Ideal specifications for crosslinkers: when viscoelastic properties meet clinical needs

Injectable dermal fillers, in their opportunity of long-term, natural outcomes rejuvenation, have become increasingly popular. From skin boosters to volumizers, manufacturers now offer beautification through minimally invasive aesthetic procedures¹ . 
In the early years of fillers, safety issues have been raised, following justified concerns that formulations included permanent silicone and were responsible for side effects such as inflammatory response and overcorrection. Research has therefore been conducted to develop low-risks soft-tissue fillers² . Recently, hyaluronic acid-based gels became the gold standard, proving biocompatibility, safety records, low toxicity, and ability to target various aesthetic indications³ .

The very nature of hyaluronic acid is what makes it suitable for its use in dermal fillers, for what it brings in terms of hydration. Despite those unique biological properties, native hyaluronic acid (HA) is also known for its very short half-life in skin, which is about 2 to 4 days^4,5. The endogenous hyaluronidase enzyme in the human body degrades hyaluronic acid by clipping glycosidic bonds⁶ . Aiming at manufacturing HA gels with prolonged half-life and improved viscoelastic properties, chemical modifications and crosslinking⁷  was the way to achieve these specifications. The goal was to produce fillers that preserved the biocompatibility of native hyaluronic acid while enhancing mechanical and chemical properties. Crosslinkers consists of small molecules creating bonds bridges between HA chains, a commonly approach to improve HA with clinically relevant properties.

In its commitment to scientific excellence, Teoxane provided a review of ideal crosslinker’s specifications.

With their crucial role of linking HA chains together, crosslinkers must therefore meet a list of requirements. Rising elastic properties, long-lasting, stable, and safe over time are among them. 
From a chemistry perspective, HA being very sensitive to temperature or pH⁶, the crosslinking reaction must occur fast and in a soft, aqueous medium to restrict HA degradation and achieve efficient crosslinking. 

A second necessity is an aqueous solubility. As dermal fillers’ purpose is to be injected, the manufacturing process and the crosslinking reaction must be thought to steer clear of any trace of organic solvent remaining in the injected gel. As a third requirement, the linkage must remain stable over a range of storage temperatures. Thus, crosslinkers must ensure exemplary stability over years of the gel’s shelf-life.  Finally, crosslinker’s quantity used during the manufacturing process will be responsible for the viscoelastic properties of the dermal filler. 
Regarding toxicity, the finished fillers must be devoid of crosslinkers residues. Under reaction conditions, attached crosslinkers must be converted into safe and inert products to avoid being a source a cell toxicity.  
Safety wise, the crosslinking must not put a stop to a rapid enzymatic degradation in case of adverse event, like the management of vascular occlusion, by using a proper amount of the HA specific degradation enzyme, called hyaluronidase⁸ .

Today, only a few crosslinkers meet these specifications for the design of dermal fillers. Among them is 1,4-butanediol diglycidylether, also commonly called BDDE, the first ever crosslinker to be used in a commercially available HA-based filler. It is now recognized as the gold standard crosslinker worldwide due to its proven and unrivaled clinical track record of more than 20 years. 
New viscoelastic properties, milder crosslinking conditions to preserve HA chains, new biomechanical features are among the novel opportunities in the design of future dermal fillers. However, this innovation require extensive stability, biocompatibility and clinical studies lasting several years to meet the highest standards which are already proven with BDDE.

You can read the full article by clicking here : https://pubmed.ncbi.nlm.nih.gov/34882503