Injectable soft tissue fillers: Overview of clinical use

INTRODUCTION — A wide variety of injectable soft tissue fillers are available for clinical use, including biodegradable products (hyaluronic acid, collagen, calcium hydroxylapatite, and poly-L-lactic acid), products that remain indefinitely in tissue (polymethylmethacrylate microspheres, hydrogel polymers, and silicone), and viable autologous fat. Soft tissue fillers are used for multiple cosmetic and therapeutic indications. Adequate clinician training in the use of these agents is essential for the prevention and appropriate management of adverse events.

Examples of indications for injectable soft tissue fillers and the basic principles of treatment will be reviewed here. Details on the efficacy, use, and adverse effects of specific soft tissue filling agents are discussed separately. (See "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Permanent agents".)

COSMETIC APPLICATIONS — Facial aging results from a combination of changes that involve the skin (eg, wrinkling, dyspigmentation, and vascular changes) and underlying tissues. A progressive loss of tissue volume due to the atrophy and displacement of subcutaneous fat, as well as a reduction in structural support due to bone remodeling, contribute significantly to facial aging [1-3].

Soft tissue fillers can be used to restore a semblance of youth through the replacement of lost tissue volume and the filling and effacement of coarse wrinkles. Examples of age-related features that may be treated with soft tissue fillers include (figure 1):

●Upper face:

•Glabellar lines – Deep vertical lines in the glabellar area form as a result of repetitive contraction of the muscles that mediate brow depression (picture 1). Soft tissue fillers can be used to soften the appearance of these lines. Because of the important role of muscular activity in the creation and exacerbation of glabellar lines, concomitant treatment with botulinum toxin is often beneficial [4,5]. (See "Botulinum toxin for cosmetic indications: Treatment of specific sites", section on 'Glabellar rhytides'.)

•Horizontal forehead lines – Horizontal forehead lines result from the repetitive elevation of the brow over time (picture 2). Similar to glabellar lines, placement of a soft tissue filler into deep horizontal forehead lines can diminish their appearance. Horizontal forehead lines may also be improved with botulinum toxin injection. (See "Botulinum toxin for cosmetic indications: Treatment of specific sites", section on 'Horizontal forehead rhytides'.)

•Lateral brow lift and temporal fossa changes – The natural loss of periorbital fat that occurs with aging results in lateral brow ptosis and reduced lateral brow projection (picture 3). Fillers can be used to elevate the lateral brow and restore its anterior projection [6].

•Temporal fossa wasting – Volume replacement with soft tissue fillers can minimize the appearance of age-related concavity in the temporal area.

●Mid-face:

•Nasojugal fold (tear trough depression) – With aging, pronounced depressions may occur between the rim of the orbital bone and the nasal sidewall due to the relaxation of suspensory ligaments of the eye and the descent of the malar fat pad. This can be difficult to correct surgically. The nasojugal fold has been successfully managed with the injection soft tissue fillers [7,8].

•Cheeks – Hypoplasia of the zygoma and the descent and atrophy of midfacial fat contribute to loss of the heart-shaped contour that is characteristic of the young female face. Injection of soft tissue fillers into the malar area increases anterior projection of the cheek and diminishes the appearance of nasolabial folds, leading to a more youthful appearance [2,6].

●Lower face:

•Nasolabial folds – Nasolabial folds are the most common sites treated with soft tissue fillers (picture 4) [9-13]. United States Food and Drug Administration approval for many products is limited to use in this area.

•Oral/perioral – Vertical perioral wrinkles and mouth frown can be corrected with soft tissue fillers (picture 5A-B); lip augmentation also can be performed with these agents [14-25].

•Chin – Melomental folds (marionette lines) and horizontal creases in the chin are amenable to treatment (picture 6A-B). Fillers have also been used for chin and mandibular augmentation [6,26].

●Nonfacial sites:

•Hand rejuvenation – Soft tissue augmentation can camouflage the skin laxity, wrinkling, and prominence of bone that characterize the appearance of the aged hand [27-30].

•Neck and chest – Soft tissue fillers can ameliorate signs of flaccidity, atrophy, and wrinkling in the neck and presternal chest [31].

In addition to the indications described above, soft tissue fillers may also be used to repair cosmetic contour defects that are unrelated to age. Soft tissue fillers are minimally invasive alternatives to traditional rhinoplasty for patients who wish to avoid surgery [32-36]. Fillers have also been used to correct post-surgical contour deficiencies and asymmetries in the nose [37].

THERAPEUTIC APPLICATIONS — Soft tissue fillers play an important role in the correction of defects that result from medical disorders, trauma, or surgery.

HIV-associated lipoatrophy — Human immunodeficiency virus (HIV)-associated lipoatrophy is the most extensively studied therapeutic indication for injectable soft tissue fillers [38-50]. Patients present with facial lipoatrophy, characterized by sunken cheeks, bitemporal wasting, and deep nasolabial folds. These features can be stigmatizing and can have a significant psychosocial impact on affected individuals [51]. Treatment has been associated with an improved sense of well-being and a high level of patient satisfaction [44-46,52,53]. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy" and "Injectable soft tissue fillers: Temporary agents", section on 'Calcium hydroxylapatite (Radiesse)' and "Injectable soft tissue fillers: Temporary agents", section on 'Poly-L-lactic acid (Sculptra)'.)

Scarring — Facial scars, particularly the pitted atrophic scars that often result from acne vulgaris, can be difficult to treat (picture 7). Soft tissue fillers can improve the appearance of individual scars and overall skin texture [54-57]. Injectable fillers have also been used to improve depressed scars that result from the treatment of skin cancer, trauma, or other causes [58,59].

Facial asymmetry and soft tissue defects — Facial asymmetry may be congenital or acquired (surgical or traumatic), and can result from bony or soft tissue abnormalities. Soft tissue fillers can be used to restore volume to underlying tissues in a manner that restores symmetry. Patients with trauma-induced lipoatrophy, hemifacial atrophy (Parry-Romberg syndrome), and linear scleroderma (linear morphea) have benefited from treatment with these agents [60-63]. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults", section on 'Linear morphea' and "Juvenile localized scleroderma", section on 'Linear scleroderma'.)

Examples of other defects that have been corrected with soft tissue fillers include mandibular prognathia, surgical or traumatic skull defects, and residual cosmetic defects following cleft palate surgery [64-66]. Multiple disorders involving the eyelids such as eyelid malposition, lid margin asymmetry, epiblepharon, and paralytic lagophthalmos, as well as loss of periorbital volume in anophthalmic enophthalmos have also been managed with these agents [67-72].

Other — Soft tissue fillers are utilized for medical purposes in nonfacial sites. Examples include nipple contouring and improvement of chest wall defects after mastectomy and breast reconstruction [73-75], and treatment of glottic insufficiency (vocal cord dysfunction) [76-80].

PATIENT SELECTION AND EVALUATION — The patient interview and clinical examination are used to identify appropriate candidates for treatment and to aid in the selection of the proper filling agent and injection technique. The assessment should begin with a review of the patient's relevant medical history that incorporates the following:

●History of prior cosmetic procedures

●Presence of bleeding disorders or immunosuppression

●Current medications, particularly anticoagulants

●Allergies and history of anaphylaxis

●Presence of contraindications to soft tissue fillers

The specific contraindications for the selected filler should be reviewed prior to treatment. General contraindications to treatment with soft tissue fillers include:

●Infection at or near the site of injection

●Allergy to product components

The safety of these agents in pregnancy and lactation has not been established. Additional contraindications for specific soft tissue fillers are reviewed separately. (See "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Permanent agents".)

The physical examination should occur while the patient is seated upright. Asking the patient to identify problematic areas with the use of a mirror will help to ensure that the clinician has a clear understanding of the patient's concerns. The unique nature of patient anatomy requires an individual approach to the management of each patient; in some cases, treatment of additional locations or the inclusion of adjunctive cosmetic procedures is necessary to achieve the best results.

FILLER SELECTION — If the patient is an appropriate candidate for treatment with a soft tissue filler, the clinician must then determine which agent should be used. The properties of fillers vary widely, and agents cannot be blindly interchanged. As an example, the use of polymethylmethacrylate microspheres in the lip or in areas of thin skin is not recommended due to a high risk for implant visibility, lumpiness, or beading after injection. (See "Injectable soft tissue fillers: Permanent agents", section on 'Polymethylmethacrylate microspheres'.)

The desired duration of effect must also be considered; fillers that are eventually degraded in tissue, such as hyaluronic acid, offer the advantage of reversibility in the case of undesirable placement, but require multiple subsequent treatments to maintain the desired effect (table 1). Permanent fillers should only be used in carefully selected patients; the use of biodegradable agents is particularly advisable for cosmetic patients who are receiving a filling agent for the first time. (See "Injectable soft tissue fillers: Permanent agents", section on 'Precautions'.)

Clinician experience also influences the choice of soft tissue filler; improper use can result in an unacceptably high risk for adverse effects. Clinicians who have not been trained in the use of particular soft tissue fillers should refrain from use of those agents.

There is an emerging body of literature detailing rheologic properties (flow-related properties) of fillers [81]. These include elastic modulus (G') and viscosity (G''). Consideration of rheologic properties can aid in selecting an appropriate filling agent.

Common clinical uses for specific types of fillers are provided in a table (table 1). The specific properties of soft tissue fillers that influence the selection of an agent are reviewed separately. (See "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Permanent agents".)

INFORMED CONSENT AND DOCUMENTATION — Realistic expectations for treatment outcomes must be thoroughly discussed with patients, as optimal patient satisfaction is dependent not only on the clinician's technical skill, but also on the fulfillment of patient expectations [82]. In addition, the risks associated with the use of the selected filler should be carefully reviewed with patients prior to treatment.

We recommend the use of an informed consent document that confirms patient understanding of the potential adverse effects and expected treatment outcome. We have also found that digital photographs taken before and after treatment are useful for clinical follow-up and for documentation of pre-existing asymmetries or defects. The latter also may be useful in the event of medicolegal disputes.

ADMINISTRATION

Before treatment — To reduce the incidence and severity of bleeding and bruising, we instruct patients to avoid substances that impair hemostasis (acetylsalicylic acid, nonsteroidal antiinflammatory agents, excessive alcohol, vitamin E supplementation, and other dietary supplements that may have an anticoagulating effect) for one week prior to treatment, provided these agents can be discontinued safely [83,84].

Due to concern for reactivation of oral herpes simplex virus (HSV) infection following lip augmentation, the use of prophylactic antiviral therapy at the time of lip augmentation with a soft tissue filler is often recommended [85,86]. However, the risk for reactivation of HSV infection following the injection of soft tissue fillers is unknown, and the value of prescribing prophylactic antiviral agents has not been evaluated.

In our practice, we typically prescribe prophylactic antiviral therapy for patients undergoing treatment of the lips. The preferred dosing for HSV prophylaxis in this setting is uncertain. We utilize 1 g of valacyclovir at the time of lip injection and 500 mg twice daily for 10 days following the procedure. Famciclovir or acyclovir may also be given for prophylactic therapy.

Skin preparation — There is insufficient data to draw definitive conclusions on the most appropriate regimen for skin cleansing in preparation for the injection of soft tissue fillers. In general, makeup should be removed and the area of injection and the surrounding skin should be cleansed with an antiseptic agent. Cleansing the skin with alcohol is commonly performed prior to the injection of hyaluronic acid or collagen fillers. Examples of alternative cleansers include povidone iodine or chloroxylenol. Although some clinicians have suggested use of chlorhexidine, we generally avoid chlorhexidine because of risk for chlorhexidine gluconate-induced corneal injury [87].

Due to concern over the risk for biofilm formation and chronic infection, some clinicians have recommended use of sterile, rather than clean surgical technique when injecting long-acting agents [88,89]. We utilize clean surgical technique during the injection of biodegradable soft tissue fillers, and sterile technique for nonbiodegradable (permanent) fillers.

Anesthesia — Topical anesthetics or local nerve blocks are commonly used to reduce pain during treatment. Additionally, a number of injectable fillers are formulated with lidocaine, which has been shown to reduce pain [90-96]. In practice, many clinicians (including ourselves) sometimes mix lidocaine with filling agents that do not contain an anesthetic.

Pain may also be reduced through use of the smallest suitable needle, slow infiltration, minimization of the number of needle punctures, and injecting through areas of previously anesthetized skin. Other interventions that may be useful for reducing pain include ice application, skin vibration, patient distraction, and treatment in a relaxed and soothing physical environment.

Injection techniques — The preferred injection technique varies according to the filler preparations used, area to be treated, and experience of the injector. The four techniques commonly used for the injection of soft tissue fillers are (figure 2) [97]:

●Linear threading – The needle is inserted into the skin and the filler is injected in a linear fashion as the needle is withdrawn (retrograde) or inserted (antegrade). Threading is commonly used for lip augmentation or the treatment of nasolabial folds. Use of antegrade injection, also known as the "push-ahead" technique, may reduce the risk for bruising when treating delicate areas, such as the upper eyelid or brow [98].

●Depot/serial puncture – A bolus of the filler is deposited into tissue at the site of needle puncture. A single puncture or a series of punctures may be performed. The serial puncture method is often used for lip augmentation or for superficial wrinkles.

●Fanning – This technique is an extension of threading. An initial retrograde injection is followed by multiple cycles of redirection of the needle and retrograde injection without complete withdrawal from the skin. Fanning is used for the treatment of larger defects.

●Cross-hatching – A series of parallel linear injections are performed followed by another series of linear injections into the same area that are perpendicular to the first set of injections. Similar to fanning, cross-hatching is typically used in the treatment of large areas.

The appropriate depth of injection is dependent upon the filler used and the site treated (figure 3). Injections that are placed too superficially may result in palpable or visible filler implants, and injections that are placed too deeply may not provide the desired effect. In general, coarse defects require more viscous fillers and deeper placement than less prominent lines or defects. The appropriate depth of placement of individual soft tissue fillers is discussed in greater detail separately. (See "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Permanent agents".)

Post-procedural care — In an attempt to reduce the risk for unintended migration of the filler after injection, we typically advise patients to avoid massaging injected areas, to refrain from strenuous cardiovascular or other highly physical activity for at least six hours after treatment, and to sleep with the head elevated for one night [99]. Short-term minimization of exaggerated and repetitive facial movements may also decrease the risk of implant migration or displacement [100]. Normal skin care regimens (including makeup) can be resumed after 24 hours.

SIDE EFFECTS AND COMPLICATIONS — Adverse effects following soft-tissue augmentation may be classified as early reactions (0 to 14 days after treatment), late (14 days to 1 year after treatment), or delayed (appearing over one year after treatment) [88]. Side effects that are common to the use of multiple filling agents are reviewed below; the adverse effects associated with specific filling agents are reviewed elsewhere. (See "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Permanent agents".)

Early adverse effects

Common adverse effects — The most common early side effects of injectable soft tissue fillers include bruising, edema, and erythema. The application of ice after injection may help to reduce swelling, and preoperative precautions regarding anticoagulating agents may help to reduce the severity of bruising. (See 'Before treatment' above.)

Vascular compromise — Rarely, vascular compromise, resulting in tissue necrosis can result from compression or obstruction of blood vessels in the glabella (supratrochlear artery) or nasolabial fold (angular artery [101-104]). Immediate regional blanching, a reticulate, violaceous discoloration of the skin, or significant pain following treatment may indicate impending tissue necrosis. (See "Anatomic danger zones for facial injection of soft tissue fillers".)

Management — Although the efficacy and safety of interventions for filler-related, vascular occlusion have not been evaluated in formal studies, the following procedure has been recommended in the event of vascular compromise [105]:

●Immediately discontinue injection

●Gently massage the affected site

●Immediately apply heat (eg, via gauze soaked in warm water)

●Apply nitroglycerin paste under occlusion (apply cyclically for 12 hours on and 12 hours off until clinical improvement)

If treatment was performed with a hyaluronic acid filler, hyaluronidase can be injected into skin in the site of filler placement [106]. Hyaluronidase has been used successfully in combination with heat and nitroglycerin paste in patients who developed signs of impending vascular necrosis after injection of hyaluronic acid fillers [107,108]. Some authors have suggested that hyaluronidase also may be useful for impending vascular necrosis following treatment with calcium hydroxylapatite or other fillers. Additional studies are necessary to clarify the best regimen and the appropriate clinical scenarios for hyaluronidase therapy [108]. Because anaphylaxis is a potential side effect of hyaluronidase, prick testing to detect an immediate hypersensitivity reaction is recommended prior to injection [109]. (See "Injectable soft tissue fillers: Temporary agents", section on 'Reversal' and "Anatomic danger zones for facial injection of soft tissue fillers", section on 'Management of vascular compromise'.)

Low molecular weight heparin has also been used in the management of patients with filler-induced, vascular occlusion [105,110].

Prevention — Examples of measures that may help to reduce the risk of vascular occlusion include using cannulas (27-gauge or larger), adopting a slow and anterograde or retrograde manner of injection, and keeping the needle constantly mobile. However, the impact of these injection strategies on decreasing the risk of necrosis is difficult to quantify.

Although typically performed as a safety measure, the utility of aspiration before injection with hyaluronic acid fillers is controversial because the viscosity of the product may not permit adequate flashback into the syringe when using fine-tipped needles. A 2015 study in which hyaluronic acid syringes were used to withdraw fresh blood from a heparinized tube found that the presence of hyaluronic acid within the needle lumen often inhibited the return of blood during both slow and fast needle aspiration, supporting the theory that the absence of visible blood does not eliminate the possibility of intravascular placement [111]. Additionally, it has not been confirmed that routine performance of aspiration reduces occurrences of vessel occlusion [112].

The proper selection of appropriate agents (eg, using fillers with smaller particle size in superficial injection planes) is also imperative in helping to minimize this complication. It is also generally advised to avoid injection in the immediate vicinity of large, named facial vessels. Finally, many experts have adopted and implemented the use of blunt-tipped cannulas, which reduce, but do not eliminate, the risk of intravascular entry. (See "Anatomic danger zones for facial injection of soft tissue fillers".)

Vision loss — Central retinal artery embolism resulting in blindness can occur as a result of retrograde flow of a filler into the central retinal artery after accidental injection of the supratrochlear or supraorbital arteries in the glabellar region, the dorsal nasal artery in the bridge of the nose, or branches of the facial artery in the cheek, nasolabial folds, or lips [113-118]. A systematic review of the literature identified 190 reported occurrences of filler-induced blindness between 2000 and 2018, with autologous fat or hyaluronic acid fillers as the most common causes [118]. (See "Anatomic danger zones for facial injection of soft tissue fillers".)

Data are insufficient to confirm the efficacy of any therapy for acute vision loss, and the best approach to treatment is unclear. Examples of treatments that may be of benefit based upon case reports and case series include hyaluronidase injection, ocular massage, systemic glucocorticoids, hyperbaric oxygen, and other interventions [117]. Immediate injection of hyaluronidase into the injection site that resulted in vision loss is typically performed in patients with vision loss secondary to injection of hyaluronic acid fillers. The addition of periocular injection of hyaluronidase has also been suggested, such as direct injection into the supratrochlear and supraorbital arteries, injection into the region of these vessels, and retrobulbar and peribulbar injections [117].

Although no treatment has been demonstrated to be consistently effective, given the risk for irreversible, disabling vision loss, clinicians performing injection of soft tissue fillers should be prepared to manage this complication. Immediate access to hyaluronidase and an ophthalmologist familiar with the acute management of filler-induced vision loss is prudent. Ideally, periocular injections of hyaluronidase are performed within 90 minutes.

Late and delayed onset adverse effects — Late and delayed onset reactions include the formation of nodules, granulomatous or other inflammatory reactions, chronic infections, and consequences of filler migration [82,88,119,120]. Although some adverse reactions improve with time, the injection of hyaluronidase in the case of hyaluronic acid fillers, corticosteroid injections, or the administration of systemic agents, others may require surgical intervention or may be impossible to completely reverse [121]. (See "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Permanent agents".)

SUMMARY AND RECOMMENDATIONS

●Multiple soft tissue fillers are utilized for cosmetic and therapeutic indications. Soft tissue fillers reduce contour defects in the face, neck, and body through the replacement of tissue volume lost due to aging, trauma, or other events. (See 'Cosmetic applications' above and 'Therapeutic applications' above.)

●Treatment with a soft tissue filler should begin with an assessment that determines whether the patient is an appropriate candidate for therapy. Infections at or near the site of injection and allergies to product components are contraindications for treatment. (See 'Patient selection and evaluation' above.)

●The selection of an appropriate soft tissue filler is dependent on factors such as the defect to be treated, product availability, and clinician expertise. Soft tissue filler properties vary widely, and product-specific clinician training is required. (See 'Administration' above.)

●The risks of treatment and expected treatment outcome should be discussed thoroughly with patients. We utilize informed consent documents and pretreatment and post-treatment photographs to document patient understanding and treatment progress. (See 'Patient selection and evaluation' above.)

●Vascular occlusion is a rare but serious complication that can occur with the use of soft tissue fillers. Initial steps for management of impending tissue necrosis include discontinuation of injection, gentle massage, heat application, nitroglycerin paste, and, for hyaluronic acid fillers, injection of hyaluronidase. (See 'Side effects and complications' above and "Anatomic danger zones for facial injection of soft tissue fillers".)

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