Comprehensive Evaluation of Injectability Attributes in OxiFree™ Dermal Fillers: MaiLi® Product Variants and Clinical Case Reports.

Dermal filler injectability is a critical factor for commercial product adoption by medical aesthetic professionals and for successful clinical administration. We have previously reported (in vitro and ex vivo) cross-linked hyaluronic acid (HA)-based dermal filler benchmarking in terms of manual and automated injectability requirements. To further enhance the function-oriented product characterization workflows and the clinical relevance of dermal filler injectability assessments, the aim of this study was to perform in vivo evaluations. Therefore, several variants of the MaiLi® product range (OxiFree™ technology) were characterized in vitro and in vivo in terms of injectability attributes, with a focus on hydrogel system homogeneity and ease of injection. Firstly, standardized in vitro assays were performed in SimSkin® cutaneous equivalents, with variations of the clinical injector, injection site, and injection technique. Then, automated injections in SimSkin® cutaneous equivalents were comparatively performed in a texture analysis setup to obtain fine-granulometry injection force profile results. Finally, five female participants were recruited for the in vivo arm of the study (case reports), with variations of the clinical injector, injection site, and injection technique. Generally, the obtained quantitative force values and injection force profiles were critically appraised from a translational viewpoint, based on discussions around the OxiFree™ manufacturing technology and on in-use specialized clinician feedback. Overall, the present study outlined a notable level of homogeneity across the MaiLi® product range in terms of injectability attributes, as well as consistently high ease of administration by medical aesthetic clinicians.

Clinical Perspectives on the Injectability of Cross-Linked Hyaluronic Acid Dermal Fillers: A Standardized Methodology for Commercial Product Benchmarking with Inter-Injector Assessments.

The injectability of cross-linked hyaluronic acid (HA) dermal fillers is influenced by polymer concentration, polymer cross-linking type and degree, the presence of lidocaine or other functional excipients, types of syringes, and injection techniques. Finished product injectability constitutes a critical quality attribute for clinical injectors, as it strongly influences product applicability and ease of use in aesthetic medicine. While injectable product extrusion force specifications are provided by the respective device manufacturers, the qualitative informative value of such datasets is low for injectors wishing to compare product brands and technologies from an injectability standpoint. Therefore, the present study comparatively assessed 28 cross-linked HA dermal fillers (JUVÉDERM®, Restylane®, BELOTERO®, TEOSYAL RHA®, and STYLAGE® brands) using various injectability benchmarking setups for enhanced clinical-oriented relevance. Manual product injections were performed by three specialized and experienced clinicians, whereas automatic product extrusion was performed using a Texture Analyzer instrument. The various hydrogel products were injected into ex vivo human skin and into SimSkin® cutaneous equivalents to appropriately account for injection-related counterpressure. The injectability results revealed important variability between and within product brands, with a strong influence of the local anesthetic lidocaine, HA contents, and needle gauge size. Critical appraisals of the investigated products were performed, notably from manufacturing process-based and clinical ease of application-based standpoints, centered on respective experimental injectability quality levels. Generally, it was confirmed that each HA-based dermal filler product requires specific expertise for optimal injection, mainly due to differing viscoelastic characteristics and injectability attributes. Overall, the present study set forth evidence-based and clinical-oriented rationale elements confirming the importance for injectors to work with injectable products with which they are experienced and comfortable to optimize clinical results.

Injectable Hyaluronan-Based Thermoresponsive Hydrogels for Dermatological Applications.

Most marketed HA-based dermal fillers use chemical cross-linking to improve mechanical properties and extend their lifetime in vivo; however, stiffer products with higher elasticity require an increased extrusion force for injection in clinical practice. To balance longevity and injectability, we propose a thermosensitive dermal filler, injectable as a low viscosity fluid that undergoes gelation in situ upon injection. To this end, HA was conjugated via a linker to poly(N-isopropylacrylamide) (pNIPAM), a thermosensitive polymer using "green chemistry", with water as the solvent. HA-L-pNIPAM hydrogels showed a comparatively low viscosity (G' was 105.1 and 233 for Candidate1 and Belotero Volume®, respectively) at room temperature and spontaneously formed a stiffer gel with submicron structure at body temperature. Hydrogel formulations exhibited superior resistance against enzymatic and oxidative degradation and could be administered using a comparatively lower injection force (49 N and >100 N for Candidate 1 and Belotero Volume®, respectively) with a 32G needle. Formulations were biocompatible (viability of L929 mouse fibroblasts was >100% and ~85% for HA-L-pNIPAM hydrogel aqueous extract and their degradation product, respectively), and offered an extended residence time (up to 72 h) at the injection site. This property could potentially be exploited to develop sustained release drug delivery systems for the management of dermatologic and systemic disorders.

Safety and efficacy of a carboxymethyl chitosan dermal injection device for the treatment of skin defects: a first-in-man, pilot, comparative, split-body study.

Injectable soft-tissue devices are increasingly used for improving skin defects and deficiencies related to ageing. To assess the safety and efficacy of KIO015, a new injectable soft-tissue device formulated with carboxymethyl chitosan for the intradermal treatment of skin defects associated with ageing. Twenty-two subjects (40-65 years) were randomized to receive injections in the neckline of KIO015 and a non-cross-linked HA-based device, and were followed for up to 10 months. Injection site reactions (ISRs) and adverse events (AEs) were documented. Skin improvement was assessed instrumentally and clinically. Skin biopsies at injection zones in the lower back were taken at Day 28 for histopathology and immunohistochemistry analyses, to further assess product performance. Histomorphometric analyses on rabbits and in vitro assessment of KIO015 antioxidant capacity were also conducted. KIO015 was very well tolerated. Only expected and transient ISRs were observed; mainly erythema and hematoma. No adverse local effects or foreign body granuloma were observed histologically. Both clinical and instrumental evaluations confirmed the performance of KIO015. The skin was firmer and more elastic. Skin hydration showed significant improvement three days after injection. KIO015 exhibited superior overall maintenance of skin hydration after 10 months as compared to HA. These clinical results were supported by in vitro trials and implantation tests in the rabbit. The results from this pilot study support the use of KIO015 as an innovative alternative to HA-based devices for intradermal treatment of skin disorders.

Hand Rejuvenation With A Hyaluronic Acid-Based Dermal Filler: A 12-Month Clinical Follow-Up Case Series.

BACKGROUND: Requests for hand rejuvenation, in particular with nonsurgical aesthetic procedures, are increasing. Several injectable dermal fillers are currently used to restore soft tissue volume; however, the anatomic complexity of the hand and extreme mobility of its underlying tissues involve the use of specific implants and adapted injection technique. We report a case series demonstrating the efficacy, durability, and safety of a hyaluronic acid-based dermal filler (HA-filler) for hand rejuvenation. METHODS: Five female subjects aged 56 to 67 with moderate to severe hand aging were treated by one physician (PM) at his private office. The HA-filler was injected in the hypodermis using a retrograde injection technique. A massage performed at the site of injection ensured optimal cosmetic results. Four subjects had a touch-up 3 months later. The aesthetic effect was evaluated on each hand, by 5 evaluators and the subjects, up to 12 months following the last injection. Adverse events, including pain, were collected. RESULTS: Merz Aesthetic Hand Aging Scale (MAS) and the Global Aesthetic Improvement Scale (GAIS) scores indicated stable and significant improvement in hand aging up to 12 months following the last injection. Despite a slight decrease over time, there was a durable enhancement of skin glow, quality, and hydration on the GAIS. The retrograde injection of the HA-filler, which was usually described as painless, was well tolerated by all subjects. CONCLUSIONS: Hand rejuvenation using a HA-filler and a retrograde injection technique was associated with subjects’ satisfaction and was proved safe for the 5 subjects of this case-series. J Drugs Dermatol. 20(4):451-459. doi:10.36849/JDD.5154.

Spreading Pattern and Tissue Response to Hyaluronic Acid Gel Injections in the Subcutis: Ultrasound Videos, Ultrasound Measurements, and Histology.

BACKGROUND: Despite the popularity of hyaluronic acid (HA) filler treatments, few publications focus on their effects on adipose tissue. OBJECTIVES: The authors assessed the deposition pattern in the subcutis of injected HA, the tissue response at short and intermediate term, and the effects of remodeling the filler by strong finger pressure immediately after the treatment. METHODS: Two brands, specifically developed by the industry for deep injection, were compared. The gels were injected subcutaneously in 5 candidates for abdominoplasty or breast reduction, in the area of excision, 6 to 98 days before surgery. Ultrasound measurements and films were compared with postoperative histological findings. Tissue response was scored semi-quantitatively. RESULTS: Real-time ultrasound showed a slightly different deposition pattern of the 2 brands. Histologically, both were present in large pools of the same magnitude and looked the same. Linear retrograde injection sometimes resulted in a globular deposit due to elastic recoil of septae. After remodeling and over time, HA deposits became difficult to detect by ultrasound. Firm remodeling of the tissue immediately after injection or time had no significant effect on filler spread or tissue response. Except for 1 zone of granuloma formation, tolerance for both fillers was good. CONCLUSIONS: HA deposition in adipose tissue occurs in much larger pools than in the dermis. Ultrasound examination is useful during and immediately after the injection but less reliable after filler remodeling or over time. Filler deposition can be less precise, and reshaping by finger pressure can have less effect than expected.

Hyaluronic Acid After Subcutaneous Injection-An Objective Assessment.

BACKGROUND: Hyaluronic acid (HA) fillers are the preferred injectable products for aesthetic correction of skin depressions and restoration of facial volume. OBJECTIVE: To investigate the subcutaneous distribution of 3, biophysically distinct, CE-marked and FDA-approved HA fillers. MATERIALS AND METHODS: BELB, JUVV, and RESL were injected ex vivo in porcine and human skin. Immediately after injection, the skin samples were snap-frozen, cross-sectioned, and visualized using stereomicroscopy and full-field optical coherence tomography. Images were compared with histological sections after hematoxylin and eosin staining. RESULTS: Hyaluronic acid fillers were distributed as homogeneous bolus in the ex vivo skin. The injection bulks were found to preserve the fibrous trabecular network, shift the fat lobules, and displace the adjacent adipocyte layers independently of the formulation injected. CONCLUSION: For the first time, the subcutaneous injection of 3 HA fillers with markedly different biophysical properties was systematically investigated by complementary visualization techniques. Despite their different properties, no difference in distribution was found after subcutaneous injection. The global preservation of the hypodermis structure observed was consistent with the good tolerability seen in clinical practice after implantation of the HA fillers in the subcutaneous skin layer.

Hyaluronic acid gel based on CPM® technology with and without lidocaine: Is there a difference?

BACKGROUND: In 2011, a cohesive polydensified matrix (CPM® ) hyaluronic acid (HA) gel filler was approved by the USA Food and Drug Administration. In 2014, lidocaine was added to the gel during its manufacturing process. OBJECTIVES: To compare the behavior and rheological properties of a CPM® HA gel with and without lidocaine. METHODS: In our office, we performed simple tests to document the cohesiveness and resistance to traction force of both gels. In two different laboratories, the rheological properties of both gels were measured. We used comparative data of the gel without lidocaine collected from over 6 years. We also observed the gels' behavior when injected into the superficial and mid-reticular dermis, comparing their distribution using both ultrasonography and histology. RESULTS: Over more than 10 years, we observed no difference between both gels, even if clinically we felt a difference in the gels' viscosity upon injection. Their behaviors during injection were similar. Using more sophisticated tests measuring the gels' rheological properties with different techniques, namely sheer sweeps, a difference was, however, noted between the two gels. CONCLUSIONS: Adding lidocaine to CPM® HA gel renders it more viscous. Whether this means a difference in the clinical results, however, would require a comparative clinical study over an extended time period.

Rheological Properties of Several Hyaluronic Acid-Based Gels: A Comparative Study.

BACKGROUND: Adding lidocaine to hyaluronic acid (HA)-based gels appeared to modify their rheological properties, in the view of the first author. OBJECTIVE: This paper sought to compare the rheological properties of three CE-marked and FDA-approved gels, administered with and without lidocaine, along with two other newly FDA-approved gels. METHODS: The tested gels were as follows: NASHA® Restylane® with and without lidocaine; CPM®; Belotero® Balance with and without lidocaine; 3-D Matrix®; Surgiderm® 30XP (without lidocaine) and Juvederm® Ultra 3- Juvederm® Ultra Plus XC (with lidocaine); Preserved Network® RHA®2 (with lidocaine); Vycross® Volbella® (with lidocaine). For rheological analyses, viscoelastic data were collected with plate-plate geometry of 25mm, temperature regulated by a Peltier-effect plate, and the following assessed: Strain sweep from 0.01% to 3000% strain at 1Hz over frequency sweep from 0.1 to 100 Hz. RESULTS: NASHA Restylane gels with and without lidocaine exhibited similar viscoelastic characteristics, with very similar tan δ values, but the elastic modulus G' proved significantly higher when the gel was injected with lidocaine vs without. 3D-Matrix Surgiderm 30XP gel without lidocaine and Juvéderm Ultra 3 with lidocaine exhibited similar viscoelastic characteristics, as well as tan δ values, yet the elastic modulus G' of Surgiderm 30XP proved significantly higher than that of Juvederm Ultra 3-Juvederm Ultra Plus XC. CPM Belotero Balance gels with and without lidocaine exhibited similar G' and G'' values. tan δ was somewhat higher when the gel was administered without lidocaine. VYCROSS Volbella gel exhibited a higher elastic modulus G' than the other Allergan gels, roughly nearing the NASHA gel values. Preserved Network RHA 2 gel exhibited values that were close to its partially cohesive "competitors", except for Vycross. CONCLUSION: Adding lidocaine to HA gels does modify their rheological properties yet this, to a variable extent depending on the product. J Drugs Dermatol. 2018;17(9):948-954.

Injection Depth in Intradermal Therapy: Update and Correction of Published Data.

BACKGROUND: This paper sought to compare calculated injection depth data with published report claims concerning intradermal therapy and skin rejuvenation of the face, hands, neck, and décolleté. OBJECTIVE: A mathematical formula was employed to assess the injection depth, and data from literature were retrieved and compared with the calculated figures to determine whether the claims about the injection depth proved correct. METHODS: Based on a study by Della Volpe et al., involving 140 skin residues adapted for plastic surgery, we have calculated injection depths from published reports on intradermal therapy and skin rejuvenation while comparing these figures with the published injection depth claims. RESULTS: Most injections were not performed at the claimed depth, with over 70% of them carried out in the fat layer, thus, the hypodermis. This is not the recommended depth for a refined injection technique in the intradermal therapy field. CONCLUSION: Whilst examining our study results, two different possibilities come to mind. We must either: 1) review and correct the existing histological classification; and/or 2) better learn to correctly inject in the superficial-dermis, mid-dermis, and deep-dermis. In other words, a perfect control over the needle penetration angle and implanted part appears urgently required.

J Drugs Dermatol. 2018;17(1):89-96.

Comparison of Two Swiss-Designed Hyaluronic Acid Gels: Six-Month Clinical Follow-Up.

The aim of this paper is to compare 2 hyaluronic acid gel fillers from the same Swiss manufacturer and with the same indications: filling of line wrinkles and folds. The products differ by their cross-linking process. With very simple easy-to-reproduce tests, cohesivity and resistance to traction forces were examined. Also, both gels were injected under ultrasound control in the mid reticular dermis of three subjects. The papules were controlled under ultrasound and biopsies at D0 and D15. Results showed significant differences between the 2 gels in all the tests. The new gel, manufactured with a lower-crosslinking density, seems to benefit from better integration in the tissue of the mid reticular dermis and to have a more cohesive nature than its comparator from a previous crosslinking technology. Under clinical observation, the range of new products present excellent tissue integration properties.

J Drugs Dermatol. 2017;16(2):154-161.

Ultrasound and Histologic Examination after Subcutaneous Injection of Two Volumizing Hyaluronic Acid Fillers: A Preliminary Study.

BACKGROUND: This study examined the influence of hyaluronic acid (HA) crosslinking technology on the ultrasound and histologic behavior of HA fillers designed for subcutaneous injection. METHODS: One subject received subcutaneous injections of 0.25 ml Cohesive Polydensified Matrix (CPM) and Vycross volumizing HA in tissue scheduled for abdominoplasty by bolus and retrograde fanning techniques. Ultrasound analyses were performed on days 0 and 8 and histologic analyses on days 0 and 21 after injection. A series of simple rheologic tests was also performed. RESULTS: Day 0 ultrasound images after bolus injection showed CPM and Vycross as hypoechogenic papules in the hypodermis. CPM appeared little changed after gentle massage, whereas Vycross appeared more hyperechogenic and diminished in size. Ultrasound images at day 8 were similar. On day 0, both gels appeared less hypoechogenic after retrograde fanning than after bolus injection. Vycross was interspersed with hyperechogenic areas (fibrous septa from the fat network structure) and unlike CPM became almost completely invisible after gentle massage. On day 8, CPM appeared as a hypoechogenic pool and Vycross as a long, thin rod. Day 0 histologic findings confirmed ultrasound results. Day 21 CPM histologic findings showed a discrete inflammatory reaction along the injection row after retrograde fanning. Vycross had a more pronounced inflammatory reaction, particularly after retrograde fanning, with macrophages and giant cells surrounding the implant. Rheologic tests showed CPM to have greater cohesivity and resistance to traction forces than Vycross. CONCLUSIONS: CPM HA volumizer appears to maintain greater tissue integrity than Vycross after subcutaneous injection with less inflammatory activity.

Two Crosslinking Technologies for Superficial Reticular Dermis Injection: A Comparative Ultrasound and Histologic Study.

Background: Few hyaluronic acid fillers have been developed for superficial injection. Objective: To compare the diffusion and integration properties of cohesive polydensified matrix and Vycross® technology hyaluronic acid fillers with lidocaine following injection into the superficial reticular dermis. Methods and materials: Two subjects received two injections each of cohesive polydensified matrix and Vycross® hyaluronic acid (0.2mL/site) in the superficial reticular dermis of the buttock under ultrasound control. Biopsies were obtained at Days 0, 15, and/or 90. Ultrasound and histologic analyses were performed, plus a series of simple rheological tests. Results: Day 0 ultrasound images showed cohesive polydensified matrix hyaluronic acid homogeneous with the surrounding dermis. Vycross® hyaluronic acid showed more heterogeneity and some leakage into the hypodermis. Day 15 and Day 90 images were similar to Day 0. Histologic examination of biopsy tissue showed cohesive polydensified matrix hyaluronic acid homogeneously distributed among collagen fibrils with no visible particles. Vycross® hyaluronic acid appeared as variable-sized pools with a particulate appearance. Neither gel was associated with an inflammatory reaction. Laboratory tests showed cohesive polydensified matrix hyaluronic acid to have greater cohesivity and resistance to traction forces than Vycross®. Conclusion: cohesive polydensified matrix gel with lidocaine is homogeneously distributed following injection in the superficial reticular dermis and may be particularly suited for aesthetic indications requiring superficial injection.

Visual, Ultrasonographic, and Microscopic Study on Hyaluronic Acid-Based Gel.

BACKGROUND: Hyaluronic acid (HA) fillers are commonly used for enhancement of lips, and for softening fine lines and correcting skin depressions. OBJECTIVE: This study sought to investigate whether the Vycross™ technology used for Volbella™ gel resulted in a cohesive gel, as documented in our previous studies with three other HA fillers (Restylane® NASHA™ [Q-MED, Uppsala, Sweden], Esthélis® Basic CPM™ [Anteis SA, Geneva, Switzerland], and Juvéderm® Ultra 3 using Hylacross technology [Allergan, Irvine, CA, USA]).
METHOD: The "resistance traction test" and "cohesiveness test" were conducted according to standard methods. Juvéderm® Volbella™ gel was injected into the buttock area, both in the superficial reticular and mid-reticular dermis. Tissue samples were analyzed at days 0, 15, and 90 by histology and immunohistochemistry, and visualized using electron microscopy. For Volbella™ gel, the same ultrasound devices as previously used were employed.
RESULTS: Prior to staining, Volbella™ gel presented resistance to spreading, suggesting a certain degree of cohesiveness. When smeared between two slides and following toluidine blue staining, the gel was visible through the microscope in the form of multiple tiny discrete particles, possibly resulting from gel desintegration. At 1/3 dilution with saline serum, Volbella™ gel disintegrated into several lumps, whereas at 1/1 dilution, Volbella gel appeared more cohesive. Yet when adding one drop 70% ethanol, the gel resembled a poorly defined magma, with numerous small lumps. On ultrasound, Volbella™ gel was found to leak in the hypodermis. On histological analysis, Volbella™ gel was visible as pools of variables sizes, particularly in the superficial and mid-reticular dermis, but also hypodermis.
CONCLUSION: Juvéderm Volbella™ gel appears to be a gel characterized by low-medium cohesiveness. The study findings, combined with our previous work, show that HA fillers using Vycross™ technology are not ideally suited for superficial use, unlike HA fillers using CPM technology™.

J Drugs Dermatol. 2016;15(9):1092-1098.

Effect of Different Crosslinking Technologies on Hyaluronic Acid Behavior: A Visual and Microscopic Study of Seven Hyaluronic Acid Gels.

BACKGROUND: The mechanical, rheological, and pharmacological properties of hyaluronic acid (HA) gels differ by their proprietary crosslinking technologies.
OBJECTIVE: To examine the different properties of a range of HA gels using simple and easily reproducible laboratory tests to better understand their suitability for particular indications.
METHODS AND MATERIALS: Hyaluronic acid gels produced by one of 7 different crosslinking technologies were subjected to tests for cohesivity, resistance to stretch, and microscopic examination. These 7 gels were: non-animal stabilized HA (NASHA® [Restylane®]), 3D Matrix (Surgiderm® 24 XP), cohesive polydensified matrix (CPM® [Belotero® Balance]), interpenetrating network-like (IPN-like [Stylage® M]), Vycross® (Juvéderm Volbella®), optimal balance technology (OBT® [Emervel Classic]), and resilient HA (RHA® [Teosyal Global Action]).
RESULTS: Cohesivity varied for the 7 gels, with NASHA being the least cohesive and CPM the most cohesive. The remaining gels could be described as partially cohesive. The resistance to stretch test confirmed the cohesivity findings, with CPM having the greatest resistance. Light microscopy of the 7 gels revealed HA particles of varying size and distribution. CPM was the only gel to have no particles visible at a microscopic level.
CONCLUSION: Hyaluronic acid gels are produced with a range of different crosslinking technologies. Simple laboratory tests show how these can influence a gel's behavior, and can help physicians select the optimal product for a specific treatment indication.

Versions of this paper have been previously published in French and in Dutch in the Belgian journal Dermatologie Actualité. Micheels P, Sarazin D, Tran C, Salomon D. Un gel d'acide hyaluronique est-il semblable à son concurrent? Derm-Actu. 2015;14:38-43.

J Drugs Dermatol. 2016;15(5):600-606..

Quantifying Depth of Injection of Hyaluronic Acid in the Dermis: Data from Clinical, Laboratory, and Ultrasound Settings.

Although manufacturers' instructions for use of dermal fillers ordinarily direct injection in the superficial, mid or deep dermis, or, in some cases, the hypodermis (subcutis), the precise depth of injection may not always be for injectors. In this article, investigators report findings gathered from histopathology, ultrasound, "live" one on one training injections, as well as application of a mathematical formula for depth calculation of the various layers within the dermis. Areas of particular interest are the superficial reticular dermis and the mid dermis. Following the depth measurements detailed by Della Volpe et al in 2012, investigators compare and contrast their own depth findings of the various layers, arriving at the conclusion that the depth of the dermis is not as deep as had been previously assumed. The investigators also develop an argument for the appropriate angles of injection for placement of dermal filler into the various layers, demonstrating that the heretofore widely used angles of 30˚ and 45˚ are far more acute than required.

A prospective, comparative survey to investigate practitioners' satisfaction with a cohesive, polydensified-matrix(®) , hyaluronic acid-based filler gel with and without lidocaine for the treatment of facial wrinkles.

BACKGROUND: Lidocaine-containing dermal fillers may reduce procedural pain compared with lidocaine-free counterparts. OBJECTIVES: To assess practitioners' administration experience with, and the efficacy and safety of, a cohesive, polydensified-matrix(®) , hyaluronic acid-based filler containing lidocaine vs. its lidocaine-free counterpart. METHODS: The lidocaine-containing formulation was injected to one side of the face and the lidocaine-free to the other in 29 females (30-85 years). Administered dose was appropriate to the treatment zone and technique varied according to zone and practitioner preference. Questionnaires assessed practitioners' administration experience, their perception of results, subject satisfaction, and product safety. RESULTS: Practitioners considered the formulations to be similar in terms of ejection force, texture, and placement. The blanching technique was used for 72% of subjects, and its ease was rated as "identical" for both products in 81% of applications and "easier" for the lidocaine-containing product in 6.9% of applications. Results with both formulations were "identical" for 86% of applications and "similar" for the remainder. In 86% of cases, practitioners would "certainly" consider continuing treatment with the lidocaine-containing formulation. All subjects were "satisfied" with treatment. Practitioners reported that, compared with the lidocaine-free product, subject-assessed pain with the lidocaine-containing product was "less prominent" for 86% and 79% of participants during and following treatment, respectively. Similarly, mean pain intensity was significantly lower for the lidocaine-containing preparation (P = 0.0001). Adverse events were similar for both treatments. CONCLUSIONS: The lidocaine-containing dermal filler significantly reduced pain during and following treatment compared with the same preparation without lidocaine, without impact on administration, aesthetic outcome, or safety.

Treatment of Age-related Mid-face Atrophy by Injection of Cohesive Polydensified Matrix Hyaluronic Acid Volumizer.

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.

In vivo bio-integration of three hyaluronic acid fillers in human skin: a histological study.

BACKGROUND: Hyaluronic acid (HA) formulations are used for aesthetic applications. Different cross-linking technologies result in HA dermal fillers with specific characteristic visco-elastic properties. OBJECTIVE: Bio-integration of three CE-marked HA dermal fillers, a cohesive (monophasic) polydensified, a cohesive (monophasic) monodensified and a non-cohesive (biphasic) filler, was analysed with a follow-up of 114 days after injection. Our aim was to study the tolerability and inflammatory response of these fillers, their patterns of distribution in the dermis, and influence on tissue integrity. METHODS: Three HA formulations were injected intradermally into the iliac crest region in 15 subjects. Tissue samples were analysed after 8 and 114 days by histology and immunohistochemistry, and visualized using optical and transmission electron microscopy. RESULTS: Histological results demonstrated that the tested HA fillers showed specific characteristic bio-integration patterns in the reticular dermis. Observations under the optical and electron microscopes revealed morphological conservation of cutaneous structures. Immunohistochemical results confirmed absence of inflammation, immune response and granuloma. CONCLUSION: The three tested dermal fillers show an excellent tolerability and preservation of the dermal cells and matrix components. Their tissue integration was dependent on their visco-elastic properties. The cohesive polydensified filler showed the most homogeneous integration with an optimal spreading within the reticular dermis, which is achieved by filling even the smallest spaces between collagen bundles and elastin fibrils, while preserving the structural integrity of the latter. Absence of adverse reactions confirms safety of the tested HA dermal fillers.

A blanching technique for intradermal injection of the hyaluronic acid Belotero.

With the proliferation of dermal fillers in the aesthetic workplace have come instructions from various manufacturers regarding dermal placement. Determination of injection needle location in the dermis has in large part been based on physician expertise, product and needle familiarity, and patient-specific skin characteristics. An understanding of the precise depth of dermal structures may help practitioners improve injection specificity. Unlike other dermal fillers that suggest intradermal and deep dermal injection planes, a new hyaluronic acid with a cohesive polydensified matrix may be more appropriate for the superficial dermis because of its structure and its high degree of integration into the dermis. To that end, the authors designed a small study to quantify the depth of the superficial dermis by means of ultrasound and histology. Using ultrasound resources, the authors determined the depths of the epidermis, the dermis, and the reticular dermis in the buttocks of six patients; the authors then extrapolated the depth of the superficial reticular dermis. Histologic studies of two of the patients showed full integration of the product in the reticular dermis. Following determination of injection depths and filler integration, the authors describe a technique ("blanching") for injection of the cohesive polydensified matrix hyaluronic acid into the superficial dermis. At this time, blanching is appropriate only for injection of the cohesive polydensified matrix hyaluronic acid known as Belotero Balance in the United States, although it may have applications for other hyaluronic acid products outside of the United States.