CLINICAL EVALUATION CONTENT Clinical Evaluation... 1 Content... 1 1. General Details... 2 2. Description of the device and its intended application... 2 3. Intended therapeutic and/or diagnostic indications and claims... 3 4. Context of the evaluation and choice of clinical data types... 6 5. Summary of the clinical data and appraisal... 8 6. Data analysis... 17 6.1. State-of-the-Art... 17 6.2. Performance... 19 6.2.1 Performance of HAs... 19 6.2.2 Performance of Juvederm Hydrate and Restylane Vital... 21 6.3. Safety... 24 6.4. Post Market Data of Hylan Solution... 27 7. Conclusion... 28 8. References... 29 9. Attachments... 31 1/31
1. General Details Manufacturer: Medical Device: BioScience GmbH Walsmühler Straße 18 19073 Dümmer Germany Hylan Solution (Trade names: GeneFill fine, CRM Soft, Hyacorp Fine) GMDN-Code: 17876 2. Description of the device and its intended application Hylan Solution is an absorbable skin implant with a high level of purity. It is a medical device produced from a hyaluronic acid that is not derived from animals. Hylan Solution is a sterile, apyrogenic, visco-elastic, biologically compatible (non-immunising, non-in flammatory, nontoxic) gel implant that is solublein water and produced from a hyaluronic acid gained through fermentation. Hyaluronic acid is a naturally occurring polysaccharide in the dermal matrix of human skin. Hyaluronic acid is chemically, physically and biologically identical in the tissues of all higher organisms. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan disaccharide composed of alternately repeating units of D-glucuronic acid and N-acetyl-D-glucosamine (Figure 2-1). It is a major component of the extracellular matrix found in many human tissues, including the skin. In contrast to other glycosaminoglycans, it occurs free and is not linked to proteins in the dermis. The highly charged nature of HA renders it soluble and allows it to bind water extensively, which determines skin viscoelasticity. Hyaluronic acid is chemically, physically and biologically identical in the tissues of all organisms (Kablik, Monheit et al. 2009). Figure 2-1 Hyaluronic Acid (HA) (Kablik, Monheit et al. 2009) 2/31
Hylan Solution is used in several products that are marketed under different names: GeneFill Fine, CRM Soft, and Hyacorp Fine. However, the composition of the products is identical. The listed products belong to one product family due to - the same mode of action - about the same application quantity - same application technique - same indications Composition 1 ml Hylan Solution contains: Hyaluronic acid sodium salt Sodium chloride Water for injection ad 14.0 mg 6.9 mg 1.9 ml Specifications: Appearance/identity Clear, transparent solution viscosity 10.000 14.000 mpas ph 7,3 7,5 osmolarity 260 360 mosmol/kg NaHA non-crosslinked 14 mg/ml sterility sterile volume 1 ml The sodium hyaluronate used in Hylan Solution is of high molecular weight (2.5 x 10 6 Da). The specifications are described in detail in the technical documentation of Hylan Solution. GeneFill Fine, CRM Soft, and Hyacorp Fine, they all contain 1 ml Hylan Solution (sterile, filled in syringe). Intended Use Hylan Solution is intended for the treatment area of dermatology. It is injected into the medium dermal tissue to supplement the intercellular matrix and the intradermal tissue and to restore lost anatomical structures of the skin. 3. Intended therapeutic and/or diagnostic indications and claims Mode of action Hylan Solution is implanted into the medium dermal tissue to supplement the intercellular matrix and the intradermal tissue and to restore lost anatomical structures of the skin. Its mechanism of action is based on the latest biotechnology in the production of injectable hyaluronic acid. 3/31
Treatment areas Face, Neck, Décolleté, Back of the hand Application instructions The areas to be treated must be marked prior to treatment. The treating person should note the facial expression and existing lines and a possible facial asymmetry. To perform the implantation as painfree as possible, a local anaesthetic should be used. The treating person must advise the patient of all precautions and possible adverse effects prior to treatment. The area to be treated must carefully be cleaned with antiseptic agents prior to treatment. The syringe is removed from the blister pack, the cap covering the tip of the syringe is removed and a needle is applied to the syringe. Hylan solution is injected with the aid of 30G nanoneedles. The implantation is effected in the dermis. Implantation technique Implant Hylan Solution flatly in the medium dermis with the aid of the 30G nanoneedle. After implanting Hylan Solution, massage the treated area with slight pressure to guarantee the even distribution of the product. Hylan Solution sports excellent flowability in tissue. ATTENTION The graduation on the syringe is intended as an orientation aid for users with regard to final volume. It does not have any measuring function, it solely provides the amount used in relation to the nominal volume of 1 ml. Injection of a sufficient amount of the material is checked by the treating person visually and through touch. Nature and contents of container Hylan Solution is supplied sterile in a 1 ml syringe with an integrated Luerlock adapter in a blister pack for single use only. Sterile 30G nanoneedles, instructions for use and labels containing the lot number and the shelf life are packaged in a carton together with the blister pack. The patient is given one of the labels to guarantee traceability of the product. Classification According to the Medical Device Directive 93/42/EEC, annex IX, rule 7, the product described in the following is classified as Class III Medical Device. The products under discussion containing Hylan Solution are certified and marketed in the EU as class III medical devices for years. GeneFill Fine: since 2009 Hyacorp Fine: since 2009 Degradation Because of the chemical equivalence of exogenously administered sodium hyaluronate to endogenous hyaluronate the metabolic pathways related to metabolism are the same. Degradation of hyaluronic acid occurs by depolymerisation of the glycosidic bonds. In particular, two different processes are assigned to the hyaluronic acid depolymerisation: enzymatic degradation and free radical degradation. During enzymatic degradation, the hyaluronidases HYAL1 and HYAL2 cleave the polymers in fragments down to tetrasaccharides, which are then converted to monosaccharides by other members of the hyaluronidase family such as beta-glucosidase or beta-n-acetylglucosaminidase. These degradation products also occur naturally in the human and animal body (De Boulle, Glogau et al. 2013). After the breakdown fragments of hyaluronic acid are degraded to D-glucuronic acid 4/31
and N-acetyl-D-glucosamine, the monosaccharides are finally metabolised to CO 2, H 2 O, and urea (Oh et al 2010; cited in (Laznicek, Laznickova et al. 2012). The turnover of Hyaluronan in tissues can be measured by injected 3 H-labeled hyaluronan and is very rapid. The half-life of the injected polymer in the skin and joints is about 12 h. In the intestine up to 9 % of the tissue HA can be washed out per hour at high lymph flow (Laurent and Fraser 1992). Subcutaneously injected hyaluronan, labelled with 125 I-thymine cellobiose into the hindpaw of rabbits revealed that 6 h after subcutaneous injection, 65 % of the injected radioactivity was recovered. The major part of HA injected in the skin was, however, catabolised by lymphatic removal and subsequent degradation in local lymph nodes and liver (Laurent, Dahl et al. 1991). Indication Hylan Solution: Replaces lost hyaluronic acid in the skin Increases elasticity Improves skin hydration Provides skin with a fresh look through its lifting effect The result that can be achieved is dependent on the skin type and the changes requested. The use is only permitted by medical personnel. Contraindications Hylan Solution may not be used in the event of: a tendency to hypertrophic and keloid scarring an intolerance towards gram-positive bacteria active inflammatory or infectious processes acute or chronic skin diseases anti-coagulant therapy a known allergy against hyaluronic acid Patients with multiple allergies should be excluded from treatment. The use of Hylan Solution for breast augmentation is contraindicated. Precautions and notices Hylan Solution is intended for intradermal injection only and may not be injected into blood vessels as this could result in an occlusion of the vessels and an embolism. No clinical data are available on the application during pregnancy or lactation or to adolescents under 18 years of age. Hylan Solution is packaged sterile and is intended only for single use. It may not be resterilised. If the packaging is open/defective, it must not be used. Hylan Solution is supplied in a sterile syringe and is ready-to-use. It may not be mixed with other injection agents. 5/31
A complete anamnesis must be established prior to treatment to exclude possible contraindications. The normal precautions that apply to all intradermal injections must be observed. The implantation of Hylan Solution involves the risk of infection. The skin must be disinfected prior to treatment. Like other implants, Hylan Solution may not be applied near the site of inflammation or infection when treating patients with existing infectious or inflammatory processes. Before treatment, patients should not ingest aspirin, steroids or high doses of vitamin E as these substances may cause bleeding or raise susceptibility towards infection at the injection site. The area treated may not be exposed to great heat (sun, solarium, laser and IPL). The syringes and needles used are considered to be contaminated and must therefore be destroyed in accordance with the accepted rules of medical practice. Adverse Effects Caused by the injection: As with any other injection, patients may suffer from the following symptoms: temporary erythema slight swelling pain itching discolouration hardening. Typically these reactions spontaneously disappear within 2 to 5 days after the injection. Caused by the product: A hypersensitivity to hyaluronic acid following the injection has been reported less than 1 % out of 5000 treatments. This hypersensitivity is shown through an extended erythema, swelling and hardening at the implantation site. These reactions can occur immediately after the injection or up to 2 to 4 weeks later. 4. Context of the evaluation and choice of clinical data types The performance and safety of Hylan Solution is demonstrated based on the equivalence to other marketed products and on established use. Hylan Solution is comparable to Teosyal Meso, Restylane vital, and Juvederm hydrate, which are established products on the market since a decade. The composition and characteristics of the products can be considered as equivalent. 6/31
Teosyal Meso The product Teosyal Meso exhibits the same composition as Hylan Solution, but no published data regarding performance and safety have been found. Juvederm hydrate Juvederm Hydrate is indicated for injection into the superficial dermis and dermo-epidermic junction of the skin and is a rehydrating agent intended to restore the quality of the skin. Restylane vital Restylane vital (Q-Med, Uppsala, Sweden) is a colorless, viscoelastic gel of nonanimal origin consisting of 20 mg/ml HA dispersed in physiologic saline solution (ph 7.0). The HA in Restylane Vital is chemically cross-linked to a small proportion (< 1 %) of the constituent polysaccharide chains using the NASHA technology (NASHA = non-animal stabilised hyaluronic acid). By stabilization of about 1 % of the hyaluronic acid three- dimensional formability as gel particles is attained. It is provided in prefilled Disposable 1.0-mL syringes supplied with three 30-gauge sterilized needles (Kerscher, Bayrhammer et al. 2008, Hartmann, Bachmann et al. 2010). The products Juvederm hydrate and Restylane vital are either non-cross linked or crosslinked to a very small amount (< 1 %) and can therefore be regarded as equivalent to the product Hylan Solution under evaluation. In contrast to Hylan Solution, Juvederm hydrate contains mannitol as further ingredient. However, clinical, biological, and technical characteristics are not significantly affected by the latter. A comparison of the products under evaluation, Juvederm hydrate, and Restylane vital is given in the following table: Parameter Hylan Solution Juvederm hydrate Restylane vital Intended use (acc to Intradermal injection Intradermal injection Intradermal injection IFU) Indication (acc. to Improving hydration IFU) and elasticity of skin Replaces lost hyaluronic acid in the skin, increases elasticity, improves skin hydration Restoration of skin hydrobalance, improving skin structure and elasticity of skin Raw material Hyaluronic acid of non-animal origin Hyaluronic acid of non-animal origin Hyaluronic acid of non-animal origin Content HA 14 mg/ml 13.5 mg/ml 14 mg/ml Form Aqueous solution Aqueous solution Aqueous solution Stability Shelf-life 36 months Shelf life 24 months - Packaging Pre-filled in 1 ml syringe Pre-filled in 1 ml syringe Storage 2 C to 25 C 2 C to 25 C Up to 25 C Reusability No No No Sterility Sterile Sterile Sterile Pre-filled in 1 ml syringe 7/31
5. Summary of the clinical data and appraisal Since HA used as dermal filler is an established procedure the safety and performance of Hylan Solution can be assessed by reviewing the literature. Protocols of the literature survey and corresponding results are outlined in attachment 1. The publications are categorized into the following sections: Description of state-of-the-art, demonstration of performance and safety of Juvederm Hydrate and Restylane Vital and safety of HA dermal fillers in general. Both Juvederm Hydrate, which contains non-cross linked HA, and Restylane, which contains cross-linked HA to a small amount, can be regarded as similar to Hylan solution with regard to their biological, technical, and clinical properties as well as to their principle of operation, and origin of material. The current state-of-the-art using HA-based dermal fillers has been assessed mainly using review articles. The performance and safety of Juvederm Hydrate and Restylane Vital is mainly described in prospective studies or case reports. The safety of HA based dermal fillers has been evaluated screening the extensive literature describing different forms of HA used in dermal fillers since many years. The final result of the appraisal of the literature is discussed below: State-of-the-Art Bailey, S. H., J. L. Cohen, et al. (2011). "Etiology, prevention, and treatment of dermal filler complications." Aesthet Surg J 31(1): 110-121. Baumann L. S. et al (2007). Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study. Dermatol Surg. Dec;33 Suppl 2:S128-35. The article describes and reviews the complications associated with the currently available dermal filling agents; the availability of dermal fillers for multiple cosmetic indications has led to a dramatic increase in their application; although fillers are generally regarded as safe tools for soft tissue augmentation, complications can occur; the authors conducted a literature review in peerreviewed journals and present the reported complication rates. They also describe current strategies to avoid, diagnose, and manage complications if they do occur. This study compared the effectiveness and safety of these smooth-gel HA dermal fillers with bovine collagen for nasolabial fold (NLF) correction. In total of 439 subjects with moderate or severe NLFs received one of three types of smooth-gel HA dermal filler (in one NLF) and cross-linked bovine collagen (in the other NLF) and were evaluated for <or=24 weeks. Overall, the smooth-gel HA dermal fillers offer longerlasting correction than bovine collagen-which may lessen the frequency that repeat treatments are needed. 8/31
Dayan S.H. (2008). Facial Dermal Fillers: Selection of Appropriate Products and Templates. Aesthet Surg J. 28: 335-347. Gold, M. (2009). "The science and art of hyaluronic acid dermal filler use in esthetic applications." J Cosmet Dermatol 8(4): 301-307. Kablik J. (2009). Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg. Feb;35 Suppl 1:302-12. Lupo, M. P. (2006). "Hyaluronic acid fillers in facial rejuvenation." Semin Cutan Med Surg 25(3): 122-126. Matarasso, S. L., J. D. Carruthers, et al. (2006). "Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane)." Plast Reconstr Surg 117(3 Suppl): 3S-34S; discussion 35S-43S. Newman, J. (2009). "Review of soft tissue augmentation in the face." Clin Cosmet Investig Dermatol 2: 141-150. Price, R.D, et al (2007). Hyaluronic acid: the science and clinical evidence. J Plast Reconstr Aesthet Surg. 60, 1110-1119 Rohrich, R. J., A. Ghavami, et al. (2007). "The role of hyaluronic acid fillers (Restylane) in facial cosmetic surgery: review and technical considerations." Plast Reconstr Surg 120(6 Suppl): 41S-54S. The authors compared the most widely used dermal fillers and injection technique. This publication has to be regarded as a review article; reflecting the start of the art mainly in the years from 2004 to 2008; consensus statements and randomized trials are discussed as well. The authors described Hyaluronic acid as nonimmunogenic, versatile and reversible agents with an excellent benefit-risk profile. Different preparations differ in their manufacturing process, viscosity, hardness, cohesivity and ease of injection. The objective of this article was to discuss the key physical properties and methods used in characterizing dermal fillers. These methods were then used to analyze several well-known commercially available fillers. Review article. This publication represents an overview for hyaluronic acid as a dermal filler. The advantage of hyaluronic acid compared other dermal fillers like collagen is discussed. The article represents and summarizes publications from 1986 to 2005. Restylane and other sorts of hyaluronic acid (avian origin) are described. Review article and consensus statement, mainly focusing on the product Restylane. Besides products, procedural aspects were discussed in detail. The time period from 2000 to 2005 is covered. Review article covering the time period from 2000 to 2008. This article compared the current options of tissue augmentation and discussed the composition and characteristics of available dermal fillers. This review represents an overview about the scientific evidence of HA used in different fields such as skin regeneration, wound healing and cosmetic surgery. Review article. The product Restylane is described in detail; procedural aspects are discussed as well. Main focus of this article is the facial rejuvenation. The performance of Restylane is shown. Possible complications and there occurrence are discussed., P2, P2, A2, P2, P2, 9/31
Smith, K. C. (2008). "Reversible vs. nonreversible fillers in facial aesthetics: concerns and considerations." Dermatol Online J 14(8): 3. Review article dealing with cross-linked hyaluronic acid as dermal filler in general. History, development and alternatives in tissue augmentation is presented. The major and unique advantage of HA dermal fillers is the quick and easy reversibility by hyaluronidase. A2, Performance of HAs Baumann, L. S., A. T. Shamban, et al. (2007). "Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study." Dermatol Surg 33 Suppl 2: S128-135. A multicenter, double-masked, randomized, within subject study has been performed to compare the effectiveness and safety of these three HA dermal fillers (Juvederm, Juvederm Ultra, Juvederm Ultra Plus) with those of a cros linked bovine collagen filler for nasolabial fold (NLF) correction. Subjects were eligible for enrolment into the study if they were at least 30 years of age and had fully visible bilateral NLFs that were approximately symmetrical. The NLFs were required to be both moderate or both severe (on a scale of none, mild, moderate, severe, and extreme) as judged by two investigators. The deepest part of the fold was used for the assessment of severity. Subjects were required to have had no hypersensitivity responses after two injections of bovine collagen within 12 months of study entry and to refrain from undergoing other anti-wrinkle treatment in the nasolabial and perioral areas before and during the study period. (Sunscreen was allowed, however.) Females of childbearing potential were required to have a negative urine pregnancy test and to use reliable contraception while participating in the study. Exclusion criteria included a history of anaphylaxis, atopy, allergy to meat or lidocaine, or multiple severe allergies; hypersensitivity to bovine collagen or HA; receipt of immune therapy or a history of autoimmune disease; a tendency to develop hypertrophic scarring; pregnancy or breastfeeding; use in the 4 weeks before study randomization (or intent to use during the study) of oral retinoids, over-the-counter or prescription anti-wrinkle treatments, microderm abrasion, or chemical peels in the NLF area; and any prior cosmetic procedure or tissue augmentation at the NLF injection site in the 6 months before study entry (or intent to undergo such a procedure during the study). The study was approved by the relevant institutional review boards, all subjects signed informed consent, and the study protocol conformed to the guidelines of the 1975 Declaration of Helsinki. 10/31
Bogdan Allemann, I. and L. Baumann (2008). "Hyaluronic acid gel (Juvederm) preparations in the treatment of facial wrinkles and folds." Clin Interv Aging 3(4): 629-634. Review article summarizing the results of two large controlled trials performed by Baumann et al (2007) and Pinsky et al (2007). In summary the performance and safety of Juvederm compared to Zyplast was investigated on 731 subjects. Carruthers, A., W. Carey, et al. (2005). "Randomized, double-blind comparison of the efficacy of two hyaluronic acid derivatives, restylane perlane and hylaform, in the treatment of nasolabial folds." Dermatol Surg 31(11 Pt 2): 1591-1598; discussion 1598. Gilbert, E., A. Hui et al. (2012). The basic science of dermal fillers: past and present Part II: adverse effects. J Drugs Dermatol 11(9): 1069-1077. Skeie, L., H. Bugge, et al. (2010). "Large particle hyaluronic acid for the treatment of facial lipoatrophy in HIVpositive patients: 3-year follow-up study." HIV Med 11(3): 170-177. 150 patients with moderate or severe nasolabial folds were randomized to contralateral treatment with Restylane Perlane and Hylaform. Efficacy was assessed using semiobjective outcome instruments at 3, 4.5, and 6 months after achievement of an optimal cosmetic result. Patients subsequently underwent open-label bilateral retreatment with Restylane Perlane (if required) and were followed up for a further 6 months. The study was performed in accordance with the principles of the Declaration of Helsinki, the International Conference of Harmonization guidelines for Good Clinical Practice, and local regulatory requirements. All subjects provided their written informed consent before enrolment into each phase of the study. Part I of this article reviews the basic science and evolution of both historical and contemporary dermal fillers; Part II examines their adverse effects. Twenty patients received injections of Restylane. Refill treatment was offered at 12 and 24 months. Treatment effects were evaluated using ultrasound, the Global Aesthetic Improvement Scale, visual analogue scale (VAS) and the Rosenberg self-esteem scale P2, P2, Smith, S. R., D. Jones, et al. (2010). "Duration of wrinkle correction following repeat treatment with Juvederm hyaluronic acid fillers." Arch Dermatol Res 302(10): 757-762. Five of the original 11 study sites were selected to participate in an extended followup evaluation and a total of 80 subjects were enrolled. Subjects were enrolled in this followup study if they had completed the pivotal study, preferred the Juvederm-treated side (versus the Zyplast-treated side) upon study exit and had undergone their optional end-ofstudy (repeat) treatment to both NLFs on the same day and with the same Juvederm formulation as was administered during the pivotal trial. The repeat treatment was administered between 24 and 36 weeks (±14 days) after the last treatment in the pivotal study. Subjects were excluded from the study if they had facial hair that would interfere with the visual assessments of NLF severity; had 11/31
undergone or had plans to undergo any confounding aesthetic procedure such as botulinum toxin injection, laser resurfacing, etc., in the lower two-thirds of the face less than 30 days prior to the repeat treatment or at any time thereafter through the end of the study; had a clinically significant organic disease, condition, illness, or circumstance that would compromise participation in the trial; or had received any other investigational treatment within 30 days prior to study enrolment. Effectiveness analyses were performed on the intent-to-treat population and safety analyses on the as treated population. A paired t-test was utilized to compare the volume at initial treatment with the volume at repeat treatment and the posttreatment NLF severity to baseline. Performance of Juvederm Hydrate Dallara JM (2012). A prospective, noninterventional study of the treatment of the aging hand with Juvederm Ultra 3 and Juvederm Hydrate. Aesthetic PlastSurg. 36(4):949-54. In this study prospective, noninterventional study of the treatment of the aging hand 99 subjects were at the first visit injected with Juvederm Ultra 3 and at the second visit (day 15) with Juvederm Hydrate. A final assessment was made at day 30. This combines treatment has been proposed to fill and smooth the skin with Juvederm Ultra 3 and to rehydrate and restore skin quality with Juvederm Hydrate.Ths combined Juvederm Ultra 3 and Juvederm Hydrate treatment showed an effective and safe method for rejuvenating the aging hand. Vent, J., F. Lefarth, T. Massing and W. Angerstein (2014). "Do you know where your fillers go? An ultrastructural investigation of the lips." Clin Cosmet Investig Dermatol 7: 191-199. There were ten patients initially included in this prospective pilot study. One patient dropped out of the study for not showing up for the follow-up exam. Included in this pilot study were volunteers who agreed to have the lower third of the face augmented after informed, written consent was obtained. Subjects who had undergone augmentation in the past 6 months, who had known allergies/intolerance against lidocaine, and who suffered from coagulopathies were excluded. Dysmorphophobic and psychologically unstable persons were also excluded. Performance of Restylane Vital Hartmann V. et al. (2010). Hand augmentation with stabilized hyaluronic acid (Macrolane VRF20 and Restylane Vital, Restylane Vital Light). J Dtsch Demato Ges. 8(1):41-44. This case report investigated the effect of Restylane vital for hand augmentation of the back of the hand. Significant adverse events did not occur and the appearance of the back of the hands was improved. 12/31
Kerscher M., et al (2008). Rejuvenating Influence of a Stabilized Hyaluronic Acid-Based Gel of Nonanimal Origin on Facial Skin Aging Dermatol Surg. 34(5): 720-726. Lee, B. M., et al. (2015). "Rejuvenating Effects of Facial Hydrofilling using Restylane Vital." Arch Plast Surg 42(3): 282-287. Lim, H. K., D. H. Suh, S. J. Lee and M. K. Shin (2014). "Rejuvenation effects of hyaluronic acid injection on nasojugal groove: prospective randomized split face clinical controlled study." J Cosmet Laser Ther 16(1): 32-36. Reuther T. et al. (2010). Effects of a three-session skin rejuvenation treatment using stabilized hyaluronic acid-based gel of nonanimal origin on skin elasticity: a pilot study. Arch Dermatol Res. 302:37-45. Streker, M., T. Reuther, N. Krueger and M. Kerscher (2013). "Stabilized hyaluronic acid-based gel of non-animal origin for skin rejuvenation: face, hand, and In this single-center, prospective pilot study, the rejuvenating influence of Restylane vital on facial skin aging was analysed in 19 female patients. In a series of 3 treatment sessions, spaced 4 weeks apart, Restylane vital was injected into the lower cheeks and elasticity, skin surface roughness, dermal thickness and density were evaluated. Skin elasticity and surface roughness improved significantly with no adverse events. These results demonstrated that Restylane vital represents an effective treatment to rejuvenate the skin without bearing risks of side effects. This study was a single-center, prospective study. A total of 30 female patients with dry and tired skin on face were enrolled in the study. The age range of patients was from 27 to 60 years. All patients provided written, informed consent. Patients were excluded if they were pregnant or breast feeding, if they had active skin disease (such as infection, eczema, various dermatitis, etc.), or if they had a known hypersensitivity to HA, autoimmune disease, or skin cancer. In addition, patients who had been treated with other skin rejuvenation procedures, such as peeling, botulinum toxin, other filler, or laser therapy and had undergone facial surgery within the previous 12 months were excluded. This was a single-centre, prospective, randomised split face clinical study. All aspects of the protocol adhered to the Helsinki guidelines, and written informed consent was obtained from all subjects prior to any study-related procedure. The study protocol was reviewed and approved by the institutional review board of Kyung Hee medical centre. The purpose of this pilot study was to evaluate the effects of micropuncture injections of Restylane Vital on skin elasticity, a major aspect of skin ageing. 19 patients underwent a series of three treatment sessions, spaced 4 weeks apart, with Restylane Vital injected into the lower facial cheeks. The treatment significantly increased skin firmness and improved its viscoelastic recovery capacities by tightening the skin and by improving the recoil capacities. This open, randomised intra-individually controlled, split side, single centre study was performed in Hamgurg, Germany in accordance with the Declaration of Helsinki. The study conformed to all relevant guidelines and received D2 A1 P1 13/31
decolletage." J Drugs Dermatol 12(9): 990-994. approval from an independen ethics committee (Ethik-Kommission der Ärztekammer Hamburg). All subjects gave informed consent. Safety of HA dermal fillers Andre, P., N. J. Lowe, et al. (2005). "Adverse reactions to dermal fillers: a review of European experiences." J Cosmet Laser Ther 7(3-4): 171-176. Bauman L. S. et al (2007). Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study. Dermatol Surg. Dec; 33 Suppl 2:S128-35. Beasley, K.L. (2009). Hyaluronic Acid Fillers: A comprehensive Review. Facial Plast Surg. 25:86-94. Bodgan Allemann I. (2008). Hyaluronic acid gel (Juvederm ) preparations in the treatment of facial wrinkles and folds). Clin Interv Aging. 3(4): 629-634 In this review several publications and case reports were summarized. It described the clinical aspects of adverse reactions following injections of different dermal fillers (absorbable, non biodegradable and permanent) It further provided valid information on safety of dermal fillers. This study compared the effectiveness and safety of these smooth-gel HA dermal fillers with bovine collagen for nasolabial fold (NLF) correction. In total of 439 subjects with moderate or severe NLFs received one of three types of smooth-gel HA dermal filler (in one NLF) and cross-linked bovine collagen (in the other NLF) and were evaluated for <or=24 weeks. Overall, the smooth-gel HA dermal fillers offer longer-lasting correction than bovine collagen-which may lessen the frequency that repeat treatments are needed. Since 85 % of all dermal filler procedures occurred with a hyaluronic acid derivate this review summarized the composition,, specific differences and pivotal clinical studies of all the hyaluronic acid fillers currently available in the US. In this article the Juvederm product line is described and the differences in particle size, HA concentration, type of cross-linking agent used and injection sites are summarized. P2, P2, Carruthers, A., W. Carey, et al. (2005). "Randomized, double-blind comparison of the efficacy of two hyaluronic acid derivatives, restylane perlane and hylaform, in the treatment of nasolabial folds." Dermatol Surg 31(11 Pt 2): 1591-1598; discussion 1598. 150 patients with moderate or severe nasolabial folds were randomized to contralateral treatment with Restylane Perlane and Hylaform. Efficacy was assessed using semiobjective outcome instruments at 3, 4.5, and 6 months after achievement of an optimal cosmetic result. Patients subsequently underwent open-label bilateral retreatment with Restylane Perlane (if required) and were followed up for a further 6 months. The study was performed in accordance with the principles of the Declaration of Helsinki, the International Conference of Harmonization guidelines for Good Clinical Practice, and local regulatory requirements. All subjects provided 14/31
Gilbert, E., A. Hui et al. (2012). The basic science of dermal fillers: past and present Part II: adverse effects. J Drugs Dermatol 11(9): 1069-1077. Hirsch R.J. and Stier M. (2008). Complications of soft tissue augmentation. J Drugs Dermatol. Sep; 7(9):841-5. Lim, H. K., D. H. Suh, S. J. Lee and M. K. Shin (2014). "Rejuvenation effects of hyaluronic acid injection on nasojugal groove: prospective randomized split face clinical controlled study." J Cosmet Laser Ther 16(1): 32-36. Lowe, N. J., C. A. Maxwell et al. (2005). Adverse reactions to dermal fillers: review. Dermatol Surgery 31(11 Pt 2): 1616-1625. Matarasso, S. L., J. D. Carruthers, et al. (2006). "Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane)." Plast Reconstr Surg 117(3 Suppl): 3S-34S; discussion 35S-43S. Newman, J. (2009). "Review of soft tissue augmentation in the face." Clin Cosmet Investig Dermatol 2: 141-150. Price, R.D, et al (2007). Hyaluronic acid: the science and clinical evidence. J Plast Reconstr Aesthet Surg. 60, 1110-1119 Streker, M., T. Reuther, N. Krueger and M. Kerscher (2013). "Stabilized hyaluronic acid-based gel of nonanimal origin for skin rejuvenation: their written informed consent before enrolment into each phase of the study. Part I of this article reviews the basic science and evolution of both historical and contemporary dermal fillers; Part II examines their adverse effects. This article describes a range of complications resulting from dermal filler injections, reviews key case studies, and discusses possible treatment options for adverse effects. While biodegradable fillers offer the least risk for the patient, location, allergic reactions, granulomas, necrosis, and infection are all serious complications that must be considered before performing soft tissue augmentation with any approved dermal filler. This was a single-centre, prospective, randomised split face clinical study. All aspects of the protocol adhered to the Helsinki guidelines, and written informed consent was obtained from all subjects prior to any studyrelated procedure. The study protocol was reviewed and approved by the institutional review board of Kyung Hee medical centre. This article reviews the incidences and types of reaction to various commonly used injectable dermal filler products by literature review and personal experiences. Review article and consensus statement, mainly focusing on the product Restylane. Besides products, procedural aspects were discussed in detail. The time period from 2000 to 2005 is covered. Review article covering the time period from 2000 to 2008. This article compared the current options of tissue augmentation and discussed the composition and characteristics of available dermal fillers. This review represents an overview about the scientific evidence of HA used in different fields such as skin regeneration, wound healing and cosmetic surgery. This open, randomised intra-individually controlled, split side, single centre study was performed in Hamgurg, Germany in accordance with the Declaration of Helsinki. P2, P2, A2, P2, A2, P2, 15/31
face, hand, and decolletage." J Drugs Dermatol 12(9): 990-994. Vent, J., F. Lefarth, T. Massing and W. Angerstein (2014). "Do you know where your fillers go? An ultrastructural investigation of the lips." Clin Cosmet Investig Dermatol 7: 191-199. Winslow, C. P. (2009). "The management of dermal filler complications." Facial Plast Surg 25(2): 124-128. The study conformed to all relevant guidelines and received approval from an independen ethics committee (Ethik-Kommission der Ärztekammer Hamburg). All subjects gave informed consent. There were ten patients initially included in this prospective pilot study. One patient dropped out of the study for not showing up for the follow-up exam. Included in this pilot study were volunteers who agreed to have the lower third of the face augmented after informed, written consent was obtained. Subjects who had undergone augmentation in the past 6 months, who had known allergies/intolerance against lidocaine, and who suffered from coagulopathies were excluded. Dysmorphophobic and psychologically unstable persons were also excluded. The purpose of this article is to review the most commonly encountered complications and management thereof. Literature published between 2006 and 2008 are taken into consideration A2, P2, 16/31
6. Data analysis 6.1. State-of-the-Art When the face ages, wrinkles, grooves, and ptotic tissue become more and more prominent. Superficial wrinkles are largely due to photo damage and resulting solar elastosis. This is characterized by loss of collagen mass in the epidermal dermal junction and an increased array of elastin whirls in the deeper dermis. Repeated muscle action produces prominent wrinkles and creases in the mimetic areas of facial skin such as the glabella, periorbital skin, nasolabial creases, and perioral skin. Grooves appear deeper in the nasolabial and marionette zones with the additional feature of fat atrophy. As a result of the loss of fat volume, the static suspensory ligaments become more lax and the face takes on attributes of ptotic jowls, ptotic malar mounds, and nasolabial folds. Skeletal changes resulting in decreased height of the maxilla and the mandible occur in the later decades of life (6th 8th decades) and accentuate the above findings. Facial rejuvenation requires an accurate diagnosis of the above findings, and therapies are directed at correcting multiple layers. There are three pillars of facial rejuvenation: 1) ensuring adequate skeletal framework and support, 2) tightening and repositioning of the investing musculofascial aponeurotic system of the face and neck (galea, superficial muscular aponeurotic system, and platysma), 3) replacement (Newman 2009). A wide range of treatment options are available for managing volume loss in the aging face, back of the hands and décolleté, including permanent, semi-permanent, and non-permanent options. A complete aesthetic evaluation of the patient and a thorough understanding of the patient s goals and preferences are crucial in any treatment plan. Interventions can include topical therapy, energy-based therapies, including laser-, radio frequency-, and light (visible and infrared)-based therapies, surgical procedures, and injectable products, including neurotoxins such as botulinum toxin type A and fillers. (Matarasso, Carruthers et al. 2006) Dermal fillers and subcutaneous volume enhancers have enjoyed the greatest degree of development and differentiation because they are also administered in an office-based setting. The ideal dermal filler is one that is biocompatible, predictable, adjustable to the anatomy of the patient, long-lasting, reversible, and natural in appearance, while no single filler possesses all of these characteristics. (Newman 2009) In recent years, the rate of soft tissue augmentation has exponentially increased for facial rejuvenation. According to statistics published by the American Society for AestheticPlastic Surgery, there were over 1.2 million dermal filler injections in 2008 in US, which represents a 200% increase since 1997 (Bailey, Cohen et al. 2011). Although soft tissue augmentation dates back over a century to when autologous fat was used, injectable fillers entered mainstream cosmetic medicine when bovine collagen injections were developed in the 1980s. Autologous fat, once a staple in the filler arena, has been largely replaced by the new generation of fillers because aesthetic results and duration of benefit after fat injection have a degree of variability that is unacceptable to many physicians and their patients. Reports on the fat-grafting technique are anecdotal and no statistics on the "take" of fat have been published (Smith 2008). In general the dermal fillers can be classified in absorbable fillers like collagen or hyaluronic acid based products, biodegradable microparticle injectable implants (calcium hydroxylapatite or Poly-L-lactic acid), or non-absorbable fillers containing poly-methylacrylate or silicone. 17/31
Injectable microparticles are absorbed much slower than collagen or hyaluronic acid. This fact is considered as an advantage if compared to absorbable fillers. The disadvantage of these materials is that the procedure is not reversible; corrections are not possible or even in an invasive way. With non-absorbable fillers there is only limited experience. Based on the available literature the risk of side effects is higher compared to absorbable material. All of the collagen products have clinical effects lasting from 1 to 4 months. The main clinical advantage of the human collagen products is their ability to correct the most superficial lines with smooth flow characteristics as their carrier is phosphate-buffered saline. The duration of clinical effects has not been able to reach that of the hyaluronic gels as demonstrated in a blinded comparative study against Zyplast (Newman 2009). Hyaluronic acid (HA)-based gels are now the gold standard in dermal fillers, with more cosmetic procedures in the United States using these fillers than all other fillers combined. The widespread acceptance of HA fillers is due to their biocompatibility (unlike protein-based fillers, they are composed of polysaccharides that exhibit no species specificity), stability, and their good record of safety and effectiveness in other countries where they have been used for many years (Baumann, Shamban et al. 2007). Hyaluronic acid, or hyaluronan, is a glycosaminoglycan that consists of regularly repeating nonsulfated disaccharide units of glucuronic acid and N-acetylglucosamine. Hyaluronan is a naturally occurring biopolymer that exhibits no species or tissue specificity. It is an essential component of the extracellular matrix of all adult animal tissues and is especially abundant in early embryos. Hyaluronan normally exists in tissues as a free polymer of linked disaccharide units and is highly negatively charged. However, in some tissues, such as cartilage and bone, hyaluronan is bound to large glycoprotein structures or specific cell receptors. In healthy tissues, the average molecular weight of hyaluronan is 5 to 10million with up to 25,000 disaccharide units, and the average adult concentration is 200 mg/kg (0.02 percent). (Matarasso, Carruthers et al. 2006, Price, Berry et al. 2007). When uncross-linked HA (endogenous or exogenous) is added to water it produces a highly viscous liquid. One very important characteristic of HA products is the ability of clinicians to break down the HA polymers by the use of an enzyme known as hyaluronidase. This result in the breakage of the three-dimensional structure and the HA can be absorbed within hours by the surrounding interstitial fluid. One note of caution is the possibility of allergic reaction with purified bovine testicular hyaluronidase or with preparations that contain metabisulfite (Newman 2009). In general, clinical trials have documented the overwhelming safety profile of all forms of HA. Transient and self-limiting redness and swelling are common following injections of HA and this is due to the hydrophilic nature of HA. Pain associated with injection of HA may be managed by the use of both topical and injected anesthetic agents. Despite adequate anesthesia, patients can expect tenderness for 1 to 2 days after injection (Lupo 2006). Potential adverse reactions are minimal and are mainly injection-related and self-resolving. These include local bruising, purpura, erythema, and tenderness, itching, and swelling. A major adverse event that has been reported is hypersensitivity, but true immunoglobulin G- and E- mediated reactions are rare (Rohrich, Ghavami et al. 2007). Although no treatment is entirely without risk, the side effect profiles of HAs and other dermal fillers have been reviewed extensively. HAs in general have demonstrated excellent benefit risk profiles. Serious adverse events are rare, and most reactions are transient, injection-site related, and mild to moderate in severity (Gold 2009). 18/31
By virtue of HAs biocompatibility and non-toxicity, it is used in many biomedical fields, such as ophthalmology, dermatology and rheumatology. In dermatology, it is used to fill tissue defects in the facial area, back of the hand, neck and décolleté. Since Hylan solutions are viscoelastic materials, no pharmacological effects are expected and their action is predominantly due to physical properties (Dayan and Bassichis 2008). 6.2. Performance HA used in dermal fillers differs in chain length molecular weight, which do not appear to have any clinical significance. The most important difference between HA fillers on the market today is the percentage of crosslinked HA (Gilbert, Hui et al. 2012). 6.2.1 Performance of HAs Carruthers et al performed a randomized, double-blind comparison of the efficacy of Restylane Perlane and Hylaform in the treatment of nasolabial folds was performed by in 2005. One hundred fifty subjects (140 women, 10 men) were screened and randomized to treatment and received both study products (intent-to-treat population). Patients ranged in age from 34 to 83 years (mean 51.9 years) and were predominantly of Caucasian background (93%). Of this population, 140 patients completed 6 months of double blind follow-up, whereas 10 patients discontinued the initial phase of the study prematurely (loss to follow-up, 8; withdrawal of consent, 1; and refusal of touch-up treatment, 1). One hundred twenty-two patients elected to enter, and subsequently completed, the extension phase of the study; among the latter, 114 patients received bilateral retreatment with Restylane Perlane at a mean of 7.0 months (range 5.1 9.7 months) after achievement of the initial cosmetic improvement (optimal cosmetic result). The mean duration of follow-up among patients completing the study was 12.4 months (range 11.1 13.6 months). At 6 months post-treatment, the response rate (proportion of patients with a 1-grade improvement in evaluator assessed Wrinkle Severity Rating Scale (WSRS) score from pre-treatment value) was significantly higher with Restylane Perlane than with Hylaform (75% vs. 38%; p<0.0001, chi-square test). A within-patient comparison of evaluator-assessed WSRS scores at this time indicated that Restylane Perlane was superior to Hylaform in 64% of patients, whereas Hylaform was superior to Restylane Perlane in 8% of patients (p<0.0001, McNemar s test). Likewise, the corresponding comparison of patient-assessed WSRS scores at 6 months post-treatment revealed that Restylane Perlane was superior to Hylaform in 48% of patients, whereas Hylaform was superior to Restylane Perlane in 7% of patients (p<0.0001, McNemar s test). In addition, Restylane Perlane was judged to offer a significant advantage over Hylaform at all intermediary time points, in the opinion of both the clinician and the patient. The initial cosmetic improvement, as assessed using the GAIS, was more effectively maintained over the 6-month follow-up period on the Restylane Perlane than on the Hylaformtreated side of the face. In the opinion of the evaluating investigator, Restylane Perlane was superior to Hylaform in 57% of patients and Hylaform was superior to Restylane Perlane in 7% of patients (p<0.0001, McNemar s test). Similarly, from the patient s perspective, Restylane Perlane was superior to Hylaform in 45% of patients and Hylaform was superior to Restylane Perlane in 12% of patients (p<0.0001, McNemar s test) (Carruthers, Carey et al. 2005). Skeie et al. investigated HA for the treatment of individuals with facial lipoatrophy suffering HIV infection. Twenty patients, one female and 19 male, were enrolled between September 2004 and April 2005 and are included in the study analysis. They had a long history of HIV infection; the mean duration from the first positive test was 13.6 years (minimum 8.5 and maximum 20.0 years). Nineteen patients were available for the 24-month analysis, and 17 patients remained at the 36-month analysis having been followed up for a period of at least 12 months since their last treatment Seventeen patients remained at 36 months. Mean (+/-standard 19/31