Biostimulant dermal fillers

1. BIOSTIMULANT
DERMAL FILLERS
Dr Fab Equizi
MB.ChB PGDip NSFA
Cosmetic Doctor

2. WHAT IS
BIOSTIMULATION?
An activation of the biological functions of the skin in order to
optimize its physiology and achieve aesthetic improvement, by
neocollagenesis, new elastin formation, dermal remodelling
Examples of biostimulants
• PLA
• LED phototherapy
• PRP
• RF
• Lasers/IPL
• Chemical peels

3. DermDermal Fillers As Biostimulants
• All dermal fillers are biostimulants to some
extent
• The 2 fillers considered to be biostimulant are
Radiesse and Ellanse

4. 4RAD118/0814/FS Date of Preparation August 2014
The unique CaHA
collagen stimulating dermal filler

5. 5
Elasticity: Radiesse vs. HA products1
Radiesse has a higher elasticity than leading HA products
i.e. Radiesse is better able to counteract forces that cause an aged look, like gravity
or skin laxity, therefore Radiesse provides greater lift to overlying tissue
0
200
400
600
800
1,000
1,200
1,400
1,600
G'(Pa)
Radiesse®
Filler
Restylane®
SubQ
Perlane® Restylane® Juvéderm®
Voluma
Juvéderm®
Ultra Plus
Juvéderm®
Ultra
Measured at 0.7 Hz
1 - Sundaram H, et al. Comparison of the rheological properties of viscosity and elasticity in two categories
of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol Surg. 2010;36:1859 - 1865.

6. 6
Viscosity: Radiesse vs. HA products1
Radiesse has a higher viscosity than leading HA products
i.e. Radiesse remains where it is injected and will not spread into the surrounding tissue
Measured at 0.7 Hz
Radiesse®
Filler
Restylane®
SubQ
Perlane® Restylane® Juvéderm®
Voluma™
Juvéderm®
Ultra Plus
Juvéderm®
Ultra
0
50,000
100,000
150,000
200,000
250,000
300,000
350,000
400,000
Viscosity(centipoises)
1 - Sundaram H, et al. Comparison of the rheological properties of viscosity and elasticity in two categories
of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol Surg. 2010;36:1859 - 1865.

7. 7
What is Radiesse?1,2
• Radiesse is a synthetically produced product which consists of
– 30% Calcium Hydroxylapatite (CaHA) microspheres (25-45µm)
– suspended in a sodium carboxy-methylcellulose resorbable aqueous gel carrier (70%)
– (GRAS-Status*)
• Lifting & volume enhancement with a dual effect
– Immediate result due to elastic gel-matrix
– Long-term effectiveness due to CaHA-microspheres acting as scaffold and inducing
collagen neogenesis
• Approvals: EU: since 2004 / USA: FDA since 2006 (NLF, Lipoatrophy)
• Pack sizes: 1.5ml, 0.8ml
• 5 million syringes shipped worldwide
• More than 2,000 patients included in clinical studies
*GRAS = Generally Recognized as Safe (by FDA)
1 - Marmur ES et al. Clinical, histological and electron microscope findings after injection of a calcium hydroxylapatite filler. J Cosmet Laser Ther 2004;6:223-226.
2 - Coleman K et al., Neocollagenesis after Injection of Calcium Hydroxylapatite Composition in a Canine Model, Derm Surg. 2008; 34:S53- S55.

8. 8
Radiesse - Mechanism of
Action1
Gel-matrix with CaHA
microspheres results in an
immediate volumising and
lifting effect
CaHA-microspheres
in scanning electron
photomicrograph:
Size: 25 – 45 μm
Before treatment
1 - Marmur ES et al. Clinical, histological and electron microscope findings after injection of a calcium hydroxylapatite filler. J Cosmet Laser Ther 2004;6:223-226.
Immediate 1:1 correction
after injection

9. 9
Radiesse - mechanism of
action1,2
Long-term effectiveness
due to CaHA-induced
collagen production
CaHA-microspheres
form a scaffold and
stimulate fibroblasts
into producing
collagen
A firm network of
collagen fibres is
newly formed in
the dermis and replaces
the gel-matrix
1 - Marmur ES et al. Clinical, histological and electron microscope findings after injection of a calcium hydroxylapatite filler. J Cosmet Laser Ther 2004;6:223-226.
2 - Berlin A, Hussain M, Goldberg D. (2008) Calcium Hydroxylapatite Filler for Facial Rejuvenation: A Histological and Immunohistochemical Analysis, Derm Surg, 34, p. S64
S67.

10. 10
Radiesse microspheres are
metabolised naturally
*Scanning electron photomicrograph
CaHA microspheres are slowly
dissolved into calcium and
phosphate ions through normal
metabolic processes
CaHA microspheres post implantation*

11. 11
Radiesse stimulates
new collagen production1
1 - Coleman K. et al., Derm Surg. 2008; 34:S53-S55.
Staining: New matrix stains red using picrosirius red
 Gel degradation
 Deposition of collagen
 Mild histiocytic (macrophage) tissue
response
Gel
After 4 Weeks
Microspheres
After 16 Weeks
New Collagen
After 32 Weeks After 78 Weeks

12. 12
Radiesse versatility
 Brow
 Temples
 Zygomatic Arch
 Nose
 Nasolabial Folds
 Cheeks
 Marionettes
 Jawline
 Back of Hands
 Ear Lobes

13. 13
Treatment results with
Radiesse
Malar region
Untreated malar region Malar region following treatment
On average 1.0 ml/ side are used to treat this area in most patients

14. One of mine!

15. 15
Treatment results with
Radiesse
Male lower cheeks and
nasolabial folds
Before After 4 weeks
Total dose: 3 ml

16. 16
Treatment results with
Radiesse
Pre-jowl sulcus
Untreated pre-jowl sulcus Pre-jowl sulcus following treatment
On average 0.4 ml/ side are used to treat this area in most patients

17. 17
Treatment results with
Radiesse
Nasolabial folds and lower
cheek
Before After 2 months
Total dose: 2.2 ml

18. 18
Treatment results with
Radiesse
Back of the hands
Untreated back of the hand Back of the hand following treatment
On average 1.5 ml/ hand are used to treat this area in most patients

19. 19
Treatment results with
Radiesse
Nose
Untreated nose Nose after treatment
On average 0.3 ml/ treatment cycle are used to treat this area

20. 20
Radiesse is one of the most
studied fillers in the world
More than 5,000,000 syringes shipped worldwide,
demonstrates an excellent safety profile and market acceptance
Studies (Aesthetics) Region Number of centres
Number of
patients
Nasolabial folds¹ USA, Germany 15 482
Lipoatrophy in face² USA, Canada 4 130
Hand augmentation³ Worldwide 35 168
Malar region4 USA 2 19
Multiple indications5 Worldwide 7 1247
Radiesse mixed with
Anaesthetic6 USA 4 66
2,112 patients

21. 21
Adverse Events Summary
(% Subjects)
Event Minimum 24 mon
post-injection
(N=101)
Minimum 36 mon
post-injection
(N=99)
Nodule 0 0
Granuloma 0 0
Necrosis 0 0
Infection 0 0
Erosion 0 0
Other 0 0
Long Term Phase III NLF Safety
Clinical Study1
1 - Bass LS et al., Calcium Hydroxylapatite (RADIESSE) for Treatment of Nasolabial Folds: Long-Term Safety and Efficacy Results.
Aesthetic Surgery J. 2010; 30(2):235-238

22. 22
Superior effectiveness and
patient preference1
60-Patient Split Face Study at two sites (Germany & Spain)
Radiesseimproves
more patients
Patients prefer Radiesse
*Time Post 2nd Injection
% of Patients Preferring Radiesse®
*Time Post 2nd Injection
9 Months*3 Months*
0%
20%
40%
60%
100%
Radiesse®
(0.88cc)
Restylane®
(1.26cc)
80%
79%
44%
6 Months*
% of Patients Improved
N = 60
P = 0.05 P < 0.0001 P < 0.0001 P < 0.05 P < 0.05 P < 0.05
GAIS
1 - Moers-Carpi MM, et al., Calcium Hydroxylapatite versus Nonanimal Stabilized Hyaluronic Acid for the Correction of Nasolabial Folds: a 12-Month, Multicenter,
Prospective, Randomized, Controlled, Split-Face Trial. Dermatol Surg; 2008;34: 210-215.

23. 23
Time post 2nd Injection
P=0.05 P<.05 P<.05
BinomialDistribution
Subject preference
Radiesse vs. Restylane1
% Subjects Preferring the Radiesse Result
1 - Moers-Carpi MM, et al., Calcium Hydroxylapatite versus Nonanimal Stabilized Hyaluronic Acid for the Correction of Nasolabial Folds: a 12-Month, Multicenter,
Prospective, Randomized, Controlled, Split-Face Trial. Dermatol Surg; 2008;34: 210-215.

24. 24
90%
58%
48%
97% 95%
73%
4 Months 8 Months 12 Months
RADIESSE Filler Perlane Juvéderm Juvéderm HV (Ultra)
P<.0015 P<.001 P<.001
Subject Satisfaction: Radiesse vs. Juvéderm®,
Juvéderm HV (Ultra) & Perlane®1
% Subjects Satisfied & Extremely Satisfied
Time post 2nd Injection
1 - Moers-Carpi M. et al.; A Multicenter, Randomized Trial Comparing Calcium Hydroxylapatite to Two Hyaluronic Acids for Treatment of Nasolabial Folds.
Dermatol Surg, 2007; 33: S144-S151.

25. 25
Mean improvement
Radiesse vs. Juvéderm and Perlane1
Mean Improvement GAIS (n=205 Split Face)
Time post 2nd Injection
1 - Moers-Carpi M. et al.; A Multicenter, Randomized Trial Comparing Calcium Hydroxylapatite to Two Hyaluronic Acids for Treatment of Nasolabial Folds.
Dermatol Surg, 2007; 33: S144-S151.

26. 26
Safety profile: summary
 Radiesse:
 Has a clinically proven safety profile
 5 million syringes have been shipped worldwide
 Reported granuloma rate of 0.00016%9 (5 cases 5 million syringes)1
 Most adverse events happen because of injection errors and are temporary
 In all clinical studies done in different aesthetic indications, no granuloma, no
ossification, no calcification have been reported
1 - Data on file. Merz Aesthetics, Inc.
9 - Data on file. Merz Aesthetics, Inc.

27. 27
Does Radiesse form bone in
soft tissue?
Bone cannot be formed BECAUSE:
•The CaHA present in RADIESSE filler is not bone, it is a mineral component
found in bones and teeth
•No osteo-progenitor cells or bone morphogenic proteins are present in the
dermis
•Micro-motion present in the soft tissue prevents osteogenesis
•Radiesse stimulates the patient’s own collagen, resulting in a soft and natural
appearance and feel.
•CaHA microspheres are synthetically derived and break down naturally over
time by the body’s own metabolic processes into Ca2+ and PO3
2+ ions.
•No ossification or calcification of CaHA has been reported in 5,000,000
syringes shipped worldwide.

28. Ellansé™
Entering a new era
in dermal filler aesthetics

29. AQTIS Medical
• Established in 2006
• Utrecht, The Netherlands
• Innovative Bioresorbable Solutions
– Full ISO-13485 certified
– In-house product development and manufacturing
• First product launch in 2009:
– Ellansé dermal filler
– Poly-caprolactone (PCL) based
– PCL is a soft fully bioresorbable medical polymer
• Working with a distribution network in over 50 countries

30. Ellansé™ Composition
• Ellansé™ contains biomaterials with well established and understood safety and performance
characteristics
• Components
• PCL Particles (30% by Volume)
• Standard GMP manufactured soft biomaterial
• Used in orthopedics, sutures, CDD
• Extensive studies on safe use as biomaterial
• Natural – non cross-linked
• Gel Carrier (70% by Volume)
• Cellulose based gel with glycerin and water
• Pharmaceutical excipients
• GRAS Classified by FDA (“Generally Recognized as Safe”)
• Ellansé™ is biocompatible, non-toxic, non-antigenic, non-allergenic

31. Poly-Caprolactone (PCL)
• Well-known bioresorbable medical polymer, used in numerous CE and US
FDA approved medical devices
• Fully bioresorbable (3H and C14 studies)
• Bi-phasic bioresorption through trans-esterfication with water molecules

32. Poly-Caprolactone (PCL)
• Advantage of bi-phasic resorption process
Controlled and Tunable process

33. PCL chain length vs.
longevity

34. Mode of Action: bio-stimulation

35. Picro-Sirius Red staining, Non-
polarized light
Biocompatible with few macrophages
Microspheres still round and intact
during bioresorption process
Collagen fibers are stained
red.
50 um
50 um
PCL Stimulates Collagen Generation
Ellansé-M
9 months post injection (rabbit)

36. Subcutaneous tissue
Picro Sirius Red (PSR),
Polarized light
Red (arrows): collagen type I
Green (arrowheads): collagen type III
Confirmation neo-collagenesis
50 um
Ellansé-M
9 months post injection (rabbit)
PCL Stimulates Collagen Generation

37. NEOCOLLAGENESIS
3737

38. Picro Sirius Staining, Polarized light
Subcutaneous tissue
Red color confirming predominant presence of
collagen type I
Ellansé-M
21 months post injection (rabbit)

39. Iso-volumetric Bioresorption
For Lasting Filling Effect
Tissue Correction
CaHAHACollagen
Time
Microspheres
Wrinkle starts returning from day 1
Sustained wrinkle correction High-quality
Neo-Collagenesis
Effect
Ellansé™

40. 24 month Clinical Trial
Results
A Randomized, Prospective, Single Center Feasibility
Study of Ellansé Dermal Filler for the Correction of Facial Wrinkles
December 2008 – December 2010
At hautok private practice, Munich, Germany
Dr. Marion Moers-Carpi

41. Study Design
• Prospective, Randomized, Single-centre study
• 40 patients
• Using 1:3 randomization for Ellansé S and Ellansé M
• Sub-optimal correction of NLF, followed by touch-up at one month
Protocol setup, database management, statistical analysis and reporting
by independent USA – based CRO Alquest Inc.

42. Inclusion Criteria
 18 years of age or older
 Moderate to severe NLF (WSRS score of 3 or 4 bilateral)
 No dermal filler treatment 6 months prior & abstinence from
other facial cosmetic procedures through 24 months
 Willing and ability to comply with study follow-up procedures
 Written informed consent

43. Efficacy: Ellansé - S
Investigator evaluated GAIS
Break-up analysis demonstrated that the ‘quality of improvement’ improved from 3 to 24 months. The percentage of subjects in the category ‘Improved’
decreased and increased from 3 to 24 months and were replaced by more subjects being added in the categories of ‘Much improved’ and ‘Very much improved’.

44. Efficacy: Ellansé - M
Investigator evaluated GAIS
Break-up analysis demonstrated that the ‘quality of improvement’ improved from 3 to 24 months. The percentage of subjects in the category ‘Improved’
decreased and increased from 3 to 24 months and were replaced by more subjects being added in the categories of ‘Much improved’ and ‘Very much improved’.

45. Before Treatment After 12 Months
Courtesy: Dr. med. Marion Moers Carpi, M.D.
Ellansé™-S
Pat: AQ-014
WSRS=3 - 4
V1+2= 2,2 ml

46. Before Treatment After 24 Months
Courtesy: Dr. med. Marion Moers Carpi, M.D.
Ellansé™-M
Pat: AQ-011
WSRS=4 - 4
V1+2= 2,5 ml

47. Before Treatment After 24 Months
Courtesy: Dr. med. Marion Moers Carpi, M.D.
Ellansé™-M
Pat: AQ-012
WSRS=4 4
V1+2= 3,2 ml

48. Satisfaction VAS at 24 months
Satisfaction with Ellansé™ Treatment (median)
Ellansé™ Repeat Preference (median)
Customer
Confidence
Ellansé™-
M
Ellansé™-
S
Satisfaction 89.5% 93.0%
Customer
Satisfaction
Ellansé™-
M
Ellansé™-
S
Satisfaction 90.0% 84.5%

49. Summary

50. October 21, 2010 After injection, 1 ml
Photograph courtesy of Alida Harb MD
Ellansé™- Hand

51. Photograph Courtesy Of Alida Harb, MD
Ellansé™ Tear troughs

52. Ellansé™ Nose

53. Ellansé™-M Before injection
Courtesy of Dr. Leo van Rozelaar
Medisch Laser Centrum, Amsterdam, The Netherlands
Ellansé™ Lipoatrophy

54. Ellansé™-M 4 days after injection, 17 ml
Courtesy of Dr. Leo van Rozelaar
Medisch Laser Centrum, Amsterdam, The Netherlands
Ellansé™ Lipoatrophy

55. My experiences
• 15 years injecting
• One time biggest user Radiesse in North west
• Followed up everything ever done
• Mentor to other practitioners
• Heard a lot of complaints about filler jobs
done by others

56. Radiesse v Ellanse
• Swelling
• After sting
• Non Reversible
• Loss of initial correction
• Performance

57. Radiesse Swelling

58. Radiesse
before 3 years!

59. Radiesse
before 4 weeks

60. Radiesse
6 months Voluma

61. Ellanse
Immediately post treatment 3 months

62. Ellanse
Immediately after 3 months-no top up!

63. Ellanse
before After 4 week top up

64. Ellanse
before 6 months

65. Ellanse
before 4 week check

66. Ellanse
4 weeks 6 months later

67. Ellanse
before 6 months later

68. Ellanse
before Post treatment swelling

69. Ellanse

70. Ellanse

71. Advantages of Ellanse
• Soft natural result
• Biocompatible
• Result genuinely develops
• The most cost effective volume filler on
market
• Generally outperforms itself

72. Sources of disappointment with
Radiesse
• Poor result after initial swelling subsides
• Rapid absorption of carrier gel
• Poor collagenesis
• Frequent top ups required
• Linear breakdown
– Patients bleating and practitioner dissatisfaction
• Merz training lacking….

73. Keys for success
• Ellanse is a volume filler, none of that
vectoring bollocks
• Don’t understate the swelling
• Don’t overcorrect
• Factor in a 50% top up at 4 weeks (was up to
100% with Radiesse)
• Price for job not per syringe

74. Keys for success
• Stay out of lips
• Stay out of tear troughs
• 25G 50mm Cannula (TSK steriglide)
• 28G ultra thin wall needle
• When training practitioners emphasis on facial
volume loss and the need for follow up
• Techniques to maximise neocollagenesis

75. Volume loss

76. Changes in Skeletal Structure

77. • The face has deep facial fat that is
separated from the superficial facial fat
• The ‘distribution’ of these pads of fat
changes as a result of weight loss and
as we age
– Sometimes it can accumulate giving the
impression of permanent puffiness,
particularly under the eyes
– More often, it thins and lowers, leading
to deep creases and sunken cheeks
• One very important fat pad in facial
aesthetics is the ‘Malar’ fat pad
Changes to the distribution of facial fat
Adapted from Rohrich and Pessa (2007)

78. Final thoughts
• Ellanse is a seriously good filler which should
be increasingly popular with experienced
injectors
• In my opinion has enough advantages to make
sculptra obsolete
• Combined with Silhouette soft…..exciting!
• Why choose biostimulant over HA?
• Justification today?