Cosmetic CaHA is a synthetic, biocompatible, biodegradable soft tissue filler, commercially available as Radiesse (Radiesse; Merz Inc.). It is composed of CaHA microspheres suspended in an aqueous glycerin–sodium carboxymethylcellulose carrier gel (Figure 2). The high viscosity and elastic properties of the gel keep the 20 to 45 μm CaHA microspheres in solution before and during injection.35 Because CaHA is identical in composition to the mineral portion of bone and teeth, immunogenicity is negligible. It has been used in multiple medical applications with no reported toxicities.35 The microspheres are designed with macropores or micropores. Macroporous CaHA is osteoinductive and readily permits fibrovascular ingrowth through pores that reach up to 500 μm in diameter.36,37 Products with macroporous CaHA are used as a scaffold for repairing bony defects because they induce and are slowly replaced by new bone.36,37 By contrast, cosmetic CaHA is microporous with pores measuring 2 to 5 μm. This is too small to permit osseointegration, and to date, there have been no documented cases of Radiesse forming bone after injection into soft tissue.20
Poly-L-lactic acid is an immunologically inert polymer of L-enantiomeric lactic acid (Figure 3). Lactic acid polymers have been used safely in medicine for 3 decades. They degrade into naturally occurring stereoisomers, which ultimately get excreted as carbon dioxide and water.38–40 Cosmetic PLLA, commercially available as Sculptra Aesthetic (Sculptra Aesthetic; Galderma Laboratories, L.P.), comprises powdered PLLA microparticles ranging from 40 to 65 μm, mannitol, and sodium carboxymethylcellulose.40 The product is reconstituted with sterile water, with or without lidocaine. It must be left to hydrate at room temperature for at least 24 hours to ensure that a smooth hydrocolloid suspension of PLLA particles in the carrier gel is achieved. If inadequately hydrated and super-concentrated PLLA is injected, nodule formation can occur.40
Physiologic Tissue Reactions
Physiologic reactions when implanted into the skin are determined by the physical and biochemical properties of soft tissue fillers. Ideally, an adverse reaction of the surrounding tissue should not occur. Inflammation must be limited to prolong product longevity, yet controlled such that stimulation of collagenesis is predictable with stimulatory fillers. The body's local reaction to foreign body through phagocytosis is arguably the most important factor in determining filler longevity.20 In this process, tissue enzymes and free radicals breakdown filler product into fragments that are removed by circulating macrophages and subsequently, lymphatic channels. Particle size, shape, and hydrophilicity influence phagocytosis.20 In general, particles larger than 15 to 20 μm in diameter resist phagocytosis. Hyaluronic acid, CaHA, and PLLA particles exceed this size range. With Radiesse, larger microspheres help prevent unwanted release of bone-resorptive cytokines by macrophages.20 For particles smaller than 15 μm, shape becomes more important for phagocyte recognition and attachment.41 Hydrophilic particles better resist phagocytosis, but become increasingly hydrophobic if opsonized.20 For each of the major classes of injectable fillers, manufacturers have manipulated particle properties to maximize product efficacy and longevity while minimizing undesired effects.
Hyaluronic Acid Tissue Integration and Longevity
Once injected into the skin, HA provokes a mild inflammatory reaction at the host-tissue border.42 This is followed by a gradual fibrous ingrowth, which anchors the gel to the surrounding host tissue, preventing product migration.42,43 Manufacturing techniques influence how fillers spread in tissue after injection. Biphasic gels form large aggregates distributed regularly throughout the dermis and seem to push apart collagen bundles (Figure 4A).23,44 Monophasic monodensified gels form smaller aggregates, whereas monophasic polydensified gels integrate uniformly into the surrounding tissue, due to their broad spectrum of particle sizes (Figure 4B).23,44 Such differences have clinical implications. If injected too superficially, the larger aggregates of polyphasic gels may appear blue beneath the skin as longer-wavelength light is transmitted and shorter-wavelength blue light is refracted. This is known as the Tyndall effect. Because monophasic polydensified gels fill extracellular spaces most similarly to endogenous HA, these products are more suitable for superficial placement. Large aggregates of biphasic gels distort and push collagen bundles causing tissue swelling and pain. Conversely, such stretching of collagen fibers may stimulate fibroblasts to synthesize new collagen, a desired effect ultimately enhancing the performance of the filler. At least one report has documented increased dermal production of collagen after injection of the biphasic NASHA filler, commercially available as Restylane (Galderma Laboratories, L.P.).45
Longevity of HA fillers is determined by particle size, manufacturing processes, volume, location of injection, and host metabolism.20 Hyaluronic acid products typically last 6 to 12 months. As mentioned, Juvéderm Voluma XC can last 24 months due to the cross-linking of high and low molecular-weight HA.8 Smaller particles have a greater total surface area exposed for enzyme and free radical degradation and last a shorter time in tissue. Suspension in a large amount of uncrosslinked HA can also shorten half-life.23 When free HA is rapidly degraded, cross-linked particles become exposed to attack. This can be demonstrated in vitro by adding hyaluronidase to HA products. Biphasic gels liquefy more quickly than monophasic gels.46 Presumably, biphasic cross-linked particles become more available to hyaluronidase after the non–cross-linked fraction is consumed. By contrast, enzymes penetrate only the outermost gel surface of monophasic products; thus, more time is needed for their breakdown.
Calcium Hydroxylapatite and Poly-L-Lactic Acid Tissue Integration and Longevity
Both cosmetic CaHA and PLLA are considered stimulatory fillers. They both stimulate fibroblasts and induce collagen synthesis.47 Unlike HA products that fill tissue directly, stimulatory fillers volumize more than they fill. Although injection creates the appearance of immediate augmentation due to mechanical expansion of the surrounding tissue, this effect is transient.48 The carrier gel disappears over 1 to 3 months, and a controlled subclinical inflammatory host response ensues, encapsulating product microparticles, leading to fibroplasia and eventual collagen biosynthesis (Figure 5). This ultimately creates gradual, naturally appearing volume that persists as filler particles degrade and inflammation fades.49
With cosmetic CaHA, fibrin has been shown to surround product microspheres at 1 month after injection.43 At 3 months, microspheres are encapsulated by a shell of fibrin, fibroblasts, and macrophages. By 9 months, microspheres become deformed, irregular, and begin to disappear. They are broken down into calcium and phosphate ions, which presumably get eliminated from the body, much like small pieces of bone. Visible correction in the appearance of the skin and rhytides typically ranges from 10 to 14 months, influenced by the amount of product injected and host metabolism.49
Poly-L-lactic acid generates a similar subclinical inflammatory response, ultimately resulting in collagen production. Because the product is much more dilute than CaHA, the immediate “fill” effect diminishes more quickly as water is absorbed and PLLA particles are distributed at lesser density. A capsule of macrophages, lymphocytes, mast cells, and fibroblasts surrounds these particles at 1 month after implantation.50 By 3 months, capsular thickness and cell density have decreased by 20%, and surrounding collagen fibers have increased. At 6 months, the capsule is 20% thinner, composed almost entirely of collagen. By 18 months, the new collagen fibers persist, whereas the inflammatory response has largely resolved.50 Compared with the scaffold of CaHA microspheres, PLLA microparticles are degraded more slowly, creating a prolonged inflammatory response. This leads to more collagen synthesis and longer-lasting clinical results. On average, correction is visualized for 18 to 24 months.49
Adverse Tissue Reactions
With all soft tissue filler injections, erythema, swelling, bruising, pain, and pruritus are common and occur almost immediately. These reactions are caused by disruptions in the vasculature and dermal structures. With HA fillers, pain and swelling tend to increase with concentration of HA. The hydration level of HA products is below equilibrium; thus, they bind large amounts of water when injected into tissue.17 Pain, erythema, swelling, and pruritus typically self-resolve within a few days. Lidocaine can be added to certain products through manufacturing or reconstitution to attenuate pain and pruritus. Although rare, inadvertent intra-arterial injection can lead to tissue necrosis, scarring, and blindness in the most severe cases.40 A thorough knowledge of anatomic vasculature, injection of small amounts of product at slow speeds, and assessment for intra-arterial placement through needle reflux can help avoid such catastrophic outcomes. Some providers preferentially select HA products to mitigate these risks, as hyaluronidase injections can be done to breakdown the HA filler and potentially circumvent a complication. Animal-derived hyaluronidase products from ovine and bovine testicular hyaluronidase are commercially available as Vitrase (Vitrase; ISTA Pharmaceuticals Inc., Irvine, CA) and Amphadase (Amphadase; Amphastar Pharmaceuticals Inc., Rancho Cucamonga, CA), respectively. Hylenex (Hylenex; Halozyme Therapeutics, San Diego, CA) is the only FDA-approved recombinant human hyaluronidase. It is considered less immunogenic, and is often used in cosmetic practice.8 Adverse reactions can be further divided into inflammatory and noninflammatory, which may be immediate or delayed.
Noninflammatory Adverse Reactions
Noninflammatory reactions include the appearance of papules and nodules. Noninflammatory nodule formation early on may be related to injection technique, excessive filler use, superficial placement, the use of an inappropriate product for a given indication, subsequent muscular activity, product impurities, or irregularities of filler surfaces.51–54 With HAs, higher product viscosities and sticky syringes can result in a sudden accidental release of too much gel, potentially resulting in a nodule. Massage, hyaluronidase, or simple incision and product expression is often curative. Rarely, if a large amount of product is deposited after depot injection, formation of a surrounding fibrous capsule occurs.46 This results in a nodule that becomes more prominent with capsular contraction. Insertion of a large bore needle to break through the capsule and aspiration of product may be necessary for correction.46
In addition to proper dilution and reconstitution, deep placement is critical with CaHA. Nodules from CaHA usually result from injections that are either too superficial or from placement of product within the muscle fibers. Intramuscular placement is particularly common around the mouth as CaHA traverses the orbicularis oris muscle to form deposits under the submucosa of the inner lip.55,56 With PLLA, nodules usually result from incorrect reconstitution or poor injection technique. Shaking the product immediately after adding water, suboptimal crystal hydration leading to in vivo hydration, and a poor suspension at the time of injection can all result in an uneven distribution of the product in the tissue, giving it a lumpy appearance.57 Regarding the injection technique, care must be taken to avoid depositing a lump of excess product at the fan apex, or needle insertion point, when a fanning motion is used to disperse product. Similarly, superficial injection of product and placement into muscles should be avoided because complications like those seen with CaHA can occur.
Inflammatory Adverse Reactions
Adverse reactions after filler injection can be inflammatory in nature. Although uncommon, infection after filler treatment can occur. Infections can be caused by bacteria, viruses, fungi, including Candida, or can be polymicrobial.58 The most common viral infection after injection of fillers is herpes simplex virus.46 In individuals with a history of oral herpes outbreaks, pretreatment with acyclovir, valacyclovir, or famciclovir is generally recommended.46 Nodule formation can be due to bacterial infections both in the early phase within a few weeks, or delayed months to years after injection.54 Erythema and pain can help differentiate infectious early nodules from noninflammatory early nodules.53 If a single facial abscess develops, the cause is usually skin contamination. If multiple abscesses occur, the cause is most often from product contamination. Early on single facial abscess is generally due to Staphylococcus aureus or Streptococcus pyogenes.52 Later-onset infections occurring greater than 2 weeks after injections may be more generalized and may be due to atypical organisms (such as mycobacteria and Escherichia coli). The risk of infection can be mitigated by skin cleansing, working in a clean space, and by following product handling and storage guidelines. In some cases, the development of biofilms can complicate filler injections.51,59 Biofilms are heterogeneous structures of bacterial colonies irreversibly bound to foreign body material.51 They secrete a self-made extracellular polymeric slime layer that interferes with immune system recognition. This allows for up to 1,000-fold improved resistance to antibiotics.60,61 Because cultures are typically negative, biofilms are best detected by molecular techniques such as polymerase chain reaction.62 Biofilm bacteria can remain dormant for months to years before spontaneously becoming active, in the right environmental conditions. Biofilms may cause abscesses, granulomatous inflammation, and recurrent infections.20 Treatment using antibiotics and anti-inflammatories is sometimes successful. Because biofilms are difficult to detect and eradicate, effort should be focused on their prevention. Antimicrobial skin preparation and limited needle insertion through mucosal surfaces with high proximity to oral flora are advisable. A study using a porcine skin model demonstrated no significant difference between alcohol, povidone iodine, and chlorhexidine in reducing the biofilm bacterial burden of S. aureus. The bacterial burden was reduced 3 logs during the wiping process. In the same study, using an in vitro injection model with artificial silicone skin, the fanning technique was found to increase the risk of transferring skin flora compared with serial puncture and linear threading. The risk of transferring viable bacteria was also increased with lower-gauge (wider bore) needles and superficial injections.63
Granulomatous inflammation after injection has been reported with nearly all soft tissue fillers.64–66 However, the incidence of clinically significant granulomas in practice is estimated to be only 0.01% to 0.1%.67 Unfortunately, the term granuloma has been used inconsistently in the literature, ranging from clinically palpable nodules to large inflammatory lesions showing histological evidence of polymorphonuclear foreign body type giant cells. Granulomatous inflammation is most accurately defined as a systemic, adverse, type IV hypersensitivity reaction.68 In a true granulomatous process, all sites initially injected with the same product should simultaneously react. The presence of only a few foreign body giant cells on histopathology does not constitute a granulomatous reaction. In the case of PLLA, histologic examination can help distinguish between nodules and granulomatous inflammation. A nodule appears as a mass of product surrounded by scattered foreign body giant cells, whereas a true granuloma appears as product fragments surrounded by a palisaded wall of multinucleated giant cells, attempting to isolate the foreign body from surrounding tissue (Figure 6).64 This is in distinct contrast to the purposeful stimulation of subclinical inflammation that is responsible for fibroplasia and tissue augmentation seen with stimulatory fillers. The occurrence of true granulomas is difficult to predict; however, they may occur more often in patients with known granulomatous disease. There have been reports of filler inducing granulomatous plaques in sarcoidosis patients, with development of sarcoidal granulomas around filler particles (Figure 7). Treatment of granulomas is challenging. Intralesional steroids, 5-fluorouracil, or a combinational approach are frequently used.68 Surgical excision is usually not recommended, given their poorly defined clinical borders, and the risk of fistula or abscess formation, and scarring.69
Since its inception, soft tissue augmentation has progressed from filling lines to more comprehensively sculpting faces and rejuvenating nonfacial sites. A better understanding of product differences in composition, physical properties, and their associated tissue reactions allows clinicians to more thoughtfully select and correctly inject products to achieve specific clinical goals. With better anticipation of tissue reactions, complications and undesired outcomes can be minimized.
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© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
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