Biomaterial of the Month
Date: June 1, 2009
Figure 1: Chemical structure of N-acetyl-glucosamine repeat units for chitin (A) and N-acetyl-glucosamine and N-glucosamine repeat units for chitosan (B)
Figure 2: SEM photomicrograph of extensive extracellular matrix produced by bone cells on chitosan-nano-calcium phosphate composite scaffolds.
The Biomaterial of the Month is chitosan, a derivative of the natural polysaccharide chitin. Chitosan is a copolymer of N-acetyl-glucosamine and N-glucosamine units and has been widely researched for a variety of biomedical applications such as such as wound healing, drug delivery systems, ophthalmology, implant coatings and tissue engineering/regeneration due to its demonstrated biocompatibility, bio-degradability, nontoxic, nonacidic degradation products, ease of chemical and physical manipulation and ability to promote healing. It is currently used clinically as a hemostatic dressing, HemCon® (HemCon Medical Technology Inc., OR). Here, chitosan microspheres approximately 800-900 microns in diameter can be formed into a variety of complex shapes to fill gaps in bone lost due to disease, injury or birth defects. The chitosan microsphere based scaffolds exhibit approximately 30-40% completely interconnected porosity with pores sizes in the 100-500 micron range which is appropriate for blood vessel and bone tissue ingrowth. The chitosan-based microsphere based scaffolds support bone cell growth and matrix production in vitro and osteoconduction in vivo.
Chitosan is a derivative of the natural polysaccharide, chitin. Chitin is second to cellulose as the most abundant biopolymer in the biosphere. Chitin is the basic high modulus fibrous component of the exoskeleton of arthropods including crab, shrimp and lobsters, as well as some fungi. It is a linear highly crystalline polymer, nominally composed of isotactic poly-N-acetyl-D- glucosamines linked in β (1-4) glycosidic bonds (Figure 1A). Generally, chitin is obtained from arthropods by crushing and washing shells, removing calcium minerals with acid and then removing proteinaceous material with alkali. Additional treatment with NaOH removes acetyl side groups [–C(=0)-CH3] and yields a copolymer of N-acetyl-glucosamine and N-glucosamine units (Figure 2B). When more than 50% of the acetyl groups are removed, the polymer is called chitosan. The ratio of glucosamine to N-acetyl glucosamine is referred to as the degree of de-acetylation, DDA and typically ranges from 50-100%. The DDA affects many physical and chemical properties of the polymer. For example, chitosan is soluble in dilute acids at pH < 6 due to protonation of amino groups, making it highly versatile and flexible for chemical and physical modification, whereas chitin is generally insoluble in aqueous solutions making processing difficult. In general, polymer crystallinity, resistance to degradation, tensile strengths and wettability also increase with DDA. Because of its solubility in aqueous/dilute acid solutions, chitosan is easily processed in to a variety of forms such as films, gels, fibers, tubes, beads and porous structures.
Chitosan has been widely researched for biomedical applications such as wound healing, drug delivery systems, and tissue engineering due to its demonstrated biocompatibility, bio-degradability, nontoxic, nonacidic degradation products, and ability to promote healing. It is currently used clinically as a hemostatic dressing, HemCon®. In particular for bone applications, chitosan has also been shown to be osteoconductive. Using a microsphere approach that provides a 3D negative template for bone formation1, chitosan microspheres approximately 800-900 microns in diameter can be formed into a variety of shapes to fill complex gaps in bone lost due to disease, injury or birth defects2-4. The chitosan microsphere based scaffolds exhibit approximately 35-40% completely interconnected porosity with pores sizes in the 100-500 micron range which is appropriate for blood vessel and bone tissue ingrowth 2-4. Scaffolds support bone cell growth and matrix production in vitro (Figure 2) and were osteoconductive in vivo2,6. The microspheres may be combined with other polymers and or calcium phosphate mineral to enhance mechanical strength as well as promote cell attachment and growth2-6. The chitosan microspheres may also be loaded with bioactive and or therapeutic agents and used a dual scaffold/local drug delivery construct3. Chitosan is a highly versatile and promising material and with many potential biomedical applications. Suggested resources are listed below.
- Borden M, Attawia M, Khan Y, Laurencin CT. Tissue engineered microsphere-based matrices for bone repair: design and evaluation. Biomaterials. 2002, 23:551-9
- Chesnutt BM, Viano AM, Yuan Y, Yang Y, Guda T, Appleford MR, Ong JL, Haggard WO, Bumgardner JD. Design and characterization of a novel chitosan/nanocrystalline calcium phosphate composite scaffold for bone regeneration. J Biomed Mater Res A. 2009, 88:491-502
- Reves BT, Bumgardner JD, Cole JA, Yang Y, Haggard WO. Lyophilization to improve drug delivery for chitosan-calcium phosphate bone scaffold construct: A preliminary investigation. J Biomed Mater Res B Appl Biomater. 2009 May 13. [Epub ahead of print].
- Malafaya PB, Santos TC, van Griensven M, Reis RL. Morphology, mechanical characterization and in vivo neo-vascularization of chitosan particle aggregated scaffolds architectures. Biomaterials. 2008, 29:3914-26.
- Jiang T, Abdel-Fattah WI, Laurencin CT. In vitro evaluation of chitosan/poly(lactic acid-glycolic acid) sintered microsphere scaffolds for bone tissue engineering. Biomaterials. 2006, 27:4894-903.
- Chesnutt BM, Yuan Y, Buddington K, Haggard WO, Bumgardner JD. Composite Chitosan/Nano-Hydroxyapatite Scaffolds Induce Osteocalcin Production by Osteoblasts In Vitro and Support Bone Formation In Vivo. Tissue Eng Part A. 2009 Mar 20. [Epub ahead of print].
- Khor, E. Chitin: Fulfilling a Biomaterials Promise. Elsevier Science, 2001.
- Muzzarelli RA, Mattioli-Belmonte M, Pugnaloni A, Biagini G. Biochemistry, histology and clinical uses of chitins and chitosans in wound healing. EXS. 1999;87:251-64.
- Alves NM, Mano JF. Chitosan derivatives obtained by chemical modifications for biomedical and environmental applications. Int J Biol Macromol. 2008, 43:401-14.
- Prabaharan M. Review paper: chitosan derivatives as promising materials for controlled drug delivery. J Biomater Appl. 2008 Jul;23(1):5-36.
- Jiang T, Kumbar SG, Nair LS, Laurencin CT. Biologically active chitosan systems for tissue engineering and regenerative medicine. Curr Top Med Chem. 2008;8:354-64.
- Kim IY, Seo SJ, Moon HS, Yoo MK, Park IY, Kim BC, Cho CS. Chitosan and its derivatives for tissue engineering applications. Biotechnol Adv. 2008;26:1-21.
- Shi C, Zhu Y, Ran X, Wang M, Su Y, Cheng T. Therapeutic potential of chitosan and its derivatives in regenerative medicine. J Surg Res. 2006;133:185-92.