aPatrick Micheels, MD; bJoan Vandeputte, MD; aMaria Kravtsov, MSc
Dr. Micheels and Ms. Kravtsov are from Geneva, Switzerland.
Dr. Vandeputte is from Oudenaarde, Belgium.
Disclosure: Drs. Micheels and Vandeputte are consultants for Anteis S.A. Dr. Kravtsov is an emploee of Anteis S.A. The evaluation was sponsored by Anteis S.A. The post-marketing clinical follow-up was sponsored by Anteis S.A. Analysis of the results as well as scientific writing was supported by Anteis S.A and Merz Pharmaceuticals GmbH. Statistical support was offered by Moritz Heinz from Merz Pharmaceuticals GmbH.
Objective: Cohesive Polydensified Matrix® Hyaluronic Acid Volumizer is designed to be injected subcutaneously or in deeper soft tissue layers to restore facial volumes. This post-marketing clinical follow-up was performed to confirm the safety and effectiveness of the product up to 18 months. Design: Injections were performed according to standard clinical practice and patients were followed-up at Months 1, 3, 6, 9, 12, and optionally at Month 18. Effectiveness measures included facial volume loss scale, global aesthetic improvement scale and patients’ satisfaction. Injection site reactions were recorded to evaluate safety. Results: Twenty patients with intermediate-to-severe volume loss in the lateral cheek hollows and/or cheekbone area were treated. Facial volume loss scale scores dropped significantly from a mean value of 3.1 at baseline to 1.3 at Day 1. Significant volume enhancement was maintained at each follow-up visit with mean scores ranging from 1.3 at Month 1 to 1.8 at Month 12. Investigators’ global aesthetic improvement scale assessment showed that up to Month 6 at least 94 percent of patients were rated as “very much improved” or “much improved.” At Month 9, all patients still showed a benefit of treatment with 81 percent rated as “very much” or “much improved” and 19 percent as “improved.” Patients’ evaluation was consistent with investigators’ results. A few expected transient injection site reactions of mild-to-moderate intensity were reported immediately after treatment. These reactions were considered related to the injection procedure, rather than the product. Conclusion: Cohesive Polydensified Matrix Hyaluronic Acid Volumizer is safe and effective for mid-face volume augmentation lasting up to Month 12 and most probably up to Month 18. The aesthetic effect was demonstrated by the effectiveness evaluations and high patient satisfaction. (J Clin Aesthet Dermatol. 2015;8(3):28–34.)
With an increase in average life expectancy and a historical strive for beauty, a growing interest in methods to achieve a natural, rejuvenated, and youthful appearance is expressed by many individuals worldwide. Minimally invasive non-permanent rejuvenation methods, such as injectable dermal fillers based on cross-linked sodium hyaluronate have become one of the most frequently performed aesthetic procedures. They represent a versatile and elegant tool for facial sculpting, contouring, and treatment of facial wrinkles. Currently available fillers differ in composition, duration of action, palpability, administration techniques, complications, and other factors.
Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan with a strong hydrophilic capacity. In the dermal extracellular matrix it provides structural support and plays a role in nutrient exchange as well as adding volume and fullness to the skin., Natural HA in the skin has an extremely rapid rate of turn-over, mostly due to catabolism by endogeneous hyaluronidases. Therefore, commercially available HAs are stabilized by different manufacturing technologies. As a result, the products vary in formulation, concentration, and degree of cross-linking. These properties affect the duration of action as well as post-procedural risks of swelling.
Cohesive Polydensified Matrix® (CPM®) Hyaluronic Acid (HA) Volumizer (Modélis® SHAPE, Anteis S.A, Geneva, Switzerland; also commercialized as Belotero® Volume, Merz Pharmaceuticals GmbH, Frankfurt, Germany) is a CE-marked dermal filler manufactured with the patented CPM technology. It is composed of 26mg/mL HA from biofermentation origin cross-linked with 1,4-butanediol diglycidyl ether (BDDE). CPM HA volumizer is designed to be injected subcutaneously or in deeper soft tissue layers to restore facial volumes. The CPM technology creates a product with variable cross-linking densities within the gel, where denser areas ensure volumizing effect and less dense areas ensure cohesivity of the matrix. These properties allow the gel to be easily extruded through the needle during the injection and prevent it from migrating once implanted. CPM HA volumizer is also characterized by the plasticity of the gel, which allows the practitioner to mold and sculpt the product easily into the desired shape once injected in order to achieve optimal aesthetic results.
Facial volume loss is one of the major signs of aging, but it can also be inherited or acquired through disease or trauma. During facial aging, the atrophy of the underlying skeleton becomes prominent and subcutaneous cell components (fat, muscle, and fascia) progressively break down resulting in an altered shape and relative position of the fat pads.[7–9] Volumetric changes in the mid-face area are associated with a sad and tired look. Enhancement of the lateral cheek hollows and cheekbone area recreates mid-face volume, smoothens nasolabial folds, and gives a more harmonious appearance associated with a younger age.,
The objective of this post-marketing clinical follow-up was to confirm the safety and effectiveness of CPM HA volumizer for enhancement of the lateral cheek hollows and cheekbone area. The durability of the aesthetic effect was evaluated up to 18 months.
Materials and methods
The evaluation was conducted in two private practices located in Belgium and Switzerland according to the standard clinical practice procedures and with respect to the product’s instructions for use. Patients were recruited at the discretion of the investigators who obtained their written informed consent prior to the treatment. Baseline and injection visits were performed on the same day. Patients received injections of CPM HA volumizer for treatment of age-related facial volume loss in the lateral cheek hollows, cheekbone area, or both up to an optimal correction. Investigators determined the appropriate volume to inject based on clinical experience and severity of facial depressions, as well as the area of injection. An optional touch-up injection could be performed if deemed necessary. No anaesthetics were used during the procedures.
At the baseline and the injection visit, investigators recorded patient’s age, treated area, and volume of the injected product per side. At baseline, patients were rated on the facial volume loss scale (FVLS). The grades were attributed as follows: 1=mild flattening/no visibility of underlying tissue; 2=intermediate between mild and moderate; 3=moderate concavity of one or more facial regions/prominence of bony landmarks/may have visibility of underlying musculature; 4=intermediate between moderate and severe; 5=severe indentation of one or more facial regions/clear visibility of underlying tissue.
The effectiveness and safety of the CPM HA volumizer were evaluated per side by both patients and investigators immediately after injection and at all follow-up visits performed at Months 1, 3, 6, 9, 12, and optionally at Month 18. Investigators took photographs and evaluated device effectiveness based on FVLS at each visit. Investigators and patients evaluated device effectiveness based on global aesthetic improvement scale (GAIS) with scores ranging from “1=very much improved” to “5=worse.” Additionally, patients reported their satisfaction with the treatment in a questionnaire. Safety was evaluated based on reporting of injection site reactions (ISR), including redness, pain, edema, bruising, itching, firmness/induration, coloration/discoloration, necrosis, and infection. The intensity of each ISR was rated from “0” to “+++” depending on the severity of the observed reactions.
The attendance at the follow-up visits by patients was as follows: Month 1=20 patients, Month 3 and Month 6=18 patients, Month 9=16 patients, Month 12=20 patients, optional Month 18=11 patients. The statistical analysis was performed in an explorative manner using observed cases. Patients’ individual values were calculated using the mean between left and right side scores. For effectiveness assessments, summaries in the form of mean (+/- standard deviation [SD]) are presented. In addition, explorative p-values for a two-sided t-test for paired samples have been taken to compare the values from baseline and follow-up visits.
Twenty patients (n=20) of both genders with a mean age of 57 years (range from 28 to 73 years) were treated with CPM HA volumizer for facial volume enhancement. A total of eight patients received injections only in their lateral cheek hollows with a mean product volume of 2.1mL for both sides of the face. A total of six patients received injections only in their cheekbone area with a mean product volume of 2.1mL for both sides of the face. A total of six patients received injections in their lateral cheek hollows and cheekbone area with a mean product volume of 3.37mL for both sides of the face. Two patients received a touch-up in the lateral cheek hollows, one in the cheekbone area, and one at both sites.
Investigators used both needles and cannulae at their discretion. One of the investigators started injecting with the deposition of an anterior bolus no larger than 0.3mL per side in the levator anguli oris muscle origin with a sharp 22g needle. Most of the product was injected on the periosteum by introducing a 22g cannula medially in the deep medial cheek fat pad, then crossing the zygomatic muscles origin and moving deep in the middle and lateral superficial cheek fat pad overlying the zygomatic arch. The product was released while retracing the cannula. Finally, a retrograde injection of no more than 0.2mL per side was performed over the anterior maxilla in the linear anterior cheek depression. The rigidity and length of a 22g cannula allowed easy penetration into all injected areas through one access point. Ease of injection of the product was appreciated, even though the other investigator used thinner cannulae of 25g and 27g internal diameter. The flow of the product was easily controlled with little pressure applied on the plunger of the syringe.
The second investigator used a different technique and started injecting the lateral compartment of the deep medial cheek fat pad and buccal fat pad with a cannula. The material was placed in the buccal fat pad to fill the hollowing without over-correcting. This allows natural results to be achieved. For the injection of the cheekbone area, the investigator used the fan technique directed from the external part of the cheekbones medially.
Effectiveness (investigators’ assessment). Investigators evaluated effectiveness at all follow-up visits based on FVLS with grades ranging from “1=mild flattening” to “5=severe flattening.” At baseline, patients were rated as having intermediate-to-severe facial volume loss (FVLS grades 2–5). Immediately after injection and up to Month 6 all patients were rated as having FVLS grades 1 or 2, corresponding to mild-to-intermediate flattening of the lateral cheek hollows/cheekbone area. As of the Month 9 visit, several patients were rated as grade 3, corresponding to moderate concavity of the lateral cheek hollows/cheekbone area. At the same time, the percentage of patients with grades 1 or 2 slightly declined with each visit.
The results presented in Figure 1 show that FVLS scores improved significantly immediately after the injection from a mean value of 3.1 (+/-1.1) to 1.3 (+/-0.5). Significant volume enhancement was then maintained at each follow-up visit with mean scores ranging from 1.3 at Day 1 to 1.8 at Month 12. Even though a slight increase in the FVLS score over time can be observed in Figure 1, the effectiveness of the CPM HA volumizer was still significant long-term. At Month 18, the mean FVLS score was 1.7, which corresponds to mild flattening and represents significant volume enhancement compared with baseline.
Investigators also evaluated effectiveness based on GAIS with scores ranging from “1=very much improved” to “5=worse.” Immediately after injection and up to Month 6, at least 94 percent of patients were rated as “very much improved” or “much improved.” As of Month 9, a few more patients were rated as “improved,” as the percentage of patients with grades “very much improved” or “much improved” slightly declined. Mean GAIS scores were calculated for all patients per visit. The results show that immediately after injection, the score was equal to 1.3 (+/-0.5), corresponding to maximum improvement in aesthetic appearance. Throughout follow-up, the mean GAIS score ranged between “very much improved” (grade 1) and “much improved” (grade 2), with mean values ranging from 1.3 at Day 1 to 1.95 at Month 12.
Figure 2 shows the distribution of GAIS scores over the follow-up visits. The majority of patients (n=68%) were “very much improved” immediately post-injection. This percentage decreased with fluctuations throughout the follow-up period. The percentage of “much improved” (grade 2) patients also had a tendency to decrease from Month 1 to Month 18. In contrast, the percentage of “improved” (grade 3) patients increased over time. Two patients considered that there was “no change” (grade 4) at Month 12 and their Month 18 data are not available. GAIS results at Month 18 were influenced by missing data.
The results obtained with investigators’ assessment of FVLS were in agreement with those of GAIS. Investigators evaluated mean patients’ aesthetic appearance on the GAIS scale as “much improved” to “very much improved” up to Month 18. All patients (n=100%) were assessed as at least “improved” at all follow-up visits, except for Month 12 (n=95%).
Effectiveness (patients’ assessment). Patients evaluated effectiveness based on GAIS with scores ranging from “1=very much improved” to “5=worse.” Mean GAIS scores for all patients per visit were calculated. The results show that mean GAIS scores for all patients ranged from 1.5 at Month 1 to 2.2 at Month 12 along the follow-up visits. At Month 12 and Month 18, mean GAIS scores were between “very much improved” and “improved”.
Figure 3 shows the distribution of GAIS scores over the follow-up visits. The percentage of patients who judged themselves as “very much improved” (grade 1) stayed more or less constant fluctuating around 20 percent over the follow-up period. The percentage of “much improved” (grade 2) patients decreased over time, while the percentage of “improved” (grade 3) patients increased. One patient detected “no change” at Month 9 and Month 12. This patient did not attend the Month 18 visit. In order to evaluate patient satisfaction with the treatment at Month 12 and Month 18, patients were asked whether they would repeat the treatment themselves and/or recommend it to their friends and relatives. Patients responded identically to both questions. At Month 12, most of the patients [95% (n=19)] were satisfied with their results and would repeat the treatment and recommend it to their friends. All 11 patients attending the Month 18 visit stated that they were satisfied with the treatment and would repeat it and recommend it to their friends. Nine patients did not attend the optional Month 18 visit.
Figure 4 shows a typical patient. At baseline, her cheek is visibly separated into different sections: The zygomatic prominence and excessive nasolabial volume, separated by the tear trough, which is further prolonged into the anterior cheek depression. In order to hide the depression between these compartments and thus smoothen the cheek, the authors recommend injecting mainly laterally, deep on the cheekbone, mimicking bone expansion, to improve soft tissue support (Figure 4A). The depression itself was treated minimally, to avoid excessive anterior cheek roundness. It is important not to position the product close to the orbital rim while injecting, nor while remodeling. It may be helpful to compress the soft tissues over the inferior orbital margin with the index finger of the non-dominant hand. The soft tissues of the orbital margin have a high propensity for edema. Less concentrated, cross-linked HA gels are more appropriate for volume replacement in this area. At Month 1, we observed restoration of the single cheek curvature reaching from the nasolabial crease to the temporal hairline, and from the preseptal area to the occlusal plane of the molar teeth, resulting in a younger looking appearance (Figure 4C). At Month 12, the cheek contour still looks improved. However, facial volume naturally degrades with time as the filler is resorbed progressively (Figure 4D).
Figure 5 shows another typical patient treated by a different investigator. This patient was injected with a cannula using a fan technique as described earlier in this article.
Safety, side effects, and complications. A total of 13 out of 20 patients experienced at least one injection site reaction of mild-to-moderate intensity during the evaluation. At Day 1, redness (n=5), pain (n=6), and edema (n=3) were the most frequent reactions reported by the investigators. While redness and pain were only observed immediately post-injection, edema persisted up to Month 3 in one patient. It was localized on the orbital margin and required hyaluronidase injection. Upon its resolution, the patient was very satisfied with the result. There was also one case each of transient bruising and itching. Firmness was reported by five patients during the evaluation and resolved within three months following the injection. Safety results reported by the patients were in accordance with those reported by the investigators. All reactions were rated as injection related and not product related.
The functional anatomical components of the facial structure are in permanent motion resulting in variable facial expression. It is therefore important to consider the three-dimensional aspect and the complexity of these interactions when performing volumetric facial enhancement.10 CPM HA volumizer is designed to integrate into the soft tissues in order to increase facial volume. At the same time, it preserves a natural appearance whether in static position or during facial expression. When injected in the mid-face region, the product allows an aged face to be restored to its “triangle of beauty” or “heart-shaped face” that is associated with a younger appearance.
Since its launch in 2010, CPM HA volumizer has been successfully used in a variety of patient populations in Europe, Canada, Australia, and other countries. The excellent safety profile of the product has been confirmed through post-marketing surveillance feedback. CPM HA volumizer is designed to be injected subcutaneously or in deeper soft tissue layers to restore facial volume. It is essential to respect these criteria when choosing the most appropriate injection technique to reduce the risk of edema and product misplacement, which may result in undesirable adverse reactions and patient disappointment. The authors recommend remodeling the product immediately after injection by applying sustained pressure with the fingertips for several seconds until the product is no longer palpable. The CPM characteristics of the product prevent it from being displaced later on. Remodeling allows a natural aesthetic enhancement to be achieved and contouring of the treated area, as the product is very supple and easily malleable.
This post-marketing clinical follow-up represents the first European experience with CPM HA volumizer. A total of 20 patients were injected with the product in the lateral cheek hollows, cheekbone area, or both by two investigators in their daily clinical practice. Investigators evaluated the effectiveness of the product based on two commonly used aesthetic scales, FVLS and GAIS. Patients evaluated effectiveness of the product based on GAIS and their satisfaction with the treatment. Results from the Month 18 visit should be interpreted with caution as the mean values are based on a very low number of patients due to the fact that the visit was optional. Even though there was a trend for improvement at Month 18 with both FVLS and GAIS assessments, which may even have reached statistical significance, this should be confirmed in further clinical studies due to the limited number of data.
According to the investigators’ evaluation of FVLS, all patients showed an immediate improvement in facial volume, which is illustrated by the drop in bar height from baseline to Day 1 in Figure 1. The effect of treatment lasted up to Month 12 to Month 18, as statistically significant post-injection values were observed at each follow-up visit. Results remained at their best level up to the Month 6 visit. At later visits, a slight increase in the mean facial volume loss score was observed, with a few patients presenting with moderate flattening starting from the M9 visit. This trend corresponds to the resorbable nature of the product. Cross-linked HA is known to have a much longer half-life when injected subcutaneously compared with naturally occurring HA, but it is eventually catabolised by endogeneous hyaluronidases and free radicals.,, Few data are available on resorption times in deeper soft tissues. A repeat treatment with the biodegradable CPM HA volumizer can be considered whenever clinically indicated.
Investigators’ assessment using FVLS and GAIS scores provided consistent results. All patients were assessed as at least “improved” on the GAIS at all follow-up visits, except for Month 12 (n=95%).
GAIS results reported by the patients were in agreement with the investigators’ evaluations, even though patients tended to be a little more critical of their aesthetic improvement compared with the experienced investigators. Patient satisfaction was clearly expressed by the wish to repeat the treatment and recommend it to their friends.
Overall, the results suggest that the volume enhancement achieved straight after implantation of CPM HA volumizer is maintained long term, demonstrating the effectiveness and durability of the product in facial volume augmentation.
From a safety perspective, expected transient injection site reactions of mild-to-moderate intensity were reported immediately after the treatment: redness, pain, edema, bruising, itching, and firmness. These reactions are already listed in the product instructions for use and are considered related to the injection as such, rather than the injected product. The reactions have also been reported with other volumizing products., One patient developed edema over the orbital margin, following injection of 1.9mL of the product in both lateral cheek hollows and the cheekbone area at each side of the face. No lump was palpable under the edema. As it was successfully resolved by one hyaluronidase injection at Month 3, the authors can only attribute it to the presence of the filler. Possible causes include inaccurate injection (too close to the orbital margin), inaccurate remodeling (moving the product too close to the orbital margin), and lymphatic spread or reactive edema, which selectively affects eyelid soft tissues. Some patients do suffer eyelid edema in reaction to small traces of HA. This does not diminish the quality record of the product tested in this study, but points out the clinical unpredictability of the eyelid response to a highly cross-linked filler. The authors do not recommend injecting a less dense HA gel over the orbital margin in the same session as CPM HA volumizer injection over the cheekbone area. If edema arises it would be impossible to know which product was the cause. Injection site edema can be caused by injection trauma, hygroscopic properties of the gel, osmotic pressure, or tissue response. Further histological studies are needed to investigate its origin.
This post-marketing clinical follow-up was limited by a relatively low number of treated patients as well as certain missing data, such as at the optional Month 18 visit. In addition, the treatments were performed using the varying injection techniques and anatomical approaches specific to each practitioner. Thus, the volumes of product injected and the type of needle or cannula used to perform the procedure differed between patients. As a result of these variables and the relatively small sample size, certain variability in the results was expected. Nevertheless, promising data on the effectiveness, durability and safety of CPM HA volumizer were obtained that should be further confirmed in controlled clinical studies with a calculated sample size.
The results of this post-marketing clinical follow-up show that CPM HA volumizer is safe and effective for mid-face volume augmentation lasting up to 12 months and most probably up to 18 months. The achieved aesthetic effect was demonstrated by high patient satisfaction. The investigators appreciated the product due to its ease of injection, malleability, and natural integration, resulting in a natural aesthetic appearance. However, prior knowledge of facial anatomy, injection techniques, and familiarity with volumizing products are prerequisites for successful treatment.
The post-marketing clinical follow-up was sponsored by Anteis S.A. Analysis of the results as well as scientific writing was supported by Anteis S.A and Merz Pharmaceuticals GmbH. Statistical support was offered by Moritz Heinz from Merz Pharmaceuticals GmbH.
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