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A SAFE AND EFFECTIVE CROSS-LINKING

MACDERMOL products are made with stabilised hyaluronic acid produced in Europe, with the highest level of purity available in the industry today, and cross-linked through a proprietary process making it possible to use little or no chemical agent.

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Hyaluronic acid

Hyaluronic acid (HA), a linear polysaccharide naturally in the skin [1], has a full biocompatibility and remarkable properties for dermal filling and tissue augmentation [2, 3].

 

However, once injected in 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 [4]. Therefore, in order 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).

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 [5,6]. HA hydrogels, formed by cross-linking, have become important for many medical and esthetic applications.


Unfortunately, these cross-linking processes involve chemical agents such as 1,4-butanediol diglycidyl ether (BDDE), formaldehyde, divinyl sulfone, 1,2,7,8-diepoxyoctane etc. which have been shown to have toxic and mutagenic activities [7-10].

This use of cross-linking agents can impair the biocompatibility with risk in both short and long-term applications [11], especially regarding the incidence of granulomas after repeated injections and large injected volumes [12]. Moreover, this type of modification can affect the ease of injectablity of the HA hydrogel as well as the natural viscoelastic and biological properties of the HA molecule which will have a more rigid structure, a lower water-binding capacity, and a lower capacity on the production of extracellular matrix components [13].


Such adverse events and disadvantages are avoided with the use of a physical cross-linking instead of a chemical one [14,15].

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NOVATEX BIOENGINEERING, an Orgev Laboratories 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 [16] 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 [17].


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 [18,19].

X-Click technology

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Fig. 1. Hydrogen bonding between –COOH groups in HA cross-linked
            by X-Click Technology

Double cross-linking

NOVATEX BIOENGINEERING can combine this technology in addition with the classic cross-linking method using BDDE for some of its products in order to also create ether bonds (ester or amide bonds). This will improve even more the molecular resistance to degradation and thus will increase the residence time of the gel in the tissue.


 

Compared to the classic cross-linking, using only chemical cross-linking, it requires much less chemical agents to reach the same effectiveness in terms of residence time.


The degree of cross-linking is also selected to provide a desirable level of durability in the tissue according to the indication of the product.

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Fig. 2. Double cross-linking with a physical cross-linking through hydrogen                  bonds and a chemical cross-linking through ether bonds.

CLASSICAL METHOD
Chemical cross-linking with BDDE

X-CLICK TECHNOLOGY

Physical cross-linking without chemical agent

LOSS OF THE NATURAL VISCOELASTIC AND BIOLOGICAL PROPERTIES OF THE HA

  • Rigid structure (low injectability, does not follow the facial movements)

  • No stimulation of collagen and HA synthesis

 

RISK OF GRANULOMAS

PRESERVATION OF THE NATURAL VISCOELASTIC AND BIOLOGICAL PROPERTIES OF THE HA

  • Dynamic structure (ease of injectability, natural-looking result)

  • Stimulation of collagen and HA synthesis

 

NO RISK OF GRANULOMAS

VS

References

1. T.C. Laurent, J.R.E. Fraser. Hyaluronan. FASEB Journal, 6 (7) (1992), pp.2397–2404

2. C.E. Schanté, G. Zuber, C. Herlin, T.F. Vandamme. Chemical modifications of hyaluronic acid for the synthesis of derivatives for a broad range of biomedical applications. Carbohydrate Polymers, 85 (3) (2011), pp. 469–489

3. N. Volpi, J. Schiller, R. Stern, L. Šoltes. Role, metabolism, chemical modifications and applications of hyaluronan. Current Medicinal Chemistry, 16 (14) (2009), pp. 1718– 1745

4. Hyaluronan catabolism: a new metabolic pathway. Stern R Eur J Cell Biol. 2004 Aug; 83(7):317-25.

5. B. Ågerup, P. Berg, C. Åkermark. Non-animal stabilized hyaluronic acid: a new formulation for the treatment of osteoarthritis. BioDrugs, 19 (1) (2005), pp. 23–30

6. K. Edsman, R. Hjelm, H. Lärkner, L.I. Nord, A. Karlsson, Å. Wiebensjö, et al. rabbit knee. Cartilage, 2 (4) (2011), pp. 384–388

7. 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.

8. 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.

9. Cancer risk assessment P020023 www.fda.gov

10. 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.

11. W.E. Hennink, C.F. van Nostrum, Adv. Drug. Deliver. Rev. 54 (2002) 13–36.

12. Jeong Min Lee and  Yu Jin Kim. Foreign Body Granulomas after the Use of Dermal Fillers: Pathophysiology, Clinical Appearance, Histologic Features, and Treatment. Arch Plast
Surg. 2015 Mar; 42(2): 232–239.

13. A. Tezel, G.H. Fredrickson. The science of hyaluronic acid dermal fillers. Journal of Cosmetic and Laser Therapy, 10 (1) (2008), pp. 35–42

14. A. Clark, S. Ross-Murphy, Structural and mechanical properties of biopolymer gels, in: Biopolymers, Springer, Berlin-Heidelberg, 1987, pp. 57–192.

15. C. Chang, L. Zhang, Carbohydr. Polym. 84 (2011) 40–53.

16. 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.

17. T. Coviello, P. Matricardi, C. Marianecci, F. Alhaique, J. Control. Release. 119 (2007) 5–24.

18. S. Van Vlierberghe, P. Dubruel, E. Schacht, Biomacromolecules 12 (2011) 1387–1408.

19. Internal data. X-Click-technology technical file. Novatex Bioengineering

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