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Biochemistry, Physiology, and Tissue Interactions of Contemporary Biodegradable Injectable Dermal Fillers

Herrmann, Jennifer L. MD*,†; Hoffmann, Rachel K. MD, MSEd; Ward, Chloe E. MD§; Schulman, Joshua M. MD; Grekin, Roy C. MD

doi: 10.1097/DSS.0000000000001582
Review Article
Free

BACKGROUND Injectable dermal fillers are becoming increasingly popular for soft tissue augmentation and rejuvenation. Most contemporary biodegradable products are derived from hyaluronic acid, calcium hydroxylapatite, or poly-L-lactic acid. Achievement of desired cosmetic outcomes is largely dependent on selection of the optimal injectable product based on the chemical composition, the physiologic interactions with surrounding tissue, product longevity, and a thorough understanding of potential adverse reactions.

OBJECTIVE To review and describe the biochemistry, physiology, and tissue interactions of the most commonly used contemporary biodegradable dermal fillers.

METHODS A thorough review of the literature was performed with additional review of pertinent clinical cases and corresponding histopathology.

RESULTS This article provides a comprehensive review of the biochemistry, physiology, and potential tissue interactions of the most commonly used biodegradable dermal fillers. The underlying biochemical properties of each product and how they contribute to specific physiologic and adverse tissue reactions is described.

CONCLUSION Understanding of the innate differences in the physical properties, and physiologic responses to soft tissue fillers allows clinicians to achieve desired aesthetic outcomes with fewer adverse events.

*Moy-Fincher-Chipps Facial Plastics/Dermatology, Beverly Hills, California;

Divison of Dermatology, Harbor-UCLA Medical Center, Torrance, California;

Department of Dermatology, New York University School of Medicine, New York, New York;

§Division of Dermatology, University of Ottawa, Ottawa, Ontario, Canada;

Dermatopathology Service, Northern California Veteran Affairs Health Care System, Sacramento, California;

Department of Dermatology, University of California, San Francisco, San Francisco, California

Address correspondence and reprint requests to: Rachel K. Hoffmann, MD, MSEd, Department of Dermatology, New York University School of Medicine, 240 East 38th Street 11th Floor, New York, NY 10016, or e-mail: RachelKHoffmann@gmail.com

The authors have indicated no significant interest with commercial supporters.

As public awareness and acceptance of fillers has grown, so have the number of injections performed annually. In 2016, 2.6 million dermal filler injections were performed, an increase of 2% from 2015, and 298% from 2000.1 Soft tissue fillers offer a less invasive alternative with less downtime than traditional surgical interventions. In the United States, the most commonly used nonpermanent fillers are hyaluronic acid (HA), calcium hydroxylapatite (CaHA), and poly-L-lactic acid (PLLA). Of the 2.6 million filler injections performed in 2015, 2.38 million (92%) were biodegradable, and 2 million (77%) were HA.1 A thorough understanding of the differences between the biology, mechanisms of action, and tissue reactions allows clinicians to successfully and safely use these products.

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Endogenous Hyaluronic Acid

To fully appreciate the HA filler group, HA should be reviewed in its native form. Hyaluronic acid is a natural glycosaminoglycan composed of glucuronic acid and N-acetyl glucosamine disaccharide units (Figure 1). Up to 30,000 units can be linked together, forming structures with molecular weights reaching 107 Da.2 It is highly water-soluble due to the presence of 1 salt (−COO Na+) and 4 hydroxyl (−OH) groups per disaccharide. The hydroxyl groups participate in hydrogen bonding with water, stabilizing the solvated state. The salt group dissociates, resulting in a more favorable, lower energy state. Hyaluronic acid surrounds extracellular spaces, and is associated with proteins and cells.3–6 It is a component of the dermis, vitreous of the eye, hyaline cartilage, synovial joint fluid, and umbilical cord.7,8 Its biologic functions range from structural support to embryonic development, cellular proliferation and differentiation, cell signaling, and wound healing.2,9,10 Critical to these functions are its helical structures that can be modified by pH, neighboring proteins, and macromolecules.

Figure 1

Figure 1

An average human body contains about 15 g of HA, half of which is located in the skin.11 In the dermis, the high flexibility of HA polymers and their hydrophilicity enables them to fill empty spaces within the extracellular network.12 Through a dynamic exchange of water molecules with its environment, HA hydrates and cushions the skin. Enzymes such as hyaluronidase and free radicals continuously degrade free HA polymers. Cleaved fragments are cleared by the lymphatics and ultimately converted to carbon dioxide and water in the liver. The half-life of native HA is 1 to 2 days.7,13 Although HA is abundant in neonatal skin, production declines with age, resulting in a structurally weakened dermis and visible signs of aging.14

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Exogenous Hyaluronic Acid

Because the basic monomeric unit of HA does not show specificity for any organ or species, HA is considered immunologically inert.15 Reports of delayed hypersensitivity reactions are rare, estimated to be less than 1 in 5,000.16 Such reactions are likely related to impurities in the manufacturing process. Excellent host tolerance as well as its viscoelastic and hydrating properties make HA an ideal soft tissue filler. In the exogenous form, HA is synthesized primarily from Streptococcus equi species of bacteria and purified by alcohol precipitation to remove reactive antigens.17 However, this product should not be used in people with a known hypersensitivity to streptococcal or gram-positive bacteria, or in patients with known lidocaine hypersensitivity, for products containing lidocaine. Hylaform fillers are composed of purified HA derived from rooster combs and are contraindicated in patients with known hypersensitivity to avian proteins.

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Cross-Linking

To overcome the short half-life of free HA polymers, manufacturers cross-link HA units using 1,4-butanediol diglycidyl ether (BDDE), divinyl sulfone, or 2,7,8-diepoxyoctane (DEO).17 Cross-linking stabilizes the superstructure through intermolecular bonds, slowing enzymatic and free radical degradation. Note that non–cross-linked HA is liquid. Cross-linking of fluid HA provides structure and adhesive stick, creating a gel.18 BDDE, the most commonly used cross-linking agent, is considered safe and nonreactive.19 Trace residual amounts of unreacted BDDE remain through purification only. In Allergan's range of fillers, the remaining unreacted BDDE is reported at less than 2 parts per million.19 The unreacted BDDE epoxide groups are neutralized over time through hydrolysis. The degradation by-products of cross-linked HA, uncrosslinked HA, and unreacted BDDE have all been described as harmless at the concentrations found in fillers, or are already found in the skin.19 There remains controversy, however, as to whether cross-linkers can introduce toxicity.8,22 Researchers are now considering potential alternative cross-linking agents, such as urea.8

Cross-linking is measured as the percentage of disaccharide units bound to a cross-linking molecule. For example, a 1% cross-linked gel has 1 cross-linking molecule for every 100 HA monomers. Higher degrees of cross-linking translate to stiffer gel products resistant to deformation.20 Note that exceptionally high percentages of cross-linking may decrease product hydrophilicity. Rarely, this can provoke a foreign body reaction by the host's immune system, which could be further compounded by increased longevity from cross-linking.20

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Particle Sizing

Although cross-linking is critical to creating a lasting HA product, the process effectively creates a large gel-like mass that must be “sized” to pass through a needle.17 Sizing can be accomplished using sieves or homogenization, creating biphasic and monophasic gels, respectively. Biphasic or particulate products consist of cross-linked particles with an average particle size proportional to the grade of sieve used.21 The particles are suspended in free or minimally cross-linked HA, which acts as a lubricant, enhancing ease of injection. The G′ of biphasic gels is high and thus they are harder.8 Particle size influences injection locations, depth, injection fluency, and product degradation times. Products with larger particle sizes are typically used for deeper injections, are stiffer to inject, and last longer in tissue.20 Monophasic or nonparticulate HA gels are monodensified if cross-linked once, or polydensified if continuously cross-linked.21–23 These products are sized through homogenization, yielding gels with a smooth consistency, a broader distribution of particle size, and a lower G′ value (see next section).23 As such, they are softer and more easily injected than biphasic products.8 Currently, only Juvéderm has monophasic, nonparticulate products.

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Rheology—Hardness and Viscosity

Rheology, the study of flow and deformation of materials between liquids and solids, is used to understand the mechanical properties of HA fillers and their implantation into soft tissue.8,24 The particle size, HA concentration, and cross-linking all influence the rheology of a product.21 Several concepts are used to describe the gel properties of fillers: G* (the complex modulus) measures the total energy needed to deform a material during sheer stress, and reflects the hardness of a gel. G* is calculated from a summation of G′ (the elastic modulus or storage modulus) and G″ (the viscous or loss modulus), which are determined by a rheometer. G′ measures the elasticity of a material or how much it can recover its shape after shear deformation (G′∼G*).24 G′ is thus often used to quantify the hardness of a product.8,24 These rheologic properties provide a framework for understanding how shear stresses, vertical forces, and compression forces from muscle movement may deform a filler product.8,24

Dermal fillers must be viscoelastic (G′ < G*) to inject under high strain through a needle, yet remain elastic to provide lasting results resistant to the shear deformation forces in soft tissue.24 Split-face trials have shown that the ideal nasolabial fold correction requires a smaller volume of a higher G′ filler.25–27 However, gels with a higher G′ may feel firmer under skin because they resist deformation. This can lead to more discomfort and swelling than with lower G′ products.21 The addition of lidocaine can enhance patient comfort during injection without substantially compromising the rheologic properties of the filler.29

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Cohesivity

The cohesivity of the gel refers to the tendency to hold form or shape under stress, proportional to the degree of attraction between the cross-linked HA units. It increases with both cross-linking degree and HA concentration.8 Low cohesivity between the gel particles can lead to separation from the deposit and filler migration.24 A correlation between filler viscosity, and the pattern and degree of tissue integration has been shown in ultrasound studies.25 Fillers with low cohesivity are often preferred for correction of small rhytides because they are easier to mold and spread evenly in the skin. High-cohesivity fillers, however, are better suited for revolumizing larger areas of loss.24 Efforts have been made to quantify the viscosity of various fillers,30 including the recently developed 5-point Gavard–Sundaram Cohesivity Scale, which the authors report reproducibly measures filler cohesivity.25 This reference scale classifies HA fillers into high cohesivity groups (Belotero Balance; Merz Inc., Raleigh, NC) with cohesive polydensified matrix technology (CPM), medium-high cohesivity (Juvéderm Ultra XC and Ultra Plus XC; Allergan, Irvine, CA) with Hylacross technology, low-medium cohesivity (Juvéderm Voluma XC; Allergan) with Vycross technology, and low cohesivity (Restylane Lyft; Galderma Laboratories, L.P., Fort Worth, TX) with nonanimal stabilized hyaluronic acid (NASHA) technology.

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Molecular Weight

Molecular weight also determines the biologic and physicochemical properties of HA.8,31 Molecular weight of HA is proportional to the number of repeating disaccharides (Figure 1). There are low molecular-weight forms of HA, and high molecular-weight forms, greater than 1,000 kDa. Most cosmetic HA products contain high molecular-weight polymers and range from 500 to 6,000 kDa.18 Juvéderm Voluma XC, however, mixes high molecular-weight polymers with some low molecular-weight polymer chains, using Vycross technology to improve cross-linking efficiency.29 This product lasts up to 24 months,8,28,32 whereas most other Food and Drug Administration (FDA)-approved HA fillers last between 6 and 12 months (Table 1).8,18,29,30,33 However, it has been found that the results for other HA fillers may have a longer lasting effect clinically, with one study showing up to 18 months for Restylane (Galderma Laboratories, L.P.).34Table 1 synthesizes various FDA-approved HA filler properties. However, in reviewing this table, it is important to consider the inherent variations in the reported rheologic properties that are calculated at different times, under different conditions, yielding widely variable results.21

TABLE 1-a

TABLE 1-a

TABLE 1-b

TABLE 1-b

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Calcium Hydroxylapatite

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

Figure 2

Figure 2

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Poly-L-Lactic Acid

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

Figure 3

Figure 3

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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.

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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

Figure 4

Figure 4

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.

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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

Figure 5

Figure 5

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

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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.

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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.

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Inflammatory Adverse Reactions

Infection

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

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Granulomatous Inflammation

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

Figure 6

Figure 6

Figure 7

Figure 7

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Conclusion

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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