Elsevier

Biotechnology Advances

Volume 26, Issue 1, January–February 2008, Pages 1-21
Biotechnology Advances

Research review paper
Chitosan and its derivatives for tissue engineering applications

https://doi.org/10.1016/j.biotechadv.2007.07.009Get rights and content

Abstract

Tissue engineering is an important therapeutic strategy for present and future medicine. Recently, functional biomaterial researches have been directed towards the development of improved scaffolds for regenerative medicine. Chitosan is a natural polymer from renewable resources, obtained from shell of shellfish, and the wastes of the seafood industry. It has novel properties such as biocompatibility, biodegradability, antibacterial, and wound-healing activity. Furthermore, recent studies suggested that chitosan and its derivatives are promising candidates as a supporting material for tissue engineering applications owing to their porous structure, gel forming properties, ease of chemical modification, high affinity to in vivo macromolecules, and so on. In this review, we focus on the various types of chitosan derivatives and their use in various tissue engineering applications namely, skin, bone, cartilage, liver, nerve and blood vessel.

Introduction

Tissue engineering consists of a multidisciplinary science, including fundamental principles from materials engineering and molecular biology in efforts to develop biological substitutes for failing tissues and organs. In the most general sense, tissue engineering seeks to fabricate living replacement parts for the body. Langer and Vacanti (1993) reported that the most common approach for engineering biological substitutes is based on living cells, signal molecules, and polymer scaffolds. The cells synthesize matrices of new tissue as well as function on behalf of the diseased or damaged tissues, while the scaffold provides the suitable environment for the cells to be able to effectively accomplish their missions such as adherence, proliferation and differentiation. The function of the signal molecules is to facilitate and promote the cells to regenerate new tissue. In this regenerative program, the scaffolds provide not only temporary three-dimensional frameworks to form the designed tissues, but also space filling and controlled release of signal molecules. To perform these varied functions in tissue engineering, the scaffold should meet the following requirements: (1) biocompatibility with the tissues, (2) biodegradability at the ideal rate corresponding to the rate of new tissue formation, (3) nontoxicity and nonimmunogenicity, (4) optimal mechanical property, and (5) adequate porosity and morphology for transporting of cells, gases, metabolites, nutrients and signal molecules both within the scaffold and between the scaffold and the local environment.

Recent biological achievements regarding cell culture using signal molecules are promising techniques with polymer scaffolds to regenerate tissues and organs. Functional biomaterial research has been directed toward the development of improved scaffolds for tissue engineering (Watanabe et al., 2003). A number of biodegradable polymers have been exhaustively explored as scaffolds for tissue engineering applications. The materials include synthetic polymers like polycaprolactone (Sarasam and Madihally, 2005, Williams et al., 2005), poly (lactic-co-glycolic acid) (Wu et al., 2006), poly(ethylene glycol) (Wozney and Seeherman, 2004, Leach and Schmidt, 2005), poly(vinyl alcohol) (Schmedlen et al., 2002, Oh et al., 2003) and polyurethane (Santerre et al., 2005) and natural polymers such as alginate (Li et al., 2005), gelatin (Li et al., 2006), collagen (Ignatius et al., 2005), starch (Gomes et al., 2002) and chitosan (Seo et al., 2006, Adekogbe and Ghanem, 2005, Huang et al., 2005). Among them naturally derived polymers are of special interest due to, as natural components of living structures, their biological and chemical similarities to natural tissues (Krajewska, 2005). In this context, chitosan has been found a fascinating candidate in a broad spectrum of applications along with unique biological properties including biocompatibility, biodegradability to harmless products, nontoxicity, physiological inertness, remarkable affinity to proteins, antibacterial, haemostatic, fungistatic, antitumoral and anticholesteremic properties (Nishimura et al., 1984, Tanigawa et al., 1992, Okamoto et al., 1993, Khnor and Lim, 2003, Mori et al., 1997, Tokura et al., 1997, Singla and Chawla, 2001). The choice of chitosan as a tissue support material is governed among others by multiple ways by which its biological, physical and chemical properties can be controlled and engineered under mild conditions (Krajewska, 2005).

The history of chitosan dates back to the 19th century, when Rouget discussed the deacetylated form of chitosan in 1859 (Valérie and Vinod, 1998). Studies on chitosan have been intensified as biomaterials for tissue engineering applications during the past 25 years. Chitin, the source material for chitosan, is one of the most abundant organic materials, being second only to cellulose in the amount produced annually by biosynthesis. It is an important constituent of the exoskeleton in animals, especially in crustacean, molluscs and insects. It is also the principal fibrillar polymer in the cell wall of certain fungi (Eugene and Lee, 2003). Chitosan is a linear polysaccharide, composed of glucosamine and N-acetyl glucosamine units linked by β (1–4) glycosidic bonds. The content of glucosamine is called as the degree of deacetylation (DD). Depending on the source and preparation procedure, its molecular weight may range from 300 to over 1000 kD with a DD from 30% to 95% (Dornish et al., 2001, VandeVord et al., 2002). In its crystalline form, chitosan is normally insoluble in aqueous solution above pH 7, however, in dilute acids (pH < 6.0), the protonated free amino groups on glucosamine facilitate solubility of the molecule (Madihally and Matthew, 1999). Generally, chitosan has three types of reactive functional groups, an amino group as well as both primary and secondary hydroxyl groups at the C(2), C(3), and C(6) positions, respectively. These groups allow modification of chitosan like graft copolymerization for specific applications, which can produce various useful scaffolds for tissue engineering applications. The chemical nature of chitosan in turn provides many possibilities for covalent and ionic modifications which allow extensive adjustment of mechanical and biological properties.

For the breakthrough in tissue engineering applications, this review will focus on the properties of chitosan as a tissue supporting material, its modification to introduce various functional groups and recently, their applications in various artificial organs such as skin, bone, cartilage, liver, nerve and blood vessel will be explained.

Section snippets

Chitosan as tissue supporting material

Chitosan-based scaffolds possess some special properties for use in tissue engineering. First, Chitosan can be formed as interconnected-porous structures by freezing and lyophilizing of chitosan solution or by processes such as an “internal bubbling process (IBP)” where CaCO3 is added to chitosan solutions to generate chitosan–CaCO3 gels in specific shapes by using suitable molds (Chow and Khor, 2000). The interconnected-porous structure is very important, so that numerous cells can be seeded,

Chitosan derivatives for tissue engineering applications

The practical use of chitosan has been mainly restricted to the unmodified forms in tissue engineering applications. Recently, there has been a growing interest in modification of chitosan to improve its solubility, introduce desired properties and widen the field of its potential applications by choosing various types of side chains. Although some of the properties have been altered by these modifications, it is possible to maintain biological properties such as biocompatibility,

Skin

The healing of a skin wound is complicated courses, including a wide range of cellular, molecular, physiological, and biological processes. Immediate coverage using wound dressing is a cornerstone of wound management. The wound repairs in cases of acute, chronic, more extensive wounds, or skin loss of the oldest would be inevitable unless some skin substitutes are used. The ultimate goal of skin tissue engineering is to rapidly produce a construct that offers the complete regeneration of

Conclusions

Tissue engineering as termed ‘Regenerative Medicine’ is regarded as an ultimately ideal medical treatment for diseases that have been too difficult to be cured by existing methods. This biomedical engineering is designed to repair injured body parts and restore their functions by using laboratory-grown tissues, materials and artificial implants. For regeneration of failed tissues, this biomedical engineering utilizes three fundamental tools: living cell, signal molecules, and scaffold. Chitosan

Acknowledgements

This review was supported by a grant (B-2005-10) from Marine Bioprocess Research Center of the Marine Bio 21 Center funded by the Ministry of Maritime Affairs & Fisheries, Republic of Korea. I. Y. Kim was supported by Brain Korea 21 program.

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