Effect of Different Crosslinking Technologies on Hyaluronic Acid Behavior: A Visual and Microscopic Study of Seven Hyaluronic Acid Gels

May 2016 | Volume 15 | Issue 5 | Original Article | 600 | Copyright © May 2016

Patrick Micheels MD,a Didier Sarazin MD,b Christian Tran MD,c and Denis Salomon MDd

aPrivate Practice, Geneva, Switzerland
bLaboratoire Viollier, Geneva, Switzerland
cDepartment of Dermatology, HCU, Geneva, Switzerland
dCIDGE International Dermatology Clinic, Geneva, Switzerland

BACKGROUND: The mechanical, rheological, and pharmacological properties of hyaluronic acid (HA) gels differ by their proprietary crosslinking technologies.
OBJECTIVE: To examine the different properties of a range of HA gels using simple and easily reproducible laboratory tests to better understand their suitability for particular indications.
METHODS AND MATERIALS: Hyaluronic acid gels produced by one of 7 different crosslinking technologies were subjected to tests for cohesivity, resistance to stretch, and microscopic examination. These 7 gels were: non-animal stabilized HA (NASHA® [Restylane®]), 3D Matrix (Surgiderm® 24 XP), cohesive polydensified matrix (CPM® [Belotero® Balance]), interpenetrating network-like (IPN-like [Stylage® M]), Vycross® (Juvéderm Volbella®), optimal balance technology (OBT® [Emervel Classic]), and resilient HA (RHA® [Teosyal Global Action]).
RESULTS: Cohesivity varied for the 7 gels, with NASHA being the least cohesive and CPM the most cohesive. The remaining gels could be described as partially cohesive. The resistance to stretch test confirmed the cohesivity findings, with CPM having the greatest resistance. Light microscopy of the 7 gels revealed HA particles of varying size and distribution. CPM was the only gel to have no particles visible at a microscopic level.
CONCLUSION: Hyaluronic acid gels are produced with a range of different crosslinking technologies. Simple laboratory tests show how these can influence a gel’s behavior, and can help physicians select the optimal product for a specific treatment indication.

Versions of this paper have been previously published in French and in Dutch in the Belgian journal Dermatologie Actualité. Micheels P, Sarazin D, Tran C, Salomon D. Un gel d’acide hyaluronique est-il semblable à son concurrent? Derm-Actu. 2015;14:38-43.

J Drugs Dermatol. 2016;15(5):600-606.


Since their introduction in Europe in 1996, crosslinked hyaluronic acid (HA) gels have progressively replaced bovine collagen as the preferred treatment for filling lines and folds,1 and account for the vast majority of non-invasive aesthetic procedures used in daily practice.
In its native form, the chemical structure of HA is identical across different species. This feature, along with its unique viscoelastic and physicochemical properties, has led to the development of numerous HA-based medical devices. However, due to the short half-life of endogenous HA, chemical modifications are required to obtain long-lasting gels.2 This is achieved by a crosslinking process, which changes the 3-dimensional structure of the HA chains and results in the formation of either HA microspheres “pearls” or a jelly. While the risk of immunogenicity to HA-derived products is generally low, the altered structure of the 3-dimensional HA gels may result in them being recognized as foreign by the dermis.3,4
The raw material in the production of HA gels for aesthetic use consists of pharmacological grade HA chains or HA powder of the same purity, but with different molecular weights, which may vary from 600 kDa to more than 2,500 kDa. The final products differ in terms of their HA concentration and method of crosslinking. Crosslinking methods may be either chemical or physical, but in the field of aesthetic medicine the crosslinking agent that is used to stabilize the majority of HA-based dermal fillers currently on the market is 1,4-butanediol diglycidyl ether (BDDE). The stability, biodegradability, and toxicity profile of BDDE put it ahead of other crosslinking agents such as divinyl sulfone.5 It should be noted that “natural” crosslinks in the form of Van der Waals forces are also found in all HA preparations developed for aesthetic use.
The basic crosslinking process takes place in 2 steps and is the same for many currently used HA products that use BDDE as the crosslinking agent: (1) dissolution in an alkaline medium and