Our technology
A safe and effective cross-linking
Arthromac® products are made with a hyaluronic acid produced in France, with the highest level of purity available in the industry today, and cross-linked through a proprietary process using no chemical agent called X-Click Technology.
About
HYALURONIC ACID
Hyaluronic acid (HA), a linear polysaccharide that occurs naturally in the synovial fluid and cartilage, is fully biocompatible and has remarkable properties for the treatment of osteoarthritis.
However, once injected into the tissues, a natural and unmodified molecule of HA will be rapidly degraded and absorbed.
This depolymerization which transforms long HA chains (polysaccharides) into smaller HA units (oligosaccharides) is due to enzymes (hyaluronidases), free radicals, heat and mechanical stresses. Therefore, to increase the residence time of HA and its beneficial action in the tissues, it is crucial to protect it against these enzymatic, oxidative, thermal and mechanical degradations by a process of cross-linking (reticulation).
About
CHEMICAL CROSS-LINKING
To improve the duration of HA in vivo, a common method is to form a hydrogel by covalently cross-linking the HA polymer chains into a three-dimensional network. Unfortunately, this cross-linking process involving chemical agents (such as such as 1,4-butanediol diglycidyl ether (BDDE), formaldehyde, divinyl sulfone etc.) impairs the biocompatibility, the ease of injectablity, as well as the natural viscoelastic and biological properties of the HA molecule. The later will have an impaired biocompatibility with a greater risk of hypersensitivity reactions [1-5], a more rigid structure, a lower water-binding capacity, and a lower capacity on the production of extracellular matrix components [6].
Such adverse events and disadvantages are avoided with the use of a physical cross-linking instead of a chemical one [1, 7, 8].
About our exclusive technology
PHYSICAL CROSS-LINKING
NOVATEX BIOENGINEERING, an Astagen Therapeutics division, through its collaboration with the CNRS (The French National Centre for Scientific Research), has developed a new cross-linking technology, called X-Click technology, making it possible to physically transform a linear HA into a stabilized three-dimensional HA network without any chemical agents.
This proprietary technology is based on the click chemistry [9] and used crystallization to create intermolecular and intramolecular hydrogen bonding (Fig 1).
This physical hydrogel is a good alternative because of the absence of organic solvents and toxic cross-linking agents [10-14].
As a result, the HA cross-linked with X-Click Technology is non-toxic, fully biocomptabible, easy to inject, with unaltered viscoelastic and biological properties [15,16].
Fig. 1. Hydrogen bonding between –COOH groups in HA cross-linked
by X-Click Technology
CLASSICAL METHOD
Chemical cross-linking
X-CLICK TECHNOLOGY
Physical cross-linking without chemical agent
LOSS OF THE NATURAL VISCOELASTIC AND BIOLOGICAL PROPERTIES OF THE HA
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Rigid structure (low injectability and elasticity)
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No stimulation of HA synthesis
HIGHER RATE OF ADVERSE EVENTS
PRESERVATION OF THE NATURAL VISCOELASTIC AND BIOLOGICAL PROPERTIES OF THE HA
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Dynamic structure (ease of injectability, good elasticity)
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Stimulation of HA synthesis
LOWER RATE OF ADVERSE EVENTS
VS
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Surg. 2015 Mar; 42(2): 232–239.
3. Fidalgo J, et al. Detection of a new reaction by-product in BDDE cross-linked autoclaved hyaluronic acid hydrogels by LC-MS analysis. Med Devices (Auckl) 2018;11:367–376. doi: 10.2147/MDER.S166999.
4. Keizers PHJ, et al. A high crosslinking grade of hyaluronic acid found in a dermal filler causing adverse effects. J Pharm Biomed Anal. 2018;159:173–178. doi: 10.1016/j.jpba.2018.06.066.
5. Yeom J, et al. Effect of cross-linking reagents for hyaluronic acid hydrogel dermal fillers on tissue augmentation and regeneration. Bioconjug Chem. 2010;21:240–247. doi: 10.1021/bc9002647.
6. A. Tezel, G.H. Fredrickson. The science of hyaluronic acid dermal fillers. Journal of Cosmetic and Laser Therapy, 10 (1) (2008), pp. 35–42
7. A. Clark, S. Ross-Murphy, Structural and mechanical properties of biopolymer gels, in: Biopolymers, Springer, Berlin-Heidelberg, 1987, pp. 57–192.
8. C. Chang, L. Zhang, Carbohydr. Polym. 84 (2011) 40–53.
9. H. C. Kolb, M. G. Finn and K. B. Sharpless (2001). «Click Chemistry: Diverse Chemical Function from a Few Good Reactions». Angewandte Chemie International Edition 40 (11): 2004–2021.
10. Chemical mutagenesis testing in Drosophila. IX. Results of 50 coded compounds tested for the National Toxicology Program. Foureman P, Mason JM, Valencia R, Zimmering S Environ Mol Mutagen. 1994; 23(1):51-63.
11. West JD, Stamm CE, Brown HA, Justice SL, Morano KA. Enhanced toxicity of the protein cross-linkers divinyl sulfone and diethyl acetylenedicarboxylate in comparison to related monofunctional electrophiles. Chem Res Toxicol. 2011 Sep 19;24(9):1457-9. doi: 10.1021/ tx200302w. Epub 2011 Aug 8.
12. Cancer risk assessment P020023 www.fda.gov
13. National Toxicology Program (June 2011). Report on Carcinogens, Twelfth Edition. Department of Health and Human Services, Public Health Service, National Toxicology Program. Retrieved June 10, 2011.
14. T. Coviello, P. Matricardi, C. Marianecci, F. Alhaique, J. Control. Release. 119 (2007) 5–24.
15. S. Van Vlierberghe, P. Dubruel, E. Schacht, Biomacromolecules 12 (2011) 1387–1408.
16. Internal data. X-Click-technology technical file. Novatex Bioengineering