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Hyaluronic acid fillers from the cohesive polydensified matrix range for the Asian patient
Recently, an injectable HA gel based on Cohesive
FOR THE ASIAN PATIENT
The Aesthetics China Expert (ACE) Steering Committee outline their insights and recommendations
ABSTRACT In conjunction with the launch of Belotero* Balance Lidocaine (Merz Aesthetics, Geneva, Switzerland) in China, the ACE (Aesthetics China Experts) Steering Committee held their inaugural meeting on 9 June 2022, during which global experts shared their clinical experience and the panel discussed current practices and recommendations on the clinical use of the Belotero range, with particular emphasis on applications in Asian populations and for currently approved indications in China. Treatment aims in Asians and current practice regarding the use of Belotero HA fillers were presented. In addition, injection techniques and indications for Belotero Balance Lidocaine and other Belotero products that have been developed in other territories with additional approved indications were introduced. The Belotero range of HA fillers offers efficacious and safe results due to excellent dermal integration that minimises tissue disruption. Belotero Balance Lidocaine possesses unique rheological characteristics that allow it to fulfil the unmet therapeutic needs of injecting superficially to address fine lines with immediate and durable results and thus is poised to be a welcome addition to the aesthetic doctor’s armamentarium in China. *Belotero is a registered trademark of Merz Pharma GmbH & Co. KGaA.
HYALURONIC ACID (HA) DERMAL fillers are a popular cosmetic treatment to correct various aesthetic issues such as lines, wrinkles, and facial volume loss, as they are minimally invasive, have a favourable safety profile, and create immediate results in a reproducible manner1,2. Recently, an injectable HA gel based on Cohesive Polydensified Matrix (CPM) technology (Belotero* Balance Lidocaine, Merz Aesthetics, Geneva, Switzerland) received approval in China for injection into the mid-dermis for filling of moderate nasolabial folds3 .
To that end, the ACE (Aesthetics China Experts) Steering Committee, a 13-member expert panel comprising plastic surgeons, dermatologists and experienced injectors practising in China, including an international expert from Germany and Hong Kong, China, gathered for the first time to disseminate knowledge gained from clinical experience and discuss current practices and recommendations on the clinical use of the Belotero range, with particular emphasis on applications in East Asian patients.
CPM technology affords Belotero HA fillers with unique rheological properties
All HA fillers undergo crosslinking modification to provide higher resistance to endogenous hyaluronidase action, thereby increasing efficacy and duration of results. The proprietary crosslinking technique, known as cohesive polydensified matrix (CPM) technology (Figure 1)2,4, utilised confers the resultant HA gel with a unique set of rheologic properties that informs its suitability for different treatment indications, injection techniques, and injection depths. A range of HA fillers based on the same technology is formulated by varying the crosslinking ratio and HA concentration.
The relevant rheological properties typically referred to when discussing a HA gel’s therapeutic indications are cohesivity, viscosity, elasticity, and plasticity5–7. Cohesivity is defined as the capacity of a material not to dissociate
WENZHI LI, PHD Beijing Anzhen Hospital, Capital Medical University, China; SHENGKANG LUO, PHD Guangdong Second Provincial General Hospital, China; HANG WANG, PHD West China School/Hospital of Stomatology Sichuan University, China; SUFAN WU, PHD Zhejiang Provincial People’s Hospital; HONGYI ZHAO, PHD Beijing Hospital, National Geriatrics Centre; HAIYAN CUI, PHD Tongji Hospital of Tongji University, Shanghai, China; BI LI, PHD Peking University Third Hospital, China
KEYWORDS Hyaluronic acid, Dermal fillers, Belotero balance, China, CPM technology
PANEL OF EXPERTS
THE ACE (Aesthetics China Experts) Steering Committee
PROF HAIYAN CUI
Tongji Hospital of Tongji University, Shanghai PROF XUEFENG HAN PROF DAN JIAN
Plastic Surgery Hospital, CAMS, PUMC Xiangya Hospital, Central South University PROF BI LI
Peking University Third Hospital
PROF SHENGKANG LUO
Guangdong Second Provicial General Hospital PROF XIONGZHENG MU
Huashan Hospital, Fudan University, Shanghai
PROF SUFAN WU
Zhejiang Province People’s Hospital PROF LEIHONG XIANG
Huashan Hospital, Fudan University, Shanghai PROF DANRU WANG
Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
PROF HONGYI ZHAO
Beijing Hospital PROF HANG WANG
West China School/Hospital of Stomatology Sichuan University PROF WENZHI LI
Beijing Anzhen Hospital, Capital Medical University
PROF LEI WANG
Zhongda Hospital Southeast University
because of its constituent molecules for each other even under mechanical stress, e.g., muscular action5 . Viscosity is the ability of a gel to resist shearing forces and can be characterized according to how it ‘flows’6. Viscosity is therefore used to define the thickness of a gel - the higher a gel’s viscosity, the more resistant it is to spreading7. Elasticity, measured as elastic modulus (G’), is defined as the ability of a gel to revert to its initial shape after mechanical stress6. Plasticity refers to the ability of a gel to be shaped. It is desirable for a gel to be malleable so as to follow the dynamic motions of the face. Together, these four parameters control the suitability of a filler to treat various treatment goals (e.g., a HA gel indicated for volumisation and tissue support as compared to one intended for superficial filling of fine lines).
The Belotero range of injectable dermal fillers is produced using cohesive polydensified matrix (CPM) technology. As with most other HA fillers, CPM uses
Figure 1 CPM technology workflow
CROSS-LINKING TECHNOLOGY
Belotero Balance is created with a dual cross-linking process
PHASE 1
Hyaluronic acid (HA) in its orginal form (single chains, random coil structure) PHASE 2
Individual HA strands are linearized: the random coil structure untangles PHASE 3
HA is cross-linked with BDDE to create a monophasic gel
PHASE 4
The monophasic gel is expanded PHASE 5
The gel is cross-linked with BDDE again and supplemented with additional noncross-linked HA STANDARD CROSS-LINKING
COHESIVE POLYDENSIFIED MATRIX (CPM) TECHNOLOGY
Phases 4 and 5 consititute the innovative part of the patented CPM technology
CPM technology produces gels with non-uniform crosslinking and molecular weight, allowing for better dermal integration. 1,4-butanediol diglycidyl ether (BDDE) as the crosslinking agent, but then undergoes a specific additional step to first stretch the initial crosslinked matrix and continue the crosslinking process dynamically through the supplementation of additional HA. CPM-based gels are cohesive with zones that have varying degrees of density8. The Belotero range is characterised by higher cohesivity, scoring 5 (fully cohesive) on the 5-point Gavard-Sundaram Cohesivity Scale5 in comparison with other HA filler ranges. This translates clinically to excellent dermal integration with similar distribution to endogenous HA in tissue, as histology and ultrasound imaging studies have shown9,10. Moreover, compared to monodensified HA gels, Belotero distributes diffusely and evenly with minimal disruption to the dermal plane structure2. This atraumatic placement, together with its non-particulate nature, is postulated to be the reason why treatment is very well-tolerated, with almost no inflammatory reactions compared to other technologybased HA gels11. No persisting nodules, granulomas, and tissue necrosis due to intravascular injection have been reported in long-term safety reports for any Belotero dermal filler12 .
Of the HA fillers in the Belotero range, Belotero Balance Lidocaine is the earliest product introduced to the market and thus is well-studied. Formulated with a HA concentration of 22.5 mg/mL, this product exhibits low elasticity, and low viscosity, which allows it to be injected easily13, and — like other products in this range — high cohesivity, allowing for seamless and optimal tissue integration properties13,14. In China, Belotero Balance Lidocaine comes with lidocaine (0.3%) to address the common side effect of injection-related discomfort3 .
Clinical applications of HA in Asian patients: treatment aims and considerations
The typical desired feminine face shape is oval, narrow, elongated and projected, especially in the mid-face, nose, and chin15. HA fillers are typically used in the young Asian female face to correct perceived inaesthetic features such as ‘flatness’ of the infraorbital and medial malar regions, a lack of projection of the midline facial features that result in a broad face, as well as an angular jawline16 . To correct age-related aesthetic defects, HA fillers are mainly used to replace age-related volume loss and subsequent tissue sagging as well as structural deficiencies that become more pronounced as a result16 . Advancements in technology have allowed the formulation of HA fillers that satisfy most of the criteria of an ‘ideal’ injectable filler, including optimal rheology to achieve seamless tissue integration, resiliency towards repeated movements, and delivery of predictable, reproducible, and natural results17. In particular, it is sometimes important to have a dermal filler with similar characteristics to the bone structure. Additionally, the filler should play a secondary role as a stable platform onto which changes in bone structure leading to ageing or aesthetic deficiency can be compensated — this creates better support and avoids product migration and
ensures the normal function of surrounding soft tissue. HA fillers that have high elasticity, plasticity, and viscosity, such as Belotero Volume, can compensate for the appearance of bone loss due to ageing-related bone resorption, acting as the aforementioned stable platform.
In addition to being age-appropriate, durable, and natural, another important consideration is how the results look at rest and in motion. The filler must therefore produce good static and dynamic results. HA also behaves as a mild moderator of muscle function and can affect the interactions between different muscles, thereby impacting muscle movement. Theories as to the pathogenesis of this mechanism include that the HA filler behaves as support and that it changes the way the muscle elongates and contracts. In this manner, filler treatment can be used to address aesthetic concerns caused by lack of bone support or distortions on animation by correcting facial structural deficiencies, either by supporting muscles to facilitate their action or mechanically obstructing muscle overaction, leading to favourable aesthetic outcomes18 .
Best practices: clinical application in aesthetic treatments
Nasolabial folds and mid-face volume loss are common aesthetic issues, even in young patients. In such patients, combination treatments of deep injections of Belotero Volume and superficial injections of Belotero Balance Lidocaine can be used to enhance the overall shape of the face. The advantages given by the unique characteristics of this gel provide immediate, natural results without the risk of overfilling19 .
With high cohesivity and low viscosity, Belotero Balance Lidocaine is suitable for superficial injection even into the superficial reticular dermis. The gel’s structure and high degree of dermal integration led to the development of the ‘blanching’ injection technique20 , which makes it possible to inject into the reticular dermis for the treatment of fine lines, such as perioral and neck lines.
As full integration into the dermis is achieved, common side effects associated with superficial injection of HA, such as the Tyndall effect, can be mitigated20. When using the ‘blanching’ technique, it is important to control the volume of product injected. Another advantage to using Belotero Balance Lidocaine — a crosslinked, highconcentration HA product — for superficial injection is the duration of effect, which has been reported to last up to 2 years in neck lines and perioral lines20. This is because other HA products with similar indications are typically non-crosslinked or lower crosslinked HA or have low HA concentration, which typically confer results with a shorter duration of effect. Similarly, there is no need to inject as much product to achieve the same results as other HA products. According to our experience, the duration of effect may also be longer in Asian patients because they have thicker skin than Caucasian patients and are thus able to accommodate slightly more product volume injected intra-dermally.
The performance of Belotero Balance Lidocaine for the improvement of moderate to severe nasolabial folds has been evaluated in several clinical trials12,13,21. A review of clinical data concerning the performance, tolerability and safety of Belotero Balance Lidocaine compared to collagen and to other HA fillers in the treatment of nasolabial folds found that Belotero Balance Lidocaine was superior to collagen and resulted in a greater reduction of wrinkle depth than a comparator HA filler 4 weeks after injection12. These findings also translated to greater patient and practitioner satisfaction, the latter particularly due to the ease of use12. The favourable performance of Belotero Balance demonstrated in Caucasian patients in the treatment of NLFs, was validated in patients with Fitzpatrick skin types IV, V, and VI12 . While Belotero Balance Lidocaine is approved in China for injection into the mid-dermis for filling of moderate nasolabial folds, it has been authorised for additional indications in other territories. For this reason, global physicians have amassed significant user experience and clinical data on the application, performance and safety of this product for other treatment areas. Other areas suited to Belotero Balance Lidocaine treatment include sensitive areas such as the infraorbital region and lip contour, where low inflammation and hydrophilicity are essential to reduce the occurrence of oedema, erythema, and other immune reactions. Treating the infraorbital hollows with Belotero Balance Lidocaine requires deep-layer injections using a stiff blunt tip cannula (of at least 25 gauge) due to special consideration of the anatomy. It has been observed that treatment of infraorbital hollows with Belotero Balance Lidocaine is not associated with the appearance of thick horizontal lines that sometimes appear 3–8 weeks after treatment, indicative of product displacement due to gel dispersal. This is an occurrence typically seen with gels of low cohesivity. Another notable observation is the absence of oedema, indicating that treatment is welltolerated. For lip contour, Belotero Balance Lidocaine is injected into the subdermal plane.
Lidocaine is suitable for superficial injection even into the superficial reticular dermis. prime-journal.com | November/December 2022 ❚ 17
Key points
Belotero Balance Lidocaine, approved in China for injection into the mid-dermis for filling of moderate nasolabial folds
The Belotero range of injectable dermal fillers is produced using cohesive polydensified matrix (CPM) technology
HA fillers are typically used in the young Asian female face to correct perceived inaesthetic features such as ‘flatness’ of the infraorbital and medial malar regions
Combination treatments of deep injections of Belotero Volume and superficial injections of Belotero Balance Lidocaine can be used to enhance the overall shape of the face
With high cohesivity and low viscosity, Belotero Balance Lidocaine is suitable for superficial injection even into the superficial reticular dermis
Volumetric restoration of the midface is the first essential step in global rejuvenation as it has the most significant impact on the malar contour and the surrounding areas22. To treat facial volume loss, the HA filler should have both projecting capacity as well as modelling capacity to allow for adequate shaping. Belotero Volume has moderate cohesivity, and high viscosity and elasticity, making it an excellent volumiser while being extremely malleable. In terms of efficacy, a split-face study evaluating the effectiveness of Belotero Volume against another HA dermal filler showed that Belotero Volume created more volume augmentation at all time points studied22 .
Final thoughts and considerations
From the presented clinical evidence and user experience, there is strong agreement among the committee that Belotero Balance Lidocaine possesses unique rheological characteristics that allow it to meet the currently unmet need for superficial injection without any Tyndall effect. This product produces long-lasting effects that are expected to be even longer lasting in Asian patients13. With over 50 HA product lines currently available in the Chinese market, Belotero Balance Lidocaine’s distinct rheological features, established track record of safety, efficacy and long-term tolerability will help it stand out in a dense HA dermal filler market13 .
Conclusions
Optimal tissue integration is key for performance and predictable results, thereby ensuring greater patient satisfaction. With high cohesivity and relatively lower viscosity, Belotero Balance Lidocaine, approved in China for injection into the mid-dermis for filling of moderate nasolabial folds, has excellent tissue integration and can be injected superficially, placing it in a unique position to fulfil the current unmet needs of the HA dermal filler market, and thus is poised to be a welcome addition to the aesthetic doctor’s armamentarium in China.
Acknowledgements The Authors wish to thank the other members of the ACE Steering Committee (listed in alphabetical order by last name): Prof. Xuefeng Han, Plastic Surgery Hospital, CAMS. PUMC ■ Prof. Dan Jian, Xiangya Hospital,
Central SU, Changsha ■ Prof. Xiongzheng Mu, Huashan Hospital, Fudan
University, Shanghai ■ Prof. Danru Wang, Shanghai Ninth People’s Hospital,
Shanghai Jiaotong University School of Medicine ■ Prof. Lei Wang, Zhongda Hospital, Affil. to Southeast
University ■ Prof. Leihong Xiang, Huashan Hospital, Fudan
University, Shanghai
And the international expert presenters: ■ Dr Wilson Ho, The Specialists: Lasers, Aesthetics and
Plastic Surgery, Central, Hong Kong, China ■ Dr Tatjana Pavicic, Private Practice for Dermatology and Aesthetics Dr. Tatjana Pavicic, Munich 80539,
Germany
Figure 1 © ACE Steering Committee
* Belotero is a registered trademark of Merz Pharma GmbH & Co. KGaA.
References
1. Cassuto D, Bellia G, Schiraldi C. An Overview of Soft Tissue Fillers for Cosmetic Dermatology: From Filling to Regenerative Medicine. Clin Cosmet Investig Dermatol 2021; 14: 1857–1866. 2. Tran C, Carraux P, Micheels P, Kaya G, Salomon D. In vivo bio-integration of three hyaluronic acid fillers in human skin: a histological study. Dermatology 2014; 228: 47–54. 3. Belotero Balance Lidocaine. Chinese IFU. Merz China. October 2021. 4. Micheels P, Besse S, Flynn TC, Sarazin D, Elbaz Y. Superficial dermal injection of hyaluronic acid soft tissue fillers: comparative ultrasound study. Dermatol Surg 2012; 38: 1162–1169. 5. Sundaram H, Rohrich RJ, Liew S, Sattler G, Talarico S, Trévidic P et al. Cohesivity of Hyaluronic Acid Fillers: Development and Clinical Implications of a Novel Assay, Pilot Validation with a Five-Point Grading Scale, and Evaluation of Six U.S. Food and Drug Administration-Approved Fillers. Plast Reconstr Surg 2015; 136: 678–686. 6. Stocks D, Sundaram H, Michaels J, Durrani MJ, Wortzman MS, Nelson DB. Rheological evaluation of the physical properties of hyaluronic acid dermal fillers. J Drugs Dermatol 2011; 10: 974–980. 7. Sundaram H. Going with the Flow: An Overview of Soft Tissue Filler Rheology and Its Potential Clinical Applications (2 of 3). Practical Dermatology 2011; : 23–28. 8. Bezzola A, Micheels P. Esthélis®, acide hyaluronique de conception suisse. Première étude complète des caractéristiques physico-chimiques et essais cliniques. J Med Esthet Chir Dermatol 2005; 32: 11–20. 9. Flynn TC, Sarazin D, Bezzola A, Terrani C, Micheels P. Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers. Dermatol Surg 2011; 37: 637–643. 10. Micheels P, Besse S, Sarazin D. Two Crosslinking Technologies for Superficial Reticular Dermis Injection: A Comparative Ultrasound and Histologic Study. J Clin Aesthet Dermatol 2017; 10: 29–36. 11. Lee JM, Kim YJ. Foreign Body Granulomas after the Use of Dermal Fillers: Pathophysiology, Clinical Appearance, Histologic Features, and Treatment. Arch Plast Surg 2015; 42: 232–239. 12. Prasetyo AD, Prager W, Rubin MG, Moretti EA, Nikolis A. Hyaluronic acid fillers with cohesive polydensified matrix for soft-tissue augmentation and rejuvenation: a literature review. CCID 2016; 9: 257–280. 13. Lorenc ZP, Fagien S, Flynn TC, Waldorf HA. Review of key Belotero Balance safety and efficacy trials. Plast Reconstr Surg 2013; 132: 33S-40S. 14. van Loghem J, Sattler S, Casabona G, Cotofana S, Fabi SG, Goldie K et al. Consensus on the Use of Hyaluronic Acid Fillers from the Cohesive Polydensified Matrix Range: Best Practice in Specific Facial Indications. Clin Cosmet Investig Dermatol 2021; 14: 1175–1199. 15. Chao YYY, Chhabra C, Corduff N, Fabi SG, Kerscher M, Lam SCK et al. PAN-ASIAN CONSENSUS—Key Recommendations for Adapting the World Congress of Dermatology Consensus on Combination Treatment with Injectable Fillers, Toxins, and Ultrasound Devices in Asian Patients. J Clin Aesthet Dermatol 2017; 10: 16–27. 16. Wu WTL, Liew S, Chan HH, Ho WWS, Supapannachart N, Lee H-K et al. Consensus on Current Injectable Treatment Strategies in the Asian Face. Aesthetic Plast Surg 2020; 44: 1195–1207. 17. Corduff N, Juniarti L, Lim TS, Lin F, Mariwalla K, Pavicic T et al. Current Practices in Hyaluronic Acid Dermal Filler Treatment in Asia Pacific and Practical Approaches to Achieving Safe and Natural-Looking Results. Clin Cosmet Investig Dermatol 2022; 15: 1213–1223. 18. de Maio M. Myomodulation with Injectable Fillers: An Innovative Approach to Addressing Facial Muscle Movement. Aesthetic Plast Surg 2018; 42: 798–814. 19. Lim T, Frank K, Hadjab B. Target-Specific Sandwich Technique: Facial rejuvenation leveraging CPM technology. J Cosmet Dermatol 2022; 21: 207–219. 20. Micheels P, Sarazin D, Besse S, Sundaram H, Flynn TC. A blanching technique for intradermal injection of the hyaluronic acid Belotero. Plast Reconstr Surg 2013; 132: 59S-68S. 21. Narins RS, Coleman W, Donofrio L, Jones DH, Maas C, Monheit G, Kaur M et al. Nonanimal Sourced Hyaluronic Acid–Based Dermal Filler Using a Cohesive Polydensified Matrix Technology is Superior to Bovine Collagen in the Correction of Moderate to Severe Nasolabial Folds: Results from a 6-Month, Randomized, Blinded, Controlled, Multicenter Study. Dermatol Surg 2010;36:730–740 22. Kerscher M, Agsten K, Kravtsov M, Prager W. Effectiveness evaluation of two volumizing hyaluronic acid dermal fillers in a controlled, randomized, double-blind, split-face clinical study. Clin Cosmet Investig Dermatol 2017; 10: 239–247.
