From Wrinkle Filler to Facial Sculptor, What's New in Dermal Fillers?

Both the American Society for Aesthetic Plastic Surgery (ASAPS) and the American Society of Plastic Surgeons (ASPS) reported in their 2007 procedural statistics that over 1.5 million soft tissue filler procedures had been undertaken by their U.S. members during the year, making dermal fillers the second most popular non-surgical treatment in the USA.

We last reviewed the expanding UK dermal filler marketplace back in March 2006, and since then the number of products available has increased yet again, with new advancements in technology also leading to the discontinuation of some older formulations in favour of more advanced and long lasting derivatives. Again we are seeing the continued move away from the practice of simply “filling” wrinkles and depressions to new state-of-the-art “volumetric” techniques which are being used to create a “liquid facelift” to restore the youthful roundness and plumpness of the face which we lose as we age.

So who are the new kids on the block? And, what’s hot in the world of dermal fillers?

Types of Dermal Fillers

It is agreed amongst experts that ideally a dermal filler product should be biocompatible (compatible with body tissues), non-toxic, non-immunogenic, (not provoke an immune system response), and non-migratory (i.e. not move to other parts of the body). Hence, various kinds of natural and man-made or synthetic materials have been developed over the years for injection into the skin.

In general, as well as classifying dermal fillers according to their temporary (resorbable) and permanent (non-resorbable) qualities, we can also split the current UK available products into seven main groups based on their primary composition.

These are:

The Collagens, either from human or animal origins - Zyderm®, Zyplast®, Cymetra®, Artecoll® and Evolence™.
The Hyaluronic Acids - Restylane®, Juvederm®, Surgiderm®, Juvéderm® ULTRA, Hydrafill®, Hylaform®, Dermalive®, Dermadeep®, Matridur®, Matridex®, Belotero®, Reviderm® Intra, Puragen™ and Teosyal®.
The Polyacrylamides - Aquamid™, Bio-Alcamid™ and Outline®.
The Poly-L-Lactic Acids - Sculptra®.
The Carboxymethylcellulose and Polyethylene Oxides - Laresse™.
The Tri-Calcium Phosphates - Atlèan™
And, the Calcium Hydroxylapatites - Radiesse™.

Many practitioners are understandably wary about using a permanent filler product, for many reasons, including worries about complications due to a patient reaction, and the concern that the patient may not like the resulting “permanent” enhancement. However, patient criteria for a dermal filler product, as well as cost, has always been heavily influenced by the length of time that a filler product will last and retain the desired correction.

So, to create this middle ground, a so-called “semi-permanent” (resorbable) filler niche has arisen, comprising those products that contain a biodegradable carrier substance, such as hyaluronic acid, plus microspheres (small balls if you like) of another substance which give the structure to the correction, which the natural tissues will bond around, giving a more permanent and long lasting effect. Examples of these longer lasting products include: Radiesse™ (Calcium Hydroxylapatite (CaHA) microspheres), Matridex® and Reviderm® Intra (Dextran microspheres), Dermalive® and Dermadeep® (Acrylic Hydrogel microspheres).

As well as filling or volumising products, a new breed of “stimulators”, which includes the semi-permanent ones listed above, has also become available which through their injection stimulate the body’s production of new collagen meaning natural added volume and correction over time. Unlike the products such as those with a hyaluronic acid base which give immediate results, and with the microspheres for longer lasting results, there are products which have no immediate volumising effect, yet are designed to cause a foreign body reaction (collagen production) over time to achieve the long lasting effects; examples include Sculptra® and the new market addition Atlèan™ which comes from the same research company and also contains a small amount of hyaluronic acid to give a visible result whilst you wait for the base product to achieve the stimulating results.

With the coming of age of so called “baby-boomers”, increased disposable income, increased media exposure and consumer awareness via TV programmes such as 10 Years Younger, the demand for quick, minimally invasive treatments will continue with the emphasis on non-animal, long-lasting, natural and safe cosmetic filler products.

Recent New Launches

Juvéderm® ULTRA

Juvéderm® ULTRA, manufactured by Allergan, the makers of Botox®, was launched in the UK in February 2008.

It is an advanced, cohesive, 3D hyaluronic acid matrix dermal filler and contains non-animal hyaluronic acid with the addition of 0.3% lidocaine (local anaesthetic) to provide more comfort both during and after injection. According to data from the manufacturer concerning the preliminary results from a study on 60 women, which compared the injection comfort of Juvéderm® ULTRA 3 and Surgiderm 30 XP, 81% who received Juvéderm® ULTRA felt only slight or no discomfort at all.¹

There are three different formulations for Juvéderm® ULTRA available which include Juvéderm® ULTRA 2 for the correction of medium lines and depressions, Juvéderm® ULTRA 3 for volumising medium to deep lines and enhancing lip volume and Juvéderm® ULTRA 4 for enhancing volume to the cheeks and chin.

According to the manufacturer Juvéderm® ULTRA has enhanced stability and resistance to degradation by heat and the body’s metabolism, providing a duration of the product up to 12 months.

1. Comparison of Injection Comfort and Ease with Juvéderm ULTRA 3 and Surgiderm 30 XP. Phillip Levy, Hervé Raspaldo, Koenrad De Boulle. Accepted as a poster for IMCAS Jan 9-12, 2008, Paris.

Atlèan™ βTCP

The French pharmacists who invented Sculptra™ launched their new volumising filler product, Atlèan™ βTCP, in the UK in June 2007.

Atlèan™ is a Tri-Calcium Phosphate (TCP) product in the form of a white gel which the manufacturer claims gives the same volumising and sculpting visual effects as the poly-l-lactic acid based filler, Sculptra™ but without the 4 - 6 week wait to see the benefits. This is due to the fact that Atlèan™ also contains hyaluronic acid which gives an immediate visible result in the treated area, thus increased patient satisfaction, whilst the tri-calcium phosphate helps to stimulate the production of new collagen in the treated area for a longer lasting result. TCP has been used in medicine for years, for example, in bone regeneration after fractures.

According to the manufacturer, treatment can last for up to 3 months for the hyaluronic acid element of the product and up to 12 - 15 months for the TCP stimulated collagen effect.

Teosyal®

The Teosyal® range, now the UK’s number two filler according to market share, was launched in the UK in 2006 and is manufactured in Switzerland by Teoxane Laboratories and distributed in the UK by Lifestyle Aesthetics. It consists of several monophasic (non-particulate) hyaluronic acid based products of non-animal origin, which are highly biocompatible, offering immediate and long-lasting results.

The range consists of a variety of concentrations designed to treat deep to superficial skin depressions and volumetric losses. They include Teosyal Ultra Deep, Teosyal Deep Lines, Teosyal Global Action, Teosyal Touch Up and Teosyal First Lines, as well as a product especially designed for injection into the lip, Teosyal Kiss and Teosyal Meso for biorejuvenation via mesotherapy.

Trials indicate that the majority of the Teosyal® range is effective foran average of 6 to 9 months for the treatment of wrinkles. Although Teosyal® Kiss is manufactured in such as way as to obtain a longer-lasting effect according to the manufacturers - averaging 9 to 12 months. Teosyal® Ultra Deep is also said to last on average 12 months.

Teosyal® was recently voted the winner of the Injectable Product of the Year at the 2008 Aesthetic Medicine Awards.

“The rapid success of the product range has been unparalleled particularly in light of the tough competitive HA market that we exist in. Practitioners have found the Teosyal range not only to be economically viable for their practices, but have also found that the range provides excellent treatment outcomes for their patients.”; comments Sandra Sheals, Sales Director at Lifestyle Aesthetics.

Belotero®

Belotero® is a monophasic double crosslinked hyaluronic acid created in Switzerland by Anteis, and distributed in the UK by Merz Pharma UK Ltd. (It is also marketed in some countries under the brand name Esthélis®.)

Belotero® has been designed from biofermentation hyaluronic acid, a substance naturally present in our body; which the makers claim makes it safe and completely biocompatible, as well as wholly biodegradable. It is created using Cohesive Polydensified Matrix (CPM) technology, a unique process which gives Belotero® hyaluronic acid unusual elasticity; (this technology adds to its “mono-phasic” nature). Belotero® therefore guarantees a considerably better result from the first hours after the injection and over the initial months, in terms of increased volume and wrinkle filling compared to “biphasic” products.

Belotero® Basic is aimed at volume enhancement treatments and can be used for deep furrows, lip augmentation, facial outlines, naso-labial furrows, glabellar lines and the correction of facial depressions. Belotero® Soft is designed for treating superficial wrinkles and can be used for perioral wrinkles, lip commissures, crow's feet, and forehead wrinkles.

Laresse™

FzioMed launched its Laresse™ dermal filler product, intendedfor the correction of facial soft tissue contour deficiencies such as wrinkles and nasolabial folds (nose-to-mouth lines), in the UK & Europe in June 2006.

Laresse™ is hailed as an innovative new filler gel which is composed of two well-studied, absorbable medical polymers called carboxymethylcellulose and polyethylene oxide. These components have a long safety history in FzioMed’s surgery products, as well as in cosmetics, nutritional products and FDA-approved pharmaceuticals.

Laresse™ is non-bacterial and non-animal based which the manufacturers claim makes it less likely to cause allergic reactions such as redness, swelling, tenderness and itching. It is also not chemically cross-linked like some hyaluronic acid based filler products, again removing potential allergy and illness causing compounds. Clinical results have shown that the duration of effect is comparable to leading hyaluronic acid fillers at 1, 3 and 6 months.

Although it has been within the UK market for almost two years now, Laresse™ will however only be available in the UK until the end of the year, while stocks last, as the American parent company has chosen to exit the UK dermal filler market due to the increasingly competitive conditions and a desire to concentrate their efforts on their surgical products business.

Macrolane™ VRF

12 years on since the launch of Restylane®, based on Q-Med's patented NASHA™ technology for the production of Non-Animal Stabilized Hyaluronic acid, comes Macrolane™ VRF, launched at the start of 2008.

Macrolane™ VRF, which stands for ‘Volume Restoration Factor’, has become the first body shaping and volume restoration product which uses hyaluronic acid. It is currently indicated and CE approved for ‘volume restoration and shaping of body surfaces’, for example, shaping of the breasts, calves and buttocks and also for evening out discrepancies in skin surface such as those sometimes caused by liposuction. Due to its formulation it cannot and should not however be used on areas of the face. Although the use of Macrolane™ in the breast is currently available under the ‘body shaping’ indication, there are a number of ongoing clinical trials researching its use in this area.

According to Q-Med, Macrolane™ is intended to last for 12-18 months in the body, depending on the area treated and the amount of volume used, although it recommends that each individual treatment programme includes a yearly top-up, as required, to maintain the optimal results. It will be some time however before long term data on the average duration for particular indications is properly known.

Prevelle™

Having launched Puragen™ in late 2005, designed for the treatment of moderate to deep lines and wrinkles, Mentor Corp went on to launch Prevelle™ in 2007, a sister product aimed at fine lines.

Despite this joint portfolio Mentor is keen to highlight that the products are in fact distinct and technologically different, however they are meant to complement one another.

Puragen™ is created using their breakthrough technology called DXL™. The patented DXL™ process double cross-links hyaluron molecules, providing greater resistance to degradation than single cross-linked products available. Prevelle™ however is a single cross-linked product which is manufactured by their partner company Genzyme Corp. Like Puragen™ it is made from a non-animal source of hyaluronic acid but is designed for a much more superficial injection level.

Ongoing partnership between Mentor and Genzyme should also see the launch of Prevelle™ Silk, another hyaluronic acid filler in the family which also incorporates lidocaine and is aimed at reducing moderate to severe facial lines and wrinkles. The product was recently given U.S. FDA approval and global marketing is expected sometime this year.

Hyaluderm™

Launched in the UK at the start of 2007 and distributed by Cambridge Medical Aesthetics Ltd, Hyaluderm™ is a non cross-linked hyaluronic acid based dermal filler which the manufacturers claim makes it less toxic as no cross linking chemicals are added to the formulation.

Hyaluderm™ is available in two concentrations with 2% sodium hyaluronate for treating mild to moderate wrinkles and for lip augmentation, available in 0.5ml, 1ml and 2ml syringes, and 2.5% for deeper wrinkles, available in 1ml syringes, both with a 30 gauge needle.

The manufacturers state that results will last between 4 and 8 months depending on the area treated.

ISOgel

ISOGel, distributed in the UK by Euromedical Sytems Ltd, is a new range of non-permanent, hyaluronic acid based dermal fillers. It comes in three strengths (Class 1, 2 and 3) for different filling requirements, ranging from fine wrinkles, frown lines and nasolabial folds to the remodelling and augmentation of the nose, cheeks, chin and lips.

The manufacturers state that Class 3 is the most highly concentrated hyaluronic acid based filler on the market indicated for prevention or as an adjunct to cosmetic and reparative surgery.

They claim that results should be still visible 4 to 6 months after treatment.

CRM®

The German company behind Matridur® and Matridex® have now launched a new range of non-animal hyaluronic acid based fillers under the brand name CRM®, which relates to their Covalent Reticulated Copolymer Matrix technology. This has now been available in the UK since March 2008.

CRM® technology uses a cross-linking agent called Butanedioldiglycidylether (BDDE), one of the least toxic of the cross-linking agents, which it is claimed increases the resistance of the gel to degradation. The manufacturers also note that CRM® Technology produces a gel of a greater purity which virtually eliminates immune reactions, making it safer for patients and it is retained longer in the tissue for a longer-lasting result.

The range consists of crm-DEX, used for treating deep wrinkles and folds such as glabellar (frown), nasolabial (nose-to-mouth) and marionette (mouth-to-chin) lines, as well as lip augmentation, crm-DX, targeted at volume replacement for tissue augmentation of the cheek or facial contours, crm-GEL, for medium to deep wrinkles and folds plus lip augmentation, crm-DUR, designed to treat superficial lines and wrinkles such as those around the eyes and mouth and crm-SOFT aimed at biorejuvenation using a mesotherapy technique.

As well as the hyaluronic acid base, both crm-DEX and crm-DX designed for volume replacement, deep folds and facial contouring also contain dextranomeres (dextran molecules) at 25 and 50 mgs respectively. These are positively charged microspheres that aim to stimulate the tissue to produce new collagen and help the regeneration of the tissue in the area treated.

Future Introductions

Varioderm™

Medical Aesthetic Group has announced that from 1st April 2008 it will be the exclusive distributor of Varioderm™ for the UK and Ireland.

This very highly cross-linked, pure non-animal hyaluronic acid filler originates from Germany and is available in 4 concentrations ranging from Varioderm™ Fine Line for the treatment of superficial lines and wrinkles, Varioderm™ for medium to deep wrinkles and lips, and Varioderm™ Plus for deep wrinkles and facial contouring to Varioderm™ Subdermal for contour correction and volume replacement.

According to the manufacturers Varioderm™ is expected to last between 6 to 16 months depending on the area treated and product used. This is due to the high degree of cross-linking which makes resorption by the body slower than with other HA products.

ELEVESS™

Anika Therapeutics Inc previously announced their family of cosmetic tissue augmentation products under the brand name REDEFYNE™, back in 2006, which they have since changed to ELEVESS™. The product is based on hyaluronic acid and incorporates lidocaine, a local anaesthetic.

ELEVESS™ was granted CE approval for marketing in the European Union in April 2007 and American FDA approval in July of the same year. Unfortunately due to a break down in the distribution agreement it shared with Galderma, the product has still yet to effectively launch. A new partner is being sought and launch is hoped to commence sometime in 2008. No further news is currently available.

News and Clinical Updates

With the acquisition of Inamed Inc. (the makers of Hydrafill®) and Corneal Group (the makers of Juvéderm™ and Surgiderm™) in recent years, Allergan Inc. has firmly placed itself as a leader in the field of the supply of products for facial aesthetics, with the addition of these dermal filler brands to its own portfolio which includes Botox®.

With continued research and development of the filler products available to them they launched Juvéderm® ULTRA early this year. To accommodate the promotion and production of this new product range, along with the continued support of the Hydrafill® Softline and Softline Max products, it is anticipated that we will see a slow discontinuation in both support and supply of some of the older Juvéderm®, Surgiderm® and Hydrafill® 1, 2 & 3 lines as the year progresses. We await a formal announcement on such plans.

In a market which is still dominated by Q-Med with the tried and trusted hyaluronic acid dermal filler range, Restylane®, the introduction of Juvéderm® ULTRA by Allergan has been likened by some to the Coca-Cola versus Pepsi war.

Another fight contender which has risen to the challenge recently is Radiesse® the calcium hydroxylapatite filler from Bioform Medical, whose usage in the US is up by 55% on the year according to the 2007 statistics from the American Society of Aesthetic Plastic Surgery (ASAPS) and up 124% from 2006 to 2007 according to the members of the American Society of Plastic Surgeons (ASPS).

Further evidence of its rise to favour and clinical credibility was seen in the publication of two trial papers at the end of 2007 and start of 2008.

The first showed the results from a European, multi-centre, randomised and blind comparative clinical trial of just over 200 patients for nasolabial treatment which highlighted a greater patient satisfaction with the use of Radiesse® than with Juvéderm® (Juvéderm 24 and 24HV) or Perlane®. This was the first direct comparison study done for Radiesse® against two leading competitor products and also demonstrated higher patient likelihood to return for additional treatment with Radiesse® and a greater likelihood to recommend the treatment. The results from the study demonstrated that at 12 months after the second and last treatment, 90% of Radiesse® treated patients rated their satisfaction as "satisfied" or "extremely satisfied" compared to 48% with Perlane® and less than 10% for each Juvéderm® group.

The second paper reported that Radiesse® was more effective than Restylane® in another European, multi-centre, randomised and blind comparative clinical trial of 60 patients treated for nasolabial folds. Again, this is a first of its kind study which showed that patients preferred Radiesse® two to one over Restylane®, they reported higher levels of likelihood to return for future Radiesse® treatments, and Radiesse® was found to provide greater improvement to the nasolabial folds than Restylane® at the end of 12 months and two treatment sessions.

In both of these studies it was also noted by Bioform Medical that fewer millilitres of Radiesse® were required to achieve the levels of correction to the area treated than were needed with the hyaluronic acid based fillers. In terms of cost per ml, as well as an extended duration of effect over HA fillers, this makes Radiesse® also appeal to those more price sensitive individuals, as a single syringe of Radiesse® is likely to achieve more correction, depending on the treatment indications, than a single syringe of the competing HA fillers studied. The average UK cost to consumers of a syringe of Restylane® (1ml) is £300, whereas a syringe of Radiesse® (1.3ml) comes in at £450.

The main criticism of papers such as these however lies in the age old “apples and pears” situation, whereby comparing a non-permanent HA filler with a semi-permanent CaHa filler is considered by many to be a wholly un-like-for-like comparison and draws questions about its validity as a benchmark study.

Regulation

Dermal fillers are largely provided in the UK by Doctors, Cosmetic Surgeons, Dentists and Nurses, and in some case Beauty Therapists. It was originally anticipated back in 2005 that following several reports conducted by industry expert groups that the government would bring the regulation of those offering dermal fillers to the public under the remit of the Healthcare Commission, already responsible for regulating and inspecting establishments offering cosmetic surgery and laser treatments.

However, in April 2007 it was announced by the Department of Health that it would be asking the industry to formulate a self-regulatory scheme instead, which would be drawn up by The Independent Healthcare Advisory Services (IHAS) and their Cosmetic Surgery Working Group to be in the form of a quality mark.

Setting up the self-regulation model is a complex task that the IHAS takes very seriously with their key objectives being to protect patients by establishing an accepted set of good practice standards for dermal filler treatments and to ensure that training courses are producing safe and competent practitioners.

Currently out to consultation from the industry, the self regulatory model will be finalised towards the middle to end of 2008, with a registration scheme and inspections being undertaken by independent inspectorate which will assess evidence and compliance with a set of standards and a code of practice.

The Government intends to re-evaluate this self-regulatory model and its success in 2010, before it decides on the long term solution.

Price Wars

As well as choosing a filler product based on its safety and efficacy, many people, patients and practitioners alike, will take a keen interest in the cost of a product and the perceived value for money that they are getting for the results it produces and the length of time that it lasts.

Depending on the specific ingredients within a filler product and the difficulty and cost of manufacture, base prices can vary quite widely. Add to that the ‘labour cost’ or the price you pay for the skill and qualification level of the practitioner who is administering it, plus a little for regional variations, and drawing an average UK price can be somewhat haphazard. For example, following a quick straw poll of the UK we noted that consumer prices for a single syringe of 1ml of Restylane® can range from £150 - £350.

With increased competition in recent years due to the elevated numbers of differing professionals now offering dermal fillers as part of either their main aesthetic business or as a side line to a doctor’s or dentist’s surgery, it seems that price positioning now plays a large part within the industry. However, as with everything in life there is still an element of ‘you get what you pay for’ and consumers should be reminded that a low price doesn’t always equate to the best service provision so should be minded to shop around for the best quality provider rather than simply the cheapest.

Summary

The UK dermal filler market place is estimated to be worth between £15-20 Million and is showing no signs of slowing, despite any talk of recent global economic woes.

As noted in previous reviews, the UK and global dermal filler markets are still dominated by the large number of different actively promoted purely hyaluronic based product lines. This highlights the success of hyaluronic acid as an effective and safe dermal filler compound; the most popular choice for most practitioners and patients alike. Increasing choice amongst HA fillers with some dozen or more currently available is fragmenting the market to some extent, although the Restylane® brand from Q-Med still appears to own the lions share after 12 years on the market.

With the recent introduction of more and more HA fillers which combine a local anaesthetic element this may change in future if the desire for maximum injection comfort rules the product choices consumers make over price and product performance. Will we see Q-Med adding Lidocaine to any of its products before the decade is out?

Additionally there is a school of thought that questions whether the addition of lidocaine to hyaluronic acid based fillers has an affect on their make-up, such as breaking down any cross-linking agents, which could ultimately affect their longevity and achievable results. As always more studies will need to be carried out before the truth is really known.

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