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^®