Biological Safety Evaluation of KiOmedine® CM-chitosan, an Innovative Non-animal Carboxymethyl-Chitosan Biomaterial Intended for Injectable Biomedical Applications
Journal of Biomaterials
Volume 4, Issue 2, December 2020, Pages: 39-50
Received: Sep. 7, 2020; Accepted: Sep. 19, 2020; Published: Sep. 25, 2020
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Authors
Pierre Douette, Kiomed Pharma, Herstal, Belgium
Mickael Chausson, Kiomed Pharma, Herstal, Belgium
Emilie Theatre, Kiomed Pharma, Herstal, Belgium
Catherine Philippart, Kiomed Pharma, Herstal, Belgium
Sandrine Gautier, Kiomed Pharma, Herstal, Belgium
Jacques Bentin, Department of rheumatology, Centre Hospitalier Universitaire Brugmann, Brussels, Belgium
Laurence Hermitte, Kiomed Pharma, Herstal, Belgium
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Abstract
When designing innovative biomaterials, biocompatibility is regarded as a prerequisite for safe clinical use in humans. In this study, the biological safety of KiOmedine® CM-chitosan, which is a non-animal carboxymethyl chitosan biomaterial, was evaluated using a large panel of both in vitro and in vivo biocompatibility tests in accordance with the ISO 10993 series. KiOmedine® CM-chitosan was non-cytotoxic and non-genotoxic in vitro. The biomaterial was neither found to be haemolytic nor was it able to potentiate the activation of the central complement component C5a or the inflammatory mediators IL-1β and IL-8 in the presence of human whole blood. Furthermore, no evidence of any significant irritation, sensitization, pyrogenicity, and organ toxicity was detected in specific animal studies conducted with KiOmedine® CM-chitosan, and only minimal local tissue effects were observed after the intra-articular or intra-dermal injection of KiOmedine® CM-chitosan in the rabbit model. KiOmedine® CM-chitosan had minimal potential to induce immunotoxic reactions in the mouse air pouch model. Its biodegradation process was appropriately characterized at the histological level. In summary, our study represents an unprecedented body of work supporting the biological safety evaluation of KiOmedine® CM-chitosan, allowing its use in injectable medical devices.
Keywords
Carboxymethyl Chitosan Biomaterial, Biocompatibility, Toxicology
To cite this article
Pierre Douette, Mickael Chausson, Emilie Theatre, Catherine Philippart, Sandrine Gautier, Jacques Bentin, Laurence Hermitte, Biological Safety Evaluation of KiOmedine® CM-chitosan, an Innovative Non-animal Carboxymethyl-Chitosan Biomaterial Intended for Injectable Biomedical Applications, Journal of Biomaterials. Vol. 4, No. 2, 2020, pp. 39-50. doi: 10.11648/j.jb.20200402.12
Copyright
Copyright © 2020 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
References
[1]
Rodríguez-Vázquez M, Vega-Ruiz B, Ramos-Zúñiga R, Saldaña-Koppel DA, Quiñones-Olvera LF. Chitosan and Its Potential Use as a Scaffold for Tissue Engineering in Regenerative Medicine. Biomed Res Int. 2015; 2015: 821279.
[2]
Cheung RC, Ng TB, Wong JH, Chan WY. Chitosan: An Update on Potential Biomedical and Pharmaceutical Applications. Mar Drugs. 2015 Aug 14; 13 (8): 5156-86.
[3]
Kumar, MNV. A Review of Chitin and Chitosan Applications. Reactive and Functional Polymers, 2000, 46, 1-27.
[4]
Kumirska J, Czerwicka M, Kaczyński Z, Bychowska A, Brzozowski K, Thöming J, Stepnowski P. Application of spectroscopic methods for structural analysis of chitin and chitosan. Mar Drugs. 2010 Apr 29; 8 (5): 1567-636.
[5]
Trujillo. Preparation of carboxymethylchitin. Carbohydr. Res. 7 (1968) 483-485.
[6]
Jimtaisong A, Saewan N. Utilization of carboxymethyl chitosan in cosmetics. Int J Cosm Sci, 2014, (36): 12–21.
[7]
Chen X-G, Park H-J. Chemical characteristics of O-carboxymethyl chitosans related to the preparation conditions. Carbohydr Polymers. 2003, 53: 355-359.
[8]
de Abreu FR, Campana-Filho SP. Preparation and characterization of carboxymethylchitosan. Polimeros. 2005, 15 (2): 79-83.
[9]
de Abreu FR, Campana-Filho, S. P. Characteristics and properties of carboxymethylchitosan. Carbohydr Polymers. 2009, 75: 214-221.
[10]
Bukzem AL, Signini R, Dos Santos DM, Lião LM, Ascheri DP. Optimization of carboxymethyl chitosan synthesis using response surface methodology and desirability function. Int J Biol Macromol. 2016 Apr; 85: 615-24.
[11]
Bellich B, D'Agostino I, Semeraro S, Gamini A, Cesàro A. The Good, the Bad and the Ugly of Chitosans. Mar Drugs. 2016 May 17; 14 (5): 99.
[12]
Ravindranathan S, Koppolu BP, Smith SG, Zaharoff DA. Effect of Chitosan Properties on Immunoreactivity. Mar Drugs. 2016 May 11; 14 (5).
[13]
Yu MM, Jiang TF, Wang YH, Wang DY, Li ZH. Identification and analysis of an impurity inducing clinical adverse effect in anti-adhesion carboxymethyl chitosan products. J Pharm Biomed Anal. 2013 Nov; 85: 21-7.
[14]
Chausson M, Douette P, Gautier S, Vaesen P, Choumane H, Rocasalbas G. Carboxyalkyl chitosan. PCT/EP2018/080767.
[15]
Laverty S, Girard CA, Williams JM, Hunziker EB, Pritzker KP. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rabbit. Osteoarthritis Cartilage. 2010 Oct; 18 Suppl 3: S53-65.
[16]
Gabriel MF, González-Delgado P, Postigo I, Fernández J, Soriano V, Cueva B, Martínez J. From respiratory sensitization to food allergy: Anaphylactic reaction after ingestion of mushrooms (Agaricus bisporus). Med Mycol Case Rep. 2015 Feb 24; 8: 14-6.
[17]
Ho MHK, Hill DJ. White button mushroom food hypersensitivity in a child. J. Paed. Child Health (2006) Volume 42, Issue 9, 555-556.
[18]
Baldrick P. The safety of chitosan as a pharmaceutical excipient. ReG. Toxicol. Pharmacol. 2010, 56: 290-299.
[19]
Dong W, et al. Pharmacokinetics and biodegradation mechanisms of a versatile carboxymethyl derivative of chitosan in rats: in vivo and in vitro evaluation. Biomacromolecules. 2010 Jun 14; 11 (6): 1527-33.
[20]
Dong W, et al. Effects of molecular weights on the absorption, distribution and urinary excretion of intraperitoneally administrated carboxymethyl chitosan in rats. J Mater Sci Mater Med. 2012 Dec; 23 (12): 2945-52.
[21]
Onishi H, Machida Y. Biodegradation and distribution of water-soluble chitosan in mice. Biomaterials 1999 (20): 175-182.
[22]
Necas J, Bartosikova L., Brauner P, Kolar J. Hyaluronic acid (hyaluronan): a review. Veterinarni Medicina, 53, 2008 (8): 397-411.
[23]
Chen AL, Desai P, Adler EM, Di Cesare PE. Granulomatous inflammation after Hylan G-F 20 viscosupplementation of the knee: a report of six cases. J Bone Joint Surg Am. 2002 Jul; 84-A (7): 1142-7.
[24]
Sasaki M, Miyazaki Y, Takahashi T. Hylan G-F 20 induces delayed foreign body inflammation in Guinea pigs and rabbits. Toxicol Pathol. 2003 May-Jun; 31 (3): 321-5.
[25]
Hamburger M, Settles M, Teutsch J. Identification of an immunogenic candidate for the elicitation of severe acute inflammatory reactions (SAIRs) to hylan G-F 20. Osteoarthritis Cartilage. 2005 Mar; 13 (3): 266-8.
[26]
Ishikawa M, Yoshioka K, Urano K, Tanaka Y, Hatanaka T, Nii A. Biocompatibility of cross-linked hyaluronate (Gel-200) for the treatment of knee osteoarthritis. Osteoarthritis Cartilage. 2014 Nov; 22 (11): 1902-9.
[27]
Dragomir CL, Scott JL, Perino G, Adler R, Fealy S, Goldring MB. Acute inflammation with induction of anaphylatoxin C5a and terminal complement complex C5b-9 associated with multiple intra-articular injections of hylan G-F 20: a case report. Osteoarthritis Cartilage. 2012 Jul; 20 (7): 791-5.
[28]
Lee JM, Kim YJ. Foreign body granulomas after the use of dermal fillers: pathophysiology, clinical appearance, histologic features, and treatment. Arch Plast Surg. 2015 Mar; 42 (2): 232-9.
[29]
Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-Klein M, Zimmermann U, Duffy DM. Foreign body granulomas after all injectable dermal fillers: part 1. Possible causes. Plast Reconstr Surg. 2009 Jun; 123 (6): 1842-63.
[30]
Nishimura K, Nishimura S, Nishi N, Saiki I, Tokura S, Azuma I. Immunological activity of chitin and its derivatives. Vaccine. 1984 Mar; 2 (1): 93-9.
[31]
Nishimura S, Ikeuchi Y, Tokura S. The adsorption of bovine blood proteins onto the surface of O-(carboxymethyl) chitin. Carbohydr Res. 1984 Dec 1; 134 (2): 305-12.
[32]
Tokura S, Tamura H, Azuma I. Immunological aspects of chitin and chitin derivatives administered to animals. EXS. 1999; 87: 279-92.
[33]
Edwards JC, Sedgwick AD, Willoughby DA. The formation of a structure with the features of synovial lining by subcutaneous injection of air: an in vivo tissue culture system. J Pathol. 1981; 134: 147–56.
[34]
Sedgwick AD, Sin YM, Edwards JC, Willoughby DA. Increased inflammatory reactivity in newly formed lining tissue. J Pathol. 1983; 141: 483–95.
[35]
Barbosa JN, Amaral IF, Aguas AP, Barbosa MA. Evaluation of the effect of the degree of acetylation on the inflammatory response to 3D porous chitosan scaffolds. J Biomed Mater Res A. 2010 Apr; 93 (1): 20-8.
[36]
Vasconcelos DP, Costa M, Amaral IF, Barbosa MA, Águas AP, Barbosa JN Modulation of the inflammatory response to chitosan through M2 macrophage polarization using pro-resolution mediators. Biomaterials. 2015 Jan; 37: 116-23.
[37]
Wooley PH, Song Z, Harrison A. Hyaluronic acid viscosupplements from avian and non-mammalian sources exhibit biocompatibility profiles with unique, source-specific, antigenic profiles. J Biomed Mater Res B Appl Biomater. 2012 Apr; 100 (3): 808-16.
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