ArteFill® Permanent Injectable for Soft Tissue Augmentation: II. Indications and Applications
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Patients ask for procedures with long-lasting effects. ArteFill is the first permanent injectable approved in 2006 by the FDA for nasolabial folds. It consists of cleaned microspheres of polymethylmethacrylate (PMMA) suspended in bovine collagen. Over the development period of 20 years most of its side effects have been eliminated to achieve the same safety standard as today’s hyaluronic acid products. A 5-year follow-up study in U.S. clinical trial patients has shown the same wrinkle improvement as seen at 6 months. Long-term follow-up in European Artecoll patients has shown successful wrinkle correction lasting up to 15 years. A wide variety of off-label indications and applications have been developed that help the physician meet the individual needs of his/her patients. Serious complications after ArteFill injections, such as granuloma formation, have not been reported due to the reduction of PMMA microspheres smaller than 20 μm to less than 1% “by the number.” Minor technique-related side effects, however, may occur during the initial learning curve. Patient and physician satisfaction with ArteFill has been shown to be greater than 90%.
KeywordsArteFill Dermal filler Permanent filler Soft tissue augmentation Wrinkle treatment
Indications are similar to those for hyaluronic acid fillers. The current FDA-approved indication is for treatment of nasolabial folds.
There is ease of injection due to a funnel in the syringe, despite a viscosity three times that of collagen injections alone.
Aesthetic correction with ArteFill appears to be sustained for many years because the PMMA microspheres cannot be broken down by enzymes or removed by phagocytosis.
Biocompatibility, safety, and stability at the implantation site persist indefinitely.
Maintenance of volume and pliability appear to be a product of natural and continuous connective tissue turnover and collagen deposition.
No migration, dislocation, or erosion through the skin has resulted, coincident with the complete encapsulation of the PMMA components .
There is minimal foreign body reaction as a result of the smooth surface of the microspheres and their uniform size.
Candidates for Treatment
The best candidates for treatment with ArteFill appear to be patients with well-defined wrinkle lines and furrows and little excess skin. If a patient is unsure about accepting the permanence of ArteFill treatment or desires to “preview” the expected effect, an initial implantation of a hyaluronic acid filler may serve to ensure that the patient will accept the “permanent” ArteFill result.
Patients with sebaceous skin and large pores but few deep folds are ideal candidates and should achieve good and long-lasting results, whereas patients with extremely thin and loose skin are poor candidates for ArteFill. In these thin-skinned patients the ArteFill implants may be palpable, show through with tension on the skin, or even be visible. Interestingly, the thickness of the facial dermis is not usually diminished in older patients as is commonly expected because of the well-known thinning of the dermis of the extremities; the facial dermis gets thicker with age , as does the size of the nose, ears, and chin.
Horizontal Forehead Lines
Transverse rhytids respond well to treatment. The gray of the needle should not show through the wrinkle line during injection. Superficial intradermal implantation may result in the formation of small granules like a string of pearls (as seen in Fig. 3) within the line. For deeper wrinkle lines, a second and third session will often be required.
Glabellar Frown Lines
Glabellar lines generally pose little problem for ArteFill treatment since the dermis is thick and the connective tissue beneath provides good support for the implant. When slight overcorrection is deemed necessary, care must be taken not to inject too far inferiorly, otherwise a nodule may appear. Deep lines and furrows may require repeated treatments. They can often be placed intradermally because of the thickness of the skin in this area. During the 20-year history of Artecoll use in Europe, no case of glabellar skin necrosis [8, 9, 10] or vision loss  was reported to the manufacturer. Unlike collagen and hyaluronic acid, ArteFill cannot be injected through a resting needle; the needle has to be moved back and forth while avoiding intravascular deposition. In severe cases of glabellar frown lines, Botox® can be administered along with ArteFill to accomplish full correction and aid the ArteFill effect.
Shadowed Lower Lids
Crow’s Feet Wrinkles
ArteFill is indicated in the lateral periocular area only if there are a few deep crow’s feet in a patient with thick skin. Treatment of multiple crow’s feet with ArteFill in patients with thin and flaccid skin is contraindicated because the implant may show through and appear as fine granules.
Facial Wasting and Cheek Depressions
If surgical or traumatic scars are mature, depressed, and soft, they can easily be filled with ArteFill in a three-dimensional fanlike manner using the tunneling technique. A second implantation may be necessary 3 months later. Depressed scars are among the most effective indications.
Irregularities of the Nose
While injecting, it is useful to hold the white roll between two fingers to prevent dislocation. Usually half of the lip can be implanted by withdrawing the needle while injecting under pressure (Fig. 18). A volume of 0.4–0.8 cc ArteFill should be sufficient for each lip. A larger volume may result in a dense mass and pain, so one must take care to augment the lips in stages. If ArteFill is well tolerated and the lips are soft after 3 months, more ArteFill can be added to the same tissue plane.
A second implantation of ArteFill applied horizontally along the dry–wet border (red line) of the inner vermilion increases fullness or the “pouting” effect (Fig. 17). At this location the serial puncture technique must be used exclusively to prevent clumping of ArteFill during early lip movement (Fig. 18).
A flattened philtrum  may be raised effectively with two vertical injections of ArteFill starting from below, i.e., from the two peaks of the Cupid’s bow within the white roll. Very rarely has an implant dislodged into the surrounding tissue. In such an unlikely event, correction is possible by molding the implant between two fingers into the philtrum or the white roll. The injections should be done using linear threading and under no circumstances should the serial puncture technique be used in the visible part of the lip.
Perioral Lip Lines
Additional augmentation of the lost philtrum from below may give the lip a more youthful look . Patients must be advised that their treated folds will improve over time. In recurrences, a second implantation between the ArteFill “base” and the dermis of the wrinkles usually provides a lasting effect. Patients should be informed that ArteFill can sometimes be felt as a rubber-like substance or eventually may be seen as a white substance in the lips when the skin is stretched.
Negative Corners of the Mouth
These may be the most difficult problems to treat but can be very rewarding areas for ArteFill implantation. Success has been achieved with a steplike approach. First, the lower white roll is augmented horizontally about 1 cm from the corner. Then, four to five vertical and horizontal threads of ArteFill are be placed absolutely subdermal (Fig. 1) using a cross-hatching technique since there is often a lack of subcutaneous fat. This supports this area and slightly lifts the corner of the mouth. It may be helpful to extend some of the implant around the upper lip in a C-shaped fashion. Be aware that if the skin is relatively thin, implanting ArteFill superficially may result in telangectasia. Avoid the orbicularis oris muscle (Fig. 17). Best results have occurred with ArteFill implanted in many different tunnels and always in two or more sessions.
The vertical elongation of the dystopic corners of the mouth as they extend to the mandibular border has been greatly improved by linear threading and deep intradermal crisscross implantation of ArteFill (Fig. 1). There is little subdermal fat between the skin and orbicularis oris muscle in this location. Therefore, implantation of any filler must be very superficial but still subdermal in order to avoid lumping.
Horizontal Chin Fold
Horizontal Neck Folds
Flat nipples and inverted nipples Grades I and II (i.e., those that can be stimulated to protrude) and nipple volume asymmetries can be augmented with 0.2–0.4 cc of ArteFill. On applying deep local anesthesia beneath the nipple, the desired amount of augmentation can be estimated by using the anesthetic to temporarily “plump” the nipple. After waiting 10 min until the anesthetic fluid is absorbed, one lifts the nipple with a small hook and implants ArteFill from the side, moving the needle back and forth to avoid implantation into the ducts. If some material extrudes into the ducts, it can easily be removed by massage. To date, there have been no reports of duct blockage by implantation of ArteFill. If treatment of inverted nipples Grades III and IV is desired, ArteFill implantation without blind severance of all ducts may increase the inversion. Therefore, in severe grades of nipple inversion, the ducts should first be severed as deeply as possible while lifting the inverted nipple with a hook. ArteFill may be implanted 3–4 days later.
Even for patients who have undergone successful facial rejuvenation, atrophied and indented dorsal spaces between the metacarpal bones is a sure manifestation of advanced age. Mitigation of the appearance of aged hands has been achieved successfully with Sculptra®  and Radiesse® . Experience with ArteFill suggests that a 1:1 dilution with saline through a Luer-lock connector to a 2-cc syringe creates easier flow and provides good volume. A long blunt 23G cannula should be applied to the 2-cc syringe and inserted between the knuckles. Fanlike injections of the dilute ArteFill into the subcutaneous space will push the veins away and fill the indentations. Massage of the area may be necessary to allow even distribution of the microspheres. Most patients require two treatments 4 weeks apart.
Laser treatment is no contraindication for ArteFill. In fact, it may be considered a complimentary treatment since ArteFill and the laser affect different layers of the skin. Laser peeling of the epidermis can be performed either 3–6 months before or preferably immediately after ArteFill implantation. Postinjection edema of the wrinkle lines and furrows seems to enhance the efficacy of the laser.
Dermabrasion and chemical peelings affect the same relatively superficial plane as laser resurfacing, i.e., the epidermis and papillary dermis. Therefore, none of these modalities should interfere with the implantation of ArteFill, which is injected deeper (in the reticular dermis). ArteFill can be injected either just before or weeks after the resurfacing procedure.
Facelifts in general do not correct very pronounced nasolabial folds or deep marionette lines. The treatment of choice for nasolabial folds is often a midface lift, which may produce scleral show in certain patients. Therefore, deep nasolabial or labiomental creases can be augmented with ArteFill just prior to a facelift, during the surgical session, or at a later time.
Botulinum toxin creates temporary paralysis of certain facial muscles but does not permanently eliminate deep facial furrows or wrinkles. ArteFill appears to be an excellent adjunct to Botox® treatments. ArteFill can be implanted concurrently or at a later time. In many instances, it appears that the long-term augmentation resulting from ArteFill is enhanced by the paralyzing effect of Botox, which eliminates the motion in a particular wrinkle line (e.g., glabellar frown lines) and therefore enhances the results with ArteFill as the collagen remodels.
Errors of Technique
Uneven distribution in the form of a string of pearls can be compensated by a second implantation of ArteFill into the gaps.
The most common mistake resulting in incomplete or inadequate treatment is placing the ArteFill too deep (into the subcutaneous fat). The implantation must be redone correctly.
Ridges and Nodules
Ridges or intradermal nodules can occur a few weeks following a too superficial (intradermal) injection of ArteFill (Fig. 3). Constant muscle movement appears to push the intradermal implant to be more superficial. Ridges or superficial nodularity can be easily removed by dermabrasion or tangential shaving without creating a noticeable scar because “exposed” ArteFill implants will epithelialize just like normal abraded skin. Dislodged nodules caused by intramuscular implantation may be softened by intralesional corticosteroid injections or, if palpable intraorally, may be excised. Excision of a nodule should always be performed thoroughly and completely since any residual ArteFill may potentially cause secondary hypertrophic scarring.
This phenomenon may occur in certain patients prone to keloid formation (Asians and African Americans) after superficial implantation of ArteFill. The therapy of choice is intralesional triamcinolone injections, which may level but do not narrow the scar.
Long-Lasting Redness or Telangectasia
This occurrence is usually caused by dilated capillaries, especially if extremely thin skin overlies the implant. This can be treated and resolved by laser or Intense-Pulse-Light (IPL) therapy .
Lumpiness in the Lip
Objectionable lip nodularity (Fig. 18) occurs frequently after implanting strands of ArteFill or any other injectable in the lip. Muscle movement during the first few days compresses the strands into nodules, which are best removed surgically (stab incision) if obvious or disturbing. They can be prevented by the serial puncture technique. Early smoking may induce nodularity. One female patient (Fig. 26) smoked immediately after implantation and compressed the injected strands into nodules. An intralesional injection of Kenalog® 4 weeks later, after the bovine collagen was replaced by connective tissue, diminished the volume by half and leveled the nodules.
Allergic reactions to the polymerized acrylic in PMMA microspheres are extraordinarily rare. However, as with all collagen preparations, allergic reactions to ArteFill’s collagen carrier may occur. Most of the allergenic telopeptides have been enzymatically removed in the partly denatured collagen of ArteFill. There were only two positive skin tests (0.2%) in an ArteFill skin test study involving 1000 patients; this result may allow removal of the FDA-required skin test for ArteFill in the future.
Subsidence of the Implant
PMMA microspheres cannot be phagocytized by macrophages or giant cells and cannot be broken down by enzymes. Therefore, the microspheres will remain permanently beneath the crease. However, if injected too deeply they will remain in the subcutaneous fat without effect on the crease. It should also be noted that facial muscle movement over several years may push the implant somewhat deeper if it is already primarily in the subcutaneous fat, and the crease may reappear after 5–10 years. If this occurs, another ArteFill implant on top of the previous one is reasonable.
With third-generation ArteFill, true granuloma formation is a rare event and has not occurred to date in the more than 15,000 ArteFill patients treated in the U.S. The incidence of granuloma formation with the second-generation product Artecoll was 0.02% (1:5000), with manifestation from 6 months to 6 years after treatment [28, 30]. Granulomas can develop after the injection of any dermal filler at a rate of 0.01–1.0% but can be treated effectively with intralesional corticosteroid (Kenalog®) injections . Granulomas are an overreaction of the body’s cellular defense system . Therefore, surgical removal of true granulomas  is the least one should consider since their borders are not confined and recurrences are almost predictable.
Treatment of Complications
Implant nodules, hypertrophic scarring, and misplaced ArteFill (Figs. 3, 19, and 26) react well to intralesional long-term crystalline corticosteroids . Local steroids inhibit fibroblast activity and collagen deposition, macrophage activity, and giant cell formation, as well as swelling, itching, and pain. A 1:1 mixture of lidocaine and triamcinolone = fluor-prednisolone (Kenalog® or Volon-A®) up to 20 mg/cc, or betamethasone (Diprosone®) up to 5 mg/cc, can be injected safely through a 1-ml syringe with a Luer-lock and a 30G needle. The steroid must be injected strictly into the nodule while guiding the needle tip back and forth. Corticosteroids injected into the surrounding soft tissue, especially fat, may cause temporary or, rarely, permanent skin atrophy. Should atrophy occur, a temporary filler such as hyaluronic acid will level the indentation until natural recovery occurs, usually within 3–12 months .
Potential Adverse Events Not Yet Reported
As with any injection into the face, ArteFill may be inadvertently implanted into a blood vessel. Theoretically, forceful injection into a dermal arterial branch of the supratrochlear artery could cause retrograde movement of the implant material into retinal arteries, resulting in vascular occlusion. Such complications have been reported with the use of collagen injections and, in rare cases, have resulted in the sudden and permanent loss of vision. Similar complications have been associated with other injectable preparations, including Brazilian PMMA products [8, 9, 10, 11, 33, 34], fat, corticosteroids, local anesthetics, and angiographic agents, but have not been reported after injection of Artecoll or ArteFill. These findings emphasize the importance of avoiding implantation into blood vessels by using blunt cannulas or by moving a sharp needle back and forth during implantation while maintaining constant pressure on the plunger.
Discussion and Conclusion
During its first two years of clinical use, ArteFill has proved to be an extremely safe and predictable soft tissue filler. Granuloma incidence, a small but consistent problem with its predecessor product, has been nil in the more than 15,000 patients treated (www.fda.gov/cdrh). Nevertheless, ArteFill still requires a learning curve and technical proficiency because of its higher viscosity and longer persistence [1, 35] than other available fillers. As physicians’ skills improve with repeated use of ArteFill, confidence builds and consistently excellent results and patient satisfaction emerge [3, 7, 36, 37].
Those who practice aesthetic surgery and dermatology are fortunate to have many tools at their disposal, including resurfacing modalities (lasers, dermabraders, chemicals), advanced surgical approaches with adjunct devices, paralytic agents to instantly mitigate adverse muscle activity, and dermal fillers, and soft tissue augmentation injectables. Until recently, however, there was no legally available permanent filler to place in the plastic surgeons’ armamentarium. Now, with ArteFill, that vacancy in the toolbox is filled. However, just as if one’s only tool is a hammer, all the world becomes a nail, ArteFill is not a panacea. So far, it has proved highly useful in creating long-lasting results in a number of desirable applications. However, its true versatility bears further exploration by those well-versed and qualified in the art and science of aesthetic patient care.
ArteFill is an important tool and adjunct to many aesthetic treatments, but its potential transcends the aesthetic niche. Difficult reconstructive challenges associated with contour deformities will no doubt benefit from expanded ArteFill indications. Many intractable medical problems, such as urinary incontinence, gastroesophageal reflux disease (GERD), stress urinary incontinence (SUI), paralytic vocal cord incompetence, and others may well benefit from this unique addition to the health care armamentarium.
Based on sound data supporting the safety and efficacy of ArteFill, the U.S. FDA approved it for the treatment of nasolabial folds. Physiologically and qualitatively, the dermal-subdermal interface of the nasolabial fold is no different than the other such planes where ArteFill may satisfy augmentation requirements. However, efficacy (good result) is very different from safety (absence of harm). The authors encourage careful and controlled use of this new and permanent filler material. The safety record of ArteFill so far is stellar. Concerns regarding “permanent filler, permanent problems” have not proved substantive. As with any new product, there exist naysayers, some of whom may have hidden agendas. Ultimately, it is sound data that will drive honest discussion and sound decisions. Five-year U.S. safety trials are presently in progress.
Drs. G. Lemperle and S. Lemperle are the developers of ArteFill®. Dr. N. Sadick is a clinical investigator of ArteFill. None of the authors has shares in any company that manufactures dermal filler.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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