Fat as a filling agent

The first attempts at soft tissue augmentation revolved around the surgical use of fat. Dr Neuber is recognized as the first to perform human fat auto-grafting. In a documented presentation in 1893, he stated that he had performed successful fat auto-grafting for several years. Dr Neuber performed auto-graft transfer in a 20-year-old man suffering from a tuberculous ostitis in childhood leaving him with a deeply retracted scar below the infraorbital margin. Dr Neuber incised a small piece of subcutaneous fat, corresponding to the size of the scar, which he then inserted and sutured leaving a nice cosmetic result.

But the modern era of fat transplantation awaited the development of liposuction surgery in 1974 by Dr Giorgio Fischer MD in Rome, and in 1978 by Drs Yves-Girard Illouz MD and Pierre Fournier MD in Paris. In the 1980s Dr Fournier began micro-lipoinjections in which 13-gauge needles attached to ordinary syringes could be used to collect fat for transplantation. The issue with fat transplantation was that longevity varied from patient to patient. Average fat survival rates were from 25% to 30% persistence when injected into the cheeks, forehead, and nasolabial folds. Despite the abundance of readily available donor material, the procedures were cumbersome, required separate local anesthesia, involved greater risks of bruising, etc., and were generally more time consuming than using an off-the-shelf injectable filler agent such as collagen. The attraction of fat as a filling agent faded in the late 1980s, and has recently become of greater interest with the current research into fat as a source of stem cells. However, in the 1970s the first novel filling agent of the modern era was collagen.

Collagen (Zyderm^®, Zyplast^®, Cosmoderm^®, Cosmoplast^®, Evolence^®)

Collagen is the most abundant protein in skin. Collagen implant material was first developed by four Stanford doctors in the early 1970s: Rodney Perkins, John Daniels, Edward Lock, and Terrence Knap. In 1977, they reported the successful injection of human-, rabbit-, and rat-derived collagen into subcutaneous tissue of rats. This successful experiment led them to try injecting the scars and depressions of volunteers with both human- and bovine-derived collagen. These volunteers had a 50–85% improvement that was sustained over 3–18 months. Following extensive clinical trials in the late 1970s, Zyderm^®1 implant (35 mg/mL of solubilized collagen) was approved by the US Food and Drug administration in 1981 (Fig. 2.1A), and Zyderm^®2 (65 mg/mL of solubilized collagen) was approved in 1983. Both products were a relatively non-viscous suspension that allowed for injection through a 30-gauge needle. Because 2–3% of treated patients developed localized allergic reactions associated with these injections, pre-treatment skin testing with 0.1 mL subcutaneous challenges was recommended prior to using the Zyderm^® 1 and 2 implants.

Figure 2.1 The first 18 years of modern soft tissue filling were dominated by collagen: (A) Zyderm^®, a bovine product, and later (B) Cosmoplast^®, a human-derived collagen.

The principal champion of collagen was Dr Arnold Klein, who reported the use of injectable bovine collagen in more than 1000 patients in 1983. At that time, he noted success in treating supple acne scars, steroid- or disease-induced areas of atrophy, glabellar furrows, crow’s feet, post-rhinoplasty irregularities, depressed skin grafts, and various other soft tissue defects such as depressed scars that could be distended. He stressed overcorrection of defects and a superficial placement of the injectables.

Drs Stegman & Tromovitch published their experience with injectable bovine collagen and included their observations in a text on cosmetic dermatologic surgery in 1984 and a second edition in 1990. In the early 1980s numerous investigators reported treatment for these same indications and also for residual cleft lip scars, facial hemiatrophy, and depressed Mohs surgery scars. As of 1983, more than 10 000 patients had been treated with Zyderm^® collagen.

All forms of injectable bovine collagen were mildly immunogenic. The threat of bovine spongiform encephalopathy from prion disease mandated the use of closed herds as the only suitable source of solubilized collagen. Non-bovine collagen sources were developed from human tissue culture lines, which eliminated the allergic reactions seen with the bovine products. Cosmoderm^® and Cosmoplast^® (Fig. 2.1B) had very different flow characteristics than Zyderm^® and Zyplast^® and lacked the allergic profile of bovine collagen, but their very limited duration of effect (generally 3–4 months) and the desire to move away from protein-based fillers led to their abandonment by the marketplace once the hyaluronic acid (HA) gels arrived on the scene. But for 18 years, from 1981 to 2003 when Restylane^® was approved by the FDA, collagen was the only commercially available FDA-approved product in the US market. The only other product that was in use during that period was silicone, and it had a more checkered history to be reviewed later. The true expansion of the commercially available fillers in the US market came instead with the introduction of the HA gels.

Hyaluronic acids (Restylane^®, Perlane^®, Juvéderm^® Ultra, and Ultra Plus)

HA was discovered from the vitreous humor of cows. HA is the main polysaccharide in human extracellular matrix tissue. It acts as a scaffold for collagen and elastin to bind to. Because it binds to water, it augments and hydrates the skin. The skin loses HA as it ages, which leads to decreased movement and elasticity. HA, when used in commercial filler agents, consists of repeating polymer chains of the polysaccharide with interval cross-links of agents that bind the polymers together. By varying the type of cross-linking material and its amount, the characteristics of the gel can vary in the degree of hardness, amount of lift, duration of survival, and resistance to degradation by heat or enzymes. At present the source of the HA used in commercial products is bacterial, leading to the designation of this class of fillers as NASHA^™ (non-animal-sourced hyaluronic acid gel) gel, which distinguishes them from the earlier bovine and human-sourced collagen products. Hyaluronic gel products can be found either as biphasic types, in which varying sized particles predominate, or as monophasic types, in which the HA is a homogeneous solution.

After years of use outside the USA, Restylane^® (Q-med, Uppsala, Sweden) became the first HA to enter the US market with FDA approval on 12 December 2003, 9 months after the FDA approval of the Cosmoderm^® human collagen implants (see www.fda.gov/MedicalDevices). This was a watershed event that marked the end of 17 years of domination of the US filler market by the collagen products. Restylane^® (Fig. 2.2A) has an HA concentration of 20 mg/mL with a gel bead size of 250 µmol and 100 000 units per mL; there is an estimated 0.5–1.0% cross-linking with butanediol diglycidyl ether. Perlane^® (Q-med, Uppsala, Sweden) contains 20 mg/mL of HA with a larger gel bead size of 1000 µmol and 10 000 units per mL, and less than 1% cross-linking. Perlane^® is positioned as a more robust HA filler in the Q-med line.

Figure 2.2 (A) The ‘game changer’ Restylane^® and (B) the market leader Juvéderm^® both created unprecedented demand for filler as they represented a quantum leap over earlier collagen technology.

The ephemeral nature of some fillers in the US market can be illustrated by the fate of Hylaform^® (Inamed, Santa Barbara, CA), which the FDA approved in April 2004. Hylaform^® had 5.5 mg/mL of HA and 20% cross-linking with divinyl sulfone. Hylaform Plus^® (Inamed, Santa Barbara, CA), approved on 13 October 2004, had 5.5 mg/mL, larger gel particle size, and 20% cross-linking. Both products were HA gels derived from rooster cockscombs; they were withdrawn because of the market’s desire to move away from animal-sourced products and the lack of duration of effect of the less concentrated Hylaform^®. In addition Inamed, the manufacturer of Hylaform^®, was acquired by Allergan in 2006. By this acquisition Allergan obtained distribution rights to the competing HA filler, Juvéderm^® (Fig. 2.2B), which is manufactured by Corneal Laboratories (Pringy, France). Juvéderm^® is a homogeneous rather than particular form of HA gel and has become the leading product in the US market. Allergan then completed its purchase of Corneal in January 2007, leaving no further purpose for Hylaform^® in the Allergan portfolio.

HA fillers as a class have become the most popular type of filler in the US market and, in one form or another, worldwide. They are reversible with hyaluronidase, which is an important safety consideration. They provide more immediate ‘lift’ than the collagens, last much longer, and require no allergy skin testing prior to treatment. They can be easily injected through a small-gauge needle, and they eliminate the problems of products that contain animal-derived protein. As a result they have virtually eliminated collagens from the market.

The next class to consider is the so-called ‘stimulant injectables’: those that rely to varying degrees upon the host response of fibroplasia to produce a change in tissue volume. The oldest of these is silicone.

Silicone

The term ‘silicone’ was initially coined by a British chemist to describe a family of polymers containing the element silicon. Siloxane is an acronym used to describe compounds containing repeating units of silicone, oxygen, and methane. Silicone was explored by Dow Corning Corporation to produce materials for the military in the 1940s. The first medical use of silicone rubber was by Dr De Nicola in 1950, when it was used to make a prosthesis of a urethra in a man who was unable to void. The liquid silicones used for medical purposes are long polymers of dimethylsiloxanes. Injectable silicones are colorless, odorless, tasteless clear fluids whose viscosity varies according to the degree of polymerization.

In 1959, the Dow Corporation introduced medical grade silicone. It established a center for research called the Aid to Medical Research in which it distributed medical grade silicone to physicians. The use of silicone soon took off and Dow created a special plant and registered it with the FDA. In 1963 Dow developed a more purified medical grade 360 silicone. The ‘360’ refers to centistokes viscosity of the agent. Dow Corning 360 was injected into subcutaneous tissues of rats and human volunteers and it was noted to cause minimal inflammation and was well tolerated. However, complications from silicone were reported when large volumes were injected. The FDA determined that silicone injections would be considered ‘drug use’. It was observed by Ben-Hur and colleagues to form paraffinoma-like granulomas on histological examination. Dow soon developed a highly purified medical grade silicone called MDX 4-4011. An FDA-approved investigation was halted in 1967, then in 1978 the FDA narrowed its scope of the study of silicone. In the 1970s and 1980s, several studies were published (e.g. by Selmanowitz & Orentreich) that purported the safety of the microdroplet technique. Studies by Barnett & Barnett and Zappi et al also reported that injection of minute amounts with a fine-bore needle was safe and effective with very few adverse effects.

Silikon 1000^® (Fig. 2.3A) is a silicone oil with a viscosity of 1000 centistokes. It was approved for use in postoperative retinal tamponade during vitreoretinal surgery. Under the FDA’s modernization act of 1997, the so-called ‘off-label’ use of approved products and devices by licensed physicians is recognized as a legitimate process by which the scope and practice of medicine are enlarged and expanded. Many dermatologists use Silikon 1000^® ‘off label’ for the treatment of acne scars, HIV lipodystrophy, traumatic fat atrophy, rhinoplasty defects, and some facial aging where volume repair gives an effective result. Illegal use of adulterated industrial grade silicone fluids by laypersons continues to produce sensational adverse reactions including deaths – a reality that has colored the public’s perception of this valuable tissue augmentation agent. Illegal use of non-medical-grade product, together with the controversy surrounding silicone breast implants fanned by FDA Commissioner David Kessler MD in 1992 when he called for a ban on silicone implants, meant that silicone has remained in the background as a filler for some time. The lack of interest of commercial sponsorship of necessary long-term safety studies virtually guarantees it will remain an ‘off-label’ use for the foreseeable future.

Figure 2.3 (A–D) Variations on the theme, generally presented as stimulatory agents that promote collagen response in the host. Currently they are all FDA approved, but remain niche products rather than enjoying the broad market appeal of the hyaluronans.

Poly-L-lactic acid (Sculptra^®)

The FDA accepted ‘non-inferiority’ comparative trials to evaluate the fillers that came after collagen. Perhaps as a result of these clinical trial designs, manufacturers continued to present the marketplace with single syringes of approximately 1.0 mL in volume. However, the HIV epidemic created a compelling need for volume restoration because of the pan-facial atrophy associated with HIV / AIDS and protease inhibitor therapies. The FDA approved poly-l-lactic acid (PLLA) (Dermik, Laboratories, Berwyn, PA) in August 2004 for the correction of facial atrophy secondary to HIV and therapy for AIDS. Off-label use for areas such as the nasolabial folds began almost immediately. The FDA then granted a second approval for treatment of nasolabial folds and facial wrinkles to the sponsor, Sanofi-Aventis US, in August 2009, and it is marketed as Sculptra^® (Fig. 2.3B). PLLA is a filler with durations reportedly of as much as 18–24 months. Treament requires that the filler be prepared in advance using sterile preserved water and that the patient come in for a series of three injections over the course of several months. The PLLA material is thought to stimulate fibroblasts in the host to produce collagen. The volume of PLLA injected in any one session usually approaches 5–10 mL. Although PLLA continues to have its advocates, the initial failure to appreciate the need for dilution prior to use, lack of reversibility, and dependence on multiple treatments to achieve results have limited wider utilization of the product. The desire to achieve ‘permanent’ results has spurred the introduction of other products that promise, and occasionally deliver, the possibility of longer durations – among them fillers that contain particles that resist biological degradation, such as calcium hydroxylapatite and polymethylmethacrylate (PMMA).

Calcium hydroxylapatite (Radiesse^®)

Calcium hydroxylapatite (Radiesse^®, now owned by Merz Aesthetics, formerly BioForm Medical, WI) was FDA approved on 22 December 2006 for the augmentation of moderate to severe facial lines and folds and for facial soft tissue loss from HIV-related lipoatrophy (Fig. 2.3C). It consists of 30% concentration of 25–45 µm calcium hydroxylapatite spherical particles suspended in sodium carboxymethylcellulose gel. It lasts approximately 1 year or more in most patients. It is inherently biocompatible because it is identical in composition to bone material. Off-label use has included volume restoration for dorsal hands and post-rhinoplasty contour correction. Lack of immediate reversibility and contraindication for use in the lips limit applicability to some extent, but the product has a steady niche market.

Polymethylmethacrylate (Artefill^®)

PMMA is composed of non-resorbable PMMA 20% and 80% bovine collagen and was FDA approved as Artefill^® (Fig. 2.3D) in October 2006 (Artes Medical, San Diego, CA) following earlier European use as Artecoll^® dating from 1998. Following corporate upheaval involving the original management under the founder, Gottfried Lemperle, the product was purchased out of bankruptcy in 2009 by Cowen Healthcare Royalty Partners and reorganized as Suneva Medical. Artefill^® is a chemically inert and biocompatible synthetic implant used in bone and dental implants. Skin allergy pre-screening tests are needed owing to bovine collagen content. The body degrades the collagen carrier within 1–3 months. The PMMA microspheres are non-biodegradable and their persistence is extremely long lasting to permanent. The use of PMMA is appropriate for patients with well-defined deep facial wrinkle lines. Granulomas appear to be less common with the current product, down to 0.01% range, but sensitivity to the bovine collagen component and the animal derivation of the collagen remain issues. Clinical trials for acne scarring are reportedly under way following reports (e.g. by Epstein & Spencer) of utility in this indication.

Conclusion

The list of filler products that are commercially available outside of the USA is protean. While admittedly many of these are refinements of existing technologies (better cross-linking, different particle size, combined with anesthetic, etc.), many are new classes of products that are different from those currently available in the USA (Fig. 2.4), e.g. polyacrylamide gels, cross-linked dextran, carboxymethylcellulose, hypromellose, etc. There are over 200 commercial products outside the USA. But we would predict that we shall see fillers moving beyond the traditional concept of inert medical devices into the realm of true biologicals: materials that will improve the texture, elasticity, radiance, and possibly color, of the skin itself. Just as the last 40 years has been the movement from two to three dimensions, the next two decades will see movement from the macro- to the microlevel and fillers will become systems for active metabolic manipulation and protection of the aging skin. The challenge for us as clinicians will be to sort through the hype and be able to choose the products that will offer the balance of risk and benefit. Given the preternatural attraction of the public for the newest and the greatest, we will have our work cut out for us.

Figure 2.4 Examples of only two products pursuing FDA approval: the first is a polyacrylamide gel, Aquamid^®, which is a permanent injectable gel implant; the second, Ellansé^®, contains polycaprolactone smooth microspheres suspended in an aqueous carboxymethylcellulose gel vehicle. There will be many more fillers pursuing approval in the US market, to be sure.