Hyaluronic acid fillers with cohesive polydensified matrix for soft-tissue augmentation and rejuvenation: a literature review

Figures & data

Table 1 Key characteristics and indications of Belotero^® dermal fillers and hyaluronic acid fillers used as comparators in split-face, randomized controlled trials

Brand name	Type of filler, crosslinking technology, and HA concentration (C)	Indications and depth of injection	Countries with marketing authorizationa
Belotero^® dermal fillers (Anteis S.A., Geneva, Switzerland, a wholly owned subsidiary of Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany)
Belotero^® Hydro   Also: Mesolis^® Plus (or +)	Non-crosslinked product; also contains glycerol; C =18 mg/mL	Improvement of skin hydration, radiance, and elasticity; to be injected into the superficial dermis	EU Canada Mexico South Africa Saudi Arabia
Belotero^® Soft   Also: Esthélis^® Soft	Crosslinked product; cohesive (monophasic) polydensified filler, CPM^® technology; C =20 mg/mL	Correction of fine lines (eg, crow’s feet, perioral lines, fine forehead lines); also suitable for lip enhancement and correction of facial atrophic scars; to be injected into the superficial-to-mid dermis	EU Canada Mexico Philippines Russia South Africa Saudi Arabia Korea Indonesia
Belotero^® Basic/Balance   Also: Esthélis^® Basic/Balance	Crosslinked product; cohesive (monophasic) polydensified filler, CPM^® technology; C =22.5 mg/mL	Correction of moderate lines (eg, moderate nasolabial wrinkles, glabellar lines, moderate perioral wrinkles, lip contouring, philtrum); also suitable for lip enhancement and correction of facial atrophic scars; to be injected into the superficial-to-mid dermis	EU Canada Mexico Russia South Africa Saudi Arabia USA Korea Indonesia
Belotero^® Intense   Also: Fortélis^® Extra	Crosslinked product; cohesive (monophasic) polydensified filler, CPM^® technology; C =25.5 mg/mL	Correction of deeper lines (eg, severe NLF, lip volume, oral commissures, marionette folds); also suitable for correction of facial atrophic scars; to be injected into the deep dermis	EU Canada Mexico Russia South Africa Saudi Arabia Korea Indonesia
Belotero^® Volume   Also: Modélis^® Shape	Crosslinked product; cohesive (monophasic) polydensified filler, CPM^® technology; C =26 mg/mL	Restoration of facial volumes (eg, cheeks, temples, facial volume loss); to be injected into the deep dermis, subcutaneously or on the upper periostea	EU Canada South Africa Saudi Arabia Korea
Hyaluronic acid fillers used as comparators in split-face randomized controlled trials
Restylane^®	Non-cohesive (biphasic) filler, NASHA^® technology; C =20 mg/mL	Correction of moderate or severe wrinkles and folds, lip enhancement; to be injected into the mid-to-deep dermis	EU USA Asia Pacific
Juvéderm^® Ultra 3	Cohesive (monophasic) monodensified filler, Hylacross^® technology; C =24 mg/mL	Correction of moderate or severe wrinkles and folds, lip enhancement; to be injected into the mid-to-deep dermis	EU USA Asia Pacific

Note:

a The listed countries are the ones where the brand Belotero^® is on the market, excluding the ones with the sister brands marketed by Anteis.

Abbreviations: CPM^®, cohesive polydensified matrix; EU, European Union; HA, hyaluronic acid; NASHA^®, nonanimal-stabilized hyaluronic acid; NLF, nasolabial fold.

Table 2 Belotero^® dermal fillers: summary of the study design, methods, and main end points

Study, design, and indication	Treatments and population	Injection technique	Mean injected volume	Time points and assessments
Belotero^® Basic/Balance
RCT (and extension) with comparator(s)
Prager and Steinkraus^Citation9,a  RCT split-face  NLF	Belotero^® Basic (n=20) vs Restylane^® (n=20)
	20 patients (19 females) Mean age: 45.8 years (range 30–60 years)	Single injection in the mid-to-deep dermis, using the standard threading and/or multiple puncture techniques	1.4 mL for each product	Baseline, 4 weeks NLF severity: skin topography by PRIMOS Pain immediately after injection (VAS) Tolerability, patient’s satisfaction, AEs
Prager et al^Citation37,a  RCT split-face  NLF	Belotero^® Basic/Balance (n=20) vs Restylane^® (n=20) (Arm A); Belotero^® Basic/Balance (n=20) vs Juvéderm^® Ultra 3 (n=20) (Arm B)
	Arm A and Arm B: 20 patients (19 females) each Mean age: 45.8 years (range 30–60 years) in Arm A; 45.9 years (range 35–64 years) in Arm B	Single injection in the mid-to-deep dermis, with a 27 G needle, using the threading or multiple puncture technique	Arm A: 1.41 mL for Belotero^®, 1.37 mL for Restylane^®; Arm B: 1.42 mL for Belotero^®, 1.43 mL for Juvéderm^®	Baseline, 4 weeks, then 6, 9, and 12 months NLF severity (MAS) Patient’s satisfaction, AEs
Narins et al^Citation36,b  RCT split-face  NLF	Belotero^® Basic/Balance vs collagen
	118 patients (92.4% females), with 106 patients completing Mean age: 52.4 years (range 25.7–75.7 years)	Injection using cross-hatching or tunneling technique (site not specified), optional touch-up session after 2 weeks	1.16 mL Belotero^® vs 1.37 mL collagen Touch-up: 0.81 mL vs 0.94 mL	Baseline, 2, 4, 8, 12, 16, and 24 weeks NLF severity: WSRS (by blinded rater and investigator), GAIS (by blinded rater, investigator, and patient), VAS fill state (by blinded rater, investigator, and patient) patient’s satisfaction and preference, investigator’s preference, AEs
Narins et al^Citation35,b  RCT split-face  Open-label extension  NLF	Belotero^® Basic/Balance (vs collagen during RCT)
	85 completed the extension study (89.5%) 95 patients (92.6% females) Mean age: 53 years (range 25.7–75.7 years)	Touch-up injection possible at 32, 48, 72, and 96 weeks Injection 24 weeks after primary RCT^Citation36 Multiple injections into mid-to-deep dermis with 27 or 30 G needle	At 24 weeks: 0.71 mL for Belotero^®, 1.04 mL for collagen (further injections at subsequent visits)	NLF severity: WSRS (by investigator), GAIS (by investigator and patient), treatment longevity 24 weeks (=baseline), then 32, 48, 72, and 96 weeks (after primary RCT) Antibodies to HA, AEs
Study design other than RCT
Gregory^Citation39  Observational study  Facial treatments (mostly NLF [45%] and lip [28%])	Belotero^® Basic/Balance
	448 patients, representing a total of 563 facial treatments Age range: 32–58 years	Injection with 30 G needle, mostly into the superficial dermis using a serial puncture technique	Not reported	Follow-up (timing not specified) Patient’s satisfaction, AEs
Dirting et al^Citation33  Prospective study	Belotero^® Basic
	114 patients (90% females) mean ± SD age: 50.2±7.1 years	Injection in the mid dermis without overcorrection, using linear technique, stratum technique, or a combination of both No touch-up allowed	1 mL on each side	Baseline, post-injection, then at 2, 4, 12, and 24 weeks, follow-up at 36 weeks optional WSRS (by blinded rater), GAIS (by investigators and by patients) Tolerability, AEs
Kühne et al^Citation38  Retrospective study  Facial treatments (mostly NLF [25%] and marionette lines [18%])	Belotero^® Basic/Balance
	317 patients (312 females, 98.4%; 309 Caucasians, 97.5%) and 668 treatments Mean age: 55 years (range 24–87 years)	Injection intradermally or superficially subdermally, with sharp needles (27, 28, or 30 G depending on the depth of injection and area to be treated), using microdroplet, linear threading, fanning, cross-hatching, or bolus	0.2–3.0 mL, depending on the area treated	5-Year review Performance not formally assessed AEs
Downie et al^Citation34  Open-label study  NLF	Belotero^® Basic/Balance
	93 patients (80 females) Mean age: 57.3, 50.9, and 51.5 years in skin types IV (n=4), V (n=37), and VI (n=52), respectively	Multiple injection in the mid-to-deep dermis with a 27 or 30 G needle, optional touch-up session after 2 weeks	Up to 3 mL per NLF over two sessions	Baseline, 2, 4, 8, 12, 16, and 24 weeks NLF severity: WSRS (by investigator and independent rater), GAIS (by patient) AEs
Gilbert and Calvisi^Citation42  Case series  Facial treatments (mostly mid-face [71%])	Belotero^® Balance (n=1), Restylane^® + lidocaine (n=1), Perlane^® + lidocaine (n=1), Juvéderm^® Voluma/Volift/Volbella + lidocaine (n=3), Radiesse^® (n=1)
	Seven patients (seven females) Age range: 40–88 years	Belotero^® Basic/Balance injected into the lips with a 32 G needle	1 mL	Discussion regarding the choice of each filler (no formal efficacy assessments)
Goh et al^Citation22  Retrospective chart review  Infraorbital hollow	Belotero^® Balance (n=5) and Restylane^®-L (n=5)
	Ten patients (eight females) Median age: 57 years (range 37–84 years) for Belotero^®, 61 years (range 47–80 years) for Restylane^®-L	Injection along or 2–6 mm below the infraorbital rim, with 30 G needle using a combination of direct serial puncture and retrograde linear threading technique	1 mL of filler (0.5 on each side)	Before and immediately after injection Distribution pattern of filler by high-resolution ultrasound AEs
Hevia et al^Citation40  Prospective study  Infraorbital hollow	Belotero^® Balance
	49 patients, with 46 patients (38 females) completers Mean age: 51 years (range 31–67 years)	Repeated injections with a 30 G needle, using retrograde injection Generally three to five entry sites medially, two to three centrally, three to five laterally; repeated as often as needed to correct the deficient volume	0.92 mL on each side at baseline, 0.27 mL at touch-up, and 0.21 mL at 6 months (re-treatment)	Baseline, 2, 8, 24, and 40 weeks Hollowness (Merz Aesthetics Infraorbital Hollow Scale™) AEs
Wollina^Citation41  Retrospective study  Tear trough	Belotero^® Basic (n=21), Glytone^® 3 (n=10), and Radiesse^® (calcium hydroxyapatite, n=9)
	40 patients (all females) mean ± SD age: 50±11.1 years (range: 32–90 years)	Single injection with a 30 G needle, using linear threading technique Touch-up if necessary at 2 or 3 weeks	0.2–0.6 mL for HA fillers (different volume for Radiesse^®)	Baseline, 2 or 3 weeks Fold severity (Hirmand’s classification) AEs
Effect of lidocaine
Moradi et al^Citation31  RCT split-face  Perioral lines	Belotero^® Balance (BEL, n=10), Belotero^® Balance with lidocaine (BEL + lido, n=10), Belotero^®Balance with lidocaine + epinephrine (BEL + lido + epi, n =10)
	30 females Age range: 18–75 years	Injection with a 30 G needle, into the superficial dermis using serial punctures and linear threading techniques	1 mL per side	Baseline, days 1, 7, and 14 Patient-assessed pain, AEs
Prager and Micheels^Citation32  Prospective survey, split-face  Facial treatments (mostly NLF [79%], marionette lines [62%])	Belotero^® Basic/Balance with/without lidocaine
	29 females Mean age: 53.5 years (range: 30.6–82.9 years)	Technique depended on the site but was identical on both half-face, use of needle or cannula, either manually or with the aid of an injection system, most often in the superficial dermis (62.1%)	1 mL maximum on each side of the face, per zone	No specific time points (survey) Physician’s experience (ease of use, distribution of product in the skin, satisfaction, etc) Patient’s pain and satisfaction, AEs
Belotero^® Hydro
Study design other than RCT
Succi et al^Citation44  Open-label study  Periorbital area	Mesolis^® Plus
	20 patients (all females) Mean age: 50 years (range 29–59 years)	Injection in the superficial dermis with 30 G needle, using the micropuncture technique Three monthly sessions	0.74 mL per session	Baseline, 2 weeks after sessions 2 and 3 Physician Clinical Global Assessment (by the three investigators and a blinded rater) Patient’s satisfaction, AEs
Belotero^® Soft (and/or other Belotero^® dermal fillers)
Bezzola and Micheels^Citation27,c  Open-label study  Facial treatments	Esthélis^® Basic and Soft
	36 patients Soft, n=11 (ten females) Basic, n=25 (20 females) Age not provided	Injection with 27 or 30 G needle into the superficial dermis, blanket method with the whitening technique, or into the middle or deep dermis, using point-by-point injection (Soft) or retro-tracing or prograde technique (Basic)	Soft: 0.1–0.6 mL per treatment session, one or two treatment sessions Basic: 0.3–1.5 mL, one or two treatment sessions	Baseline, day 180 (~6 months) Soft: performance not formally assessed Basic: persistence of treatment effect over time Safety based on physician’s experience (no formal count of AEs)
Micheels^Citation26,c  Safety follow-up report  Facial treatments	Esthélis^® Basic and Soft
	13 patients (ten females) out of the 36 included in the pilot study Mean age: 55 years (range 40–71 years)	Single injection with 30 G needle (for the patients who did the follow-up) Regular treatments until month 24 (5.7 injections per patients on average)	Not reported	24 months safety follow-up 74 injections (Basic 65 injections, Soft nine injections) in the 13 patients Average treatment duration: 13.3 months AEs
Hasson and Romero^Citation25  Prospective study  Facial atrophic scars	Esthélis^® Basic or Soft
	12 patients Age: 18–56 years	Injection with 30 G needle into the superficial or mid dermis, using linear threading, serial puncture, or a combination of both	Injected volume depended on the depth and extension of the scar	Baseline, 1 week, and 1 month Investigator’s satisfaction Patient’s satisfaction Patient-assessed pain, AEs
Pavicic et al^Citation30  Case series  Whole-face rejuvenation	Belotero^® (Soft/Basic/Intense) after Bocouture^®(botulinum toxin) and Radiesse^®(calcium hydroxyapatite)/[Bocouture^® + Radiesse^®] + Belotero^® Soft, Basic, and Intense (Patient A), Belotero^® Basic and Intense (Patient B), or Belotero^® Soft and Basic (Patient C)
	Three patients (all females) Age: 59, 46, and 52 years	Sequential approach: Bocouture^® first, then Radiesse^® 1 month later, and Belotero^® 2–4 weeks later	Soft: 0.1–0.2 mL per site Basic: 0.05–0.85 mL Intense: 0.1–0.65 mL	Baseline, at each treatment visit, then 11 or 14 days after the last treatment Fold severity by independent rater (MAS) Tolerability (safety results not detailed)
Belotero^® Intense
RCT with comparator(s)
Buntrock et al^Citation19  RCT split-face  NLF	Belotero^® Intense vs Perlane^®
	20 patients (18 females) Mean age: 52.0±5.6 years	Single injection in deep dermis, using 27 G needle and standard serial puncture technique	1 mL per side	Baseline, 2, 24, and 48 weeks NLF severity: WSRS (blinded investigator, blinded rater, and patient), skin topography (PRIMOS) Patient’s satisfaction, pain after injection, AEs
Study design other than RCT
Pavicic et al^Citation29  Case series  HIV-associated facial lipoatrophy	Belotero^® Basic and Belotero^® Intense combined
	Two HIV-infected patients Case 1: 38-year-old man Case 2: 56-year-old man	Case 1: three syringes Basic at baseline, then two and one syringes Basic at 6 and 12months, respectively, then two syringes Intense at 18 months; no further treatment at 30 months Case 2: two syringes Basic at baseline, then two syringes Basic at 8 months, then two syringes Intense at 20 months	Up to 2 mL at each treatment session, in both cases	Case 1: baseline, then 6, 12, 18, and 30 months Case 2: baseline, then 8, 20, and 26 months Severity of the facial lipoatrophy (facial lipoatrophy severity scale) AEs
Micheels^Citation45  Observational study (+ histology)  Facial treatments	Fortélis^® Extra
	28 patients (20 females) Mean age: 53 years (range 33–67 years) One patient for histology (skin of the thigh)	Injection in the mid-to-deep dermis, with a Kendall-type 27 G needle, using preferably the retrograde tunneling (or slow local infiltration to create volume)	Reported for some patients but not the whole sample	Efficacy: baseline, 6 months, ≥10 months Esthetic improvement discussed but not quantified Histology: day 0, day 90 AEs
Pavicic^Citation28  Open-label study  Facial treatments (mostly NLF [84%])	Belotero^® Intense alone (n=110) or combined with Belotero^® Basic (sandwich procedure, n =39)
	149 patients (88.9% females) Mean age: 52.2 years (range 25–77 years)	Injection of Belotero^® Intense into the deep dermis with a 27 G needle, using varioustechniques: linear threading, serial puncture, fanning, criss-cross, or the sandwich technique (Intense first, then Basic into the mid dermis)	1 mL on each side (range 0.3–5.0 mL) With sandwich technique: 0.73 mL of Basic (range 0.3–1.0 mL)	Baseline, immediately after injection, and at 2 and 12 weeks Fold severity: WSRS, GAIS Overall esthetic effect (by physician) Investigator’s satisfaction Patient’s satisfaction, AEs
Belotero^® Volume
Study design other than RCTs
Micheels et al^Citation47  Observational study  Facial volume loss (mostly cheeks [38.6%], cheekbones [18.1%], tear trough [18.1%])	Belotero^® Volume
	56 patients Mean age: 59.8±13.6 years (range: 25–76 years)	Majority of injections performed at a deep dermal/hypodermal depth or to the level of the supraperiosteal plane, using needle or cannula (most common size: 27 G, 46.3% of cases; 25 G, 25.9% of cases) Optional touch-up at 1 month (n=2)	0.58 mL per side	Baseline, 1, 3, and 6 months Esthetic effect: FVLS by investigator, GAIS by investigator and patient Patient’s satisfaction Investigator’s experience AEs
Becker et al^Citation21  Observational study  HIV-associated facial lipoatrophy	Modélis^® Shape
	Ten male patients Mean age: 56.4±6.4 years	Subdermal injection in submalar area with 25 G short needle completed with 22 G microcannula of 50 mm length, using a retrograde and fanning technique, optional touch-up session after 2 weeks Two or three punctures per session	1.3 mL per cheek	Baseline, 1, 6, and 12 months HA volume, skin thickness, and tissue vascularization by MRI Patient’s satisfaction GAIS (by investigator and patient) AEs
Micheels et al^Citation46  Post-marketing clinical follow-up  Age-related mid face atrophy	Modélis^® Shape/Belotero^® Volume
	20 patients Mean age: 57 years (range 28–73 years)	Injection in lateral cheek hollow (n=8), cheekbone area (n=6), or both (n=6), with needles and cannulae, using different methods depending on the investigator. Optional touch-up injection	2.1 mL for both sides for injection in lateral cheek hollow, 2.1 mL for injection in cheekbone area, 3.37 mL for injection in both	Baseline, immediately after injection, and 1, 3, 6, 9, 12 (and optionally 18) months Esthetic effect: FVLS by investigator, GAIS by investigator and patient Patient’s satisfaction AEs

Note:

a–c Studies with the same superscript letter were conducted in the same patients (eg, RCT and extension study).

Abbreviations: AEs, adverse events; FVLS, Facial Volume Loss Scale; GAIS, Global Aesthetic Improvement Scale; HA, hyaluronic acid; MAS, Merz Aesthetics Scales; MRI, magnetic resonance imaging; NLF, nasolabial fold; PRIMOS, phase-shift rapid in vivo measurement of skin; RCT, randomized controlled trial; VAS, visual analog scale; WSRS, Wrinkle Severity Rating Scale.

Table 3 Performance assessment of dermal fillers: rating scales, and investigator’s and patient’s satisfaction

Assessment Rating scales	Description	End points/definition	Reference
WSRS	Discrete 5-point scale	Fold severity From 0 – absent (no visible fold; continuous skin line), to 4 – extreme (extremely deep and long folds detrimental to facial appearance to 4 mm V-shaped fold when stretched)	^Citation58
GAIS (not validated)	Discrete 5-point scale	Esthetic outcomes compared to baseline From 1 – worse to 5 – very much improved
VAS fill state	Continuous scale (0%–100%)	Fold correction (ie, improvement) rated from 0% to 100%
Overall esthetic effect	Discrete 6-point scale	From 1 – excellent to 6 – unsatisfactory
FVLS	Discrete 5-point scale	From 1 – mild flattening/no visibility of underlying tissue, to 5 – severe indentation of one or more facial regions/clear visibility of underlying tissue	^Citation59
Facial lipoatrophy severity scale	Discrete 4-point scale	From 1 – mild and localized facial lipoatrophy, to 4 – lipoatrophy covers a wide area, extending up toward the eye sockets, and the facial skin lies directly on the muscles
MAS	Discrete 5-point scales	Scales for the lower face (NLFs, marionette lines, upper and lower lip fullness, lip wrinkles, oral commissures, and jawline) Scales for the mid face (infraorbital hollow and upper and lower cheek fullness) Scales for the upper face (forehead lines, glabellar lines, crow’s feet, sex-specific brow positioning, and summary scores of forehead and crow’s feet areas and of the entire upper face unit)	^Citation60^–^Citation62
Hirmand’s classification	Discrete 3-point scale	Severity of tear trough deformity From Class I – loss of volume limited medially down to Class III – full depression circumferentially to the orbital rim	^Citation63
Physician’s clinical global assessment	Discrete 7-point scale	Rating of skin’s appearance (brightness, texture, and turgor), from 100% improvement down to worsening
Satisfaction with the product (and related factors)
Practitioner’s satisfaction	Ease of use, esthetic outcomes, etc	Overall satisfaction/preference
Patient’s satisfaction	Various assessments	Overall satisfaction/preference Specific questions such as whether the patient felt the implant, whether the patient would recommend the treatment, whether the patient’s expectations were met and he/she would repeat the treatment course Quality-of-life questionnaire
Pain (VAS)	Discrete 11-point scale	0 – no pain to 10 – worst imaginable pain
Treatment longevity	Various assessments	Percentage of patients not requiring injections; percentage of patients who persist without repeat treatment for a given length of time; cumulative number of injections received for a given length of time; average time between injections; time lag between the first and the second treatment sessions

Note: The last column (“Reference”) refers to the publication describing/validating the scale, if any.

Abbreviations: FVLS, Facial Volume Loss Scale; GAIS, Global Aesthetic Improvement Scale; MAS, Merz Aesthetics Scales; NLF, nasolabial fold; VAS, visual analog scale; WSRS, Wrinkle Severity Rating Scale.

Table 4 Belotero^® dermal fillers: summary of clinical findings

Study, design, and indication	Treatments and performance	Pain, safety, and tolerability	Investigator’s and patient’s satisfaction
Belotero^® Basic/Balance
RCT (and extension) with comparator(s)
Prager and Steinkraus^Citation9,a  RCT split-face  NLF	Belotero^® Basic (n=20) vs Restylane^® (n=20)
	Mean reduction in wrinkle depth at 4 weeks: greater with Belotero^® (−109.5 µm) than with Restylane^® (−71.8 µm, P<0.0001)	Pain immediately after injection (by VAS): lower with Belotero^® (ns) Most common AEs: injection-site erythema (Belotero^® n=7, 35%; Restylane^® n=6, 30%), hematoma (Belotero^® n=1, 5%; Restylane^®n=2, 10%) All AEs of mild or moderate severity No SAEs, no AEs leading to discontinuation Tolerability rated as good/very good by 85% of patients with Belotero^® vs 80% of patients with Restylane^® (and in 90% of cases with both treatments, by the investigators)	Patient’s satisfaction: felt the implant: 65% with Belotero^®, 75% with Restylane^® 55% would recommend both products Of those who would recommend one product: 25% Belotero^®, 10% Restylane^®
Prager et al^Citation37,a  RCT split-face  NLF	Belotero^® Basic/Balance (n=20) vs Restylane^® (n=20) (Arm A); Belotero^® Basic/Balance (n=20) vs Juvéderm^® Ultra 3 (n=20) (Arm B)
	NLF severity: lowest score obtained at week 4, regardless of the filler (0.8 or 0.9, depending on Arm). Scores still lower at 12 months (1.5 or 1.6) than at baseline (2.3), for all fillers No statistical difference between fillers	Most common AEs: erythema (Belotero^® Arm A + B n=14, 35%; Restylane^® n=6, 30%; Juvéderm^® n=8, 40%), hematoma (Belotero^® Arm A + B n=4, 10%; Restylane^® n=3, 15%; Juvéderm^® n=4, 20%), edema (Belotero^® Arm A + B n=1, 2.5%; Restylane^® n=0, 0%; Juvéderm^® n=5, 25%) Most AEs of mild or moderate severity, except one severe AE (pain in one patient with Belotero^® in Arm B). No SAEs, no AEs leading to discontinuation	Patient’s satisfaction: both fillers acceptable: Arm A 55%, Arm B 25% Preferred Belotero^®: Arm A 25%, Arm B 40% Preferred other filler: Arm A Restylane^® 10%, Arm B Juvéderm^® 35% No preference: Arm A 10%, Arm B 0%
Narins et al^Citation36,b  RCT split-face  NLF	Belotero^® Basic/Balance vs collagen (n=118)
	Change in WSRS at 12 weeks (by blinded rater) greater with Belotero^® (P<0.001): from 2.50 to 1.25 (−1.25) vs 2.49 to 1.51 (−0.98) with collagen Other significant differences in favor of Belotero^®: WSRS (blinded rater) at 8, 12, 16, and 24 weeks; WSRS (investigator) at 12, 16, and 24 weeks; GAIS (blinded rater and investigator) at 8, 12, 16, and 24 weeks; GAIS (patient) at 8, 16, and 24 weeks; VAS fill state (blinded rater, investigator, and patient) at 8, 12, 16, and 24 weeks (except patient VAS at week 8) Responder rate (% of patients showing a difference in WSRS of ≥1 point between Belotero^® and collagen): 15.9% at 2 weeks, 55.1% at 24 weeks	Injection-site pain: 44.9% with Belotero^®, 53.4% with collagen; generally mild to moderate Related AEs in ≥2% of full analysis set: 167 AEs with Belotero^®, 217 AEs with collagen Injection-site AEs (Belotero^® vs collagen): nodule (33.1% vs 55.1%), induration (33.9% vs 40.7%), swelling (22.9% vs 22.0%), pruritus (5.1% vs 7.6%), pain (5.1% vs 4.2%), erythema (2.5% vs 4.2%), bruising (3.4% vs 0.8%), discoloration (0% vs 4.2%) Most injection-site AEs mild or moderate in intensity and resolved within 7 days Severe procedure-related AEs: with Belotero^®, swelling (6.8%) and bruising (8.5%); with collagen (and occurring in ≥5% of patients) erythema (8.5%) and swelling (8.5%) Severe AEs related to product itself: with Belotero^®, nodule only AE reported in ≥5% of patients (5.9%); with collagen, AEs reported in ≥5% of patients were nodule (7.6%) and induration (5.9%) Bruising, nodules, swelling, and induration were the AEs that lasted longer than a week in >10% of patients	Patient’s questionnaire (n=107): 79.4% preferred Belotero^® at 24 weeks. Improvement and satisfaction (VAS) rated at 74.7% and 78.2% with Belotero^® vs 66.0% and 65.1% with collagen Five out of six investigators preferred Belotero^® because of its storage and handling, and comfort, and design of its syringe (two out of six investigators also preferred Belotero^® because of the ease of injection)
Narins et al^Citation35,b  Open-label extension RCT split-face  NLF	Belotero^® Basic/Balance (vs collagen during RCT) (n =95 out of the 106 completers of RCT)
	At weeks 32, 48, 72, and 96, decrease in NLF severity on both sides, but greater with Belotero^® (statistical comparison not performed) Mean GAIS score (by investigator) was at 2 (improved) or 3 (much improved) at all time points. Better results on Belotero^® side (according to either GAIS investigator or GAIS patient) Predictors of longevity: 80.2% of patients persisted without treatment for an interval of 48 weeks, regardless of treatment	34 AEs reported in 24.2% of patients Only one AE (2.9%) considered related: injection-site bruising, on both sides of the face (moderate severity, resolved within 3 days) Antibodies to HA at week 32 (n=79): no detectable anti-HA IgG antibodies in 86.1% of patients; borderline positive in 10.1% (pretreatment) In the 10.1%, three patients had positive anti-HA titers, with only one patient showing significant increase pre- to posttreatment Anti-HA IgE antibodies: assays all negative	Not assessed
Study design other than RCT
Gregory^Citation39  Observational study  Facial treatments (mostly NLF [45%] and lip [28%])	Belotero^® Basic/Balance (n=448) Performance not formally assessed No patient returned between months 1 and 3 because of early reabsorption of the product	Exact count of AEs not provided Short-term AEs (within 1 month): swelling, redness, and bruising (only three AEs lasted for ≥24 hours) No infection, lumps, or product migration Long-term AEs (ie, persisted for ≥1 month after injection): no infection, granuloma, persistent lumps	Of the 475 patients, 473 were satisfied or more than satisfied. (note: results in contradiction with the sample size reported in the methods, n=448)
Dirting et al^Citation33  Prospective study  NLF	Belotero^® Basic (n=114, with 109 completed treatment period, 35 completers of 36-week follow-up)
	% of patients with improvement in WSRS of ≥1 point: 100% after injection, 97% at 2 and 4 weeks, 91% at 12 weeks, and 81% at 24 weeks Percentage down to 66% in the 35 patients who did the follow-up (other patients were back to their baseline score) GAIS by patient: 82% of patients assessed the esthetic results as improved at 24 weeks	Related AEs in 61% of patients Most common AEs: hematoma, erythema, swelling, and induration of mild intensity No AEs leading to discontinuation No related SAEs during the study, nor the follow-up After 2 weeks, AEs reported in 23% of patients. After 6 months, only two AEs reported (one discoloration, one nodule) Tolerability considered good/very good by the investigators in 96% of patients at 24 weeks	Not assessed
Kühne et al^Citation38  Retrospective study  Facial treatments	Belotero^® Basic/Balance (n=317)
	Performance not formally assessed	Most common AEs: erythema, edema, ecchymosis (all of short duration, count not provided) No persisting nodules, no granulomas, no Tyndall effect No SAEs	Not formally assessed
Downie et al^Citation34  Open-label study  NLF	Belotero^® Basic/Balance (n=93)
	WSRS: improvement at 2, 4, 8, 12, 16, and 24 weeks for both NLFs, according to investigator and independent rater.  GAIS: same results as WSRS, based on the patient’s assessment	Related AEs in 77.4% of patients; most frequent (>50% of patients): swelling, induration, and pain at injection site AEs related to injection in 32.3% of patients; most frequent (>10% of patients): bruising and discoloration. Systemic AEs in 11.8% of patients, all unrelated. No SAEs	Not assessed
Gilbert and Calvisi^Citation42  Case series  Facial treatments (mostly mid face [71%])	Belotero^® Balance (n=1), Restylane^® + lidocaine (n =1), Perlane^® + lidocaine (n=1), Juvéderm^® Voluma/Volift/Volbella + lidocaine (n=3), Radiesse^® (n=1)
	Discussion regarding the choice of each filler. Performance not reported	AE reported in four out of seven cases: minimal trauma (Juvéderm^® Voluma + lidocaine n=1); minimal post-injection bleeding (Juvéderm^® Volift + lidocaine n=1); moderate swelling (Restylane^® + lidocaine n=1); moderate bruising with no vascular compromise (Radiesse^®, n=1) No AE reported with Belotero^® Balance and Juvéderm^® Volbella + lidocaine	Not assessed
Goh et al^Citation22  Retrospective chart review  Infraorbital hollow	Belotero^® Balance (n=5) and Restylane^®-L (n =5)
	Belotero^® Basic/Balance spread more widely in the tissue plane, compared to Restylane^® Belotero^®: “elongated, spindle-shaped configuration” Restylane^®: “bubble or pearl-like configuration”	Only reported AE: edema, ~2 weeks after injection (Belotero^® n=1; Restylane^® n=1)	Not assessed
Hevia et al^Citation40  Prospective study Infraorbital hollow	Belotero^® Balance (n=49, with 46 completers)
	Decrease in hollowness from baseline (P<0.001) At 2 months, an improvement in hollowness of ≥1 point was seen in 76.1% of patients (and ≥2 points in 19.6%) At 10 months, 27 out of 31 (87%) patients still showed an improvement of ≥1 point	Mild-to-moderate delayed swelling (n=4) at 2 weeks, which resolved within 2–10 months Other AEs: erythema, ecchymosis, edema (count not provided) No SAEs	Two-thirds of patients did not elect complimentary additional treatment at 6 months (but remained in the study for analysis)
Wollina ^Citation41  Retrospective study  Tear trough	Belotero^® Basic (n=21), Glytone^® 3 (n=10), and Radiesse^® (calcium hydroxyapatite, n=9)
	100% of patients improved after the first procedure, two patients needed a touch-up Average improvement: 1 class on the Hirmand’s classification; 12 patients originally in Class II had a 2-class improvement Duration of effect: between 9 and 12 months with HA fillers (10.1±2.4 months), and between 11 and 15 months with Radiesse^® (12.8±3.9 months)	AEs in 25 out of 31 patients (80.6%) with HA fillers (Belotero^® and Glytone^® pooled): bruising (n=13), edema (n=6), and redness (n=6) All AEs mild and temporary; resolved within 2–3 weeks without treatment No Tyndall effect, bumps, or nodules Radiesse^® group: AEs in four out of nine patients (44.4%), all mild and temporary (bruising n=4, redness n=2, edema n=2)	38 out of 40 patients (95%) were very satisfied with HA fillers (data not provided for Belotero^® alone)
Effect of lidocaine
Moradi et al^Citation31  RCT split-face  Perioral lines	Belotero^® Balance (BEL, n=10), Belotero^® Balance with lidocaine (BEL + lido, n=10), Belotero^® Balance with lidocaine + epinephrine (BEL + lido + epi, n=10)
	Not assessed	Most common AEs: bruising and pain No significant difference in pain and bruising scores between treatments No lumps or nodules reported	Not assessed
Prager and Micheels^Citation32  Prospective survey, split-face  Facial treatments (mostly NLF [79%] and marionette lines [62%])	Belotero^® Basic/Balance with/without lidocaine (n=29), blanching technique used in 21 patients (72%)
	Physician’s experience: Belotero^® with/without lidocaine similar in terms of ejection force, texture, and placement Blanching technique with lidocaine: easier than without lidocaine n=2, similar/identical n=19 Same skin distribution of products: 76% applications. Esthetic outcomes rated by investigator: similar or identical between products in all patients	Pain reported in 20 out of 29 patients, with lower mean pain intensity with lidocaine than without lidocaine (2.8±1.1 vs 5.8±2.1, P=0.0001) Redness after injection in 52% of patients with both products Bruising after injection in 10% of patients without lidocaine, and 14% of patients with lidocaine	Patient-assessed satisfaction (n=21): 21 patients (100%) were satisfied
Belotero^® Hydro
Study design other than RCT
Succi et al^Citation44  Open-label study  Periorbital area	Mesolis^® Plus (n=20, with 18 completers)
	Investigator #1: 52.6% of patients showed 25% improvement; Investigators #2 and #3: ~60% of patients had a 25% or 50% improvement Independent rater: ≥50% of patients showed 50% improvement	Mild pain during injection in ~80% of patients; one case of severe pain (during the first session). Injection-site AEs: edema (80% of all sessions, lasting for 6 days on average), hematoma (in 76% of patients, lasting for ^Citation7 days), erythema (in 10%, 0%, and 30% of patients after sessions 1, 2, and 3, respectively) Papules in most patients (lasting for 5 days). No SAEs	Patient’s satisfaction (from 0 –worst to 10 – best): mean score of 5.9 (range: 0 in 1 patient to 8 in 4 patients)
Belotero^® Soft (and/or other Belotero^® dermal fillers)
Bezzola and Micheels^Citation27,c  Open-label study  Facial treatments	Esthélis^® Basic (n=25) and Soft (n=11)
	Soft: performance not formally assessed Basic: persistence of treatment effect over time, ranging from 3 to 7 months in the 25 patients	No formal count of AEs Based on the physician’s experience, AEs to be expected are: minor edema, bruising/hematoma, post-injection erythema lasting for ≤48–72 hours No infection, granuloma, or allergy reported	Not assessed
Micheels ^Citation26,c  Safety follow-up  Facial treatments	Esthélis^® Basic and Soft (n=13, out of the 36 included in the pilot study)
	Not assessed	AEs: rare bruises, erythema (≤24 hours), very light swelling (≤24 hours) (exact count of AEs not provided) No allergic reaction or granuloma	Not assessed
Hasson and Romero^Citation25  Prospective study  Facial atrophic scars	Esthélis^® Basic or Soft (n=12)
	Esthetic improvement rated by the investigator as moderate (27%), good (57%), or excellent (17%) immediately, ^Citation1 week, and 1 month after injection. Patient’s rating: moderate (17%), good (33%), or excellent (50%) immediately after injection, and good (42%) or excellent (58%) 1 week and 1 month after injection	Mild or moderate pain during injection Mild erythema immediately after injection (count not reported); resolved spontaneously within a few hours. No Tyndall effect	Not assessed
Pavicic et al^Citation30  Case series  Whole-face rejuvenation	Belotero^® (Soft/Basic/Intense) after Bocouture^® (botulinum toxin) and Radiesse^® (calcium hydroxyapatite)/[Bocouture^® + Radiesse^®] + Belotero^® Soft, Basic, and Intense (Patient A), Belotero^® Basic and Intense (Patient B), or Belotero^® Soft and Basic (Patient C)
	At 11–14 days after last treatment, improvement of ≥1 point: nine out of eleven sites (82%) in Patients A and C, ten out of eleven sites (91%) in Patient B	Procedure well tolerated (detailed safety results not provided)	Not formally assessed
Belotero^® Intense
RCT with comparator(s)
Buntrock et al^Citation19  RCT split-face  NLF	Belotero^® Intense vs Perlane^® (n=20)
	WSRS (blinded investigator): decrease between baseline (4.0) and week 2 (Belotero^® 2.1 vs Perlane^® 2.4), week 24 (2.4 and 2.7), and week 48 (2.7 and 2.8) (P<0.001). No significant difference between treatments. WSRS (blinded rater): similar findings, WSRS still lower at week 48 (Belotero^® P<0.001; Perlane^® P=0.046) Patient WSRS: similar results, except significant difference between treatments at week 2 (WSRS −49% with Belotero^® vs−36% with Perlane^®, P=0.01). Reduction in wrinkle depth at 2, 24, and 48 weeks with both fillers (P<0.05) – trend favorable to Belotero^®. Depth reduction at 2, 24, and 48 weeks: Belotero^® −98.1 (36%), −76.9 (28%), and −57.8 µm (21%); Perlane^® −69.4 (31%), −44.1 (20%), and −37.2 µm (17%)	Pain after injection lower with Belotero^® than Perlane^® (3.9 vs 5.0, P=0.01) Short-term AEs (within the first 10 days): mild- to-severe bruising, redness, swelling, pain, mild- to-moderate tenderness, nodules, and itching (count not provided). Similar distribution of AEs with the two treatments No SAEs, no AEs leading to discontinuation	% of patients satisfied higher with Belotero^® than Perlane^® at week 24 (62% vs 51%, P=0.002) and week 48 (43% vs 33%, P=0.005) 80% of patients would repeat treatment with Belotero^® vs 65% of patients with Perlane^®
Study design other than RCT
Pavicic et al^Citation29  Case series  HIV-associated facial lipoatrophy	Belotero^® Basic and Belotero^® Intense combined (n =2)
	Case 1: at 30 months, no facial lipoatrophy and no NLF visible (just lines)	Case 1: mild erythema but no edema, hematoma, or other AEs after first injection	Case 1: not reported
	Case 2: 1 month after first injection, lipoatrophy at grade 0–1; 8 months later, loss of filling effect – second injection, 10 days later lipoatrophy grade 1; at 20 months, lipoatrophy grade 2–3 – third injection; at 26 months, lipoatrophy at grade 0	Case 2: no AEs after the first injection, injection-site erythema after the second injection (resolved within 1 day). In both cases, no difference between the two fillers regarding pain and other AEs	Case 2: fully satisfied 1 month after first injection and 10 days after second injection
Micheels^Citation45  Observational study (+ histology)  Facial treatments	Fortélis^® Extra (n=28, histology n=1)
	At 6 months, clinical improvement for all treated areas (not quantified) At ≥10 months, improvement persisted for most patients (not quantified)	Erythema and mild edema (n=1), translucent cord (n=1), overcorrection in the lip (n=1), slightly asymmetrical injection with a mild edema (n=1) No delayed inflammatory reaction at 12 months. Histology on day 90: no inflammatory reaction or fibrosis	Two patients were not satisfied: injected volume too large in the lip (1.5 mL), injection slightly asymmetrical
Pavicic^Citation28  Open-label study  Facial treatments (mostly NLF [84%])	Belotero^® Intense alone (n=110) or combined with Belotero^® Basic (sandwich procedure, n=39)
	WSRS improved after injection (3.98–2.28, P<0.001), with no decline over 12 weeks GAIS immediately after injection: 89.9% achieved improvement, of whom 59.7% much/very much improved Effect well maintained throughout the three-month study	Results pooled for the 149 patients Injection-site pain was mild (mean score of 2.7 on VAS). Post-injection AEs in 85.9% of patients, mostly related to injection procedure Most common AEs: erythema (63.8%), swelling (52.3%), pain (49.7%), hematoma (27.5%), induration (21.5%)	Esthetic outcomes rated by physician as good/excellent in 83.3% of patients at 12 weeks. After injection, excellent/good satisfaction in 94% of patients and 90.6% of investigators (nearly maintained over 12 weeks)
Belotero^® Volume
Study design other than RCTs
Micheels et al^Citation47  Observational study  Facial volume loss (mostly cheeks [38.6%], cheekbones [18.1%], and tear trough [18.1%])	Belotero^® Volume (n=56)
	FVLS scores improved from moderate at baseline to mild at 6 months with improvements of 53%, 57%, and 74% for the cheeks (3.5–1.6), cheek bones (3.8–1.6), and tear trough (3.8–1.0), respectively GAIS by investigator: improvement at ^Citation6 months for all indications, more particularly for the cheeks (1.13) and tear trough (1.75). Cheekbones also responded well (2.0) GAIS by patients: “improved” to “very much improved”; from day 1 to 6 months	Only injection-site AEs On day 1, AEs in 14 patients (25%): swelling n=5, bruising n=3, redness n=2, pain n=2, induration n=2. At month 1, AEs in five patients (8.9%): swelling n=4, induration n=1 At month 3, AEs in five patients (8.9%): swelling n=3, induration n=1, discoloration n=1 All mild except pain on day 1, one case of swelling at month 1, and discoloration at month 3 (all moderate)	All investigators reported that the volumizing effect was similar to (50%) or better than (50%) other volumizers. Injections rated as easy/very easy (50%) or equivalent to other products (40%) All patients reported they wanted to pursue treatment
Becker et al^Citation21  Observational study  HIV-associated facial lipoatrophy	Modélis^® Shape (n=10)
	MRI: HA volume +331% at 1 month (P<0.0001), with no reduction at 12 months; skin thickness and tissue vascularization increased during the first ^Citation6 months. GAIS: very much improved n=2, much improved n=5, improved n=3	Slight erythema after injection n=2 (resolved in 2–3 days) No skin hyperpigmentation, no pain, no itching No swelling, discomfort, or induration after injection No allergic reaction, no product-related complications	Patient’s satisfaction (QoL from 0 to 100): baseline 68.0±24.0, 12 months 83.5±7.4 (+15.5%, P=0.04)
Micheels et al^Citation46  Post-marketing clinical follow-up  Age-related mid face atrophy	Modélis^® Shape/Belotero^® Volume (n=20, with eleven completers at month 18)
	Investigator’s FVLS: mean score 3.1 at baseline, 1.3 immediately after injection, 1.3–1.8 between month 1 and month 18 (P<0.0001) Investigator’s GAIS: immediately after injection and up to month 6, ≥94% of patients rated as very much/much improved; ≥65% from months 9 to 18 Patient’s GAIS: corresponding % were ≥83% immediately after injection up to month 6, and ≥50% from months 9 to 18	Mild or moderate injection-site reaction (n=13 out of 20, 65%) Most frequent AEs on day 1: redness (n=5, 25%), pain (n=6, 30%), edema (n=3, 15%) Also transient bruising (n=1, 5%) and itching (n=1, 5%). Firmness (n=5, 25%), which resolved within 3 months	At month 12, 95% of patients were satisfied (ie, would repeat treatment) At month 18, 100% of patients (11/11) satisfied

Notes:

a–c Studies with the same superscript letter were conducted in the same patients (eg, RCT and extension study).“Not formally assessed” means the outcomes are mentioned in the publication but without supportive numerical data.

Abbreviations: AEs, adverse events; FVLS, Facial Volume Loss Scale; GAIS, Global Aesthetic Improvement Scale; HA, hyaluronic acid; MRI, magnetic resonance imaging; NLF, nasolabial fold; ns, not significant; QoL, quality of life; RCT, randomized controlled trial; SAEs, serious adverse events; VAS, visual analog scale; WSRS, Wrinkle Severity Rating Scale.

Figure 1 Two-dimensional surface profiles before (black lines) and 4 weeks after treatment (gray lines) with Belotero^® Basic and Restylane^®.

Notes: Height (µm) on the vertical axis corresponds to wrinkle depth. It was calculated as the mean of 50 profile lines across the wrinkles of the target area, using the phase-shift rapid in vivo measurement of skin system. Adapted from Prager W, Steinkraus V. A prospective, rater-blind, randomized comparison of the effectiveness and tolerability of Belotero^® Basic versus Restylane^® for correction of nasolabial folds. Eur J Dermatol. 2010;20(6):748–752.⁹

Figure 2 Change in nasolabial fold severity with Belotero^® Basic/Balance treatment, re-treatment, and optional touch-ups.

Notes: In Prager et al’s study,³⁷ fold severity was rated using the Merz Aesthetics Scales at baseline and at 1, 6, 9, and 12 months. In Narins et al’s study,^35,36 fold severity was rated using the Wrinkle Severity Rating Scale at baseline and at 24, 32, 48, 72, and 96 weeks. Baseline is before the injection. Data from Narins et al,³⁵ Narins et al,³⁶ and Prager et al.³⁷
Abbreviation: t-u, touch-up allowed.

Figure 3 Esthetic effect of Belotero^® Soft.

Notes: A 30-year-old female patient with congenital unilateral (left) upper eyelid hollowness received 0.2 mL of Belotero^® Soft in the suborbicularis fibroadipose tissue (pre-septal) layer using a blunt tip cannula to prevent bruising and intravascular injection. The product was spread as a thin layer to avoid swelling and lumps. Photo courtesy of AD Prasetyo.

Figure 4 Long-term change in nasolabial fold severity with Belotero^® Intense treatment based on the investigators’ rating on the Wrinkle Severity Rating Scale.

Notes: The difference from baseline was statistically significant at each time point, in both studies (P<0.001). The mean trend shows the average scores when pooling data from the two studies. In Buntrock et al’s study,¹⁹ the ratings were performed by a blinded investigator at baseline (ie, before injection) and at 2, 24, and 48 weeks. In Pavicic’s study,²⁸ the ratings were performed by an unblinded investigator at baseline, immediately post-injection, and then at 2 and 12 weeks. In both studies, touch-ups were not allowed. Data from Buntrock et al.¹⁹ Adapted from Pavicic T. Efficacy and tolerability of a new monophasic, double-crosslinked hyaluronic acid filler for correction of deep lines and wrinkles. J Drugs Dermatol. 2011;10(2):134–139.²⁸
Abbreviation: WSRS, Wrinkle Severity Rating Scale.

Figure 5 Long-term change in facial volume loss (cheeks) with Belotero^® Volume treatment based on the investigators’ rating on the Facial Volume Loss Scale.

Notes: The difference from baseline was tested by Micheels et al⁴⁶ and was statistically significant at each time point (P<0.0001). The mean trend shows the average scores when pooling data from the two studies. In Micheels et al’s study,⁴⁷ other facial areas than the cheeks were assessed. Only results for cheeks are presented here for comparison with Micheels et al.⁴⁶ Assessments were performed at baseline, the day following the injection (ie, post-injection), and then at 1, 3, and 6 months. Touch-up at 1 month was performed in two out of 56 patients (3.6%).⁴⁷ In Micheels et al’s study,⁴⁶ assessments were performed at baseline, immediately post-injection, and then at 1, 3, 6, 9, and 12 months, with an optional follow-up at 18 months (n=11). Touch-up was performed in two out of 20 patients (10%, timing not provided).⁴⁶ Baseline is before the injection. Reproduced from Micheels P, Ascher B, Beilin G, Elias B, Rummaneethorn P, Sattler G. Evaluation clinique de l’efficacité et l’innocuité d’un acide hyaluronique volumateur de technologie CPM^® pour le traitement de multiples zones du visage [Clinical evaluation of the efficacy and safety of a hyaluronic acid volumizer with CPM^® technology for the treatment of multiple facial areas]. Réal Thér Dermato-Vénérol. 2014;235(3):2–8. French.⁴⁷ Micheels P, Vandeputte J, Kravtsov M. Treatment of age-related midface atrophy by injection of cohesive polydensified matrix hyaluronic acid volumizer. J Clin Aesthet Dermatol. 2015;8(3):28–34.46 Copyright ©2015 Matrix Medical Communications. All rights reserved.⁴⁶
Abbreviations: FVLS, Facial Volume Loss Scale; t-u, touch-up allowed.

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