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INTRODUCTION
The aging process is a very complex phenomenon, engendered by genetically determined intrinsic and extrinsic factors. Sun exposure with its cumulative ultraviolet effects, even not related to intrinsic aging, represents the most important leading cause of aging of the skin and its undesirable aesthetic effects. Ultraviolet exposure is aggravated by lifestyle and habits, such as cigarette smoking, poor nutritional practices and chemical exposure to different pollutants and irritants, which lead to biological and immunological changes. As a consequence, we see visible and histological signs of skin aging, such as decreased thickness of the epidermis, dermis and subcutaneous tissue, which are clinically manifested by smile lines, crow’s feet and facial creases. Over the last few decades, soft tissue augmentation using injectable fillers, combined with other modalities, has become the standard clinical approach for correcting these age-related defects ( Fig. 9.1 ). Soft tissue fillers can temporarily restore a smoother, younger-looking skin by helping to fill in these lines and creases, to recreate symmetry, volume and a smooth skin surface. The ease of performance, lack of down time and infrequency of complications have increased the popularity and patient acceptance of injectable fillers.
Ideal fillers (SCALES 1953):
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are not modified by liquids or organic tissues
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are chemically inert
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do not cause inflammatory reactions
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are non-carcinogenic or mutagenic
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are capable of resisting to mechanical tensions
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do not produce allergic reactions
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are capable of resisting to mechanical strains
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can be manufactured in different formats
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can be sterilized.
After the decision has been made to perform soft tissue augmentation, selecting the filling substance and proper technique are of utmost importance. However, with so many new products of different nature and longevity, and so many others waiting for approval for use in a particular market, it becomes increasingly important to know the properties, composition and mechanism of action of each particular filler, as well as their interactions and tissue responses. None of the currently available fillers meets all the desired criteria, but, while we still search for the ideal fillers, hyaluronic acid (HA) fillers have become the new gold standard in soft tissue augmentation, fulfilling many of our desired criteria. Although they are very well tolerated, the durability of the HA fillers and, to a lesser degree, collagen fillers varies from several months up to 1–2 years, depending on stabilization methods, molecular size and injection site. In contrast, silicone oil lasts for life and some other synthetic fillers stay for decades.
Whether they are permanent or temporary, all fillers have similar application techniques and are part of the treatment planning for use either alone or in combination with other modalities. In this chapter, we will discuss the current and most recent fillers, FDA and non-FDA approved, their characteristics and skin interactions, different formulations and presentation, best indications ( Fig. 9.2 ), techniques and complications.
EVOLUTION
The implantation of gold plates to correct cranial facial defects was first described by Fallopius in the 16th century. The search for the ideal material for correcting facial skin irregularities has continued for over 500 years. Many injectable or implantable substances that are not compatible with the human skin, or that have been adulterated in their formulation, have been proposed for cosmetically improving soft tissue defects. Over 100 years ago, autologous fat was one of the earliest agents used for soft tissue augmentation. Interest in autologous fat has continued, with the development of new and improved application techniques of structured fat grafting and microinjections (see Chapter 10 ).
The original concept of tissue augmentation in the modern era involved injecting collagen into the skin. It was believed that the collagen, which has been used for more than 30 years, would incorporate into the skin’s own collagen. However, it turned out that collagen only occupies space. That concept continued and was recently altered to include fillers derived from HA, which was also believed to be a passive filler. As it turned out, HA does promote a certain degree of fibroblastic activity. During the last decade, the technology of fillers and volumizers has begun evolving toward using fillers that would induce hyperplasia and make filling more efficient and long lasting.
Silicone is the oldest filling material to be used in the USA. It was first used in 1930. Since1965, both Orenttreich and associates and Barnett have used it for nasolabial augmentation, with good cosmetic results. The FDA has never approved silicone for cosmetic use.
In the 1950s, Gottlieb developed another dermal filler (Fibrel®), a gelatin matrix implant that is now only of historical interest. The principle was to use a fraction of plasma containing fibrinogen and prothrombin to fill up scars and wrinkles. The mechanism of action was based on the normal coagulation and wound healing process, resulting in new collagen formation. Fibrel is no longer available. In 1981, for the first time, a form of xenogenic agent, bovine collagen, received FDA approval. Although those bovine collagen-derived fillers had great potential for hypersensitivity reactions, they had a good safety record and, therefore, have been the most widely used agents for the last 30 years. However, their short duration is a big disadvantage. The HA and hylan fillers represent a big breakthrough for augmentation technology, and they are among the most popularly used dermal fillers. Restylane® (Q-Med, Upsala, Sweden) was the first HA to be approved in the USA in 2003.
CLASSIFICATION
There are many different ways to classify fillers and volumizers, which leads to some degree of confusion. Traditional fillers have been biodegradable, meaning that they are absorbed and eliminated from the body. We will describe the most popular fillers in detail, according to their properties, tissue interaction, source and longevity, application techniques, side effects and complications. Since this is a market that is developing rapidly, there are many fillers waiting for FDA approval and the CE mark in Europe, which is much less rigorous than in the USA. We will discuss the most used fillers with biodegradable and non-biodegradable properties ( Table 9.1 ).
| Biodegradable | Non-biodegradable | Slowly biodegradable | Biodegradable with fibroplastic properties |
|---|---|---|---|
| AcHyal | Aquamid | Radiesse | Radiesse |
| Alloderm | Artefill (Artesense) | New Fill/Sculptra | Hyaluronic Acid/Hylan fillers |
| Autologen | Bioplastique | New Fill/Sculptra | |
| Cymetra | Evolution | ||
| Bioinblue | Gore-Tex | ||
| Dermal grafting | Meta-Crill | ||
| Dermaplant | Silicone oil (Adatosil, Silikon 1000) | ||
| Elevess | Softform | ||
| Endoplast 50 | |||
| Fascian | |||
| Fat | |||
| Human placental collagen | |||
| Hyal system | |||
| Isologen | |||
| Evolence | |||
| Juvederm | |||
| NewFill/Sculptra | |||
| Belotero | |||
| Perlane | |||
| Restylane (family) | |||
| Reviderm | |||
| Surgilift | |||
| Teosyal | |||
| Cosmoderm/Cosmoplast | |||
| Zyderm/Zyplast |
BIODEGRADABLE FILLERS
Collagen Products
For more than 30 years, collagen products have been the most readily available and widely used injectable soft fillers for facial rejuvenation. The main idea was that once injected into the skin the product would be incorporated into new collagen, producing long-lasting correction. This concept was abandoned when it became apparent that injectable collagen was just a passive space occupier. Collagen products today include human combination collagen, cultured collagen, bovine and porcine, and collagen combined with synthetic and natural substances. Some of them require skin pretesting for hypersensitivity and others do not.
Animal Collagen (Bovine and Porcine) – Xenogenic
Bovine collagen is made from extracted cow skin that is highly purified, sterilized and processed into a liquid form before being used for cosmetic purposes. Because collagen is a protein that is eventually metabolized by the body, bovine collagen injections are not permanent. Three variations of bovine collagen are currently available: Zyderm I, Zyderm II and Zyplast® (Allergan, Irvine, CA). They are 95–98% type I collagen, and the remainder is type III.
Zyderm I, the least concentrated, is available in a concentration of 35 mg/mL, dispersed in phosphate-buffered physiological saline. It is indicated for superficial rhytids or for layering on top of a deeper filling agent. It should be placed in the superficial papillary dermis. As much of Zyderm I is saline, the treatment area should be overcorrected 150–200%.
Zyderm II is more viscous, with a concentration of 65 mg/mL dispersed in phosphate-buffered physiological saline. It is recommended for the treatment of deeper lines and wrinkles with a deeper placement into the papillary dermis and a recommended overcorrection of 100–150%. It has twice the viscosity of Zyderm I. Both contain 0.3% lidocaine (3 mg/mL) to provide local anesthesia at the time of the injection. They are provided in sterile disposable syringes ready for use and should be kept refrigerated until usage. Each syringe should only be used once. Since they are produced from animal sources, a skin sensitivity test should be performed, at 8 and 4 weeks prior to treatment. Zyderm I and II last for an average of 3 months, but some have been reported to last longer.
Zyplast® contains purified bovine dermal glutaraldehyde cross-linked collagen in a concentration of 35 mg/mL because the cross-linkage with glutaraldehyde makes the collagen fibers stronger. Zyplast® is indicated for correction of deeper skin wrinkles and deformities. Since the agent does not decompose at the same rate as non-cross-linked collagen, it lasts longer (more than 3 months). Zyplast® should be injected without overcorrection.
Bovine collagens may be easier to inject in facial areas, such as lip borders, because they are liquid and not thick. They may also be less painful for patients because they are mixed with anesthetics.
Evolence® is a porcine collagen gel implant composed of 35 mg/mL homogenous Type I collagen that received FDA approval in June 2008. It is extracted and purified from porcine tendons, suspended in phosphate-buffered saline (PBS) and cross-linked with a technology that uses sugar (ribose) instead of chemicals – ‘Glymatrix’ technology. This porcine collagen-derived dermal filler is supposed to be less immunogenic, since the allergenic telopeptides are removed, making it more compatible with human collagen. No pretesting is necessary.
Evolence® is supplied as single-use 1 cm 3 prefilled sterile syringe. It is indicated for dermis correction of moderate-to-deep facial wrinkles and folds, such as nasolabial folds, and meets the criteria for correction lasting from 9 to 12 months. As there has been some postinjection granuloma formation, some doctors do not recommend using it for lips. Patients with a history of dietary porcine allergy should not use Evolence®. Based on preclinical studies, the use of Evolence® in individual patients should be limited to 10 mL over a 1-year period. The safety of injecting greater amounts has not been established.
Other Non-FDA-Approved Xenogenic Collagen
Permacol® (Tissue Science Laboratories, Aldershot, UK), a porcine dermal–collagen matrix graft, is a micronized and cross-linked injectable form of the sheet material used to reconstruct dermal tissue defects. It is produced in a saline vehicle and is available in Europe in 2.5 cm 3 syringes. It is an off-label use because it is approved in Europe for urinary incontinence.
Atelocollagen® (Koken Co. Ltd, Tokyo, Japan) is a collagen-derived filler from breeds of very young Australian calves to decrease the risk of transmission of bovine spongiform encephalitis. It is supplied with 1 cm 3 /mg cartridges and is injected with dental syringes. We have not found too much information on Atelocollagen® in the literature.
Allogenic Collagen (Synthetic or Cadaveric)
Human synthetic collagen products are derived from a single human fibroblastic cell culture from a source other than the recipient. They are purified and prepared in the form of a buffered saline suspension, with lidocaine being added to reduce the pain associated with injection. Human synthetic injectable collagen is similar to bovine collagen in its properties and durability, and it is used in much the same way; allergy testing is not required prior to use. There are currently three FDA-approved injectable synthetic human collagen products available in the USA: CosmoDerm1®, CosmoDerm 2® and Cosmoplast™ (Allergan, Irvine, CA), and unlike Dermalogen™ and Cymetra®, which are described below, they are not cadaveric.
CosmoDerm 1® and CosmoDerm 2® have the same indications as the bovine collagens, Zyderm I and Zyderm II, and similar longevity. CosmoDerm 1® has a concentration of 35 mg/mL and CosmoDerm 2® has a concentration of 65 /mL; they are not recommended for individuals who have severe allergies that include a history of anaphylaxis to bovine or other collagen products.
Cosmoplast™ is a concentration of 35 mg/mL of human-derived collagen, which is cross-linked with glutaraldehyde and recommended for correcting deeper wrinkles – the FDA approved both CosmoDerm® and Cosmoplast™ on March 11, 2003. They do not require a pretreatment skin test. Because of the flow characteristics and lidocaine content of the cell culture collagen products, there may be some practical advantages to combining these products with HA injections. For instance, using Cosmoplast™ to first outline upper lip borders may facilitate augmentation of the body of the lip with Restylane®.
Cadaveric collagen products are allograft materials that are derived from tissue banks and subject to FDA screening for transmissible diseases. Cadaveric collagen products are tightly regulated by the FDA, as is other donated tissue. They are intact human collagen fibers or acellular dermal matrix from cadavers for human implants. There are three products: Alloderm®, Cymetra® and Dermalogen™.
Alloderm® and Cymetra® (LifeCell Corporation, Branchburg, NJ) are approved by the FDA for cosmetic corrective use. They are harvested from donated and acellular human donor tissue, freeze dried and processed to eliminate infections, and available from most tissue banks. Alloderm is indicated for transplantation to repair dermal tissue and is widely used to treat full-thickness burns as well as soft tissue augmentation. It requires surgical implantation. Cymetra® is a micronized form of Alloderm® that is more suitable for injection. Both Alloderm® and Cymetra® are rehydrated with saline solution or lidocaine in the physician’s office 1 hour prior to injection. Cymetra® is injected deep into the dermis for lip augmentation and to treat rhytids and scars. Since the material is still viscous and generally requires a 23–26-gauge needle for injection, regional blocks are recommended. The manufacturer does not require pretesting for allergies, but 2.1% of patients develop temporary local reactions. Host tissue incorporation, with fibroblast in-growth, and collagen deposition are seen 1 month after implantation. Cymetra® has been contraindicated in patients with history of autoimmune connective disorder.
Dermalogen™ (Collagenesis, Beverly, MA) is another injectable human dermal implant material made from a suspension of pooled human cadaver collagen. It is the allogenic version of Autologen (discussed below). Apparently, development of new collagen and neovascularization is possible, but it is a long process requiring many sessions and is very expensive. Although they are, theoretically, non-immunogenic and incapable of potential allergic reactions, these cadaveric agents have lost their initial appeal, and the two injectable forms (Cymetra® and Dermalogen™) are no longer available.
Autologous Collagen
Although autologous human collagen is derived from the patient’s own collagen, this is still technically difficult to produce with consistency and with adequate volume. These products are ideal because there is no immunological response and less chance of infectious complications.
Autologen™ (Collagenesis Inc., Beverly, MA) is collagen harvested and reformulated from the patient’s own skin so allergic reactions are considered impossible. Theoretically, it should last longer than other biological fillers. The patient’s own skin is harvested during a previous procedure – such as blepharoplasty, facelift or another operation in which skin is removed – and sent to a commercial laboratory where the collagen is extracted, sterilized and prepared for reinjection. The amount of collagen available for injection is limited by the amount of skin removed and the quality of the skin. A total of two to four injections of Autologen may be performed at 1–3-month intervals. If not needed, the remaining processed liquid collagen can be stored for 5 years. Autologen™ injections seem to last longer than bovine collagen injections, but longevity varies. Unfortunately, the company manufacturing Autologen™ is no longer in business.
Isolagen® (Isolagen Inc., Houston, TX) is another autologous collagen that has been temporarily taken off the market pending FDA approval. It is composed of injectable autologous fibroblasts cultured for 4–6 weeks from a 3 mm punch biopsy taken from postauricular skin. Like Autologen™, the patient’s own collagen is harvested, purified and packaged in a suspension for injection into the skin. A minimum of three injections, given at 2-week intervals, is recommended. A 70% improvement can be expected following the third injection and, because live cells are used, improvement may continue for several months after the last injection. Because the material is from the patient’s body, little risk of allergic response exists. Phase III clinical trials are taking place, for FDA approval. Research has shown it to be effective, and it can last for up to 4 years. Several other autologous and allogenic collagen products have been intermittently available. They initially require multiple injection sessions to attain an acceptable result and the residence time is limited.
Recombinant Collagen
Recombinant collagen is still in initial FDA trial phases, for non-cosmetic applications.
Collagen combined with different materials is discussed under non-biodegradable fillers (Artefill®, FDA approved since 2005, and its precursor Artecoll®) ( Table 9.2 ).
| Type | Collagen concentration | Indication | Volume (cc) | Placement | Overcorrection | Year approval |
|---|---|---|---|---|---|---|
| Zyderm I | 35 mg/mL bovine | Fine superficial lines | 0.5, 1.0,1.5 | Superficial papillary dermis | 150–200× | 1981 |
| Zyderm II | 65 mg/mL bovine | Mild/moderate rhytids, scars | 0.5, 1.0 | Mid dermis | 100×150× | 1983 |
| Zyplast | 35 mg/mL bovine (cross-linked glutaraldehyde) | Deep lines and folds | 1.0, 2.0, 2.5 | Deep dermis | None | 1985 |
| CosmoDerm1 | 35 mg/mL human derived | Fine/superficial rhytids | 1.0 | Superficial papillary dermis | 150–200× | 2003 |
| CosmoDerm2 | 65 mg/mL human derived | Mild/moderate rhytids, scars | 0.5, 1.0 | Mid-dermis | 100–150 | 2005 |
| CosmoPlast | 35 mg/mL human derived | Deeper rhytids and folds | 1.0 | Deep dermis | None | 2003 |
| Evolence | 30 mg/mL porcine derived | Fine to mild wrinkles | 1.0 | Mid dermis | None | 2008 |
HYALURONIC ACID AND HYALURONANS
HA is a naturally occurring substance found in the skin and connective tissues of all mammals that plays an important role in keeping tissue lubricated. Because it is a uniform, unbranched linear polysaccharide with a simple chemical structure that is identical in all species and tissues, it can be considered an ideal biomaterial. HA supports collagen and elastin fibers and helps retain moisture to give skin its characteristic texture. To produce a gel suitable for use as an injectable filler, HA is chemically modified by cross-linking the molecules. It can be used to fill out facial lines and remove wrinkles, and for soft tissue augmentation, such as lip plumping ( Fig. 9.3 ). Injectable HA fillers remove wrinkles immediately, and the results last longer than other biodegradable fillers. Because HA is a natural substance, hyaluronic fillers are associated with fewer hypersensitivity reactions than other collagen products. Although they can be either animal based or non-animal based, no pretreatment skin testing is required. Most of the HA preparations are synthesized by bacteria, purified and cross-linked to provide a variety of viscosities for injection. The FDA has approved Restylane®, Perlane®, Captique®, Juvéderm™, Hylaform®, Hylaform Plus® and Elevess® HA gels for use in the USA. With the exception of Hylaform® and Hylaform Plus®, which are derived from the rooster combs, they are all non-animal stabilized HA (NASHA™) fillers.
Recent studies have shown that HAs also induce a certain degree of fibroplasias. To minimize the probability of protein impurities bound to the entangled HA, they are biosynthesized from a non-animal source and stabilized with relatively few cross-links in a continuous three-dimensional molecular network to create a gel that can take any form or shape.
The longevity of the HA products depends on the size of the gel particle, the concentration, the area to be injected and the presence of inflammation in the area. In healthy tissue, the extracellular capacity to degrade HA (into carbon dioxide and water) is extremely low. Because the molecule is extremely hydrophilic and the amount of HA in the gel bead is about five times larger than needed to maintain its volume, NASHA™ gels will remain approximately the same size and shape despite continuous degradation. The excess material allows the gel bead to last longer, a process called isovolemic degradation. The limited cross-linking allows for significant ability to absorb water and maintain volume. HAs are hyaluronans, whether or not they are derived from bacterial fermentation or an animal.
Restylane® (Q-Med, Upsala, Sweden or, in the USA, Medicis, Scottsdale, AZ) was the first HA to receive USA FDA approval, in December 2002. For many, it is considered the ‘ideal filler.’ It has 20 mg/mL of HA with a gel bead size of 250 μm and 100 000 units per mL. Restylane® is indicated for fine and moderate lines and wrinkles, and for lip augmentation and tear trough defect repair. The authors have used HA to reshape nasal deformities while a patient was contemplating corrective rhinoplasty ( Fig. 9.4 ). All the Restylane® products have a concentration of 20 mg/cm 3 , but the particle size varies. It is dispensed in a 1.0 cm 3 and 0.5 cm 3 prepacked syringe, with a 30-gauge × 1.5-inch-long needle. Restylane Fine Lines® has 20 mg/mL of HA with a gel bead size of 100 μm and 200 000 units per mL. It is good for very fine perioral lines and temporary correction of double Asian eyelid creases ( Fig. 9.5 ), with great patient satisfaction level and instant gratification. Restylane Lipp® was designed for the vermilion border of the lip or to create more volume. Restylane SubQ® is the thickest version of the Restylane® family with cosmetic indication. It is a volumizer, with 1000 gel particles per milliliter.
Perlane® (Q-Med, Upsala, Sweden), which gained USA FDA approval in 2006, has 20 mg/mL of HA with a gel bead size of 1000 μm and 10 000 units per milliliter. It is dispensed in a 1.0 cm 3 and 0.5 cm 3 prepacked syringe, with a 27-gauge × 1.5-inch long needle. It is indicated for deeper defects and for broader areas such as nasolabial folds, malar enhancement and other facial irregularities.
Captique® (Genzyme and Allergan, Irvine, CA) received FDA approval for cosmetic use in August 2004. It is a product derived from bacterial fermentation (non-animal) HA. Captique® is plant based. No pretest is needed. Captique® is a clear gel that is indicated for injection into the mid-to-deep dermis for correction of moderate-to-severe wrinkles.
Juvéderm™ (Genzyme, Framingham, MA, and distributed by Allergan, Irvine, CA) was approved by the FDA in June 2006 for treating facial wrinkles and folds. It is developed by bacterial fermentation and differs from the other HA products because it is a homogeneous gel, with the highest concentration of cross-linked HA (above 90%) of any dermal filler currently available. According to the manufacturer, because of its soft consistency, Juvéderm creates a smooth, natural look and a feel that lasts longer, and requires fewer touchups following the initial treatment. In Europe, Juvéderm™ is available in five formulations: Juvéderm™ 18, 24, 24 HV, 30 and 30 HV. HV indicates a higher viscosity and a greater degree of cross-linking for that product. They all have a concentration of 24 mg/mL of HA and are differentiated by the degree of cross-linking. The FDA approved three formulations for Juvéderm™, offering physicians the flexibility to tailor treatments to the particular needs of each patient. They are JuvédermUltra™ 24 HV, recommended for contouring and volumizing facial wrinkles and folds; JuvédermUltra Plus™ 30 HV, recommended for deeper folds and wrinkles; and Juvéderm 30™, for subtle correction of facial wrinkles and for lip augmentation ( Fig. 9.6 ) and folds.
