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Injectable Dermal and Subcutaneous Fillers
Questions
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Q59.1 Which fillers require allergy testing before injection? (Pgs. 651, 653)
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Q59.2 How does the ‘moldability’ of hyaluronic acid compare with that of calcium hydroxyapatite? (Pg. 651x2)
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Q59.3 Which fillers can be dissolved if there are undesirable effects? What product is used to dissolve the filler? (Pg. 651)
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Q59.4 Which fillers currently on the market are manufactured with lidocaine? (Pgs. 651, 653 Table 59.1 )
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Q59.5 Which fillers are US Food and Drug Administration approved for human immunodeficiency virus (HIV) lipoatrophy? (Pgs. 651, 653)
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Q59.6 Which filler can be visualized on radiographic studies? (Pg. 651)
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Q59.7 What is the recommended injection technique for silicone? (Pg. 653)
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Q59.8 Which fillers have anticoagulant effects? (Pg. 653)
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Q59.9 What are the main causes of nodule formation with poly- L -lactic acid injection? (Pg. 654x2)
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Q59.10 What is a biofilm, and what measures can be used to eliminate this biofilm? (Pg. 655)
Abbreviations used in this chapter
CaHA
Calcium hydroxyapatite
FDA
US Food and Drug Administration
HA
Hyaluronic acid
HIV
Human immunodeficiency virus
LS
Liquid silicone
NASHA
Nonanimal stabilized hyaluronic acid
NLF
Nasolabial fold
RHA
Resilient hyaluronic acid
PLLA
Poly- l -lactic acid
PMMA
Polymethylmethacrylate
Acknowledgment
The authors would like to acknowledge Dr. Andrei I. Metelitsa for his contributions to the previous edition of this chapter.
Introduction
As we age, we experience dermal thinning, bony resorption, and a reduction in our collagen and elastic tissue, leading to the signs of aging skin. With the development of filler substances, it is now possible to slow down and even correct these changes, which was previously believed to be impossible.
Soft tissue augmentation using filler products was pioneered in the late 1800s with the use of fat transplantation to correct cosmetic defects. Since that time, experimental filler products have been increasingly developed and implemented around the world. However, it was not until 1981 that the US Food and Drug Administration (FDA) approved the use of bovine collagen for the treatment of fine lines. Since then, the art of dermal filling has seen tremendous advancements with the introduction of new product formulations and injection techniques. Thus, it is important for the treating physician to be knowledgeable and up to date concerning these developments. Clinicians must be well educated on product formulations, indications, contraindications and possible complications, and how to address these complications should they occur. Every patient has unique characteristics; therefore, an individualized treatment plan that is both safe and effective should be designed for each patient.
Categories of Dermal Fillers
Collagen
Bovine collagen was the first dermal filler to receive FDA approval. It was introduced to the market as Zyderm I (INAMED Aesthetics) and rapidly gained popularity. Zyderm I was superb for correcting fine lines, but was not as successful in treating moderate to deep rhytides.
Zyderm II, containing a higher percentage of bovine collagen, was introduced a few years later, followed by Zyplast, in which bovine collagen was cross-linked with glutaraldehyde to produce a thicker product with longer duration. Both products were developed for the correction of deeper rhytides.
Bovine collagen filler lasts on average about 3 months. Q59.1 It carries the potential of a bovine allergy; therefore two allergy tests are necessary before initiating treatment. At least 6 weeks before treatment, allergy testing is performed by injecting 0.1 mL of collagen filler into the superficial dermis on the volar forearm. Readings are performed within 48 hours after injection and visible redness, induration, edema, and tenderness are documented. A second test on a contralateral site can be performed 4 weeks later to capture patients with negative preliminary tests. If there are no visible reactions, patients can be safely treated within 2 weeks of the second test.
Bioengineered human collagen, Cosmoderm and Cosmoplast (INAMED Aesthetics), was introduced to the market in March 2003. These products allowed immediate treatment, thereby bypassing the need for baseline allergy testing.
The bovine and bioengineered human collagen products contain lidocaine, which makes the procedure more tolerable. These products are no longer available in the United States after their voluntary removal in 2010 in response to decreased market demand.
In 2004, a porcine collagen filler known as Evolence (Colbar LifeScience) became available for moderate to deep rhytides. No pretreatment allergy testing is required, as porcine and human collagen are structurally similar. Evolence has greater longevity than the traditional collagen fillers, lasting up to 1 year. The stability of Evolence is attributed to its cross-linking with porcine-derived collagen and the natural sugar D -ribose; this is referred to as Glymatrix technology. This product was removed voluntarily from the US market in 2009, mainly because of decreased market demand.
Hyaluronic Acid
Hyaluronic acid (HA) is a naturally occurring polysaccharide that is a natural component of our dermal extracellular matrix. The currently FDA-approved HA filler products are produced through bacterial fermentation and have a very low risk of allergenicity, therefore baseline skin testing is not required. Earlier HA products, such as Hylaform (Allergan), were developed from avian species, but are no longer on the market.
Hylaform was the first HA introduced to the market, followed by Restylane (Galderma Laboratories), which received FDA approval in 2003. Since then, many HA products have become available. They all work very similarly, but each has unique characteristics. They differ in their concentration of HA, particle size, cross-linking, G’ modulus (gel hardness), viscosity and lidocaine content ( Table 59.1 ).
Table 59.1
Common Fillers Used in Dermatology
| Product | Vendor | Material | Duration of Action | G’ (Pa) | |
|---|---|---|---|---|---|
| Nonpermanent | |||||
| HA | Belotero Balance | Merz Aesthetics | NASHA (22.5 mg/mL) | 6–12 months | 30 |
| Hylaform | INAMED Aesthetics | HA from rooster combs (5.5 mg/mL Hylan B) | 2–4 months | n/a | |
| Hylaform Plus | INAMED Aesthetics | HA from rooster combs (5.5 mg/mL Hylan B)—larger particles than Hylaform) | 2–4 months | n/a | |
| Hydrelle | Anika Therapeutics | NASHA (28 mg/mL + 0.3% lidocaine) | Up to 1 year | n/a | |
| Juvederm Ultra XC | Allergan | NASHA (24 mg/mL + 0.3% lidocaine) | 6–9 months | 111 | |
| Juvederm Ultra Plus XC | Allergan | NASHA (24 mg/mL + 0.3% lidocaine)—higher proportion of cross-linked HA vs Juvederm Ultra XC | 6–9 months | 136 | |
| Juvederm Volbella XC | Allergan | NASHA (15 mg/mL + 0.3% lidocaine) | Up to 1 year | n/a | |
| Juvederm Vollure XC | Allergan | NASHA (17.5 mg/mL + 0.3% lidocaine) | Up to 18 months | n/a | |
| Juvederm Voluma XC | Allergan | NASHA (20 mg/mL + 0.3% lidocaine) | Up to 2 years | 274 | |
| Prevelle Silk | Mentor | NASHA (4.5–6 mg/mL) | 3–6 months | 230–260 | |
| Restylane-L | Galderma Laboratories | NASHA (20 mg/mL, 100,000 gel particles/mL + 0.3% lidocaine) | 6-9 months | 565 | |
| Restylane Lyft (previously Perlane) | Galderma Laboratories | NASHA (20 mg/mL, 10,000 gel particles/mL + 0.3% lidocaine) | 6-9 months | 549 | |
| Restylane Defyne | Galderma Laboratories | NASHA (20 mg/mL + 3 mg/mL lidocaine)—higher proportion of cross-linked HA vs Restylane Refyne | 9–12 months | n/a | |
| Restylane Refyne | Galderma Laboratories | NASHA (20 mg/mL + 3 mg/mL lidocaine) | 6–9 months | n/a | |
| Restylane Silk | Galderma Laboratories | NASHA (20 mg/mL, 500,000 gel particles/mL + 0.3% lidocaine) | 6–12 months | 459 | |
| Revanesse Ultra | Prollenium Medical Technologies | NASHA (22–28 mg/mL) | 9–12 months | n/a | |
| Teoxane RHA2/3/4 | Teoxane SA | NASHA (23 mg/mL + 0.3% lidocaine) | Up to 2 years | n/a | |
| Other | Laviv | Fibrocell Technologies | Autologous human fibroblasts | Up to 12 months | n/a |
| Radiesse Plus | Merz Aesthetics | CaHA + 0.3% lidocaine | 9–18 months | 1180 | |
| Sculptra | Galderma Laboratories | PLLA | 12–22 months | n/a | |
| Permanent | |||||
| Bellafill (previously Artefill) | Suneva Medical | 20% Microspheres polymethylmethacrylate (PMMA) and 80% purified bovine collagen with 0.3% lidocaine | Permanent | n/a | |
| Silikon 1000 | Alcon Laboratories | Liquid silicone | Permanent | n/a | |
All collagen products are currently off the market in the United States.
HA, Hyaluronic acid; NASHA, nonanimal stabilized hyaluronic acid.
HA fillers are FDA approved for the correction of moderate to severe rhytides (nasolabial folds [NLF]), perioral rhytides, lip and cheek augmentation, lipoatrophy, and hand rejuvenation. There are many off-label uses, including, but not limited to, filling in the tear troughs and nasal recontouring ( Box 59.1 ).
Box 59.1
Indications and Contraindications for Injectable Fillers
| US Food and Drug Administration-Approved Indications | |
|---|---|
Moderate-severe facial wrinkles and folds
Lip augmentation/perioral rhytids
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Human immunodeficiency virus HIV-associated facial lipoatrophy
Prolonged retinal tamponade
Cheek augmentation
Hand rejuvenation
Off-label uses
|
| Contraindications | |
|
|
The HA fillers last on average 6 to 9 months in mobile areas such as the NLF and the lips. In areas of limited mobility, such as the temple and tear troughs, HA lasts over a year. Q59.2 Benefits of HA include moldability even months after injection, and a very low risk of allergic reactions. Q59.3 In addition, the ability to easily remove the injected HA with hyaluronidase is a huge benefit over other fillers. Hyaluronidase is a naturally occurring enzyme which degrades HA, typically within 24 hours.
Q59.4 Most HA fillers are premixed with lidocaine. Patients are finding better tolerability, and physicians are discovering a decreased need for topical anesthesia and nerve blocks. Two separate randomized, double-blind, split-face studies reported noticeable pain relief, documented as 50% less pain, with the lidocaine-containing products. At the same time, similar efficacy and safety profiles were noted compared with their lidocaine-free equivalents.
In addition to the volumizing effects of HA, Wang and colleagues reported that HA injections promote collagen synthesis secondary to mechanical dermal tension from the filler. This tension leads to fibroblast stretching and ultimately collagen production, which helps explain the phenomenon of long-standing correction of the defect months to years after the initial injection.
Calcium Hydroxyapatite
Whereas the HA fillers are better categorized as volumizers, calcium hydroxyapatite (CaHA) is noted for both volumizing and stimulatory effects. CaHA is a naturally occurring mineral that is a major component of our bone; therefore, it has a very low risk of initiating an immune response and no baseline allergy testing is required.
Q59.5 Radiesse (Merz North America) is the only CaHA product available for dermal filling. It was first FDA approved in 2006 for the treatment of moderate to severe rhytides and human immunodeficiency virus (HIV) lipoatrophy. In 2015, it was approved for hand augmentation to correct volume loss in the dorsum of hands. Radiesse is a formulation composed of CaHA microspheres within an aqueous gel suspension containing sodium carboxymethylcellulose, glycerin, and sterile water.
This product has greater longevity than HA, with the potential for therapeutic results for 12 to 18 months. It also has a stimulatory effect leading to fibroplasia and neocollagenesis. A foreign body reaction is induced by the injected material, leading to accumulation of fibroblasts which surround and protect the CaHA, allowing slower degradation of the microspheres. This foreign body response also results in new collagen formation.
Q59.2 CaHA is less forgiving than HA fillers. The product must be molded immediately after placement and cannot be altered once the product has set.
Q59.6 Inform patients that the CaHA filler can be visualized on radiographic studies, but reassure that the product will not interfere with surrounding tissue evaluation.
In 2015, the FDA approved Radiesse Plus for treatment of moderate to severe rhytides. Radiesse Plus is the newest formulation of CaHA with integral 0.3% lidocaine hydrochloride. A multicenter, split-face, double-blind study randomized subjects to receive treatment with CaHA plus lidocaine in one NLF and CaHA without lidocaine in the contralateral NLF. A majority of subjects reported reduction in pain immediately after injection with CaHA plus lidocaine compared with CaHA only and both treatment groups achieved aesthetic improvement. Another study by Meland and colleagues reported that CaHA with integral lidocaine has a similar rheological profile to CaHA without lidocaine.
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