Elsevier

Biomaterials

Volume 30, Issue 29, October 2009, Pages 5534-5540
Biomaterials

A thermosensitive chitosan-based hydrogel barrier for post-operative adhesions' prevention

https://doi.org/10.1016/j.biomaterials.2009.05.084Get rights and content

Abstract

Post-operative peritoneal adhesions are common and serious complications for surgeons. They can cause pelvic pain, infertility, and potentially lethal bowel obstruction. We synthesized injectable hydrogels that formed by chemical modification through grafted hydrobutyl groups to chitosan chains. Gelation of hydroxybutyl chitosan (HBC) occurs in less than 60 s. Once formed, it can also be recovered completely. The residue time of hydrogels can extend to 4 weeks in Kunming mice. HBC hydrogels showed mild cytotoxicity to mice fibroblast cell (L929) and human vascular endothelial cell (ECV-304) in vitro and were biocompatible in the murine muscles, causing no adhesions for 4 weeks. HBC gels can form a durable barrier between defected cecum and abdominal wall. In a mice sidewall defect-bowel abrasion model, HBC gels showed significant efficacy in reducing adhesion formation.

Introduction

Postsurgical adhesions are common and serious complications for surgeons and patients. They occur after almost all abdominal and pelvic surgery. Indeed, after laparotomy, almost 93% of patients have been shown to have adhesions at subsequent surgery [1], [2]. Abdominal adhesions are an everyday problem in clinical and surgical practice, a major cause of morbidity and expense, an occasional of mortality, and a leading and debilitating cause of chronic pain [3], [4].

Numerous pharmacological and barrier-based approaches to treat adhesion have been tested [5], [6], [7], [8]. Among these methods, barriers are currently the most useful adjuncts to reduce adhesion formation. They act by effectively separating the traumatized peritoneal surfaces during the critical period of adhesion development at 3–5 days after surgery. This separation can be achieved by the use of solid mechanical barriers (films and gels) to keep tissue surfaces physically separated during the healing process, or by the use of fluids for hydroflotation [9], [10], [11], [12], [13], [14]. While these barrier approaches have been effective in preventing adhesion formation to various degrees in animal models, their clinical efficacy has been equivocal. For solid sheets or pre-formed hydrogels, complete coverage of injured tissues may be difficult [7]. However, for polymer solutions, the residence time at the affected tissues is brief, and there are difficulties in handling and fixation to tissue [15]. All these disadvantages may compromise their effectiveness as a barrier system. Therefore, an ideal barrier system should be easy to apply via laparoscopic and open surgical procedures, provide complete coverage of the affected tissues, and remain effective throughout the healing process.

As a result of the limitations mentioned above, in situ cross-linkable hydrogel systems (i.e., polymer solutions that can form hydrogels when applied in situ) have been explored [16], [17], [18]. These cross-linkable hydrogel systems are prepared by UV illumination or chemical modification. Recently, many cross-linkable hydrogels based on hyaluronic acid (HA) have been applied to the prevention of abdominal adhesion. However, the relatively long gelation time may be impractical [16].

Here, we describe a new thermosensitive hydrogel system for prevention of postoperative adhesions, which can be easily applied as a mildly viscous solution without spatial restriction, but which quickly transforms into a pliable and durable hydrogel when the temperature is increased. This system is based on a new derivative of chitosan – hydroxybutyl chitosan (HBC). It has been reported previously that chemical modification does not alter the biocompatibility of HBC [19]. Here, we characterized the material's degradation in vitro, and its biocompatibility, cytotoxicity and effectiveness in preventing adhesions in vivo.

Section snippets

Materials

Chitosan with a molecular weight (MW) of 1000 kDa and a degree of deacetylation of 90% was provided by Shanghai Qisheng Biological Preparation Co. Ltd. (Shanghai, China). 1, 2-Butene oxide was purchased from Sigma Co. Ltd.

Preparation of HBC

HBC was prepared according to a previously described method, with modification. Briefly, 10 g chitosan was alkalinized by 100 ml KOH (50%, w/w) under the protection of N2 at 15 °C. After the removal of additional KOH solution, chitosan was dispersed in 200 ml isopropanol/water

Characterization of HBC

The MWs of original and purified HBC are summarized in Table 1. After purification, products with low MWs were removed and the MW of HBC was greatly increased.

Rheological analysis

Gel temperature was defined as the temperature at which storage modulus (G′) and loss modulus (G″) were equal. At 20 °C, the HBC solution began to form gels (Fig. 1). When the temperature was increased, more solution was transformed into hydrogels. The process was reversible, and when the temperature was decreased, the gels formed into

Discussion

It is known that hydroxy polymers can stabilize certain compounds and promote the formation of a shield of water around some macromolecules in aqueous solution [24]. When hydroxybutyl groups are added to chitosan chains, at low temperature, hydrogen bonds exist between the OH group of hydroxybutyl groups and the OH and NH2 groups of the chitosan chains, and between the hydroxybutyl groups and water, because of the high hydrophilicity of the hydroxybutyl groups. At the same time, the low

Conclusions

Thermosensitive HBC hydrogels were highly effective in reducing the formation of postoperative abdominal adhesions. The thermosensitive system provides substantial advantages over existing barrier systems. It is easy to handle and can be applied with great flexibility, which provides a durable physical barrier that can last sufficiently long to reduce adhesion formation until the healing process is ended.

Acknowledgments

The authors acknowledge financial support from China Postdoctoral Science Foundation Funded Project (No. 20080430229).

References (29)

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