Wm. Philip Werschler, MD

In this presentation, Dr Werschler provides an overview of the fillers currently available on the market by class and by product, and how they can be utilized in clinical practice along with some key takeaway points for clinicians.

How did we get here today?

Beginning in 1981, bovine collagen was introduced to the US marketplace. As people began to get their winkles and fold augmented to look younger they discovered that,unfortunately, the duration of collagen was only three months or so, thus the market for collagen injections never grew to meet expectations   And it was subsequently withdrawn from the market. In  December, 2003, the US FDA approved  Restylane (Hyaluronic Acid), whichrevolutionized the dermal filler market . With a duration  of correction to 6+ months, no pre-treatment skin testing, ease of use, room temperature storage and modest cost, there was now a viable product for the emerging, if nascent, dermal filler market.

PMMA (Radiesse), a novel “next-generation” filler was approved in 2006 by the FDA for the correction of wrinkles and folds (such as Nasolabial Folds), and for the correction of HIV-associated lipoatrophy. Unique and distinctly different in its’ mechanism of action, Radiesse is termed a “stimulatory” or “collagen-stimulator” product.  This differs from the previous generation “replacement” space occupying materials collagen and hyaluronic acid.  With the addition of collagen stimulation, the duration of effect of Radiesse was extended to 9-18 months.

On the same day that Radiesse was approved, the FDA also approved the first and only “permanent” dermal filler, Artefill (collagen + PMMA).  Artefill consists of bovine collagen in combination with polymethmethacrylate spheres.   As these spheres are non-biodegradable, they represent a permanent placement into the tissue.  Well tolerated with an excellent safety profile, Artefill does require pre-treatment skin testing because of the bovine collagen present. Special handling includes refrigeration, and collagen stimulation gradually anchors the PMMA spheres into place typically after 2-3 treatments.

In 2007/2008 Hyaluronic Acid plus manufacturer added lidocaine was FDA approved for the hyaluronic acids, Juvederm, Restylane and Perlane. Similarly, the FDA approved the mixing of lidocaine and Radiesse by the injector at the time of use.  These approvals resulted in greater patient comfort during injection and further expanded the dermal filler marketplace. Stabilized Porcine Collagen came onto the market briefly during this time, however due to problems with patient tolerance and complications, the manufacturer withdrew the product and it is no longer available.

In 2009, the FDA approved Sculptra, poly L lactic acid, for aesthetic use (it received FDA approval in 2004 for HIV associated facial lipoatrophy).  A pure collagen stimulator, Sculptra is technically not a dermal filler, however it is best thought of in this category.  Sculptra is routinely mixed with lidocaine and sterile water for injection, requires 3-5 injections sessions to gradually grow new collagen leading to the clinical effect developing over a period of  3-6 months.  Duration is a 2+ years effect based on extensive clinical trials and experience.

More recently, an advanced technology hyaluronic acid  (Belotero) and  an autologous cultured dermal fibroblast  (LAVIV)  were approved. Belotero is a “cohesive polydensified matrix” hyaluronic acid which possess different tissue integration properties than previous generation products.  The net clinical result is that the product may be injected more superficially than other HAs without risk of the Tindall or Rayleigh effect tinting the skin blue.

Laviv, like Sculptra, is technically not a dermal filler but rather a tissue stimulator that upregulates native collagen production.  This process includes harvesting tissue from the patient (post-auricular) and sending it to a processing laboratory which then amplifies the cell count and returns a viable culture for re-injection. The first FDA approved tissue therapy for aesthetics, Laviv presents a multitude of intriguing possibilities in the future.

Ever since fillers first came onto the market, experts have been trying to develop a methodology  to differentiate them and there are many ways  to do so:

• Chemical components
• Duration of action
• Natural/Synthetic
• MOA
  • Replacement Filler or Bio-Stimulatory/collagen stimulator

Looking at fillers by their MOA has seemed to work very well when differentiating the products.

Dermatologists should be aware that fillers exist in two primary categories:

• Volume Replacement
• Collagen Stimulation

When you use the above descriptive methodology, you can see that collagen and hyaluronic acids are replacement fillers and PLLA and LAVIV are bio-stimulatory. And notably, CaHA ad PMMA are blends of both MOAs.

There are many ways to categorize fillers within a class.

Volume Replacement

Hyaluronic Acid

HAs have a very simple chemical structure and is identical in all species and tissues; thus it is non-immunogenic. It is found in all vertebrates and synthesized by some bacteria. The identical structure of HA from all sources makes it an ideal substance for use as a biomaterial in health and medicine.  HAs are highly hydrophilic; therefore, they absorb water, i.e., their principal method of giving a volumizing effect. They are also rapidly metabolized in vivo.

Gel Mass Sizing

In addition to crosslinking, manufacturers use other techniques to improve HA filler properties.  For example, Medicis uses a process that creates specific sizes and shapes to form granular consistency gels Restylane^® and Perlane^®.

In creating the JUVÉDERM^® family of products, Allergan uses Hylacross™ Technology to create random sizes and shapes that form a smooth cohesive gel. While the new to market Beletero uses yet another technology (CPM) to achieve unique properties.

Does this make a difference clinically? It depends on who you ask…

Hyaluronic acids can be used virtually everywhere for anything and everything and they are the most versatile of all of the filler products. These fillers may be ideal for novice patients because they have an  “eraser” (hyaluronidase) which can be injected to make the product dissolve, if so desired for either aesthetic effect or for treatment of necrosis. . This is a unique feature of  this category.

New Approaches to Fillers: Pure Neocollagenesis

PLLA

The question is…Are these products really stimulators? Dr Werschler believes, they are for lack of a better descriptive term. Through a variety of mechanisms of action, they stimulate fibroblasts to make collagen.

PLLA was first approved for HIV-related facial lipoatrophy in the United Sates in 2004 and the aesthetic approval was received in 2009.  It is the only approved pure collagen stimulator currently available in the US; therefore, it is considered “stimulatory” and “biodegradable” in classification. PLLA is indicated for the correction of nasolabial folds. Of note, Dermik aesthetics, a division of sanofi-aventis, recently sold the product to Valeant Pharmaceuticals Intl. based in Canada.

What is the composition of PLLA?

• Poly-L-lactic acid
• Sodium  carboxymethylcellulose (CMC)
• Non-pyrogenic mannitol
• Sterile water (added) for injection (USP)
• Lidocaine (optional—most dermatologists and plastic surgeons add lidocaine for patient comfort)

Sculptra™ is composed of microparticles of PLLA, a biocompatible, biodegradable, synthetic polymer from the alpha-hydroxy-acid family.  It is derived from natural components, it is a crystalline, amorphous mixture with microparticles averaging 40 to 63 μm in size. The slow resorption of PLLA after implantation is due to the high molecular weight (140,000 Daltons) of the polymer and the irregular crystalline shape of the microparticles.

Lactic acid can be converted through polymerization to a variety of polymers, including poly-L-lactic acid. Many of these polymers, including polylactic acid, have been used for many years in medical devices and sutures, including absorbable sealants, flow restrictors, fixation systems, suture anchors/absorbable sutures, fixation screws, and tissue regeneration.

The slide below is very important looking at skin thickness of HIV patients using ultrasound. The plot includes the data points for all patients in the VEGA study. All patients experienced increases in skin thickness in the treatment area (minimum increase of 2.2 mm noted at Week 8 visit).

Statistically significant increases above baseline values of mean skin thickness were noted at all time points (Weeks 8, 24, 48, 72, and 96) during the study.  This slide demonstrates the product’s MOA of growing collagen and therefore, thickening the dermis.

The slide below demonstrates marked improvement in wrinkle assessment score (WAS) utilizing Sculptra^®Aesthetic at all time points through 25 months.

Each Wrinkle Assessment Score, or WAS, at the time points shown represented the median of 3 investigator’s scores, and each of the investigator’s evaluations represented an average of scores for the left and right nasolabial folds.¹

In the WAS coding system, 0 equals no wrinkles; 1 refers to a just-perceptible wrinkle; 2 indicates a shallow wrinkle; 3, a moderately deep wrinkle; 4, a deep wrinkle with well-defined edges; and 5, a very deep wrinkle or redundant fold.²

Investigator evaluations throughout the study confirmed that improvements in facial appearance with Sculptra^®Aesthetic achieved improvement in WAS. As this graph shows, improvements from baseline at 25 months proved to be consistent, progressive, and statistically significant at each time point (P<0.001): 100% of patients improved at week 3; 88.7% at month 13; and 86.3% at month 25.¹

How long does it last? Maybe two to three years. It is important to remember that it is difficult to establish exact duration of the product because of one’s natural course of aging.

References:

1. Data on file, Dermik Laboratories.

2. Sculptra^®Aesthetic Prescribing Information, Dermik Laboratories; 2009.

Where is it used?

Poly-L-lactic acid treatment primarily to add volume, and as such is used to thicken dermis and to stimulate collagen growth in the pre-periosteal plane.  Placement may include the temporal hollows, across the zygomata, in the mid face, nasolabial folds, labiomental sulcus, prejowl sulcus, mandibular sweep, angle and for genioplasty.  Sculptra is not recommended for use in areas of concentric movement such as the lips and eyelids.

Personalized Dermal Technology

LaViv is an innovative technology to isolate, purify, and regenerate a patient’s own fibroblast cells for re-injection.

Fibroblast cells produce collagen and play key role in the continued health of skin. Collagen provides firmness and structure to the skin and is essential in supporting the dermis.. As skin ages, fibroblast cells decrease and the collagen matrix that provide the skin its structure breaks down.

This is a way to restore the equilibrium.  LaViv is the first autologous cell therapy for use in aesthetics filed with the FDA. There is strict release testing on each clinical lot to ensure performance and safety including:

• Collagen content testing results must achieve specification for each prepped injection, indicating cells are biologically active and produce collagen
• Cell suspension must consist of at least 98% fibroblasts prior to release
• Cells in suspension must achieve a viability level of at least 85%

The LaViv Treatment Process:

• Extraction
  • A small cell sample (ideally three small skin bioposies) is removed behind the ear from a small skin punch biopsy with the use of local anesthetics
• Purification & Culturing
  • A proprietary manufacturing process multiplies fibroblasts from the sample into tens of millions of new cells in approximately 3 months
  • Fibroblasts are tested by quality control and released by quality assurance prior to shipment
  • Cells are frozen for use in potentially multiple treatment sessions
• Injection
  • Recommended regimen is three treatment sessions at 3-6 week intervals
  • In clinical trials, a statistically significant difference between LAVIV™ and placebo was seen by the time of the third treatment

As far as side effects with LaViv, there is an increase in erythema, swelling, pain, and a slight urticarial-like response.

New Approaches to Fillers: Volume Replacement + NeoCollagenesis

Calcium Hydroxylapatite (CaHa)-Radiesse

CaHa is best used for facial contouring. It’s mechanism of action is to serve as a filler material initially (particles + gel) then provide long term benefit through natural collagen integration in and around the particles. The result is a long lasting, but not permanent correction augmentation that feels like the patient’s own tissue.

The advantages of Radiesse  include immediate site-specific correction in one to two sessions and strong structural tissue support withno Tyndall effect. CaHa is malleable up to two weeks and has a long duration of nine to 18 months. No pretreatment testing is required, it is also cost-effective and does not migrate or obscure radiographic studies and it doesn’t ossify in the skin.

Radiesse received approval in the United Sates in 2006 for both HIV and aesthetic use and is the only approved biodegradable dual collagen stimulator and replacement filler currently available in the US. When utilizing Radiesse, no skin or allergy testing is needed and there is no special handling. The product is available in 0.3, 0.8 and 1.5 mL and recently approved 3.0 mL syringes through Merz Aesthetics.

Where is it used?

CaHA is used most everywhere; however, it is not ideally used in the lips or the eyelids. Some people do use the product in those areas; however, Dr Werschler does not recommend it.

PMMA Dermal Filler-Artefill

Artefill was approved in the United Sates in 2006 and is the only approved PMMA-enhanced dermal filler currently available in the US. It is indicated for the correction of nasolabial folds. Suneva Medical acquired (ARTES) Artefill in 2009 and is currently manufacturing, selling, and distributing Artefill in the US.

The slide above depicts that initially your percent implant volume is mostly collagen. The bovine collagen goes away rather quickly and you have the PMMA microspheres that stay in the skin. (Of note, PMMA is similar to Lucite, in that, it is a non-biodegrable substance that will remain in the skin forever.) The remaining PMMA  elicits this fibroplasia-like response, the autologous collagen is produced by fibroblasts, it surrounds the microspheres, anchors them in place and that is what gives patients the long-term effect.

 

 

There is a long-term extended duration of action which is what one would expect.

Conclusions

Injectables are:

• FACIAL SHAPING AGENTS (FSA)
  • They can enhance natural features
  • They can rejuvenate fading youth
  • They can restore aged, facial features
  • They can even improve natural beauty
  • Each product has features that result in certain benefits in clinical use
  • Put another way, they are not all alike!

 Clinical Pearls

• Use filling agents appropriate to the requirements of the job
• Not all products are created equal – understand the differences!
• Some areas are more difficult to correct than others  (e.g. lips and tear troughs) so master the basic indications first such as NLF
• Evaluate and approach filling from a multi-step progression:
  • Volume, shape, contour, wrinkle, line and crinkle filling.
  • Product duration claims are a slippery slope- be careful with those and be conservative with your ranges. Underpromise and over deliver.