Introduction

Biological dermal fillers reliably and safely augment facial wrinkles and folds, but necessitate repeat treatments after they have been resorbed, generally within a 12-month period. Artefill^®, a novel permanent implant, was developed to overcome this limitation. This soft tissue filler is composed of polymethylmethacrylate (PMMA) microspheres suspended in a collagen gel matrix containing 0.3% lidocaine. It is a third-generation PMMA-based filler product that contains an optimized collagen matrix with PMMA microspheres that have enhanced uniformity and consistency as well as near elimination of nanoparticles. It is critical to distinguish Artefill^® from prior generation PMMA products (Artecoll^® and Arteplast^®). Not all PMMA products are the same and scanning electron microscopy can show a wide variation of nanoparticles, sphere irregularities, and sphere shapes and sizes (Fig. 8.1), all of which might contribute to early or late adverse events.

Figure 8.1 Scanning electron microscopy of PMMA in commercially available products: (A) Artecoll^®, Canada; (B) Artecoll^®, Europe; (C) Metacril^®, Brazil; (D) NewPlastic^®, Brazil; (E) Artefill^®, USA.

Artefill^® was approved in the USA by the Food and Drug Administration (FDA) in October 2006 for the correction of nasolabial folds, based upon results of a pivotal trial in the USA with the second-generation predecessor product, Artecoll^®, and manufacturing changes. Since the initiation of that pivotal trial, substantial improvements to the second-generation PMMA product have been made in cooperation with the FDA, resulting in the approval of Artefill^®. Refinements in manufacturing have increased the uniformity in the size of the PMMA microspheres. The proportion of particles less than 20 µm in diameter has been reduced to <1%, and these are typically non-detectable in the finished product. As smaller particle size elements (e.g. <20 µm) are thought to promote phagocytosis, the elimination of these smaller particles is believed to have further improved the tolerability of the implant. Furthermore, the PMMA filler product is now manufactured as Artefill^® using bovine collagen sourced from a restricted closed herd in the USA.

Biocompatibility

The chemical inertness and biocompatibility of PMMA have been well accepted ever since Judet introduced the first hip prosthesis made from PMMA in 1947. Animal experiments by Klemm and by Lemperle et al have demonstrated that an important key to biocompatibility in the skin is the absolutely round shape and smooth surface and the size of the PMMA microspheres. In comparison, other synthetic fillers such as Teflon^® or silicone particles have irregular surfaces that are more prone to cause chronic granulomatous reactions. Microscopically, the predominant cells seen in the reaction to Teflon^® or silicone particles are foreign-body giant cells. In contrast, in the rare case of foreign-body reaction to Artefill^®, the true granulomas show histologically broad bands of collagen fibers between microspheres, which are pushed apart, with rare lymphocytes, macrophages, and giant cells. These granulomas almost always respond to intralesional injection with corticosteroid, and there is some suggestion (by Gelfer and colleagues) that they tend to spontaneously improve.

Most materials that are used as biological fillers to increase the thickness of the dermis in a wrinkle line are phagocytosed within a few months. Therefore, a lasting effect can be achieved only by using either an autogenous material that becomes vascularized and survives as a graft or a non-resorbable synthetic substance. There are approximately 6 million PMMA microspheres in each milliliter of Artefill^®. Beneath the wrinkle crease, the microspheres act as a matrix and stimulate fibroblasts to encapsulate each individual microsphere. Collagen is used as a carrier substance that prevents clumping during injection and stimulates tissue growth. The 20% volume of PMMA microspheres provides the scaffold for the 80% volume of autologous connective tissue deposition. The Artefill^® serves as a filler that seems to provide structural support to the wrinkle crease, preventing further folding and allowing the dermis to regenerate in the wrinkle fold.

Patient selection / treatment areas

A comprehensive evaluation is carried out to determine whether the patient is a good candidate for Artefill^®. Generally, patients who have had initial experience with temporary fillers are the best candidates. More superficial wrinkles and creases are generally not treated with Artefill^®. Deeper creases and folds, especially the nasolabial folds, are primary clinical indications for use, and in the USA the only FDA-approved indication for Artefill^® is for the correction of nasolabial folds. Post-rhinoplasty defects may be initially treated with a temporary filler and, if the patient is satisfied with the outcome, Artefill^® can be substituted when the filler dissolves or is reversed. All patients undergoing injection of permanent fillers such as Artefill^® absolutely must be apprised of the potential for late problems because of the permanent nature of the implant. As for all aesthetic procedures, it is mandatory to inform a patient of all potential adverse events.

The results of nasolabial fold augmentation with Artefill^® have generally been excellent. Nasolabial creases are best supported by two or three strands of Artefill^® implanted parallel and medial to the fold. During the first several days after implantation, Artefill^® can be moved laterally by facial muscle movement. Care must be taken not to place the Artefill^® too superficially. Otherwise, in patients with thin skin the implant may appear erythematous for several weeks and the implant may be visualized as small white granules. An injection ridge may also occur. Placement too deep may result in a cord of material that can be felt by the patient’s tongue underlying the mucosa. A second session is often necessary especially in the inferior aspect of the nasolabial crease.

Wrinkles at the corners of the mouth and marionette lines may be difficult to treat, but often yield excellent results. First, the lower white roll itself is treated horizontally about 1 cm in length from the corner. Next, 5–10 vertical and horizontal threads of Artefill^® should be implanted using a criss-crossing technique. This supports the region and slightly lifts the corners of the mouth. The skin is thin in this area and superficial injection may lead to telangiectasias. Preferably, Artefill^® should be implanted in many different tunnels in two or more sessions. Injection of Artefill^® into the orbicularis oris muscle is to be avoided as it may result in the formation of nodules that can be palpated in the wet mucosa. The marionette lines that extend vertically from the corners of the mouth down to the mandibular border can be improved by linear threading combined with deep intradermal criss-cross injection of Artefill^®.

The glabellar lines have posed little problem with injection since the dermis is thick and the underlying connective tissue provides good support of the implant. Slight overcorrection may be necessary and deeper lines may require repeat injections. It is difficult to explain the lack of statistical difference found between collagen and Artefill^® in the glabellar frown region using masked observer ratings, as in the pivotal clinical study. Initial overcorrection was common for other collagen treatments. However, there was a general reluctance among US clinical trial investigators to inject as much Artefill^® as other collagens in each of the four study areas owing to its long-term effect, which may account for the absence of clear-cut statistical significance in studied areas with the exception of nasolabial folds. Nevertheless, subject satisfaction ratings and investigator success ratings were higher for Artefill^® at the 6-month point in each of the four study areas. Caution must be exercised when injecting any autogenous or synthetic product in the glabellar region because of the fear of retinal artery embolization. Care should be taken with the injection technique to minimize this possibility – the injector should withdraw the needle to ensure that a blood vessel had not been inadvertently penetrated. The injector should be familiar with the location of the arterial blood supply in the vicinity of the nose and orbits, including the supratrochlear, superior orbital, angular, and dorsal nasal arteries.

Radial lip lines extend upward or downward from tiny notches in the vermilion–cutaneous border. In younger patients with nice projection of the white roll, each wrinkle can be treated individually. In patients with four or more vertical lines and in whom the projection of the white roll is diminished, Artefill^® can be injected in notably small amounts transversely along the entire white roll as well as beneath the individual vertical lines. There is a natural pocket between the white roll and the orbicularis oris muscle, which is easily filled centripetally from the corners of the mouth. Injection around the lips may be painful and field or nerve blocks with local anesthesia are routinely used in clinical practice. Artefill^® is not intended for injection into the vermilion of the lip.

Some of the other potential off-label indications for Artefill^® are in the permanent treatment of selected primary and secondary nasal deformities and for dorsal nasal augmentation (Fig. 8.2). Permanent reconstruction of lateral chin contour abnormalities following genioplasty, small depression defects about the head and neck, permanent nipple augmentation and acne scar injection are other off-label indications that might benefit from Artefill^®.

Figure 8.2 Patient treated with 0.8 mL Artefill^®: (A, C) before; (B, D) after.

Patient evaluation and injection technique

At least 1 month prior to injection, and not longer than 2 years prior to injection, the patient must be skin tested to ensure that there is no allergy to the bovine collagen component of Artefill^®. Skin testing is accomplished by intradermal placement of the bovine collagen in an inconspicuous body location. Patients should be instructed to call in the event of redness, swelling, or pruritus at the site of the skin test as these signs may indicate an allergy to bovine collagen. In this event, the use of Artefill^® is contraindicated.

The authors prefer to treat most patients first with temporary fillers to assess the effects and amount of material needed prior to committing to injection of permanent filler. Patients should refrain from taking any aspirin or non-steroidal anti-inflammatory medications for 2 weeks prior to injection to minimize bruising. The ingestion of red wine is also discouraged. Supplementation with Arnica a day or two prior to the injection may reduce the likelihood of purpura.

As always, careful aseptic technique is recommended during all injections and proper technique is the best means of prevention of complications. For patients undergoing injection along the vermilion–cutaneous border, herpes prophylaxis is indicated as appropriate.

Pre-injection, patients may be treated with topical anesthesia. When injecting the vermilion–cutaneous border or radial wrinkle lines of the lips, perioral nerve blocks are routinely performed. Rarely, local anesthesia with epinephrine is utilized to take advantage of the vasoconstrictive effect and to limit bruising. Artefill^® is pre-mixed with lidocaine, also making treatment more tolerable.

It is important to allow the Artefill^® syringe to come to room temperature for up to 10 minutes prior to injection. The material injects very easily, but provides nice tactile feedback to the injector when it is still on the cold side. Once room temperature is reached the material injects very rapidly and may surprise the injector, so it is important to be aware of this fact.

Injection of Artefill^® into the nasolabial fold is generally very straightforward. It is important to be in the proper depth, which is the deep dermis (Fig. 8.3). Artefill^® is injected using a 26- or 27-gauge, 5/8-inch (16 mm) needle. It is critical that the needle be placed at the correct depth. If the silver of the needle is seen through the skin, do not inject as a ridge or lump could easily occur. When the needle is placed too deep, the material will be largely deposited in the fat. When injecting into the correct deep dermal plane, the needle should slightly tent the overlying skin (see Fig. 8.3). Injection should be stopped prior to the needle being removed from the skin to avoid leaving a small bump. If this were to occur, it is important to immediately drain the material in a retrograde fashion through a needle puncture. Generally, using a gloved fingernail, the material is easily expressed through the puncture hole. Ideally, injection is carried out using a linear threading technique as the needle is withdrawn. Radial or fanning injections are most effective in the corners of the mouth, the marionette lines, and in the wedge-shaped depression just below and lateral to the alar attachment. As one gains more experience with the material, injection can be done in a pushing fashion. In some specialized areas such as the nose, microdroplets can be placed and then massaged into shape. As one gains more confidence with the material, serial injections will be less necessary, but when starting out it is best to inform patients that optimum filling should be performed over two or three sessions.

Figure 8.3 Injection depth: (A) too deep; (B) too superficial; (C) proper level of injection, deep dermis.

Pitfalls and how to correct them

In clinical trials, lumps and bumps were the most commonly observed adverse events following PMMA filler injection. In some cases these are recognized immediately and can be easily evacuated by the injector’s gloved fingernail at the time of injection. Lumps may appear early or late after injection. Those associated with redness may or may not be granulomas. True granulomas are thought to represent expanding implants and are thought to occur at all injection sites simultaneously. Most bumps are nodules and these can be treated effectively with intralesional steroids. Only a small amount is injected to avoid skin atrophy. The patient is then asked to vigorously massage several times a day for 3 weeks. In some circumstances, it is necessary to remove the Artefill^®. This is generally a simple matter at the nasolabial folds; a small intraoral incision can be made and, under finger palpation, a hemostat can be inserted and the material grasped and removed until the bump disappears. Should granuloma formation occur, intralesional steroids, potentially a short course of oral steroids, and in some cases intralesional 5-fluorouracil may be needed. Histological confirmation of the presence of a granulomatous reaction is useful to differentiate this from a nodule.

Post-injection care

Ice is immediately applied following injection to minimize swelling and discomfort. Some may suggest oral supplementation with Arnica. Those patients with a history of herpes are given prophylaxis and asked to continue for several days post-injection. Patients may be asked to return 2–4 weeks later for follow-up and if necessary a repeat injection.

Clinical trials

Summary of 5-year follow-up safety and efficacy study

This is a long-term follow-up study of PMMA-filler-treated subjects who participated in the original multi-center pivotal study by Cohen and colleagues. The same methodology used in the pivotal trial to substantiate the safety and efficacy of the product was applied to evaluate the product in subjects 5 years after their last treatment. During the pivotal trial, this PMMA filler had been used to treat a variety of other anatomical sites (e.g. glabellar folds, mouth corners). In this follow-up report, however, the focus was limited to the FDA-approved indication only: the treatment of nasolabial folds. The primary objective of the study was to determine efficacy for nasolabial folds based upon masked observers’ FFA evaluations, and safety using unanticipated event assessments. Secondary objectives were to evaluate efficacy by means of investigators’ FFA evaluations, investigators’ success ratings, patients’ satisfaction ratings, and masked observers’ FFA evaluations for 5 years versus 6 months. All of the investigators (eight US sites) involved in the original pivotal trial participated in this study. For all participating sites, the 5-year follow-up study protocol and associated consent were reviewed and approved by a central Institutional Review Board.

Study candidates included those subjects initially randomized to be treated with the PMMA filler (n = 128) plus the subjects in the collagen control group who had elected to cross over to the PMMA filler therapy at the conclusion of their 6-month collagen control treatment period (n = 106), for a total of 234 potential subjects. On or about the 5-year anniversary date from their last treatment, each investigator contacted their PMMA filler subject(s) by telephone and/or certified letter and encouraged them to be enrolled in the trial.

All subjects were asked to participate in a single follow-up visit. At this visit the following tasks were performed: investigator clinical grading (FFA scale and clinical success), facial photographs (for masked observer assessments), subjects’ ratings of satisfaction, recorded adverse events, and the documentation of any additional facial aesthetic procedures that had occurred since the last PMMA filler treatment. Investigators judged whether the additional aesthetic treatments had a possible or probable impact on the effect of the novel PMMA filler’s correction. Nasolabial folds were considered possibly affected by an intervening facial aesthetic treatment if it occurred in the same region as the PMMA filler injection or if it were applied to the entire face. Nasolabial folds were considered to be probably affected by an intervening facial aesthetic treatment if it affected the area of correction achieved by the PMMA filler injections.

Assessment of nasolabial folds was based upon grading using the FFA grading scale. The primary efficacy variable for this study was based upon the review of standardized subject facial photographs using this measure. Photographs of patients were taken using the same photography system and processed by the same film laboratory as in the pivotal trial. To minimize grader biases, photographs from the pivotal study 6-month timepoint as well as the 5-year timepoint for each enrolled subject were evaluated. The photographs were provided to three independent masked observers (board-certified dermatologist or plastic surgeon) in random order, to be evaluated during the same session using the FFA scale. The observers were masked with respect to the timepoint and treatment of the patients in the photographs. The subject’s facial fold severity score was then determined based upon the average of their three independent evaluations using the FFA scale. In the case of bilateral treatments, the ratings for the two sides were averaged. The change from pre-treatment to 6 months was computed using the original set of 6-month photograph ratings. Change from 6 months to 5 years was computed using the new set of 6-month photograph ratings. Finally, the cumulative improvement over the 5-year interval was computed as the sum of these two changes. This technique avoided any potential bias due to rater drift in the analyses. This FFA grading scale was also used by the investigator to clinically grade each subject’s nasolabial folds as a secondary measure of correction.

Ratings of success and satisfaction

In addition to assessing the degree of nasolabial fold correction using the FFA scale, other methods were used to evaluate cosmetic correction. A five-point ordinal scale was used by the investigators to rate the success of treatment with the novel PMMA filler, ranging from ‘Not at all successful’ to ‘Completely successful’. Likewise, subjects rated their satisfaction with the PMMA filler according to a similar five-point scale ranging from ‘Very dissatisfied’ to ‘Very satisfied’ (Box 8.1).

Box 8.1

Scales for rating efficacy of implant

Investigator success scale

Completely successful

Very successful

Moderately successful

Somewhat successful

Not at all successful

Patient satisfaction scale

Very satisfied

Satisfied

Somewhat satisfied

Dissatisfied

Very dissatisfied

Statistics

Efficacy data were analyzed for normal distribution by the Kolmogorov–Smirnov test. Paired t-tests were employed unless distributions were found to deviate significantly from normality, in which case the Wilcoxon matched-pairs signed-ranks test was used. Other statistical tests are identified individually in the Results section.

Patient demographics and response rates

From the original pivotal study subject pool, 145 patients responded (145/234 or 62%). Three subjects, however, were excluded from the efficacy analysis because their long-term follow-up period was less than 4.5 years. Of the remaining 142 subjects, 15 were males and 127 females (mean age 52.4 years), 82 subjects were from the original Artefill^® group (64.1%) and 60 subjects were from the crossover group (56.6%), with a mean follow-up period of 5.36 years (range 4.53–6.32 years) after their final treatment with the PMMA filler. Comparison of the original PMMA filler and crossover groups revealed no significant difference in terms of follow-up rates (chi-squared, P = 0.245).

In this group of 5-year follow-up subjects, 124 had nasolabial fold correction; most treatments were bilateral, one was unilateral. These subjects provided the basis for the efficacy evaluation.

Masked observer facial fold assessment ratings of efficacy at 5 years compared with baseline

The PMMA filler maintained significant cosmetic correction in nasolabial folds at 5 years after subjects’ last treatment compared with baseline (n = 119). Five of the 124 nasolabial fold subjects were excluded from this analysis because they did not have either baseline or 5-year photographs. Figure 8.4 shows an improvement of 1.01 points in masked observer FFA rating for this time period (P < 0.001, paired t-test); as the FFA is a 0–5 scale, a change of 1 point represents a substantial improvement in cosmetic effect. Actual results are illustrated in photographs of a male (Fig. 8.5) and female (Fig. 8.6) patient. Before treatment (baseline), the male patient exhibited a pronounced nasolabial fold, which was dramatically improved by 6 months following the injection of a total volume of 4 mL of PMMA filler per nasolabial fold over three injection sessions. The improvement was maintained and even continued to develop at 12 months and 5 years. The female patient received 1.2 mL of PMMA filler per nasolabial fold. The inter-rater agreement for nasolabial folds was found to be high (intraclass correlation coefficient = 0.845).

Figure 8.4 Improvement of nasolabial folds over time with Artefill^® vs control (collagen).

Figure 8.5 Male patient – baseline (pre-treatment) to year 5.

From Cohen SR, Berner CF, Busso M, et al 2006 Artefill^®: A long-lasting injectable wrinkle filler material – summary of the US Food and Drug Administration trials and a progress report on 4- to 5-year outcomes. Plastic and Reconstructive Surgery 118:64S-76S

Figure 8.6 Female patient – baseline (pre-treatment) to year 5.

From Cohen SR, Berner CF, Busso M, et al 2006 Artefill^®: A long-lasting injectable wrinkle filler material – summary of the US Food and Drug Administration trials and a progress report on 4- to 5-year outcomes. Plastic and Reconstructive Surgery 118:64S-76S.

Secondary measures of efficacy at 5 years compared with baseline

Secondary efficacy measures also revealed favorable findings for the durability of the PMMA filler. Investigator FFA scores significantly improved at 5 years compared with baseline, by 1.67 points (n = 122, P < 0.001, paired t-test). These results were consistent with the 5-year success rated by investigators (90% described the cosmetic effect as ‘Completely successful’ or ‘Very successful’, n = 123) and satisfaction by the patients (90% described themselves as ‘Very satisfied’ or ‘Satisfied’ with the cosmetic outcome, n = 123).

Efficacy at 5 years compared with efficacy at 6 months

The PMMA filler not only maintained nasolabial fold augmentation between baseline and 5 years, but masked observer FFA ratings also improved by an average of 0.20 points for the time period between 6 months and 5 years (see Fig. 8.4, item B), indicating that the cosmetic effect improved gradually but significantly (P = 0.002, n = 113, paired t-test). This is evident in the patient photographs, particularly when comparing the 1-year and 5-year timepoints (see Figs 8.5 and 8.6). In a paired analysis of the group of crossover patients (n = 45), the PMMA filler-induced improvement assessed 5 years after treatment with this novel filler (0.91 points) was significantly greater than the collagen-induced improvement measured at 6 months (0.01 points) as rated by masked observer FFA (P < 0.001, paired t-test).

Conclusion

In summary, Artefill^®, a third-generation PMMA filler, offers an unprecedented durability of nasolabial fold correction not previously available with other filler agents. It is composed of PMMA microspheres of uniform size suspended in a collagen gel matrix containing 0.3% lidocaine. The microspheres are thought to stimulate the patient’s fibroblasts to deposit collagen on and between the beads, eventually resulting in the replacement of the bovine collagen with the patient’s own collagen. This yields a volume replacement matrix of the patient’s own collagen interspersed with small microspheres of PMMA. Safety concerns are consistent with other products in the category. The permanent nature of the correction, however, should be taken into consideration when discussing treatment alternatives with patients. Off-label uses such as injection of radial wrinkle lines of the lips, the vermilion cutaneous border of the lips, corner of the mouth lines, and marionette lines as well as residual or primary minor nasal defects may also be considered.

Acknowledgments

Disclosures: Dr Cohen is a member of the medical advisory board of Artes Medical, the maker of Artefill^®, and is a minor shareholder; Drs Graber and Born have nothing to disclose relative to this topic.