Dr Kam Lally provides an overview of the development of dermal filler in aesthetic medicine
Dermal filler is a term that we as aesthetic practitioners are immediately comfortable with as mainstays of our practices. In recent years, the public has become increasingly familiar with it too, as it has taken off among celebrities and on social media. But what led to the treatment’s formation and how do today’s products differ to their forebears?
Looking at the ‘origin story’ of dermal fillers takes us back to the vehicle that allowed such treatments to take place – the syringe. This implement was first invented in 1853 by two separate doctors for different indications.1 Scottish physician Alexander Wood used it to administer morphine in small doses to treat neuralgia, whilst French surgeon Charles Pravaz used it for intra-arterial injections when treating aneurysms.1
The first reported ‘cosmetic’ use of a foreign substance injected into the body was in Vienna in 1899, when Austrian plastic surgeon Robert Gersuny used liquid paraffin as a testicular prosthesis in a patient who required castration due to tuberculous epididymitis.2
Over the next few years, multiple substances of a similar consistency began to be used as filler to volumise and restructure – namely vegetable oil, mineral oil, lanolin and bees wax.1 This is until the complications started stacking up. These products, despite being relatively inert, often migrated and triggered chronic inflammation, leading to granulomas and scarring.1
At the turn of the 20th century, autologous fat was also beginning to be used for facial augmentation. German surgeon Gustav Neuber described the injection of fat taken from the upper arms to help treat facial defects.3 Autologous fat is still used today and can be taken from fleshy areas like the stomach and thighs, but the longevity and predictability of long-term results, caused by the high variability in graft volume retention, is as variable as it always has been.4 This unpredictability is attributed to the various techniques used for the procuring, processing and placement stages of fat-grafting.4
The next iteration of fillers came a few decades later with liquid silicone, following disfiguring reactions to previously used foreign-body fillers. Silicone had been used in the 1940s for breast augmentation in Japan before becoming popular in the 1960s in the US (especially with Las Vegas showgirls).5 Silicone is similar to paraffin and unfortunately had similar consequences, triggering chronic and disfiguring inflammatory immune reactions.6
In 1981, the US Food and Drug Administration (FDA) formally approved bovine collagen under the trade name Zyderm (Allergan Inc) as the first filler of its kind approved for cosmetic use. This was followed four years later by Zyderm II (using different concentrations of collagen sub-types leading to a more viscous gel) and Zyplast (cross-linked bovine collagen to increase longevity). An allergy test against bovine collagen was required prior to any facial injections with these products.7
Due to concerns raised about the allergenicity of bovine collagen, work began on autologous human collagen in the 1990s, leading to the creation of Autologen (Autogenesis Technologies). This was a relatively expensive product to manufacture due to the necessary harvesting and purification of the autologous human collagen (via a surgical procedure), not to mention the difficulty in administering uniform concentrations of collagen. In addition to this, there was no lidocaine added, so injection of the product was often painful. Trying to address the logistical issues with Autologen led to the idea of using cadaveric donor tissue (from approved tissue banks) from which the human collagen matrix was harvested. This led to the creation of Dermalogen (Collagenesis Inc).8,9
The next real evolution came with the advent of hyaluronic acid (HA) based fillers, as society pushed for increased filler longevity without the need for a skin test. It was soon recognised that HA was a safer and more effective base ingredient for dermal filler.10 Two different methodologies were used to obtain the HA: one was from rooster combs (Hylaform by INAMED Corp), and the other was bacterial fermentation (Restylane by Medicis Aesthetics Inc). Both worked well, but the animal product had a shorter longevity so was soon superseded by the bacterial fermentation method.10 Following FDA approval of Restylane (Galderma) in 2003, the floodgates opened for HA dermal filler manufacture by companies worldwide.11
HA is composed of repeat disaccharide units of glucuronic acid and N-acetylglucosamine that form a glycosaminoglycan (GAG) polymer.12 It is naturally occurring, with 50% of the body’s HA found in the skin.12 It acts as a scaffold for the extra-cellular matrix, giving it structure and hydration while aiding cell movement and regeneration. It also helps protect against free radical damage from UV exposure. It is rapidly metabolised by endogenous hyaluronidase enzymes, with approximately one third of total body HA turned over daily.12
Due to this turnover rate, most HA dermal filler products are ‘cross-linked’ to increase their longevity and tweak their physical characteristics. The cross-linking reaction relies on a chemical called 1,4-butanedioldiglycidyl ether, commonly known as BDDE. This enables the formation of long HA chains suspended in a physiological solution.13 Various methods are used in the manufacture of HA filler products that have an impact on the degree of cross-linkage, HA concentration and particle size. These elements are key in determining the clinical performance of the filler, tissue integration, longevity and product rheology.
Rheological properties encompass terms such as elasticity, viscosity and cohesivity. These properties, when matched with patient anatomy, tissue quality and expectations, guide filler selection. The complex modulus (G*) is a measure offirmness/hardness, or the energy needed to deform a filler. Low G* fillers are preferable for superficial filling, whereas high G* fillers are better suited for deep volumisation. The elastic (or storage) modulus, commonly known as G prime (G′), is a traditionally touted parameter; it is similar to G* and represents the measure of a material’s ability to resist compression. The viscous modulus (also known as the loss modulus) G double prime (G′′) represents dissipated energy during product flow, caused by friction.14-16
Cohesivity is an increasingly important parameter when the filler is in-situ. It describes the adhesion between cross-linked HA molecules. Low cohesivity fillers spread easily after being injected, making them ideal for superficial and highly dynamic areas, whereas high cohesivity fillers maintain their structure and projection, making them better suited for deeper tissue volumisation and restructuring.15 Without getting entrenched in the physics of rheology, HA fillers are impacted by multiple physicochemical properties. The trend for modern, 21st century HA fillers is to take a ‘tissue-tailored’ approach whereby rheological parameters are engineered with the end-tissue in sight to give better integration and more natural results.
Another reason HA fillers are most commonly used is due to them being relatively easily reversible with the use of hyaluronidase in the case of emergencies or adverse cosmetic outcomes.
There is a category of products that we haven’t discussed yet, as they usually fall into the category of ‘biostimulators’. These stimulatory fillers are fundamentally constructed of different compounds. The first in this category to get FDA approval was Sculptra (Galderma) in 2004, which is made of poly-L-lactic acid (PLLA). This is a synthetic biodegradable compound that is eventually hydrolysed in carbon dioxide and water, stimulating fibroblasts to upregulate collagen production and deposition.17 Often, multiple treatments are required, but the effects can be seen up to 24 months after treatment.17
Radiesse – FDA approved for Merz Aesthetics in 2006 – is composed of calcium hydroxylapatite (CaHA) microspheres suspended in an aqueous gel. The concentration of CaHA is 30%, and it has a similar structure to the calcium complexes that form bone. The CaHA acts as a biostimulator and increases fibroblast activity, thus increasing collagen production. It has almost no immunogenicity and is enzymatically degraded within approximately 12 months.18 This also means that there is a much lower chance of injection-site reactions or adverse reactions to the product.18 Due to the nature of CaHA, there is very little product migration, but as with Sculptra, there is no ‘antidote’ to reverse or dissolve the filler if incorrectly placed or if intravascular injection occurs.18
These stimulatory fillers were both initially licensed for use in HIV patients with facial lipoatrophy.19,20 Sculptra is placed into the deep (reticular) dermis or the subcutaneous fat, whereas modern HA fillers can be placed at all depths (dependent on the indication of the filler used). Stimulatory fillers must not be placed too superficially as they have a higher chance of causing skin discolouration, nodules and granulomas.21
Various ‘biostimulators’ are emerging onto the market as they grow in popularity. Lanluma (Sinclair Pharma) is the latest iteration of PLLA, with specific indications for the face, hands and body. Ellansé (AQTIS Medical) is another biostimulator that has poly-caprolactone (PCL) microspheres suspended in a carboxymethylcellulose based gel-carrier. Gouri (Dexlevo Inc) is a recent modification of PCL in that it comes in a fully liquid form. HArmonyCa from Allergan Aesthetics is a hybrid dermal filler combining hyaluronic acid (HA) and calcium hydroxyapatite (CaHA), intended for facial soft tissue augmentation.
Looking towards the horizon, biostimulatory products are truly here to stay, as we can learn to harness pre-existing physiological pathways and give them a boost. Nonetheless, the familiarity and safety associated with the reversibility of HA will always draw us back to this ancient molecule that unites all animal kingdoms. Moving forward, we will increasingly see hybrid products that combine HA with other biostimulatory compounds to get the best of both worlds. Fillers have certainly evolved since their inception as the challenges of the aesthetic arena apply pressures to research and development units globally. This creates an element of competition between manufacturers to satisfy the increasing experience levels of injectors and the demands of their patients.
Competition is always a good thing, and leads to further innovation. As such, it really is an exciting time to be at either end of the humble syringe that sparked what has become a multi-billion dollar industry almost 200 years on.
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