PVA/CMC) hydrogel (A-Part) was characterized in vitro. Three different traumatization methods were evaluated in a rabbit uterine study. To determine its anti-adhesion efficacy, the hydrogel was first tested in an in vivo pilot study and then in a larger trial to compare it with icodextrin 4% solution (Adept^®) and controls.

Results

Rheological measurements showed an increased elasticity of the hydrogel after freezing. In vivo experiments revealed a clear reduction in incidence, extent and severity of adhesions compared to the icodextrin 4% solution and the untreated control group.

Conclusions

These results warrant further investigation of the PVA/CMC A-Part hydrogel in clinical trials focused on gynaecological procedures.

Introduction

The formation of adhesions after surgery is a well-known complication with serious consequences, such as female infertility and pelvic pain, and entails a substantial medical economic burden [1], [2], [3]. Defined as the union of two normally separate tissue surfaces due to surgical trauma or inflammation, adhesions are observed at rates of more than 50% of patients who have undergone abdominal surgery for any reason [4]. This union can vary from a thin film of connective tissue to a thick fibrous bridge containing blood vessels. When the fibrin deposited after peritoneal damage is not lysed, it leads to the formation of permanent fibrous adhesions which might need adhesiolysis [5].

Adhesions remain an important and clinically relevant problem and adhesion-related problems are likely to increase in the future. Considering the medical and financial impact of postsurgical adhesions, various methods for preventing adhesions have been the focus of extensive research [6]. An approach to reducing peritoneal adhesions is to apply physical barriers which separate the injured regions during peritoneal healing [7] and thus limit contact between adjacent areas of wounded tissue during the critical healing period [8]. Here, wounded surfaces must be protected by the barrier until a new mesothelial layer has developed. Various materials have been investigated to prevent adhesion formation. Several clinical studies suggest that absorbable patches such as sodium hyaluronate and carboxymethylcellulose (CMC; Seprafilm^®) [9], gels such as the viscoelastic gel based on polyethylene oxide and CMC (Oxiplex^®/Intercoat^®) [10], or liquid agents such isotonic solutions of icodextrin (Adept^®) [11] may reduce adhesion formation. So far, however, no therapy has been adopted as the gold standard, primarily because of the difficulty of conducting clinical trials since usually a second surgical procedure is needed for adhesion assessment.

In particular, biocompatible hydrogels seem to be an interesting option for developing potent adhesion barriers. In contrast to the polymer solutions, the chains in hydrogels are crosslinked, either chemically or physically [12]. Due to their excellent biocompatibility and adjustable permeability, they are widely used in various applications including contact lenses, diapers and bioartificial organs [13].

The aim of this study was to characterize a physically crosslinked polyvinyl alcohol (PVA)/CMC hydrogel in vitro and investigate its anti-adhesion properties in an in vivo pilot trial using a gynaecological rabbit model. A reliable model that could be reproduced and scored was also developed. The gel (A-Part) consists of the synthetic water-soluble polymers PVA and CMC chosen because of their known biocompatibility and pharmaceutical acceptability [14], [15]. Previous studies have shown that PVA membranes and elastic PVA hydrogel sheets significantly reduced adhesion formation in animal models [16]. Jaenigen et al. have shown that A-Part in membrane form significantly reduced adhesion formation in a rabbit abdominal sidewall model; the membrane form, however, is not likely to be capable of preventing adhesions in three-dimensional areas, e.g. by covering the reproductive organs. The novel hydrogel formulation is developed to be used as an anti-adhesion agent in gynaecological and abdominal surgery [17]. The gel has already been tested in an abdominal sidewall model [17] and is currently under clinical evaluation in patients undergoing general surgery to reduce intraperitoneal adhesions with the abdominal wall [18]. As yet, it has not been tested to reduce adhesion formation in gynaecological procedures.