Injectable Soft Tissue Augmentation

Historical Perspective

Dating back to 1893, Neuber used blocks of autologous fat harvested from the arms for tissue augmentation of depressed facial defects. In 1899, Gersvny injected paraffin into the scrotum as a testicular prosthesis for a patient with advanced tuberculosis. Twelve years later, Brunings first described using the syringe technique to transfer free fat. Then, in 1953, Baronders published a review of permanent soft tissue augmentation with liquid silicone. Finally, in 1981, bovine collagen became the first US Food and Drug Administration (FDA)-approved xenogeneic agent for soft tissue augmentation, and it remained the standard filler for over 20 years.

In 1981, Zyderm® I was the first bovine collagen filler approved by the FDA, followed by Zyderm® II and Zyplast®. As a group, they have a long safety track record having been used in more than a million patients . All three products were derived from a closed US cattle herd carefully monitored to prevent transmission of bovine spongiform encephalitis, a prion-mediated disease. Cutaneous hypersensitivity reactions to these bovine collagen fillers occurred in 3% of patients; therefore, pre-treatment skin testing became mandatory . After the introduction of other fillers, especially the newer hyaluronic acid derivatives, the popularity of bovine collagen fillers waned because of their limited duration of results (2–3 months), manufacturing cost, and risk for hypersensitivity reactions. While no longer available in the US ( Table 158.3 ), the bovine collagen fillers are important because they set the standard to which other temporary fillers are often compared.

In an attempt to reduce the risk of hypersensitivity reactions, a dermal filler consisting of bioengineered human collagen derived from a single human fibroblast cell line was developed. The CosmoDerm®/CosmoPlast® family of dermal fillers closely resembled the bovine-derived products except that no skin tests were required. However, they are no longer commercially available due to high manufacturing costs and low demand.

In 2008, Evolence®, a porcine form of type I collagen, was introduced for the correction of moderate to deep facial wrinkles and folds. Benefits included the rarity of hypersensitivity reactions, thus precluding skin testing, as well as a possibly longer duration of correction (up to 1 year) . It was recommended that Evolence® not be injected into the lips for augmentation because of the risk of subsequent nodule formation . As of 2009, manufacturing was discontinued due to low market demand.

In the late 1980s, research began into the use of preserved particulate allograft material derived from human cadaveric connective tissue, including dermis and fascia lata. The indications for Dermalogen®, Cymetra®, and Fascian® were similar to those for bovine collagen: facial rhytides, atrophic scars, and lip enhancement. Their use also declined with the introduction of newer soft tissue fillers.

In 2003, the FDA approved Restylane®, which ushered in a new era of agents made from hyaluronic acid (HA). Many of the HA formulations proved to be superior in longevity compared to their collagen predecessors. Globally, HA quickly became the most popular soft tissue filler. Currently available FDA-approved formulations of HA are outlined in Table 158.4 . Historic formulations of HA include Hylaform®, which was derived from rooster combs, and Captique®, a similar but bacterially derived formulation. Additional HA formulations no longer available in the US include Elevess® and Prevelle Silk® (see Table 158.3 ).

Longer-lasting injectable products are also commercially available including calcium hydroxylapatite (Radiesse®), poly-L-lactic acid (Sculptra®), and the permanent polymethylmethacrylate microspheres (Bellafill®) .

General Injection Technique

There is an ever-expanding array of materials and devices for soft tissue augmentation (see Table 158.4 ), and Table 158.5 lists the characteristics of the ideal filler. While soft tissue fillers can be subdivided based upon derivation, depth of cutaneous placement or duration of effect, most physicians will develop preferences based on location of desired augmentation.

During the initial consultation, baseline asymmetry, subjective defects, and realistic expectations should be discussed with the patient ( Table 158.6 ). In order to fully appreciate the depth and scope of the defect, patients should be placed in a gravity-dependent or seated position with adequate lighting. The latter should be at an acute angle in order to accentuate surface irregularities and deficits. A careful patient selection process will assist in determining if the patient is an ideal candidate for soft tissue augmentation. Contraindications include prior allergy to the filler material or its constituents (e.g. lidocaine). Pre-existing conditions in the planned treatment area such as dermatitis, herpetic lesions, or impetigo may require postponement of the procedure. The expected level of improvement and longevity also need to be discussed with the patient during the initial consultation.

Prior to the procedure, patients should be instructed to abstain from all nonessential medications that can inhibit coagulation and platelet aggregation. For example, patients may be asked to avoid aspirin for 10–14 days and NSAIDs for 5–7 days in order to decrease the risk of bleeding and bruising. In addition, omega-3 fatty acids, fish oil, and a number of over-the-counter supplements should be discontinued (see Table 133.3 ). Prior to the procedure, written consent is obtained and both make-up and cutaneous debris are removed . Pre- and post-treatment photographs are strongly recommended.

Clean technique is critical in preventing contamination during the initial handling, mixing, and injecting of the filler. Cleansing the skin with alcohol or chlorhexidine and changing gloves after intraoral manipulation is recommended. Percutaneous injections of fillers can be painful, necessitating the consideration of adding anesthesia to the treatment protocol. Although the physician can combine fillers with lidocaine in order to reduce the pain at the time of injection, a number of commercial products are now premixed with lidocaine (see Table 158.4 ). Some injectable products may require nerve blocks and/or regional anesthesia (see Ch. 143 ). More commonly, however, ice or topical anesthetic preparations that contain lidocaine, prilocaine, tetracaine, and/or benzocaine are placed on the areas to be injected.

Proper placement of the filler material is crucial. Injection techniques that are commonly used include serial puncture, linear threading, fanning, cross-hatching, and depot injection . In the serial punctur e technique , small amounts of filler are sequentially deposited along the wrinkle or fold. The injections are placed close to one another so that the filler can blend in a continuous fashion; post-injection massage can also help to blend the filler so that it is evenly distributed. Using the linear threading technique , the full length of the needle is inserted into the proper dermal or subcutaneous plane, and the filler is injected in a retrograde manner as the needle is withdrawn. Conversely, the material can be injected as the needle is advanced (anterograde), creating blunt dissection within the tissue space. The fanning technique involves multiple passes in different, but evenly spaced, directions without withdrawing the needle from its original site of insertion. The cross-hatching or radial injection technique involves evenly spaced, linear injections in a grid-like pattern; this technique is used for filling large areas and for the oral commissures . Finally, depot injections are useful when placing volumizing fillers within the subcutaneous fat or along the periosteum near the malar eminence. Occasionally, small depot aliquots are also placed along the infraorbital ridge. Depot placement of filler is immediately followed by massage by the injector in order to blend the product into the natural contour of the region.

Injectable Soft Tissue Filler Materials

Hyaluronic Acid Derivatives

Hyaluronic acid derivatives are currently the most commonly employed soft tissue fillers ( Table 158.7 ). The term hyaluronic acid is derived from the Greek word for glass, hyalos , and is so named because of its clear, glassy appearance. Hyaluronic acid (HA) is a key glycosaminoglycan (GAG; previously referred to as mucopolysaccharides) within the extrafibrillar matrix of the dermis (see Ch. 95 ). It is a ubiquitous component of connective tissue and is conserved amongst mammals, making it species-nonspecific. Within connective tissue, HA forms a gelatinous matrix that surrounds collagen and elastin fibers and it creates volume via its water-binding capability. HA also plays a role in cellular migration and therefore is important in the development and remodeling of tissues. A direct correlation exists between the amount of HA in the dermis and its water content as well as between HA content and the viscoelastic properties of the extracellular matrix. The concentration of naturally occurring HA within the skin decreases with age, resulting in a decreased ability to retain water, rendering the dermis less voluminous and increasing its propensity to wrinkle.

Table 158.7

Benefits of hyaluronic acid derivatives.

BENEFITS OF HYALURONIC ACID DERIVATIVES

Identical in all species and all tissue types Minimal risk of hypersensitivity reaction (no skin test required) Room temperature storage Biodegradable Long-lasting and stable High degree of safety (biocompatible, resorbable, reversible)

The HA molecule consists of a polysaccharide chain comprised of numerous repeating disaccharides of N-acetylglucosamine and D-glucuronic acid. The longer the chain, the higher the molecular weight. All currently available, FDA-approved HA fillers are derived from bacterial ( Streptococcus ) fermentation. “Raw” or non-crosslinked HA is supplied as a powder that forms a viscous liquid when exposed to water. If injected in this unmodified state, exogenous HA imparts a duration of correction of only 12 to 24 hours. In order to increase tissue residence time, HA molecules must be stabilized via chemical crosslinking of the polysaccharide chains; this modification slows enzymatic breakdown and provides an acceptable duration of correction. Commercially available, FDA-approved HAs are crosslinked by BDDE (1,4- b uane d iol d iglycidyl e ther), with each filler differing in its manufacturing process.

Following the initial crosslinking, HA exists as a gel similar in consistency to Jell-O®. Subsequent post-crosslinking modifications, which vary depending upon the specific product, impart different attributes. For example, with the Restylane®/Perlane® family, the gelatin is passed through a sieve that creates microscopic particles of identical shape and size. Restylane® (approved in 2003) is then suspended in phosphate-buffered saline at a concentration of 20 mg/ml with 100 000 gel particles/ml. Compared to Restylane®, Perlane® has a larger mean gel particle size with 10 000 particles/ml. The Juvéderm® family relies on a proprietary technology that creates particles of random shapes and sizes. Juvéderm® products (first approved in 2006) have an HA concentration of 24 mg/ml, with Juvéderm® Ultra Plus being more heavily crosslinked than Juvéderm® Ultra ( Fig. 158.1 ). Belotero Balance® is a monophasic, non-particulate gel crosslinked in two consecutive reactions, resulting in a cohesive HA gel with varying zones of crosslinking density. The HA concentration in Belotero Balance® (approved in 2011) is 22.5 mg/ml.

The pivotal, phase III trials leading to FDA approval of Restylane®, Juvéderm®, and Belotero Balance® were six-month, randomized, blinded, multicenter, split-face, controlled trials that compared Zyplast® collagen to the respective HA for the treatment of moderate to severe nasolabial folds . At six months, all three HA fillers demonstrated superiority over Zyplast® collagen, with inter-study design and results having more similarities than differences ( Fig. 158.2A ). The HA products have been shown to be safe in all skin types. Further studies, focusing on repeat treatment after six months with the three families of HA, suggested that less volume is required to regain optimal correction . Often, an extended duration of 1–2 years or more was observed ( Fig. 158.2B ).

For the treatment of moderate to severe wrinkles and folds, the Restylane® and Juvéderm® families are usually injected into the immediate subdermal plane. If injected too superficially into the dermis, contour irregularity as well as a bluish discoloration due to the Tyndall effect can occur. The latter results from the optical scatter of different wavelengths of light encountering a clear substance. Recent studies suggest that Belotero Balance®, if injected more superficially within the dermis, integrates more smoothly into the dermis as compared to the Restylane® and Juvéderm® families. The former is also less likely to create a Tyndall effect . This makes Belotero Balance® particularly well suited for treatment of superficial, etched-in lines such as vertical lip lines ( Figs 158.3 & 158.4 ). Both Restylane® and Juvéderm® Ultra are FDA-approved for lip augmentation ( Fig. 158.5 ), although Belotero Balance® is often used off-label for this indication .

In 2013, Juvéderm Voluma® XC (“Voluma”) was the first HA filler to be FDA-approved for deep injection for cheek augmentation as a means of restoring age-related volume loss in the mid face ( Video 158.2 ). This filler consists of a 20 mg/ml mixture of low- and high-molecular-weight HA. Voluma® differs from other HA fillers in that its lower-molecular-weight component, composed of shorter polysaccharide chains, allows for more efficient crosslinking. This in turn produces a highly cohesive gel with a greater lift capability. Results from the pivotal phase III multicenter, single-blinded, randomized, controlled study showed significant improvement in moderate to severe, age-related midfacial volume loss at six months (compared to the no-treatment control group; Fig. 158.6 ). Data suggest that nearly half of the patients maintained correction up to 24 months, emphasizing its long-term effectiveness. Adverse events were similar to other HA fillers and included swelling, tenderness and purpura, which resolved within a week in the majority of individuals . Juvéderm Voluma® XC is intended for injection into deeper subcutaneous and periosteal planes and should not be injected intradermally; nor should it be injected into the lip or glabellar areas.

More recently, in 2016 and 2017, two additional fillers based upon Vycross® technology received FDA approval. Vobella XC® is indicated for lip augmentation and correction of perioral rhytides in adults over the age of 21 years whereas Vollure XC® corrects moderate to severe wrinkles and folds such as the nasolabial fold (see Table 158.4 ). Unlike previously FDA-approved products with these indications, Vollure® is the first HA filler reported to last up to 18 months in the pivotal trials.

A unique feature of HA is its reversibility, and complications from HA fillers can often be easily corrected. Injections of hyaluronidase (Vitrase®, Hylenex®) can dissolve previously injected HA; this is very helpful if the filler has been misplaced, if there is a complication post-injection (e.g. vascular occlusion, delayed granulomatous reaction), or if there is impending vascular necrosis. A recent in vitro , dose-response study suggested that Juvéderm® was more resistant to hyaluronidase when compared to Restylane®. In the authors' experience, 10 units (U) of hyaluronidase (Vitrase®) per 0.1 cc of Juvéderm or 5 U per 0.1 cc of Restylane® may be the most appropriate dose to dissolve the HA . The need for the greater amount of hyaluronidase for Juvéderm® correction likely reflects the more highly crosslinked nature of the product.

With the exception of Belotero Balance®, all currently FDA-approved HA families have a product that is pre-packaged admixed with lidocaine, which significantly reduces pain on injection (see Table 158.4 ).