Elsevier

Advanced Drug Delivery Reviews

Volume 52, Issue 2, 5 November 2001, Pages 105-115
Advanced Drug Delivery Reviews

Topical formulations and wound healing applications of chitosan

https://doi.org/10.1016/S0169-409X(01)00189-2Get rights and content

Abstract

Chitosan is being used as a wound-healing accelerator in veterinary medicine. To our knowledge, chitosan enhances the functions of inflammatory cells such as polymorphonuclear leukocytes (PMN) (phagocytosis, production of osteopontin and leukotriene B4), macrophages (phagocytosis, production of interleukin (IL)-1, transforming growth factor β1 and platelet derived growth factor), and fibroblasts (production of IL-8). As a result, chitosan promotes granulation and organization, therefore chitosan is beneficial for the large open wounds of animals. However, there are some reported complications of chitosan application. Firstly, chitosan causes lethal pneumonia in dogs which are given a high dose of chitosan. In spite of application of chitosan to various species, this finding is observed only in dogs. Secondly, intratumor injection of chitosan on mice bearing tumor increases the rate of metastasis and tumor growth. Therefore, it is important to consider these effects of chitosan, prior to drug delivery.

Introduction

The history of chitin and its derivatives as wound healing accelerators began with the studies of Prudden et al. [1], [2]. They noticed that the shark cartilage had accelerated wound healing and suggested glucosamine, which is a component of shark cartilage, functioned mainly as a healing accelerator. Therefore they identified N-acetyl-d-glucosamine (GlcNAc), which was derived from glucosamine, as a wound healing accelerator. On the other hand, chitosan is a polysaccharide made up of β-(1→4)-linked GlcNAc and d-glucosamine (GlcN) units. The topical finding of healing of wounds treated with chitosan is accelerated granulation [3]. Chitosan is now used in veterinary clinical medicine. In large open wounds, the process of new tissue formation is recognized as granulation, which must form before wound epithelialization can start. Therefore chitosan has an adaptable property for the wound. We have researched the mechanism of wound healing with chitosan in vivo and in vitro and had interesting findings. These findings are shown in this review with our knowledge evaluated by another research group. The biological functions of chitosan may be of importance for designing carriers for drug delivery.

Section snippets

Topical findings of healing with chitosan at early phase of experimental open skin wound

In order to evaluate the effect of chitosan as an accelerator of wound healing, experimental open skin wounds on the dorsal side in normal beagles were made. Chitosan was applied for 15 days, and the wounds were evaluated histologically and immunohistochemically [3].

Effects of chitosan on PMN

Chitosan accelerates the migration of PMN to the wound area. Activated PMN secrete inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-8, IL-12, macrophage inflammatory protein (MIP)-1α and MIP-1β in addition to phagocytosis [4], [5], [6]. In this section, PMN functions, which are promoted by chitosan, are described.

Effects of chitosan on macrophages

Chitosan is composed of GlcN and GlcNAc. Macrophages appear to express the receptors for mannose- and GlcNAc-glycoproteins, which mediate the uptake of such glycoproteins into macrophage. The binding of GlcNAc to the specific receptors is thought to be a prerequisite for enhancing macrophage activation [21], [22], [23], [24]. Macrophages play an important role in the process of wound healing. The activation of macrophages leads to the release of various biological mediators and phagocytosis of

Effects of chitosan on fibroblasts

Reformation of connective tissue follows more fibroblast proliferation and extracellular matrix (ECM) synthesis [25]. In Section 2.2, we showed that the collagenous layer of granulation tissue is increased by chitosan application. According to this finding, chitosan may stimulate more fibroblast proliferation and ECM production directly or indirectly. The indirect mechanism of enhanced granulation by chitosan is described in the section above. In this section, we show the findings of the

Complications in the application of large doses of chitosan

The safety of chitosan has been demonstrated in mice and rats when used as food additives and base materials for cosmetics [31], [32]. In the acute toxicity test, the LD50 was reported as over 1.5 g/kg orally in rats, over 10 g/kg subcutaneously in mice, 5.2 g/kg intraperitoneally in mice and 3.0 g/kg in rats [31]. However, a characteristic effect was found in dogs [33].

Various amounts of chitosan (10–200 mg/kg) were administered subcutaneously to dogs. Anorexia and mortality were observed in

Conclusions

From these reports, chitosan activates immunocytes and inflammatory cells such as PMN, macrophage, fibroblasts and angioendothelial cells. On the other hand, the biological effects of chitin have also been studied. These effects were almost similar to that of chitosan, except that the strength of the effects observed was weaker. Therefore, it is suggested that the degree of deacetylation causes the difference in biological effects. However, the effects of chitin and its derivatives have not

References (33)

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