Clinical Evaluation - Genefill · • a tendency to hypertrophic and keloid scarring ... A complete anamnesis must be established prior to treatment to exclude possible contraindications

Hylan Solution (STED-01)

Clinical Evaluation – rev07

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: BioScience GmbH

Walsmühler Straße 18

19073 Dümmer

Germany

Medical Device: 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, non-

toxic) 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 14.0 mg

Sodium chloride 6.9 mg

Water for injection ad 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 106 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 CO2, H2O, and

urea (Oh et al 2010; cited in (Laznicek, Laznickova et al. 2012).

The turnover of Hyaluronan in tissues can be measured by injected 3H-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 re-

sterilised. 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 cross-

linked 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

IFU)

Intradermal injection Intradermal injection Intradermal injection

Indication (acc. to

IFU)

Replaces lost

hyaluronic acid in the

skin, increases

elasticity, improves

skin hydration

Improving hydration

and elasticity of skin

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

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

_____________________________________________________________________________

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.

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 peer-reviewed journals and present the reported complication rates. They also describe current strategies to avoid, diagnose, and manage complications if they do occur.

R1

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.

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.

D2, A1, P1, R1

_____________________________________________________________________________

8/31



Dayan S.H. (2008). “Facial Dermal Fillers: Selection of Appropriate Products and Templates”. Aesthet Surg J. 28: 335-347.

The authors compared the most widely used dermal fillers and injection technique.

A1, P1, R1,

Gold, M. (2009). "The science and art of hyaluronic acid dermal filler use in esthetic applications." J Cosmet Dermatol 8(4): 301-307.

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.

A1, P2, R1

Kablik J. (2009). “Comparative physical properties of hyaluronic acid dermal fillers”. Dermatol Surg. Feb;35 Suppl 1:302-12.

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.

R1

Lupo, M. P. (2006). "Hyaluronic acid fillers in facial rejuvenation." Semin Cutan Med Surg 25(3): 122-126.

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.

A1, P1, R2

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.

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.

D2, A1, P2, R2

Newman, J. (2009). "Review of soft tissue augmentation in the face." Clin Cosmet Investig Dermatol 2: 141-150.

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.

D2, A1, P1, R2

Price, R.D, et al (2007). “Hyaluronic acid: the science and clinical evidence”. J Plast Reconstr Aesthet Surg. 60, 1110-1119

This review represents an overview about the scientific evidence of HA used in different fields such as skin regeneration, wound healing and cosmetic surgery.

D2, A2, P2, R1

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.

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.

A1, P2, R1

_____________________________________________________________________________

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, P1, R2

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 croslinked 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.

D2, A1, P1, R1

_____________________________________________________________________________

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.

D2, A1, P1, R2

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 contra-lateral treatment with Restylane Perlane and Hylaform. Efficacy was assessed using semi-objective 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.

D2, A1, P1, R1

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.

Part I of this article reviews the basic science and evolution of both historical and contemporary dermal fillers; Part II examines their adverse effects.

D2, A1, P2, R2

Skeie, L., H. Bugge, et al. (2010). "Large particle hyaluronic acid for the treatment of facial lipoatrophy in HIV-positive patients: 3-year follow-up study." HIV Med 11(3): 170-177.

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

D2, A1, P2, R2

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 follow-up evaluation and a total of 80 subjects were enrolled. Subjects were enrolled in this follow-up 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-of-study (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

D2, A1, P1, R2

_____________________________________________________________________________

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 post-treatment 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.

D2, A1, P1, R2

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.

D2, A1, P1, R2

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.

D2, A1, P1, R2

_____________________________________________________________________________

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.

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.

D2, A1, P1, R2

Lee, B. M., et al. (2015). "Rejuvenating Effects of Facial Hydrofilling using Restylane Vital." Arch Plast Surg 42(3): 282-287.

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.

D2 A1 P1 R2

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.

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.

D2, A1, P1, R1

Reuther T. et al. (2010). “Effects of a three-session skin rejuvenation treatment using stabilized hyaluronic acid-based gel of non-animal origin on skin elasticity: a pilot study”. Arch Dermatol Res. 302:37-45.

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.

D2, A1, P1, R2

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

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, R1

_____________________________________________________________________________

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.

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.

D2, A1, P2, R1

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.

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.

D2, A1, P1, R1

Beasley, K.L. (2009). “Hyaluronic Acid Fillers: A comprehensive Review”. Facial Plast Surg. 25:86-94.

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.

D2, A1, P2, R1

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 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.

D2, A1, P1, R2

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 contra-lateral treatment with Restylane Perlane and Hylaform. Efficacy was assessed using semi-objective 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

D2, A1, P1, R1

_____________________________________________________________________________

14/31



their written informed consent before enrolment into each phase of the study.

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.

Part I of this article reviews the basic science and evolution of both historical and contemporary dermal fillers; Part II examines their adverse effects.

D2, A1, P2, R2

Hirsch R.J. and Stier M. (2008). “Complications of soft tissue augmentation”. J Drugs Dermatol. Sep; 7(9):841-5.

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.

D2, A1, P2, R2

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.

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.

D2, A1, P1, R1

Lowe, N. J., C. A. Maxwell et al. (2005). “Adverse reactions to dermal fillers: review.” Dermatol Surgery 31(11 Pt 2): 1616-1625.

This article reviews the incidences and types of reaction to various commonly used injectable dermal filler products by literature review and personal experiences.

D2, A2, P1, R2

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.

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.

D2, A1, P2, R2

Newman, J. (2009). "Review of soft tissue augmentation in the face." Clin Cosmet Investig Dermatol 2: 141-150.

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.

D2, A1, P1, R2

Price, R.D, et al (2007). “Hyaluronic acid: the science and clinical evidence”. J Plast Reconstr Aesthet Surg. 60, 1110-1119

This review represents an overview about the scientific evidence of HA used in different fields such as skin regeneration, wound healing and cosmetic surgery.

D2, A2, P2, R1

Streker, M., T. Reuther, N. Krueger and M. Kerscher (2013). "Stabilized hyaluronic acid-based gel of non-animal origin for skin rejuvenation:

This open, randomised intra-individually controlled, split side, single centre study was performed in Hamgurg, Germany in accordance with the Declaration of Helsinki.

D2, A1, P1, R1

_____________________________________________________________________________

15/31



face, hand, and decolletage." J Drugs Dermatol 12(9): 990-994.

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.

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 psychologi-cally unstable persons were also excluded.

D2, A1, P1, R2

Winslow, C. P. (2009). "The management of dermal filler complications." Facial Plast Surg 25(2): 124-128.

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

D2, A2, P2, R1

_____________________________________________________________________________

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 non-

sulfated 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 visco-

elastic 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 Hylaform-

treated 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



deviation) total cutaneous thickness increased from 6 +/- 1mm at baseline to 12 +/- 1mm

(P<0.001) at 36 months. Response rate (total cutaneous thickness410mm) was 70%. Fifteen

patients classified their facial appearance as very much or moderately improved. VAS increased

from 39 +/- 25 to 70 +/- 20 (P<0.05) and higher self-esteem scores were reported. Local

swelling and tenderness after treatment was common. Persistent papules found in several

patients after treatment were removed effectively with hyaluronidase injections. Three patients,

treated only at baseline, still had higher total cutaneous thickness scores at 36 months. Results

indicate that a large particle hyaluronic acid formulation is durable and well-tolerated dermal

filler for treating HIV-positive patients with facial lipoatrophy (Skeie, Bugge et al. 2010).

In the pivotal trial that led to FDA approval of Juvederm, Baumann et al (2007) compared the

safety and effectiveness of 3 types of smooth-gel HA dermal fillers vs. cross-linked collagen in

the treatment of NLF in 439 subjects in a multicenter, double-masked, randomized, within-

subject study. The subjects randomly received one of three types of smooth-gel HA dermal

filler in one NLF and cross-linked bovine collagen in the other. The three different smooth-gel

HAs used were Juvederm, Juvederm Ultra, or Juvederm Ultra Plus. The cross-linked bovine

collagen filler used was Zyplast (Allergan, formerly Inamed). The NLFs were to be filled to full

correction (100% of the defect), and not overcorrected, and a maximum of 3 treatments – first

treatment and up to 2 touch-ups at roughly 2-week intervals – were allowed to achieve optimal

correction. NLF severity was assessed using the 5-point Wrinkle Assessment Scale (WAS),

with 0 = none (no wrinkle); 1 = mild (shallow, just perceptible wrinkle); 2 = moderate

(moderately deep wrinkle); 3 = severe (deep wrinkle, well defined edges but not overlapping); 4

= extreme (very deep wrinkle, redundant fold with overlapping skin). The results showed that

all three dermal fillers proved longer-lasting clinical corrections than bovine collagen. Twenty-

four weeks after the last treatment, 90% of subjects treated with Juvederm Ultra Plus dermal

filler retained a clinically significant improvement, 88% treated with Juvederm Ultra and 81%

with dermal filler. The bovine collagen–treated NLFs showed clearly shorter longevity with

lasting improvement after 24 weeks ranging from 36% to 45%. In addition to its superior

longevity, the injection volume for HA dermal fillers proved to be lower (median, 1.6 mL)

compared with bovine collagen (median, 2.0 mL), representing an additional important

advantage for the patient in treatment costs and comfort. The only treatment-related adverse

events observed were localized site reactions in the area of injection, which were mild to

moderate in severity and did not differ between any filler type. In decreasing percentage those

were injection site induration, erythema, edema, pain, nodule formation, bruising, discoloration,

and pruritus; they lasted no more than 7 days. The preferred filler by the patients used was

Juvederm Ultra with 88%, followed by 84% for Juvederm Ultra Plus and 78% for Juvederm;

the majority of subjects preferred HA fillers to the collagen fillers (Baumann, Shamban et al.

2007, Bogdan Allemann and Baumann 2008).

Upon completion of the pivotal IDE clinical trial for Juvederm, Juvederm Ultra, and Juvederm

Ultra Plus, five of the original 11 study sites were selected to participate in an extended follow-

up evaluation. Sites were selected based on their continued abilities to participate in the follow-

up protocol, their track record of visit schedule compliance, and the planned sample size of 150

subjects. No consideration was given to duration of filler correction in the selection of sites.

Subjects who were eligible and agreed to participate in the follow-up study signed an informed

consent and were followed from 4 through 48 weeks after their repeat treatments. Routine

follow-up visits for effectiveness occurred at 4, 12, and 24 weeks, and an amendment to the

protocol added visits at 36 and 48 weeks after repeat treatment. Safety and effectiveness were

evaluated at each office visit. At the end of the pivotal study, subjects were asked which

treatment they preferred and were subsequently un-blinded. Subjects were offered repeat

treatment of both NLFs with the original Juvederm formulation after the 24-week visit. For this

follow-up study, subjects remained non-randomized and un-blinded. 80 individuals signed

consent forms and enrolled in the follow- up study. The mean improvement in NLF severity

_____________________________________________________________________________

20/31



remained clinically significant from 4 weeks after initial treatment through 48 weeks after

repeat treatment. Thus, subjects sustained a total of 18–21 months of wrinkle correction with a

repeat treatment at 6–9 months. Furthermore, a full 78–90% of subjects were responders at 48

weeks post-repeat treatment, and the long-term results showed a smooth, natural looking

wrinkle correction. No serious or unanticipated adverse events were reported. One subject had

positive serum IgG antibody titers at 24 weeks after initial and 4 weeks after repeat treatment,

but no clinical signs or symptoms of hypersensitivity (Smith, Jones et al. 2010).

6.2.2 Performance of Juvederm Hydrate and Restylane Vital

Juvederm Hydrate

In a prospective, noninterventional study by Dallara (2012) a combined treatment of Juvederm

Ultra® and Juvederm Hydrate® is effective and safe for rejuvenating the aging hand.

Both Juvederm Ultra® and Juvederm Hydrate® have been developed as class III medical

devices in accordance with the criteria of the European Directive 93/42/EC, and were CE

marked in 2007 ands 2008, respectively. Juvederm Ultra® 3 is indicated for injection in the

mid-deep dermis and also subcutaneously. It is designed to fill and smooth the skin as well as

return some fullness. 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.

The primary objective of this study was to evaluate the combined action of these two agents on

hand rejuvenation at days 0 and 30 using a validated grading scale. Secondary objectives were

to collect details of injection techniques used at days 0 and 15. The Global Aesthetic

Improvement Scale (GAIS) was used for evaluation at days 0, 15 and 30 for both physicians

and subjects. 99 subjects have been enrolled and the hands were injected with Juvederm Ultra®

3 at the first visit and at the second visit (day 15) with Juvederm® Hydrate. A final assessment

was made at day 30.

The patients GAIS scores showed that the proportion of “much improved” was significantly

higher at day 30 than at day 15 (53.1 versus 43.9%). The physician GAIS score showed that the

proportion of “very much/much improved” was significantly higher at days 15 and 30

compared to baseline (63.7 and 70.3 versus 41.8%). The adverse rate was 8.2 % (32 AEs in 390

injection sessions) including edema, hematoma, redness, and pain (Dallara 2012).

In a prospective pilot study, nine patients were injected with Juvederm Ultra III and Ultra Smile

(Allergan, Inc.), and six were additionally injected with non-crosslinked HA (Juvederm

Hydrate). Juvederm Hydrate was deposited subcutaneously in the philtrum and upper lip area to

even out small rhytides and augment the subcutaneous tissue. The patients were followed-up for

16 days. Treatment success was measured by slit-light optical coherence tomography of the lip

surface to objectify even minimal wrinkles of the lips. Using a cross-linked, longer HA (Ultra

III and Ultra Smile) resulted in longer lasting, more stable results and hygroscopic effects,

whereas the unlinked HA (Juvederm Hydrate) had the most immediate rhytide-reducing effects.

After combined treatment, clinically and in self-rating of the patients, the lips were smoother,

moister, and less wrinkled, which could be demonstrated and objectified by optical coherence

tomography. The optical coherence tomography imaging could support the scientific insight

that HA saves water and can thus contribute to wetter/more hydrated and fuller lips as

demonstrated by significantly reduced rhytides and scaling. The amount of augmentation

achieved to a natural-looking result was rated by the Carruthers’ scale from 0 to 4. The results

are as follows (Vent, Lefarth et al. 2014):

_____________________________________________________________________________

21/31



Table 6.2.2-1: Carruther´s scale grading of patients´ lip fullness before and after injection Patient Additional

Juvederm Hydrate treatment

Carruther´s scale Before injection After injection

1 no 0 1 2 yes 1 3 3 yes 0 2 4 yes 0 2 5 yes 3 3 6 yes 0 1 7 yes 1 3 8 no 0 1 9 no 0 1

It can be deduced from the presented table that patients with a combined treatment had a better

outcome than patients without additional Juvederm Hydrate treatment. In four of six patients

with additional Juvederm Hydrate treatment, an improvement of the Carruther´s scale by two

points was recorded, whereas in all three patients without additional Juvederm Hydrate

treatment, the rating increased by one point only after treatment.

Restylane Vital

Restylane® Vital (Q-Med, Uppsala Sweden), is a coulorless viscoelastic gel consisting of

20 mg/mL NASHA, a stabilized hyaluronic acid-based gel of nonanimal origin, dispersed in

physiologic saline solution (pH 7.0). To stabilize the hyaluronic acid used in Restylane® Vital,

chemical cross-links are introduced to a small proportion (< 1 %) of the constituent

polysaccharide chains. The product is provided in prefilled disposable 1.0 mL syringes supplied

with three 30-gauge sterilized needles. In a pilot, prospective, single-center study 19 female

patients underwent a series of three treatment sessions, spaced 4 weeks apart, with Restylane®

Vital injected into the lower cheeks. The patients received bilateral injections of HA into the

lower part of the cheeks in three sessions (in total 8 weeks). Biophysical measurements were

taken at 12 weeks and 24 weeks.

No serious adverse events occurred during the course of the study, and no patient withdrew

from the study due to an adverse event. Four patients developed transient, mild hematomas after

injection. Two patients experienced temporary, mild erythema after injection (lasting

approximately 2 weeks. One patient developed a nodule approximately 3 mm in diameter after

the second injection, which persisted for approximately 2 weeks before disappearing without

treatment. This study showed that the micropuncture injection of Restylane® Vital can improve

dermal elasticity and reduce skin surface roughness (Kerscher, Bayrhammer et al. 2008).

The same patients have been described in another publication by Reuther et al (2010). The

rejuvenation treatment was performed using NASHA gel (Restylane® Vital, Q-Med AB,

Uppsala Sweden). As described above, Restylane® Vital can improve skin’s viscoelastic

behaviour both by tightening the skin and by improving the recoil capacities, making it very

interesting as a rejuvenation approach, particularly in patients with a high degree of skin laxity

(Reuther, Bayrhammer et al. 2010).

Lim et al performed a prospective randomized split face controlled study to evaluate the

rejuvenation effects of Restylane® Vital injection on the nasojugal groove. Ten Korean female

patients were included who ranged in age from 27 to 59 years, with an average age of 31.2

years. Treatment was given in one session. Subjects were randomised and blinded to receive

Restylane® Vital injection in the treated side and saline injection in the control side of the

infraorbital area. Assessments were performed before treatment, immediately after treatment,

_____________________________________________________________________________

22/31



and at follow-up visits (after 4, 8, 12, and 24 weeks). Patients were requested to self-assess

treatment response of volume and skin tone correction using a three point scale (-1, 0, 1). For

objective evaluation, photographs were taken at every visit and they were assessed by three

blinded evaluators. All patients reported satisfaction with their treatment. The mean score at the

4-week follow-up visit was 0.8. The score of the treated side gradually decreased over time but

still maintained higher up to the last visit compared to the score of the control side. By objective

evaluation, the mean score on the treated side was statistically significant higher than for

control side at the 4-week and 8-week follow-up visit. The objective improvement of treated

sides was maintained up to the last visit, however, the difference to the control sides did not

reach statistical significance anymore (Lim, Suh et al. 2014). It can be concluded that

Restylane® Vital demonstrated a good performance in this clinical trial.

The rejuvenating effects of Restylane® Vital were studied by Lee et al. This study was a single-

center, prospective study. A total of 30 female patients with dry and tired skin on face were

enrolled (age range 27 to 60 years). For treatment, 2 mL of Restylane® Vital mixed with 3 mL

of normal saline and 1 mL of 2% lidocaine was injected into the whole face per treatment

session. Eligible patients received injection of HA into whole face from forehead to chin in

three sessions at intervals of four weeks. In order to minimize the risk of complication, such as

hematoma, the injection site was gently compressed, and cooled with an ice pack for several

minutes after procedures. Of 30 patients, all patients completed the treatment session. The

majority of patients (77%) were satisfied with the therapeutic outcomes. Approximately 66% of

patients responded that the effects of this procedure persisted for longer than four months, and

the majority of patients (77%) wanted to undergo this procedure again and would recommend

this procedure to acquaintances. Regarding doctors’ evaluation, scores for improvement of skin

surface roughness, elasticity, and brightness were significantly higher than those for

improvement of moisture and fine wrinkle (Lee, Han et al. 2015).

In a case report, Restylane® Vital was injected by tunnelling or tenting technique with a 30

gauge needle into the back of the hand for volume augmentation. No significant adverse event

did occur and the appearance of the back of the hand was improved (Hartmann, Bachmann et al.

2010).

In an open, randomised, intra-individually controlled, split side single centre study, 30 patients

aged 40-65 years were enrolled. Of these, 27 patients completed the study, two subjects

withdrew consent and one was lost to follow-up. The product Restylane® Vital light was

administered to one side of the face, the dorsum of the hands and one side of the décolletage

leaving the other side untreated. Treatment at each area was undertaken at 0, 4, and 8 weeks.

Injection was performed into the mid-dermal layer using a 30 gauge needle. Subject follow-up

was scheduled for weeks 12, 20, 28, and 36 after the first treatment. Blinded live evaluation of

skin quality was undertaken by an independent dermatologist at 12, 20, 28, and 36 weeks.

Additionally, grading of the aesthetic change based upon subject photographs took place at

every study visit, performed by a blinded evaluator and also independently by the subjects. The

5-grade Global Aesthetic Improvement Scale (GAIS) was used to rate the aesthetic change.

Furthermore, subject satisfaction regarding the feel and look of the treated skin at weeks 12, 20,

28, and 36 compared to before-treatment was assessed using a questionnaire. When assessed by

blinded live evaluation, the best overall skin quality across all three treatment areas was judged

to be on the treated side in over 80% of subjects throughout the follow-up period. When

subjects were questioned regarding treatment satisfaction, responses relating to skin

rejuvenation elasticity, rehydration, softness, freshness and structure were recorded. The highest

satisfaction rate was found for the face, where more than 70% of subjects indicated

improvements at one or more study visits. The greatest improvement throughout the study was

seen in sensation of elasticity. For all treatment areas, subjects reported greatest overall

satisfaction at 12 weeks, with the face (85%, P <0.01) and the dorsum of the hand (63%,

_____________________________________________________________________________

23/31



P<0.01) response rates significantly higher compared with baseline. Overall satisfaction rates

for the face and hand remained significantly increased during the follow-up period compared

with baseline. In summary, Restylane® Vital light treatment resulted in high satisfaction with

the treatment results in both the subjects and the blinded evaluators. It can be concluded that

Restylane® Vital light treatment was effective in skin rejuvenation in this study (Streker,

Reuther et al. 2013).

6.3. Safety

Since HA occurs naturally in the human body, the risk of allergic reactions is very low and thus,

the manufacturers suggest that there is no need for skin testing before. The differences in chain

length molecular weight do not appear to have any clinical significance. Adverse effects related

to HA injection are most commonly localized, immediate, and non-allergic, and include pain,

edema, and ecchymoses. Additional side effects to consider are an angioedema-like swelling

and hypersensitivity as well as the rare rapidly developing baterial infection acquired

transdermally while injecting (Gilbert, Hui et al. 2012).

In the small prospective study by Vent et al, patients were treated with a combination of

crosslinked HA and non-crosslinked HA (Juvederm Hydrate). In nine patients, no compression

of lip structures such as vessels or nerves occurred, nor did any severe complications such as

major bleeding, infection, or thromboembolism result from injection. Minor side effects

disappeared within one week. Recorded adverse events included bruising, pain/tension, and

dysfunction due to swelling (such as problems in speaking, swallowing, or biting). On a visual

analogue scale pain was graded as ~3.8 during injection and decreased to zero until day 1 to 4

post-injection. Bruising linearly raised until day 1 to 4 post-injection and decreased rapidly in

the following days. Slight dysfunction (VAS score ~0.4) was only recorded 3 to 4 hours after

injection (Vent, Lefarth et al. 2014).

Restylane® Vital light was well tolerated in 27 patients receiving three injections into the face,

dorsum of the hand, and décolletage. No treatment-related serious adverse events were reported.

Non-serious treatment-related adverse events occurred in one patient only. These events

included site induration of the skin in the face and dorsum of the hand and of the décolletage.

These events were mild to moderate in intensity and resolved without intervention. Of the

procedure-related reactions, the most common complaints were bruising (in 74-88% of

subjects) and redness (60-85% of subjects). Thereby, bruising to the dorsum of the hand

occurred less frequently than in the other two treatment areas. The majority of the procedure-

related reactions were resolved within 14 days after each treatment session (Streker, Reuther et

al. 2013).

A retrospective European survey has evaluated the risk of the most prominent adverse reactions

after HA injection from Q-Med from 1997 to 2001. A total of 4,320 patients were evaluated and

12,344 syringes were injected. 34 cases of hypersensitivity were reported: 16 cases of

immediate hypersensitivity and 18 cases of delayed reactions. Global risk was 0.8%. Since

2000, the load of proteins of the Q-Med product has decreased, and the incidence of

hypersensitivity reactions has become around 0.6%. As 50% of theses reactions occurred

immediately and resolved within less than three weeks, the risk of transient delayed reactions

was around 0.3% using the old formulations. These reactions were less frequent (less than 1 in

2000 treatments) applying the current Q-Med products ((Lowe, Maxwell et al. 2005)), which

have been the most used products in the UK. Sterile abscess, lividoid pattern after intra vascular

injection has been reported, whereas no systemic reactions have been reported. Non-animal HA

from the Q-Med company does not need skin testing. In cases of ‘‘inflammatory’’ reactions, the

histological aspects can be either a moderate lymphocytic infiltrate with some plasma cells in

_____________________________________________________________________________

24/31



the dermis and the hypodermis or a lymphocytic infiltrate with macrophages and presence of

foreign body giant cells (Andre, Lowe et al. 2005).

Since HA dermal fillers in general are very well tolerated infections occur very rarely.

Hypersensitivity reactions are also uncommon, and may result from a reaction to the cross-

linking agent used to stabilize the HA. Occasionally HA can be palpated or a blue-gray tinge

can be seen in the area of injection. This can be the result of superficial injection allowing more

water binding in the dermis which selectively reflects blue wavelength of light making and

appearing darker than the surrounding skin. An improvement can be achieved by camouflage

with makeup, needle puncture, and massage of excess gel from the dermis or injection of

hyaluronidase. The injection technique can lead to clumping of HA especially in the lips.

Massaging the affected area immediately following injection is the best way to prevent lumps

from persisting. It is important to inform patients about the expected clinical course of swelling,

firmness, and the subsequent softening, which typically occurs after 1 week (Newman 2009).

Since Hylan Solution is mainly composed of non-crosslinked HA, these adverse events could be

neglected in this clinical evaluation.

The most frequent types of reactions are needle marks at the site of injection, erythema,

swelling, tenderness, mild pruritus, bruising, and small lumps/bumps. These are generally mild

and are usually gone in less than a week (Beasley, Weiss et al. 2009). The observed frequency

of transient erythema and mild swelling after injecting HA as dermal filler is about 12%.

Other studies also reported injection-related reactions, including redness, swelling, darkening of

the treatment site, and slight pain in about 13% of patients. Ongoing analysis of the adverse

event databases indicated that in 1999, with an estimated 144,000 patients treated with

Restylane, only one of every 650 (0.15%) reported redness, swelling, localized granulomatous

reactions, bacterial infection, or acneiform lesions. Delayed implant hypersensitivity reactions

were reported in several case series at low incidences (0.4 to 3.7%) in early (before mid-1999)

non–United States use of Restylane. In mid 1999, a hyaluronic acid raw material with trace

amounts of protein six times lower than the raw material previously used was introduced. The

amount of protein in the more purified product was reported to be in the range of 13 to 17

mg/ml of product. In contrast to 1999, reported adverse events were reduced to 0.06% and

hypersensitivity reactions were reduced to 0.02% (Matarasso, Carruthers et al. 2006).

Baumann et al. reported the only treatment-related adverse events observed were localized site

reactions in the injection area, which were mild to moderate in severity and did not differ

between any filler type (Juvederm or Zyplast). In decreasing percentage those were injection

site induration, erythema, edema, pain, nodule formation, bruising, discoloration, and pruritus;

they lasted no more than 7 days (Baumann, Shamban et al. 2007, Bogdan Allemann and

Baumann 2008).

Other complications published include a case report of a clinical picture similar to a sterile

abscess over injection sites and injections of any form may trigger sarcoidosis at the injection

site, and HA has not escaped. A recent review also quoted an overall significant complication

rate of 1 in 1600 applications. The mild tissue reaction seen with many injections may, on

occasion, be so profound as to elicit a formal inflammatory response and a range of reactions

has been documented, varying from simple hypersensitivity, to angioedema with positive titres

of anti-HA immunoglobulin G and E (Price, Berry et al. 2007).

Serious complications are rarely seen when injecting HA, but many of these complications

directly correlate with the skill and experience of the physician-injector. These true

complications include injection into or compression of vascular supply, tissue necrosis,

persistent nodule formation, granuloma formation, allergic reaction, infection, and visible blue

hue (Tyndall effect). It has been well documented that nitropaste and hyaluronidase must be

readily available in your office for the immediate treatment of any vascular compromise.

_____________________________________________________________________________

25/31



Hyaluronidase and extrusion techniques are also helpful for treating persistent nodules and the

Tyndall effect (Beasley, Weiss et al. 2009).

There is another important study investigating the Tyndall effect. Although the depth of dermal

filler placement is particularly important in preventing discoloration, novice injectors

occasionally inject too superficially causing a blue-gray discoloration known as the Tyndall

effect. The Tyndall effect refers to the fact that different wavelengths of light scatter depending

on the size of substances they encounter. According to Rayleigh scattering, for sufficiently

small particles, the amount of light scattered is inversely proportional to the fourth power of

wavelength. For example, blue light is scattered more than red light by a factor of (700/400) = ~

10. Thus, within the skin, long red wavelengths penetrate can deeper into the tissue while

shorter blue wavelengths are more easily scattered and reflected outwards. The incidence of the

Tyndall effect is most likely to occur if filler meant to be injected deeply is injected too

superficially in the skin. The high-risk areas include the so-called I zone of the central face, (the

nasojugal folds, nasal dorsum, and lip), the infraorbital troughs, and fine superficial lines such

as periorbital and perioral rhytids ("crow's feet" and "pucker lines") (Hirsch and Stier 2008).

In the split face clinical trial of Lim et al, ten female Korean patients were treated with

Restylane® Vital. There were no serious adverse events reported. No patient in this study

required reduction of volume by means of hyaluronidase injection. Mild treatment-associated

adverse events such as redness, swelling, and ecchymosis, were commonly reported yet

transient in nature (duration < 1 week). No patient exhibited the Tyndall effect (Lim, Suh et al.

2014).

Although NASHA is derived from a non-animal source, there is minimal risk of its

contamination with animal allergens or pathogens during the manufacturing process. The

possibility of contamination with allergens from the source bacteria or the fermentation medium

cannot be excluded, as well. Clinical experience indicates that NASHA is well tolerated

following intradermal injection and provides good initial efficacy in correcting facial wrinkles

and folds (Carruthers, Carey et al. 2005).

The management of dermal filler complications is summarized in an article of C. Winslow.

Bruising is a potential complication to all fillers. The potential to bruise can be affected by

needle size, location of infection, and type of filler. Medication such as aspirin, ibuprofen, or

other anticoagulants may make the patient more susceptible to bruises. Herbal supplements

such as fish oil, glucosamine, or chondroitin can also adversely impact bruising. Swelling is the

most common and ubiquitous complication experienced with fillers. HA fillers are sugar

molecules that bind and hold water and should be expected to cause more swelling than do

other classes of fillers. Post treatment ice application and elevation of there head may help.

Patient troubled by swelling may benefit from short prednisone taper or antihistamines.

Formation of lumps under the skin can occur due to the consistency of the filler, reaction to the

product, or poor technique. Small lumps resulting from HA injection can easily be treated with

hyaluronidase. Improvement can be seen within hours. The ability to contour the injection site

after injection is unique to HA class and is attractive to many patients. Erythema after injection

is common, especially if massage is performed immediately after filler placement. Some

amount of pain during and after injection is common and can be prevented with topical

numbing and/or nerve blocks administered before injecting the filler. Skin necrosis is a well

known complication that has a predilection for certain “danger zone”. The dorsal nasal artery

may cause compromise of skin at the alar region. Collagen and hyaluronic acid are commonly

injected in the lips. Filler injections in there perioral area can induce cold sore formation by

reactivation of the latent virus. Stress, swelling, and massage may also contribute. Patients with

a strong history of cold sore activation or those who had cold sores with prior injections should

be treated with an antiviral such as acyclovir. Infection is fortunately quite rare after filler

_____________________________________________________________________________

26/31



injection in an acutely inflamed area, such as skin with active acneic breakout. Focal or

systemic infections should be considered a contraindication to injection. True allergic reactions

are quite rare with HA. Immediate allergic reactions are manifested by significant swelling,

itching, and pain. Swelling may involve the oral cavity, lips, and tongue, depending on the

severity of reaction and location of injection. Skin testing for HA is not standard or required but

should be considered in atopic individuals. Despite its rare nature, hypersensitivity to HA or its

derivatives of its preparation may still be seen in < 1% of patients injected. Granulomas

typically appear late, month or years after injection, and remain localized to the injection site.

They are typically soft and dark red or purple. Intralesional steroids remain the mainstay of

granuloma treatment. The most dreaded complication because of its unsightly nature and

permanence, a scar can result from injection or a complication thereof. Treatment of scares

includes intralesional steroid, pulsed dye laser or pulsed light treatments, pressure, and silicone

(Winslow 2009).

6.4. Post Market Data on Hylan Solution

Product Certified since Units sold in

EU

(until July

2014)

Units sold

outside EU

Serious

adverse events

or incidents

reported

GeneFill Fine 2009 3179 10356 -

Hyacorp Fine 2009 1798 12938 -

CRM Soft 2003 29015 75171 -

_____________________________________________________________________________

27/31



7. Conclusion

The first dermal fillers used in the 1980s were animal-derived collagen fillers. However, the

need for products with longer clinical duration and no requirement for prior skin allergy testing

lead to the development of HA fillers. Today, HAs have become the new gold standard, and

have almost replaced collagen fillers (Bogdan Allemann and Baumann 2008).

Features that differentiate the various HA fillers are particle size, the type of cross-linking agent

used, the degree of crosslinking, the percentage of cross-linked HA, the amount of free

(unmodified) HA present, and G’ (elastic modus). All these physical and chemical attributes

will influence the clinical characteristics of each filler, such as clinical indication, ease of

injection, degree of tissue filling, longevity, clinical appearance, and side effects. The amount of

HA in a product may contribute to its stiffness and longevity. Since not all of the HA in the

product is crosslinked one must take into account the overall percentage of crosslinking (how

much of the HA is crosslinked) and the degree of crosslinking (is the HA molecule completely

or partially crosslinked). Often, uncrossed HA is added to a filler product to increase its ease of

injection as it functions as a lubricant (Bogdan Allemann and Baumann 2008).

One of the benefits of using HA for the less experienced user is the fact that they can be readily

broken down by the hyaluronidase. Hyaluronidase can correct areas where there is excess HA

filler injected. Due to its natural presence in the skin and its capacity to bind large amount of

water, HA is very well tolerated and efficient. Additionally, HA has the lowest rate of the side

effects of all dermal fillers and represent a broader range of application. .

The product under evaluation – Hylan Solution – is regarded to be equivalent to the currently

used and well established products Restylane Vital and Juvederm hydrate regarding technical,

biological, and clinical characteristics. Therefore, the scientific literature discussing these

products was analysed. Additionally, articles related to the safety and performance of HA in

dermal fillers in general, have been evaluated. These reports demonstrated only a very low rate

of side effects and complications. The complication rate of permanent fillers and collagen, or

other absorbable material (alginates) is higher compared to hyaluronic acid. No unexpected side

effects, complication, or incidents were reported. Furthermore, the performance and safety of

hyaluronic acid is well supported by additional review articles issued during the last years.

The post market surveillance of Hylan Solution reflects these results reported in scientific

literature, since no serious adverse events or incidents have been reported during the last years.

In summary hyaluronic acid provides the best performance and safety of all commercial

available dermal fillers. Especially the non-crosslinked HA dermal fillers described in this

clinical evaluation show an even lower rate of adverse events than crosslinked HA fillers due to

its fast degradation. Hylan Solution is equivalent to the well established products Restylane

Vital and Juvederm hydrate. Performance and safety can be demonstrated for all these products.

The rate of risks is very low compared to other available products. Therefore the benefit-to-risk

ratio for Hylan Solution can be regarded very positive.

The widespread acceptance of HA fillers is testament to their biocompatibility (unlike protein-

based fillers, they are composed of polysaccharides that exhibit no species specificity) and their

good record of safety and effectiveness in all countries where they have been in use for many

years.

_____________________________________________________________________________

28/31



Compiled by Reviewed and approved by

i.DRAS GmbH, 2016-03-10 BioScience GmbH, 2016-03-10

Dr. med. Christian Schübel Kirsten Krollmann

Head Clinical Affairs Product Management

8. References

Andre, P., N. J. Lowe, A. Parc, T. H. Clerici and U. Zimmermann (2005). "Adverse reactions to

dermal fillers: a review of European experiences." J Cosmet Laser Ther 7(3-4): 171-176.

Bailey, S. H., J. L. Cohen and J. M. Kenkel (2011). "Etiology, prevention, and treatment of

dermal filler complications." Aesthet Surg J 31(1): 110-121.

Baumann, L. S., A. T. Shamban, M. P. Lupo, G. D. Monheit, J. A. Thomas, D. K. Murphy and

P. S. Walker (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.

Beasley, K. L., M. A. Weiss and R. A. Weiss (2009). "Hyaluronic acid fillers: a comprehensive

review." Facial Plast Surg 25(2): 86-94.

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.

Carruthers, A., W. Carey, C. De Lorenzi, K. Remington, D. Schachter and S. Sapra (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.

Dallara, J. M. (2012). "A prospective, noninterventional study of the treatment of the aging

hand with Juvederm Ultra(R) 3 and Juvederm (R) Hydrate." Aesthetic Plast Surg 36(4): 949-

954.

Dayan, S. H. and B. A. Bassichis (2008). "Facial dermal fillers: selection of appropriate

products and techniques." Aesthet Surg J 28(3): 335-347.

De Boulle, K., R. Glogau, T. Kono, M. Nathan, A. Tezel, J. X. Roca-Martinez, S. Paliwal and

D. Stroumpoulis (2013). "A Review of the Metabolism of 1,4-Butanediol Diglycidyl Ether-

Crosslinked Hyaluronic Acid Dermal Fillers." Dermatol Surg.

Gilbert, E., A. Hui and H. A. Waldorf (2012). "The basic science of dermal fillers: past and

present Part I: background and mechanisms of action." J Drugs Dermatol 11(9): 1059-1068.

_____________________________________________________________________________

29/31



Gold, M. (2009). "The science and art of hyaluronic acid dermal filler use in esthetic

applications." J Cosmet Dermatol 8(4): 301-307.

Hartmann, V., F. Bachmann, M. Plaschke, T. Gottermeier, A. Nast and B. Rzany (2010). "Hand

augmentation with stabilized hyaluronic acid (Macrolane VRF20 and Restylane Vital,

Restylane Vital Light)." J Dtsch Dermatol Ges 8(1): 41-44.

Hirsch, R. J. and M. Stier (2008). "Complications of soft tissue augmentation." J Drugs

Dermatol 7(9): 841-845.

Kablik, J., G. D. Monheit, L. Yu, G. Chang and J. Gershkovich (2009). "Comparative physical

properties of hyaluronic acid dermal fillers." Dermatol Surg 35 Suppl 1: 302-312.

Kerscher, M., J. Bayrhammer and T. Reuther (2008). "Rejuvenating influence of a stabilized

hyaluronic acid-based gel of nonanimal origin on facial skin aging." Dermatol Surg 34(5): 720-

726.

Laurent, T. C. and J. R. Fraser (1992). "Hyaluronan." FASEB J 6(7): 2397-2404.

Laurent, U. B., L. B. Dahl and R. K. Reed (1991). "Catabolism of hyaluronan in rabbit skin

takes place locally, in lymph nodes and liver." Exp Physiol 76(5): 695-703.

Laznicek, M., A. Laznickova, D. Cozikova and V. Velebny (2012). "Preclinical

pharmacokinetics of radiolabelled hyaluronan." Pharmacol Rep 64(2): 428-437.

Lee, B. M., D. G. Han and W. S. Choi (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.

Lowe, N. J., C. A. Maxwell and R. Patnaik (2005). "Adverse reactions to dermal fillers:

review." Dermatol Surg 31(11 Pt 2): 1616-1625.

Lupo, M. P. (2006). "Hyaluronic acid fillers in facial rejuvenation." Semin Cutan Med Surg

25(3): 122-126.

Matarasso, S. L., J. D. Carruthers and M. L. Jewell (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., M. G. Berry and H. A. Navsaria (2007). "Hyaluronic acid: the scientific and

clinical evidence." J Plast Reconstr Aesthet Surg 60(10): 1110-1119.

Reuther, T., J. Bayrhammer and M. Kerscher (2010). "Effects of a three-session skin

rejuvenation treatment using stabilized hyaluronic acid-based gel of non-animal origin on skin

elasticity: a pilot study." Arch Dermatol Res 302(1): 37-45.

_____________________________________________________________________________

30/31



Rohrich, R. J., A. Ghavami and M. A. Crosby (2007). "The role of hyaluronic acid fillers

(Restylane) in facial cosmetic surgery: review and technical considerations." Plast Reconstr

Surg 120(6 Suppl): 41S-54S.

Skeie, L., H. Bugge, A. Negaard and B. M. Bergersen (2010). "Large particle hyaluronic acid

for the treatment of facial lipoatrophy in HIV-positive patients: 3-year follow-up study." HIV

Med 11(3): 170-177.

Smith, K. C. (2008). "Reversible vs. nonreversible fillers in facial aesthetics: concerns and

considerations." Dermatol Online J 14(8): 3.

Smith, S. R., D. Jones, J. A. Thomas, D. K. Murphy and F. C. Beddingfield, 3rd (2010).

"Duration of wrinkle correction following repeat treatment with Juvederm hyaluronic acid

fillers." Arch Dermatol Res 302(10): 757-762.

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 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.

9. Attachments

Attachment 1 - Literature Search and Outcome

_____________________________________________________________________________

31/31

Documents

Clinical Evaluation - Genefill · • a tendency to hypertrophic and keloid scarring ... A complete anamnesis must be established prior to treatment to exclude possible contraindications