TMCnet Feature
June 18, 2019

Science uses joined-up thinking to preserve the beauty molecule

For generations, beauty experts have been trying to halt the ageing process – or at least the signs of ageing – without much success.

But now science has come to the rescue in the form of an anionic, nonsulfated glycosaminoglycan called Hyaluronic Acid (HA), the “Beauty Molecule”.

HA – a complex compound based on a long-chain polysaccharide – was discovered in 1934 by researchers Karl Meyer and John Palmer (News - Alert) by dissecting cow eyes.

HA occurs naturally in connective tissues and body fluids, especially in the eyes and joints. However, while it is now used widely in medical and surgical treatments, and even in daily skincare regimens, its first recorded use was in 1942 as an egg-white substitute.

Today most HA is used to treat joint disorders, including osteoarthritis, and can be taken by mouth or even injected directly into affected areas as a moisture-binding ingredient to keep the area plump and hydrated. The FDA has approved its use in cataract removal, corneal transplantation, and the repair of detached retinas, where it is used to help replace natural fluids.

But because HA in cells can hold more than 1,000 times its weight in water, it is used widely in aesthetic surgery as a safe and stable filler replacing bovine collagen, and – topically – as an excellent moisturiser.

Studies show HA can improve hydration and the production of collagen, fight free radicals, maintain skin elasticity, and its antibacterial and anti-inflammatory properties can even help with wound healing.

On average, human bodies contain just 15 grams of HA, and a third is lost daily to the environment. Production also decreases with age.

Applied as an Hyaluronic Acid serum or cream, it produces effective results, because while the HA molecules are too large to penetrate the dermis layer, even on the surface its water-attracting properties draw in moisture and keep skin hydrated, supple and functioning effectively as a barrier.

But natural HA has a short half-life, so to increase durability and efficacy it is chemically modified using  a crosslinking process to create microsphere “pearls” or a jelly. Artificial crosslinks are augmented by “natural” crosslinks in the form of Van der Waals forces. The tighter the crosslinking, the higher the percentage of HA molecules, and the thicker the gel.

Most HA-based dermal fillers use 1,4-butanediol diglycidyl ether (BDDE) as a crosslinking agent. BDDE’s stability, biodegradability, and low toxicity put it well ahead of other agents such as divinyl sulfone. Crosslinking slows down degradation but also affects the rheological properties of HA gels, determining how it is used.

Crosslinking is a two-stage process. First, HA is dissolved in an alkaline medium to straighten out the polysaccharide chains. Then a crosslinking agent (e.g. BDDE) is added  under temperature control. Different techniques produce different crosslink densities and hardnesses.

HA gels are currently made via seven commercial processes, all used for aesthetic medicine (filling lines or creating volume).

  1. Non-Animal Stabilized Hyaluronic Acid (NASHA®)
    In this process, the addition of small quantities of BDDE creates just a few crosslinks, producing water-soluble polymer crosslinks via chemical or physical bonds. This “biphasic” gel consists of semi-solid crosslinked HA particles suspended in a liquid phase, which is dried and sieved to create solid “pearls” suspended in a vector such as phosphate-buffered saline or a non-crosslinked HA gel. The size and quantity of pearls varies but Restylane® has an average diameter of 250 μm (100,000 pearls/mL).
  2. 3D Matrix
    This is a variation of the Hylacross process where all crosslinked HA molecules have uniform molecular weights. Surgiderm® products use 3D Matrix and contain more high molecular weight HA than lower. The HA is mixed in a one-step crosslinking process which binds more BDDE to the ends of the polysaccharide chains.
  3. Vycross®
    This employs the reverse ratio to 3D Matrix, favoring more low molecular weight molecules, and therefore lower HA concentration.
  4. Optimal Balance Technology (OBT®)
    OBT is used to produce Emervel® HA gels. Unlike Restylane it has a range of crosslinks and gel calibration ratios. Differences in thickness are obtained by varying gel calibration, while firmness varies with the amount of crosslinking.
  5. Cohesive Polydensified Matrix (CPM®)
    The process behind Belotero® uses dynamic double crosslinking, adding extra HA and further crosslinking to produce a monophasic polydensified gel combining high and low levels of crosslinks in a cohesive matrix.
  6. Resilient Hyaluronic Acid (RHA®)
    This produces Teosyal® gels, with long HA chains stabilized by natural and chemical crosslinks. Only a small amount of BDDE is used, which results in variations in the amount of crosslinking and HA concentration.
  7. Interpenetrating Network-Like (IPN-Like®)
    Stylage® gels have several individual crosslinked matrices, resulting in an interpenetrating network-like (IPN-like®) structure to achieve a monophasic gel with higher density crosslinks.

Tests reveal differences in behavior between available HA gels. Cohesivity – how well gels hold together in water –  indicates a filler’s ability to resist deformation and maintain integrity and, along with a gel’s elastic modulus (G prime), it is an important factor in lift capability.

Cohesivity is measured by the pressure required to compress it between two plates. High cohesivity gels such as CPM stay as long continuous strands when mixed.

Cohesivity can also be measured by testing resistance to stretch. CPM demonstrates best resistance to stretching (3.5 cm-5 cm) while other gels barely make 2cm.

Tests reveal how different gels integrate with collagen and elastin fibers in the skin, and . post-injection biopsies show predictable histologic behavior based on crosslinking.

CPM’s ability to distribute homogeneously across and around the targeted area is due to its variable crosslinking density, with areas of higher (harder) concentration interspersed with lower (softer) concentration, creating a gel that retains integrity on injection with high resistance to deformation, for example in facial areas with lots of movement. CPM’s low viscosity also makes it easy to inject using smaller diameter, less invasive needles.

Conversely, Vycross’s mix of long- and short-chain HA crosslinks is biased towards low molecular weight. The resulting high G prime and medium cohesivity, makes it suitable for volumizing and subcutaneous or supraperiosteal injection.

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