Injectable soft tissue fillers: Temporary agents

INTRODUCTION — Soft-tissue fillers can be used alone or in combination with other aesthetic procedures to correct wrinkles and to restore tissue volume lost due to aging, lipoatrophy, or other causes. As opposed to permanent fillers, which persist indefinitely, temporary fillers are eventually resorbed by the body. Some agents, such as injectable collagen and hyaluronic acids, function primarily through a volume-filling effect. Others, including calcium hydroxylapatite and poly-L-lactic acid fillers, act as scaffolds for endogenous collagen formation.

The type of defect to be treated and the desired duration of effect influence the selection of a soft tissue filler (table 1). Regardless of which agent is selected, clinician familiarity with the product utilized is crucial; improper injection techniques result in poor cosmetic outcomes and an increased incidence of adverse effects. Although some adverse effects resolve spontaneously with time, other adverse effects (eg, tissue necrosis) may result in permanent sequelae, such as scarring.

The characteristics, efficacy, and adverse effects of several types of biodegradable soft tissue fillers will be reviewed here. An overview of the principles of the clinical use and complications of soft tissue fillers, as well as a discussion of permanent soft tissue fillers are available elsewhere. (See "Injectable soft tissue fillers: Permanent agents" and "Injectable soft tissue fillers: Overview of clinical use".)

HYALURONIC ACID — Hyaluronic acid is a naturally occurring glycosaminoglycan that is an essential component of the extracellular matrix of the dermis. The molecule plays a key role in the maintenance of skin structure and function, and its high water-binding capacity is of value for the maintenance of moisture in the skin [1].

The injection of exogenous hyaluronic acid into the skin effectively reduces visible signs of volume loss, while simultaneously providing a natural look and feel after treatment. These features, plus a relatively low risk for adverse effects have made hyaluronic acid-based fillers the most commonly used injectable soft tissue fillers worldwide (table 1) [2]. The US Food and Drug Administration (FDA)-approved uses for hyaluronic acid fillers vary for specific products; examples of indications include moderate to severe facial wrinkles and folds (eg, nasolabial folds), augmentation of lips or cheeks, and volume deficits in the dorsal hands. The clinical effects of treatment typically persist for 6 to 12 months (table 1) [3].

Product characteristics — A shared feature of all hyaluronic acid fillers is the inclusion of hyaluronic acid that is chemically altered through cross-linking, which allows the molecule to resist rapid degradation by hyaluronidase and other factors in the skin. In contrast, naturally occurring or uncross-linked hyaluronic acid is degraded in skin within a few days.

Examples of the chemical processes utilized for cross-linking hyaluronic acid include:

●Butanediol diglycidyl ether (BDDE) cross-linking – Restylane, Belotero Balance, and Juvéderm (multiple types)

●Divinyl sulfone cross-linking – Prevelle Silk and Captique

●Biscarbodiimide cross-linking – Elevess

●1,2,7,8-diepoxyoctane cross-linking – Puragen

Additional factors distinguish the hyaluronic acid filling agents, including the source of hyaluronic acid and the expected duration of effect (table 1). Moreover, specific gel characteristics, such as the concentration of hyaluronic acid and gel properties that affect product consistency, act in concert to determine the clinical behavior of each filling agent (table 2) [1,4,5]:

●Origin – The chemical composition of hyaluronic acid is similar across species. Hylaform, an older form of hyaluronic acid filler, contained hyaluronic acid derived from rooster combs. The majority of hyaluronic acid-based filling agents now contain nonanimal stabilized hyaluronic acid (NASHA) derived from the fermentation of Streptococcus equi bacteria.

●Concentration – The total concentration of hyaluronic acid in filling agents is readily available in package inserts. Provided other gel characteristics are similar, agents with higher concentrations of hyaluronic acid can be incompletely hydrated, resulting in a higher capacity for water-binding once placed in tissue [4]. This can manifest as slight swelling of the product after placement in the skin [5].

●Consistency and flow – Factors such as particles, gel hardness, and concentration of cross-linked hyaluronic acid affect the consistency and fluidity of hyaluronic acid fillers (table 2) [1,4,5]:

•Particulate versus nonparticulate gels – Large particles provide greater filling power and more resistance to degradation in tissues, which may be beneficial for the treatment of deep skin folds and rhytides and for volumizing skin [1]. Products that contain large particles require larger gauge needles (eg, 27-gauge needles) for injection, as opposed to the 30-gauge needles that can be used with smaller particle agents.

Nonparticulate gels are characterized by a smoother consistency. Juvéderm Ultra, Ultra Plus, Voluma, Volift, and Volbella, which are nonparticulate gels, incorporate a relatively high degree of cross-linking to counterbalance the loss of filling power and product longevity that can result from the elimination of particles [1]. Belotero Balance and Teosyal are additional examples of nonparticulate gel fillers.

•Gel hardness – G’ is a measure of the amount of gel displaced based upon the degree of stress applied to the gel [1]. Gels with a high G’ (hard gels) exhibit greater resistance to deformation, require greater pressure to inject into the skin, and tend to provide a firmer feel under the skin. Soft gels may be beneficial for the treatment of areas with thin skin, such as the periorbital area or lips [1]. Restylane is a relatively hard (higher G’) gel.

•Degree of cross-linking – The amount of uncross-linked (soluble) and cross-linked (insoluble) hyaluronic acid in a gel influences gel viscosity [4]. Decreasing the proportion of cross-linked hyaluronic acid contributes to a less viscous product and a smoother flow during injection, but may contribute to a shorter duration of effect [4,6]. Decreasing the amount of cross-linked hyaluronic acid also decreases the hardness of a gel.

Mechanism of action — The efficacy of hyaluronic acid fillers has been primarily attributed to a space-filling effect of hyaluronic acid and water bound to hyaluronic acid molecules. However, a study that compared the histopathologic findings in forearm skin injected with a hyaluronic acid filler (Restylane) to sites injected isotonic saline found that the stimulation of collagen synthesis may contribute to treatment efficacy [7]. The authors proposed that mechanical tension on fibroblasts, which has been associated with the regulation of collagen synthesis in other studies [8-10], may contribute to the clinical effect of Restylane. Additional studies are necessary to determine whether similar findings occur with other hyaluronic acid filling agents and in facial skin.

Formulations — A wide variety of hyaluronic acid fillers are available (table 1). The Juvéderm and Restylane lines are among the most commonly used products in the United States.

Examples of other hyaluronic acid agents used in soft tissue filling worldwide include Belotero Balance, Elevess, Elravie, Puragen and Puragen Plus [11,12], Prevelle Silk, Revanesse, and Teosyal.

Efficacy — The utility of hyaluronic acid filling agents for soft tissue augmentation of the nasolabial folds and other sites has been documented in multiple randomized trials, uncontrolled studies, and case reports [3,6,13-34].

Versus bovine collagen — Randomized trials comparing the efficacy of hyaluronic acid fillers with bovine collagen, a filling agent that preceded the development of hyaluronic acid filling agents, for nasolabial folds have found superior results with hyaluronic acid fillers. Examples include:

●In a randomized, split-face trial of 439 patients with moderate to severe nasolabial folds, patients were treated with either one of three hyaluronic acid fillers (Juvéderm 30, Juvéderm Ultra, or Juvéderm Ultra Plus) or bovine collagen (Zyplast). Clinically significant improvement persisted for longer after treatment with the hyaluronic acid agents [22]. Twenty-four weeks after the last treatment, 81 to 90 percent of nasolabial folds treated with the hyaluronic acid fillers maintained statistically significant improvement, compared with only 36 to 45 percent of nasolabial folds treated with bovine collagen. Treatment was well-tolerated in all groups. Juvéderm 30 is not available in the United States.

●A randomized, split-face trial of 138 patients with mild to severe nasolabial folds treated with a hyaluronic acid filler (Restylane) or bovine collagen (Zyplast) found that the degree of improvement at two, four, and six months after treatment was superior for the hyaluronic acid filler [19]. Six months after treatment, 67 percent of patients treated with bovine collagen had returned to baseline severity, compared with 30 percent of patients treated with hyaluronic acid. Patient tolerance to the treatments was similar; local adverse events were mild to moderate and resolved within seven days in most patients.

Versus calcium hydroxylapatite — The results of two randomized trials suggest that injectable calcium hydroxylapatite (Radiesse) may have a greater duration of effect than hyaluronic acid-based fillers in the treatment of nasolabial folds (see 'Calcium hydroxylapatite (Radiesse)' below):

●In a randomized trial of 205 patients with moderate to severe nasolabial folds treated with calcium hydroxylapatite or hyaluronic acid (Perlane, Juvéderm 24, or Juvéderm 24HV), significantly greater proportions of patients treated with calcium hydroxylapatite than with hyaluronic acid were improved at all time points up to eight months [35]. However, the changes in wrinkle severity scores were similar among all of the products. Juvéderm 24 is not available in the United States, and Juvéderm 24HV is equivalent to Juvéderm Ultra.

●The results of a split-face randomized trial of 60 patients with moderate to severe nasolabial folds treated calcium hydroxylapatite or hyaluronic acid (Restylane) found that more nasolabial folds treated with calcium hydroxylapatite remained improved 12 months after the initial injection (79 versus 43 percent) [36]. In addition, at the same time point, nasolabial folds treated with calcium hydroxylapatite treated exhibited superior results significantly more often than the sides treated with hyaluronic acid (47 versus 5 percent of patients).

With lidocaine — The inclusion of lidocaine in hyaluronic acid fillers has made the injection of these fillers far less uncomfortable. The results of several randomized trials indicate that lidocaine-containing hyaluronic acid fillers reduce patient discomfort and can be used safely without affecting product efficacy [37-43].

With botulinum toxin — Combination therapy with hyaluronic acid fillers and botulinum toxin may improve the longevity of treatment results when treating sites of dynamic wrinkles, such as glabellar lines [16,44]. Reduced deformation of the filler in the dermis as a result of botulinum-toxin induced local muscle relaxation is theorized to contribute to this finding. (See "Overview of botulinum toxin for cosmetic indications", section on 'Soft-tissue augmentation'.)

Use — Although some randomized trials have compared the efficacy of individual hyaluronic acid fillers [12,20,21,45-47], factors such as the type of defect to be corrected, treatment site, and preferred duration of effect are the most important factors to consider during treatment selection. Clinician familiarity with a product is also critical; improper injection technique can lead to poor results or adverse effects. (See "Injectable soft tissue fillers: Overview of clinical use", section on 'Injection techniques'.)

The ideal placement and depth of injection is dependent on the defect and site treated. In vivo and ex vivo pathologic studies suggest that the subcutis and deep dermis are the primary sites of deposition of hyaluronic acid after injection into nasolabial folds [48,49]. In contrast to treatment with Zyderm and CosmoDerm, overcorrection of defects is not required.

Juvéderm and Restylane products are supplied in prefilled syringes. The manufacturers of these agents recommend the following dose guidelines:

●Juvéderm Ultra, Juvéderm Ultra Plus, Juvéderm Ultra XC, Juvéderm Ultra Plus XC, and Juvéderm Volbella XC – No more than 20 mL per 60 kg of patient weight should be administered per year [50].

●Restylane and Restylane-L – Package inserts state that no more than 6 mL should be administered per treatment session because the safety of injecting higher amounts has not been established [51].

Juvéderm and Restylane products are contraindicated in patients with a history of anaphylaxis, multiple severe allergies, and allergies to gram positive bacterial proteins. Additionally, Restylane is contraindicated in patients with bleeding disorders.

Adverse effects — The most frequent adverse effects associated with hyaluronic acid filling agents are transient and mild, and include pain bruising, edema, and erythema at the injection site [52,53]. Fan-like needle use, rapid injection (>0.3 mL/minute), and high volume injections have been associated with increased rates of adverse effects [46]. In addition, noninflammatory nodules or a bluish discoloration of the skin (secondary to the Tyndall effect) can occur when injections are placed too superficially [53-56].

Delayed hypersensitivity and granulomatous reactions to hyaluronic acid filling agents are rare [53,57-77]. It is estimated that such reactions occur in only 0.02 percent of treatments. Differences in risk for delayed reactions based upon product type have been proposed based upon a retrospective study in which 17 of 400 patients (4 percent) treated with Juvéderm Volbella in the tear troughs or lips developed delayed reactions [78]. Delayed reactions typically manifest as inflammatory papules or nodules that appear weeks to months after injection.

Complications such as bacterial and mycobacterial infections or vascular occlusion resulting in tissue necrosis or compromise of the retinal artery are also uncommon [79-84]. The development of lower eyelid xanthelasmata following periorbital injection of a hyaluronic acid filler has been reported in two patients; however, causality has not been confirmed [85].

Reversal — Misplacement or excessive injection of hyaluronic acid fillers can be treated with injection of hyaluronidase [54,55,86-91]. Hyaluronidase appears to be well tolerated; local injection site reactions occur infrequently, and urticaria, angioedema, or anaphylaxis rarely occur [92]. Due to the potential for anaphylaxis, patients should be prick tested to evaluate for immediate hypersensitivity reactions prior to the injection of hyaluronidase [93]. The use of hyaluronidase to reverse the effects of hyaluronic acid fillers is not approved by the FDA. The management of patients with signs of impending tissue necrosis due to vascular occlusion is reviewed separately. (See "Injectable soft tissue fillers: Overview of clinical use", section on 'Early adverse effects'.)

The optimum dosing of hyaluronidase has not been established; doses reported in the literature vary from less than 5 units to 75 units per injection site. Doses of 10 units were effective for the dissolution of a hyaluronic acid-based filler (Restylane) injected into forearm skin in a randomized trial [91]; doses as low as 1.5 to 3 units may also be effective [94].

Hyaluronidase has also been used successfully in the management of patients with hyaluronic acid filler-induced granulomatous reactions, including a patient who failed to improve with intralesional and topical corticosteroids, oral prednisone, topical tacrolimus, and systemic antibiotic therapy [76,86]. In a woman with multiple granulomatous nodules that developed after hyaluronic acid filler injection, reductions in nodule size, tenderness, and erythema attained with intralesional triamcinolone were followed by complete resolution of nodules after intralesional hyaluronidase therapy [76]. Treatment with hyaluronidase has also been linked to the successful management of a patient with a presumed hyaluronic acid embolic event in the distribution of the angular artery [81].

COLLAGEN — With the advent of hyaluronic acid fillers, the use of collagen fillers has become uncommon and generally is no longer recommended. Collagen filling agents are associated a relatively shorter duration of effect, and skin testing is required prior to the use of bovine-derived agents.

CALCIUM HYDROXYLAPATITE (RADIESSE) — The calcium hydroxylapatite filler (Radiesse; formerly known as Radiance) is composed of synthetic, uniform, and smooth calcium hydroxylapatite microspheres suspended in an aqueous carboxymethylcellulose gel carrier [95]. The US Food and Drug Administration (FDA)-approved uses of Radiesse include the correction of moderate to severe facial folds and wrinkles, such as nasolabial folds, the correction of facial lipoatrophy in patients with HIV infection, and the correction of volume loss in the dorsum of the hands. However, diluted and hyperdiluted calcium hydroxylapatite have also been used for skin tightening [96].

Mechanism of action — Once injected into the skin, the carrier gel is gradually resorbed and the remaining calcium hydroxylapatite microspheres stimulate the local production of endogenous collagen. Eventually, the microspheres are degraded into calcium and phosphate ions and are excreted [97-99].

Efficacy — The efficacy of calcium hydroxylapatite for the treatment of nasolabial folds and other facial sites in healthy patients is supported by multiple studies [99-108]. As an example, the benefit of this agent was evident in a cohort study of 1000 patients treated for a variety of cosmetic indications (most commonly nasolabial folds, marionette lines, and oral commissures) [99]. More than 80 percent of patients in the study reported persistence of treatment benefit after 12 months.

Randomized trials comparing calcium hydroxylapatite with other temporary filling agents have also supported the efficacy of this product for nasolabial folds; calcium hydroxylapatite has exhibited greater duration of effect when compared with hyaluronic acid and human collagen fillers [35,36,101]. (See 'Versus calcium hydroxylapatite' above.)

Several uncontrolled studies have documented beneficial effects of calcium hydroxylapatite injections for HIV-associated lipoatrophy [102,109-113]. In one open-label study of 100 patients with this disorder, treatment led to improvement in all patients through 12 months, and 91 percent of patients remained improved after 18 months [112].

Use — Radiesse is supplied as a gel in a prefilled syringe; use of a 25 to 27 gauge needle is recommended for injection. A formulation of Radiesse that contains lidocaine is not available; however, premixing Radiesse with lidocaine prior to injection can be used to reduce patient discomfort [114]. The depth of injection is subdermal (figure 1) and overcorrection of defects should be avoided. Massage of the treatment site immediately after injection facilitates even distribution of the product.

Treatment with Radiesse is contraindicated in patients with a history of anaphylaxis, multiple severe allergies, or known hypersensitivity to any of the product components.

Adverse effects — Injectable calcium hydroxylapatite is generally well tolerated [115]. Injection-site reactions, including transient erythema, edema, ecchymosis, pain on injection, and pruritus are the most frequently reported side effects [95]. Noninflammatory nodules secondary to aggregation of the filling agent can occur after treatment of the lips; the formation of nodules in other sites is rare [99,102,105,107,108]. One retrospective study that included 349 lip augmentation patients found an incidence of nodule formation of 6 percent [99]. The development of inflammatory nodules in the lip due to a foreign body reaction to calcium hydroxylapatite has also been reported [116].

Nodules can resolve over time; there is no injectable product that can be used to dissolve the product after injection. If treatment is desired, massage, needle disruption, or surgical excision can be utilized to accelerate resolution [99,102]. In one patient, a calcium hydroxylapatite nodule disappeared following treatment with a fractional carbon dioxide laser for skin laxity [117].

Vascular occlusion resulting in skin necrosis and ocular ischemia has occurred in at least one patient after injection of a calcium hydroxylapatite filler [118]. The management of patients with signs of impending skin necrosis is reviewed separately. (See "Injectable soft tissue fillers: Overview of clinical use", section on 'Side effects and complications'.)

Although calcium hydroxylapatite implants are usually visible on computed tomography (CT) scans and are sometimes detectable on radiograph imaging, they do not appear to be detrimental for the interpretation of these studies [119,120].

Large particle calcium hydroxylapatite — Improvement in nasolabial folds and mid-facial atrophy after injection with a large particle formulation of calcium hydroxylapatite (Coaptite) has been reported in a few patients [121]. FDA approval for Coaptite is limited to the treatment of urinary incontinence, and additional studies are necessary to explore the efficacy and safety of this agent as a cosmetic filler. (See "Stress urinary incontinence in females: Persistent/recurrent symptoms after surgical treatment", section on 'Periurethral injection therapy'.)

POLY-L-LACTIC ACID (SCULPTRA) — Sculptra and Sculptra Aesthetic contain microparticles of poly-L-lactic acid (PLLA), a biocompatible and biodegradable synthetic polymer [122]. Sculptra is US Food and Drug Administration (FDA) approved for the treatment of HIV-associated lipoatrophy; Sculptra Aesthetic is approved for the correction of shallow to deep nasolabial fold contour deficiencies and other facial wrinkles.

Mechanism of action — Technically, PLLA does not "fill" the skin. Once injected, PLLA induces a subclinical inflammatory response that stimulates fibroblast proliferation and collagen formation, leading to a progressive increase in volume of the dermis. PLLA is gradually degraded over the course of 9 to 24 months [100].

Efficacy — The efficacy of PLLA for HIV-associated facial lipoatrophy is supported by randomized trials and uncontrolled studies that have demonstrated improvement in patient appearance and cutaneous thickness [123-136]. As an example, in an uncontrolled study of 61 HIV-positive patients who were treated with PLLA every three to six weeks over a five-month period, all patients improved after treatment [127].

The utility of PLLA for nasolabial folds was established in a randomized trial of 233 patients who were given up to four treatment sessions with either PLLA or human collagen. Patients treated with PLLA exhibited statistically significant improvement in nasolabial fold severity over baseline at all study time points, and improvement was superior to collagen 3, 6, 9, and 13 months after treatment. Multiple other studies have supported the efficacy of PLLA for nasolabial folds, acne scars, facial asymmetry, and other cosmetic indications [133,137-147]. Clinical improvement has been documented for up to two years after PLLA treatment in immunocompetent and HIV-positive patients [127,133,146]. The duration of effect exceeds that of hyaluronic acid and collagen fillers (table 1).

Use — Sculptra and Sculptra Aesthetic must be reconstituted with sterile water at least two hours prior to injection to ensure complete hydration of the product. The injection should be placed in the deep dermis or subcutaneous fat with a 26-gauge or larger needle (figure 1). When treating the nasolabial folds, injection is usually performed in a cross-hatch (grid-like) pattern.

Because treatment results progressively improve over time, undercorrection of the defect is the goal. Of note, transient tissue edema may develop immediately after injection, resulting in the appearance of full correction. Subsequent treatments should be spaced by at least three weeks to allow for assessment of response.

Treatment should also be avoided in patients with a history of keloidal or hypertrophic scarring and patients with a known hypersensitivity to any of the product components [148,149]. In addition, we typically avoid the use of this agent in the lip and periorbital region due to an increased likelihood for nodule formation in these areas [145,147]. (See 'Adverse effects' above.)

Adverse effects — Potential adverse effects of injection include hematoma, bruising, edema, discomfort, inflammation, and erythema [122]. Another common complication is the occurrence of asymptomatic, subcutaneous papules weeks to months after treatment [122,150]. In one series of 130 immunocompetent patients treated with PLLA, nodule formation occurred in 8.5 percent. Subcutaneous papule formation has been reported in 6 to 44 percent of patients treated for HIV-associated lipoatrophy [151].

Proper dilution of the product, avoidance of poor injection technique (eg, superficial injections, overcorrection), and manual tissue massage immediately after injection may decrease the risk for this adverse effect nodule formation [152]. Nodules typically resolve spontaneously without intervention. Nodules that fail to resolve may require subcision (disruption of papules with a needle), excision, or intralesional corticosteroid therapy [133,148,149].

Delayed appearance of granulomatous reactions has also been reported in a few patients [147,153-155].

PLATELET-RICH FIBRIN MATRIX — Platelet-rich fibrin matrices (PRFM), which can be created through the centrifugation of blood, may have utility for cosmetic soft tissue augmentation [156]. In a series of 15 patients, nasolabial wrinkle severity was significantly reduced after injection of autologous PRFM [157]. The authors proposed that growth factors released from the injected platelets may have contributed to treatment benefit. Additional studies are necessary to determine the safety and efficacy of PRFM for this indication.

SUMMARY AND RECOMMENDATIONS

●A variety of injectable filling agents are available for the treatment of prominent skin lines, fat atrophy, and other contour defects involving soft tissue. Temporary fillers are composed of biodegradable ingredients, such as hyaluronic acid, collagen, calcium hydroxylapatite, and poly-L-lactic acid. (See 'Introduction' above.)

●Hyaluronic acid-based fillers are the most common injectable agents used for soft tissue augmentation. A wide variety of products are commercially available. All hyaluronic acid fillers contain chemically cross-linked hyaluronic acid, which allows the product to resist immediate degradation. Factors such as the defect type and location, the preferred duration of effect, and clinician expertise with specific agents determine the most appropriate choice of agent. (See 'Hyaluronic acid' above.)

●Transient bruising, discomfort, edema, and erythema are the most common adverse effects associated with the injection of hyaluronic acid fillers. Infrequently, patients may develop hypersensitivity reactions, granulomatous reactions, infections, or complications of vascular occlusion. (See 'Use' above and 'Adverse effects' above.)The effects of hyaluronic acid fillers diminish over time. Hyaluronidase injections have been used for the removal of hyaluronic acid filling agents after improper placement. However, the safety and efficacy of hyaluronidase for this indication have not been evaluated. (See 'Reversal' above.)

●Calcium hydroxylapatite is effective for the correction of soft-tissue defects, including nasolabial folds and HIV-associated lipodystrophy. Calcium hydroxylapatite is injected subdermally, and overcorrection of defects should be avoided. Adverse nodule formation after treatment is most likely to occur after injection of the lips. (See 'Calcium hydroxylapatite (Radiesse)' above.)

●The effects of poly-L-lactic acid are long lasting; improvement has been documented in patients treated for HIV-associated lipoatrophy and other soft tissue defects two years after treatment. Injections should be placed into the deep dermis or subcutaneous fat. Defects should be undercorrected at the time of treatment. (See 'Poly-L-lactic acid (Sculptra)' above.)

●Subcutaneous papules are a common adverse effect of treatment with poly-L-lactic acid. In addition, treatment is not recommended for patients with a history of keloidal or hypertrophic scarring. (See 'Adverse effects' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Alastair Carruthers, FRCPC, who contributed to an earlier version of this topic review.