Fillers: evolution, regression, and the future

Published on 16/03/2015 by admin

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2 Fillers

evolution, regression, and the future

Richard G. Glogau, Haydee M. Knott

Summary and Key Features

• The first pre-modern era filler was fat

• The first commercial modern era US Food and Drug Administration (FDA)-approved filler was bovine collagen

• The first non-commercial modern era non-FDA approved filler was silicone

• Collagen was offered in 0.5 mL and 1 mL syringes for correction of ‘two-dimensional’ problems, i.e. wrinkles, scars

• Collagen had two major problems: delayed hypersensitivity and brief duration

• The introduction of botulinum toxin eliminated dynamic movement as a cause of wrinkles and lines, and allowed true volume deficits to be appreciated

• The introduction of hyaluronic acid (HA) gel fillers from Europe was a game changer, initially because of duration of effect; other benefits were seen later

• With HAs, attention shifted from ‘two-dimensional’ to ‘three-dimensional’ problems, i.e. from lines and wrinkles to subcutaneous atrophy and fat loss

• Fillers that followed, e.g. polylactic acid, calcium hydroxylapatite, polymethylmethacrylate, focused more on host response and endogenous collagen production than true volume replacement, mimicking the phenomenon seen with micro-droplet silicone

• Almost all fillers in the foreseeable future are entering the USA from Europe

• Newer fillers seek ability to control length of duration, enhanced stimulation of dermal collagen, reversibility, and greater lift

The chronology of the development of soft tissue augmentation in the field of dermatology has followed a distinctly non-linear path. The remarkable arrival of literally dozens of injectable filler materials on the modern European, global, and domestic scenes is, however, a direct reflection of the increasingly sophisticated understanding of the aesthetic challenges of the human face. What began with the introduction of collagen as a treatment for a line or wrinkle led to use of fillers for treatment of dynamic lines of facial expression, e.g. nasolabial folds, and most recently to the concept of volumizing the face. This progression of the conceptual understanding of treating the aging face has moved from the flat world – two-dimensional problems such as a static wrinkle – to incomplete solutions for the dynamic lines of movement – e.g. glabellar lines with filler. It is fascinating that the initial movement into three-dimensional correction began with the dramatic improvement seen in lip volume with the initial collagen fillers championed by Arnold W. Klein MD in the 1980s. This initial success in volume correction sustained both the product and our interest in volume as a therapeutic goal for many years, but clearly the lack of duration of the product and the inability to achieve significant volume correction with 1 mL syringes of collagen hampered the recognition of volume correction in non-lip areas: mid-face, temple, brow, and perioral tissue – where the newer fillers are so much more effective. But the litany of fillers that follows shows that each filler has come along at a different point as we moved from static lines, to dynamic lines, to volume and the problem of three dimensions in the face.

Pearl 1

The US market is lacking the range of ‘fine line’ products that are available in Europe. Nothing has replaced collagen for the management of fine lines.

After the introduction of botulinum toxin to the physician’s arsenal, muscle movement could be eliminated as a contributing factor to facial aging and the true impact of volume loss could be more completely appreciated. We began to understand that the partial responses seen with fillers in dynamic lines of expression were overshadowed by the dramatic effect of botulinum toxin on movement in the glabella, and the transition to three-dimensional thinking was under way. Suddenly fillers were needed to address the atrophy of the tissues beneath the skin – a process that changed the round faces of youth to the flat and hollow convexities of aging faces. With the demographics of the post-World War II ‘baby boomers’, the need for volume replacement has never been more obvious and multiple targets for soft tissue augmentation lay before us: premalar cheeks, mid-face, chin, jowl sulcus, cheek hollows, the brow, etc., etc.

Yet vestiges of the initial single line wrinkle-fillers linger on, specifically the 1 mL syringes that still dominate the marketplace. How is the volume of filler originally designed to treat a line / wrinkle supposed to provide the quantities of volume required for all the three-dimensional filling that we and our patients now require? One might as well expect to play an entire symphony with a single stringed violin as to meet all the aesthetic demands of the aging human face with a 1 mL syringe. But let us turn to the early 1970s, when the modern filler era truly began.

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.

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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®

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