Aesthetic Oculofacial Rejuvenation

CONCLUSION
Lasers are powerful instruments for many different
indications. They are technical miracles requiring
basic biophysical and biooptical knowledge in order
to use them adequately. In principle, lasers are
excellent tools to treat multiple skin disorders with
safety and efficacy but a training course is necessary
to obtain maximum benefits while reducing risks.
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39 Herd RM, Dover JS, Arndt KA. Basic laser principles. Dermatol
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40 Goldberg DJ. Laser treatment of pigmented lesions. Dermatol
Clin. 1997;15:397–407.
41 Schweiger ES, Kwasniak L, Aires DJ. Treatment of dermatosis
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43 Anderson RR, Geronemus R, Kilmer SL, et al. Cosmetic tattoo
ink darkening. A complication of Q-switched and pulsed laser
treatment. Arch Dermatol. 1993;129:1010.
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45 Wheeland RG. Laser-assisted hair removal. Dermatol Clin.
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Surg Med. 1995;7S:47.
47 Nanni CA, Alster TS. Optimizing treatment parameters for hair
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48 Bencini PL, Luci A, Galimberti M, Ferranti G. Longterm epilation
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49 Grossman MC, Dierickx C, Farinelli BS, Flotte T, Anderson RR.
Damage to hair follicles by normal-mode ruby laser pulses. J Am
Acad Dermatol. 1996;35:889–894.
50 Boss WK, Usal H, Thompson RC, Fiorillo MA. A comparison of
the long-pulse alexandrite laser hair removal system. Ann Plast
Surg. 1999;42:381–384.
51 Goldberg DJ, Ahkami R. Evaluation comparing multiple treat-
ments with a 2-msec and 10-msec alexandrite laser for hair
removal. Lasers Surg Med. 1999;25:223–228.
52 Lloyd JR, Mirkov M. Long-term evaluation of the long-pulsed
alexandrite laser for the removal of bikini hair at shortened treat-
ment intervals. Dermatol Surg. 2000;26:633–637.
53 McDaniel DH, Lord J, Ash K, Newman J, Zukowski M. Laser hair
removal: a review and report on the use of the long-pulsed alexan-
drite laser for hair reduction of the upper lip, leg, back, and bikini
region. Dermatol Surg. 1999;25:425–430.
54 Nanni C, Alster TS. Long-pulsed alexandrite laser-assisted hair
removal at 5, 10, and 20 millisecond pulse durations. Lasers Surg
Med. 1999;24:332–337.
55 Bernstein EF. Pneumatic skin flattening reduces pain during laser
hair reduction. Lasers Surg Med. 2008;40:183–187.
56 Williams RM, Gladstone HB, Moy RL. Hair removal using an
810 nm gallium aluminum arsenide semiconductor diode laser.
A preliminary study. Dermatol Surg. 1999;25:935–937.
57 Campos VB, Dierickx CC, Farinelli WA, Lin TY, Manuskiatti W,
Anderson RR. Hair removal with an 800 nm pulsed diode laser.
J Am Acad Dermatol. 2000;43:442–447.
58 Lou WW, Quintana AT, Geronemus RG, Grossman MC. Prop-
sective study of hair reduction by diode laser (800 nm) with
long-term follow-up. Dermatol Surg. 2000;26:428–432.
59 Greve B, Raulin C. Medizinische dermatologische Lasertherapie.
Hautarzt. 2003;54:594–602.
60 Ash C, Town G, Bjerring P. Relevance of the structure of time-
resolved spectral output to light-tissue interaction using intense
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61 Schroeter CA, Raulin C, Hu¨rlimann W, Reineke T, De Potter C,
Neumann M. Hair loss in 40 hirsute women with an intense light
source, the Photoderm VL. Eur J Dermatol. 1999;9:374–379.
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broad spectrum intense pulsed light source – long-term follow-
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63 Weiss RA, Weiss MA, Marwaha S, Harrington AC. Hair removal
with a non-coherent filtered flash-lamp intense pulsed light
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Long-term photoepilation using a broad-spectrum insense pulsed
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65 Alster TS. Improvement of erythematous and hypertrophic scars
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66 Alster TS. Laser treatment of erythematous/hypertrophic pig-
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69 Chrastil B, Glaich A, Goldberg LH, et al. Fraxel SR1500 for
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70 Glaich AS, Chrastil B, Rahman Z, et al. Fractional photothermo-
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55
Lasers and Intense Light Sources

Photodynamic Treatment
Eckart Haneke
Included on DVD
INTRODUCTION
Photodynamic treatment (PDT) was first described
more than a century ago, but due to lack of appropri-
ate photosensitizers it was virtually forgotten for over
50 years. General photosensitization brought about
by the systemic nature of the drugs that were avail-
able at the time prevented its general use. With the
development of a range of new drugs, PDT is now
readily available as a new therapeutic option in vari-
ous fields of medicine, particularly dermatology.
DEFINITION OF PDT
PDT is defined as the selective destruction of
malignant or fast-growing cells by light activation
of a photosensitizing substance in the presence of
oxygen. However, new research has now broadened
its indications.1 Of the many modern photosensiti-
zers, the most commonly used in dermatology are
the prodrugs 5-aminolevulinic acid (ALA) and its
methyl ester (Me-ALA).
Living cells are capable of heme biosynthesis. This
is, however, quantitatively restricted by the activity
of intracellular ALA synthase, which limits the
endogenous synthesis of ALA and thus all further
steps of the heme synthesis. Heme itself, by means
of a negative feedback, inhibits ALA synthase.
There is little ALA synthase activity in the normal
cell nucleus, which makes ALA from the aminoacid
glycine and succinyl coenzyme A. Normally, ALA is
transferred from the mitochondrion into the cytosol
where it is synthesized to coproporphyrinogen via
porphobilinogen and uroporphyrinogen. The copro-
porphyrine is again transferred into the mitochon-
drion and protoporphyrinogen is synthesized. This
then undergoes molecular transformation to proto-
porphyrin IX (PpIX). This is the origin of heme,
which is made by adding Fe++ via ferrochelatase.
Heme has a strong negative feedback on the
mitochondrial ALA synthase. Since the amount of
intracellular iron is limited, PpIX – the photosensi-
tizer – accumulates, rendering the cell susceptible
to light of the appropriate wavelength.
Adding exogenous ALA bypasses the limiting
step of endogenous ALA synthesis and leads to a
significant increase in the intracellular quantity of
porphyrins (Fig. 6.1). Since heme synthesis depends
on the cell’s activity, malignant cells, which are
highly active, take up relatively more exogenous
ALA and produce more PpIX, rendering them more
sensitive to light irradiation. Neither ALA nor
Me-ALA – the substances currently approved for
the treatment of superficial skin cancer – are by
themselves active, but they are precursors of the
light-sensitizing compound PpIX.
ALA selectivity for malignant cells is about 1.5
times that for normal ones, while that of Me-ALA
is over 8 times.2 This allows shorter application
times for Me-ALA cream compared to ALA cream.
Furthermore, most non-malignant cells are virtually
left
intact.
Absorption
of
ALA
and
Me-ALA
through normal skin is minimal and there is no
increase in light sensitivity.3 Thus, in contrast to
injectable photosensitizers, the topical application
of the precursor of a physiological porphyrin has
nearly zero systemic risk and general photosensitiv-
ity does not develop.
The preferential uptake of the completely innoc-
uous precursor and subsequent endogenous synthe-
sis of protoporphyrin by the target cells is the
major advantage of using ALA or Me-ALA, thereby
restricting the phototoxic effect to the application
site. Irradiation with light, which induces an active
state in the photosensitizer,3 stimulates it to gener-
ate reactive oxygen species (ROS). These then kill
those target cells that preferentially synthesized
or took up the photosensitizer (Table 6.1). ROS
induces cellular damage, causing in turn cytotoxicity
and immunomodulation, and finally apoptosis, necro-
sis and vessel occlusion (Fig. 6.2).3,4 The damage
6

resulting from PDT needs to overwhelm cellular
repair mechanisms, a level that is reached at what
is referred to as the minimum photodynamic dose.
The role of heat during light irradiation is not yet
entirely clear.5 The photosensitizer is activated by
light, which elevates electrons to a higher energy
level causing fluorescence. Upon return of the photo-
sensitizer to its normal state, electrons are donated to
the oxygen, turning it into reactive oxygen species.
These in turn cause direct cellular damage with
immunomodulation and cytotoxicity, leading to apo-
ptosis, cell death and vascular effects (Fig. 6.2).
DRUGS USED FOR PHOTODYNAMIC
TREATMENT IN DERMATOLOGY
In dermatology two prodrugs are used that are
taken up by the cells and converted into the potent
photosensitizer protoporphyrin IX: ALA and Me-
ALA.6 Other drugs that are used in ophthalmology,
urology, cancer treatment and internal medicine
(for example systemic ALA, verteporphin, ethyl
etiopurpurin and mesotetraphenylporphine sulfo-
nate) do not play an important role in dermatology.
5-Aminolevulinic Acid
In the USA, the Food and Drug Administration
(FDA) approved ALA as the first topical photosensi-
tizing agent for the treatment of actinic keratoses.
Because it is a small hydrophilic molecule, ALA is
readily absorbed through abnormal keratin while nor-
mal keratin protects healthy surrounding skin.7 ALA
is converted to PpIX, which, as described above, is a
potent photosensitizer, and cannot be further con-
verted to the non-photosensitizing heme because of
limited supplies of iron. Application times of up to
Table 6.1
Requirements for effectiveness of
photodynamic treatment
• Tissue affinity to the photosensitizer
• Incubation time of photosensitizer on the skin (time of
application)
• Light source
• Tissue oxygenation
• Type of target cell
Excited state of photosensitizer
Tissue molecular
ROS
Direct cellular
damage
Cytotoxicity
Immunomodulation
Apoptosis, necrosis,
vascular effects
O2
Normal state of photosensitizer
Light excitation
412–422 nm
570–560 nm
Fig. 6.2 Principle of photodynamic treatment.
ALA
MeALA
PBG
ProtoPgen
ProtoP IX
Heme
Succinyl-CoA
+ glycine
ALA
ALA
ALA
synthase
UroPgen
CoproPgen
Fe
Ferrochelatase
+
−
Cytosol
Mitochondrion
Fig. 6.1 Protoporphyrin synthesis in the cell after
exogenous application of ALA or MeALA, respectively.
58
Aesthetic Oculofacial Rejuvenation

4 hours confine PpIX production mainly to the target
site. Longer application may lead to a larger reaction
area.8 Since PpIX is readily degraded by the absorbed
light – a process called photobleaching or photo-
decomposition – photosensitization typically resolves
within 24 hours of application, but patients should
be advised not to expose the treatment area to (sun)
light immediately after treatment. The maximal light
absorption peak is at 409 nm, but smaller peaks occur
at 509, 544, 584 and 635 nm. The FDA approval is
based on a 14- to 18-hour application period even
though efficacy has been demonstrated with shorter
incubation periods (1 hour), which is more conve-
nient for both patients and physicians.9
Recently, a low-concentration, liposome-encap-
sulated ALA cream has become available for use in
light-induced skin rejuvenation. Measurements of
skin fluorescence distribution patterns by fluorescent
photography after topical application of low con-
centrations
of
ALA
(0.5
and
1%
preparations
encapsulated in liposomes) were compared to those
obtained after treatment with 20% ALA in moistur-
izing cream. These showed that skin fluorescence
intensity
with
the
low-concentration,
liposome-
encapsulated ALA reached saturation level after
approximately 2 hours. The fluorescence decayed
linearly within 15 minutes of the end of the applica-
tion and was back to baseline within 8 hours. In con-
trast, the fluorescence of areas treated for more than
1 hour with the more concentrated ALA preparation
in moisturizing cream was very uniform, with a linear
relationship to incubation time (0–3 hours). The
fluorescent intensity (15.2–57.9%) continued to
increase after the end of the treatment application,
eventually reaching a fluorescence of 1.6–9 times
that at the end of the application, 8 hours after-
wards. Thus, by changing the ALA vehicle from a
moisturizing cream to liposome encapsulation, the
ALA concentration can be lowered by a factor of
40 and still induce the same skin fluorescence. This
also eliminates the need for occlusion, and the low
post-treatment fluorescence suggests a significantly
reduced risk of post-treatment phototoxicity.10
Aminolevulinic Acid Methyl Ester
Me-ALA was approved by the FDA in 2004 for the
treatment of actinic keratoses. Me-ALA is provided
as a 160 mg/g cream to be applied under occlusion
for 3 hours followed by red light activation (570–
670 nm with a total dose of 75 J/cm2, or by red
LED light at a light dose of 37.5 J/cm2), after which
complete photobleaching should have occurred.
Me-ALA is more lipophilic and has better specific-
ity for tumors and diseased skin than ALA.2,3,11
However, Me-ALA and ALA were recently sug-
gested to exhibit similar levels of efficacy.12
LIGHT SOURCES FOR PDT
Red light activation generates heat, which makes
PDT for tumors almost unbearable without cold
air cooling; local anesthesia is an alternative. Red
LED light causes much less discomfort.
ALA and Me-ALA are converted to PpIX, the
main absorption peak of which is in the blue light
spectrum at 409 nm. The use of this wavelength is
limited, however, by its maximal penetration of only
1.5–2 mm. In the USA, Blu-U® (DUSA Pharmaceu-
ticals, Wilmington, MA) and Omnilux Blue™(Photo
Therapeautics Inc., Carlsbad, CA) are available as
blue light sources. Red light (>600 nm) is absorbed
much less and higher energy levels are necessary to
get the same effect as blue light, but red light has
the advantage
that it penetrates approximately
8–10 mm. This deeper penetration can, however,
be limited by melanin.13 Red LED light sources are
widely used in Europe, while intense pulsed light
(IPL) is used in both the USA and Europe, particu-
larly for photorejuvenation.
A great number of indications have been investi-
gated in the last 20 years (Table 6.2), but not all
have proven to be of value.
Table 6.2
Indications of PDT described in the
literature1
Premalignant and
malignant lesions
Actinic keratoses, Bowen’s
disease (squamous cell
carcinoma in situ), superficial
basal cell carcinoma, other
non-melanotic skin cancers*,
cutaneous T cell lymphoma,
extramammary Paget’s disease*
Inflammatory
conditions
Acne vulgaris, psoriasis*
Infections
Dermatophytosis,
onychomycosis, leishmaniasis,
warts*, molluscum contagiosum
Benign conditions
Sebaceous hyperplasia,
sebaceous nevus
Cosmetic
indications
Photorejuvenation
*We, personally, do not consider these diagnoses to be good
indications for PDT
59
Photodynamic Treatment

PHOTODYNAMIC DIAGNOSIS
PDT is also useful for diagnosis (photodynamic
diagnosis, PDD) of malignant skin lesions and their
precursors, since dysplastic cells, which selectively
take up more ALA or Me-ALA than normal ones,
exhibit
a characteristic
purple-red
fluorescence
upon irradiation with violet-blue light (Wood’s
light), thus outlining the extent of superficial skin
cancers and/or differentiating them from inflamma-
tory lesions.14
Blue light treatment of acne is most probably a kind
of endogenous PDT as Propionibacterium acnes pro-
duces porphyrins that act as endogenous photosensiti-
zers. Propionibacterium acnes-inhabited follicles also
show the characteristic porphyrin fluorescence.
CONTRAINDICATIONS AND RESTRICTIONS
Contraindications are rare, and limited to some
specific photodermatoses as well as allergies to ALA
and Me-ALA. Pigmented lesions are not indicated
for PDT, as melanin is a fluorescence quencher
and may also inhibit light penetration4 (Table 6.3).
PDT of precancerous lesions and superficial skin
cancers has some restrictions:4
v PDT is a blind method, i.e. a biopsy is needed to
make or confirm the diagnosis and the
therapeutic result.
v Drug penetration cannot be measured exactly in
routine practice.
v Light penetration cannot be measured and may
not only depend on the depth of tumor invasion
but also on skin type and pigmentation.
v The ideal light for treatment would be blue light
at around the absorption and excitation
wavelength of PpIX, but this penetrates only
1–1.5 mm, which may be sufficient for actinic
keratoses, but not for lesions deeper than the
level of the dermo–epidermal junction. Red light
is an alternative as it penetrates much deeper,
but higher energy is needed. Fortunately, it is no
problem to administer enough light energy in the
red color range to treatment sites. However,
treating the superficial part of an early invasive
lesion and leaving the deeper parts behind, thus
burying it, is probably one of the main reasons for
recurrences.
THERAPEUTIC ALTERNATIVES
There are a variety of therapeutic alternatives, both
for medical and cosmetic indications. Imiquimod, a
biological response modifier, is also indicated for
precancerous lesions and superficial skin cancers
and has shown a rejuvenation potential when used
for field cancer treatment.15 Chemical peels, alone
and in combination with cryotherapy, are effective
in
eradicating
superficial
actinic
keratoses
and
considerably improving skin quality. Even topical
5-fluorouracil can be used for single and multiple
actinic keratoses and superficial basal cell carcino-
mas, and gives some skin improvement.
PATIENT SELECTION
Patients are selected according to their skin condi-
tion. Those with serious photodamage, exhibiting
multiple actinic keratoses and/or superficial basal
cell carcinomas (BCCs), are particularly good candi-
dates for PDT as this is one of the ideal methods for
field cancer treatment. When ALA or Me-ALA are
applied over a larger area and irradiated, even sub-
clinical lesions become obvious, their extent shown
by post-treatment redness.
LESION PREPARATION AND TREATMENT
Before starting PDT a precise diagnosis is made.
Hyperkeratotic, invasive and pigmented lesions should
not be treated using PDT. Most benign lesions, except
for sebaceous glands, which do take up ALA and Me-
ALA, also fail to respond.
Depending on the type of treatment intended,
patients have to be prepared in different ways. The
most common indication, actinic keratoses (Fig. 6.3),
requires removal of hyperkeratoses, either by light
curettage or salicylic acid ointment, because they
protect the lesions from drug and light penetration.
Superficial BCCs are treated with two sessions, 4 to
6 weeks apart (Fig. 6.4). Nodular BCCs are not a good
Table 6.3
Photosensitizing drugs
contraindicated in PDT
• Griseofulvin
• Thiazidics
• Tetracycline
• Sulfonylurea
• Sulfonamides
• Phenothiazine
60
Aesthetic Oculofacial Rejuvenation

indication, but they may be treated after debulking,
for example by curettage. Blood, however, should
not be allowed to remain on the bottom of the lesion.
Each single lesion is marked and painted with the
ALA solution (or covered with the Me-ALA cream),
which is then occluded with a non-transparent tape.
Light irradiation is applied for the duration required
for the drug used. For field therapy, the entire face
or cosmetic unit is treated with the ALA solution or
Me-ALA cream and is usually irradiated after a
shorter application time. The eyes are protected with
goggles. Blue light is used for ALA, and both red LED
or IPL light may be used for Me-ALA. Cold-air
cooling reduces the pain from the hot red light, and
gel cooled by the handpiece diminishes pain during
IPL treatment. When treating the eyelids or other
areas near the eyes corneal shields should be used.
For sebaceous hyperplasias, deepithelialization
prior to ALA/Me-ALA application is useful; this
can be achieved with one or two pulses with the
Er-YAG or CO2 laser or by superficial shaving. No
anesthesia is necessary. This allows better penetra-
tion of the drug and gives fewer recurrences. We
have also successfully used a similar approach for
treatment of a sebaceous nevus which was planed
with a #23 scalpel blade. After re-epithelialization,
A
B
Fig. 6.3 Actinic keratoses on the left side of the forehead in a 63-year-old female patient with skin type II. A, Before
treatment. B, 6 weeks after Me-ALA PDT.
A
B
C
D
E
Fig. 6.4 Superficial basal cell
carcinoma. A, Before treatment.
B, 4 days after first Me-ALA PDT
session. C, 6 weeks after first session,
immediately before second PDT
session. D, 2 weeks after second PDT.
E, 1 year after completion of PDT.
61
Photodynamic Treatment

the remaining, deeper-seated glands were then irra-
diated with red light after Me-ALA application for
3 hours under occlusion (Fig. 6.5) (unpublished
observation).
After treatment of actinic keratoses, a red area is
usually visible for 1 to 3 days, but some patients
develop intense erythema and crusting, which can
last for more than a week (Fig. 6.6). We have seen
this particularly in red haired and blond people.
Post-treatment care involves applying emollients and
cooling in case of edema. Topical steroids are rarely
needed.
Bowen’s disease and BCC require a second session
of PDT after approximately 6 weeks (Fig. 6.7),
which is also performed when an actinic keratosis
does not completely disappear. An attempt has been
made to overcome the problem of incomplete drug
and light penetration by debulking nodular BCCs,
applying fractionated irradiation to reduce photo-
bleaching of the PpIX, giving intralesional injections
of ALA and applying interstitial light irradiation.
However, we feel that complete excision combined
with histologic margin control should be the first
option for high-risk tumors. Invasive squamous cell
carcinoma is not a PDT indication.
When using PDT for photorejuvenation, red
spots may occur as a sign that subclinical actinic ker-
atoses were in the treatment field. With telangieta-
sias being the major problem, a cut-off filter at
around 500 nm is used, while for blotchy skin wave-
lengths from 560 nm are preferred with the use of
an IPL. However, the latter treatment relies more
on the IPL light power than on the PDT action.
Cure and improvement rates are summarized in
Table 6.4.
PDT FOR PHOTOREJUVENATION
Improvement of photodamage after PDT with 20%
ALA solution applied for 15–20 hours was observed
in patients who were irradiated with blue light.
Of 32 patients, 72% were observed to have an
A
B
Fig. 6.5 Sebaceous nevus. A, After superficial shaving. B, 6 weeks after Me-ALA PDT.
A
B
C
Fig. 6.6 Multiple actinic keratoses in a 45-year-old man with skin type I, freckles and red hair. A, Before PDT. B, 1 week
after MeALA PDT. C, Completely normal skin a year after PDT.
62
Aesthetic Oculofacial Rejuvenation

improvement in skin texture. Application of ALA
for short periods (1–3 hours) followed by blue light
exposure was also seen to decrease sallowness and
fine skin wrinkling as well as to improve mottled
hyperpigmentation.9 Nowadays, most authors use
IPL as the activating light source (Fig. 6.8), as it
has a therapeutic effect even without the use of
ALA (see Chapter 5). A split-face study compared
two treatments 1 month apart of either IPL alone
or IPL plus ALA. An enhanced cosmetic effect
was observed in the group with the combination of
IPL plus ALA.16 Another study designed to measure
Table 6.4
Cure and improvement rates of various skin conditions with PDT
Diagnosis
Cure rate/improvement
Recurrence rate
Actinic keratosis
Single treatment: 65% (25–100%)
Repeated treatments: 85% (70–90%)
~20%
Bowen’s disease (squamous cell carcinoma in situ)
80% (60–100%)
Superficial basal cell carcinoma
50–100%
44%*/18%**
Other basal cell carcinoma
10–100%
57%
Cutaneous T cell lymphoma, extramammary
Paget’s disease
Acne
Comedones
Inflammatory lesions
Improvement:
45% red/58% blue þ red, no ALA
63% red/76% blue þ ered, no ALA
Photorejuvenation
Improvement in:
photoaging 80%
dyspigmentation 95%
fine lines 55%
*ALA
**Me-ALA
A
B
C
D
E
Fig. 6.7 BCC recurrence after
cryosurgery. A, Before PDT.
B, 2 days after Me-ALA PDT.
C, 6 weeks after first PDT.
D, Immediately after second PDT.
E, 1 year after second PDT.
63
Photodynamic Treatment

the effects of treatment with combined ALA and
IPL and with IPL alone, compared two groups of
patients, both of whom received three treatments,
3 weeks apart. It was found that the combined
treatment produced greater improvement for the
effects of photoaging (80% versus 50%), mottled
pigmentation (95% versus 65%), and fine lines
(55% versus 20%).17 While in the first study there
were more adverse effects in the combination treat-
ment group (erythema, edema and peeling, for
example), there was no difference in adverse side
effects between the two groups in the latter
study.17–19 Post-procedure treatment usually does
not require more than normal skincare, although
immediately afterwards a cool pack may reduce
any hot or burning feelings. On the other hand,
the inflammation that may be induced by the treat-
ment probably also adds to the positive rejuvenation
effect.
A small study evaluated the effect of fractionated
laser treatment plus Me-ALA-PDT. Four women
with Fitzpatrick skin types II or III, mild to moder-
ate rhytides and no actinic keratosis in the perioral
area were treated. The perioral area was treated
with two sessions of fractional resurfacing with the
Fraxel SR laser, 3 weeks apart. Immediately after
each fractional treatment Me-ALA was applied
on one half of the perioral area and 3 hours later
the area was illuminated with red light in a dose of
37 J/cm2. There was more improvement in superfi-
cial wrinkles in three out of four patients on the
combined treatment side. In one patient, the inves-
tigator found no significant difference when com-
paring the two sides whereas all patients noted
greater improvement in the combined fractional
and PDT-treated side compared to the side treated
only with fractional surfacing.20
Guidelines for PDT photorejuvenation using IPL
devices and ALA have recently been described.21
Long-term results from photodynamic rejuve-
nation are comparable to other rejuvenation tech-
niques. For tumor PDT, consistent follow-up is
A
B
C
Fig. 6.8 Perioral wrinkles in a 49-year-old female patient.
A, Before treatment. B, After 3 hours of Me-ALA cream
and immediately before IPL irradiation. C, 8 weeks after
one PDT–IPL session, wrinkling has considerably
improved.
64
Aesthetic Oculofacial Rejuvenation

necessary in order to detect potential recurrences as
early as possible and in order to decide whether fur-
ther PDT or an alternative treatment may be
necessary.
Adverse effects include photosensitivity, which
depends on the amount and duration of ALA or
Me-ALA applied, skin necrosis of tumor cells with
consecutive scarring as well as hypopigmentation
and hyperpigmentation.20 The degree of scarring,
however, is entirely dependent on the amount of
tissue destruction by the treated tumor.
CONCLUSIONS
In conclusion, PDT is a relatively new therapeutic
method with the potential for scarless removal of
cutaneous precancers and superficial cancers, as well
as improvement of photodamaged skin. Its main
advantage in the treatment of malignancy is the ability
to perform field therapy. In acne, its advantage is to
reduce the need for antibiotics.
REFERENCES
1 MacCormack MA. Photodynamic therapy in dermatology: An
update on applications and outcomes. Sem Cut Med Surg.
2008;27:52–62.
2 Peng Q, Warloe T, Berg K, et al. 5-aminolevulinic acid based
photodynamic therapy. Cancer. 1997;79:2282–2308.
3 Braathen LR. Photodynamic therapy: when and why? J Eur Acad
Dermatol Venereol. 2002;16:227.
4 Haneke E. Photodynamic therapy for scarless removal of facial
precancer and superficial carcinomas. In: Bosniak S, Cantisano-
Zilkha M, eds. Minimally Invasive Techniques of Oculofacial
Rejuvenation. New York: Thieme; 2005:151–157.
5 Orenstein A, Kostenich G, Tsur H, Kogan L, Malik Z. Tempera-
ture monitoring during photodynamic therapy of skin tumours
with topical 5-aminolevulinic acid application. Cancer Lett.
1995;95:227–232.
6 Wolf P, Rieger E, Kerl H. Topical photodynamic therapy with
endogenous porphyrins after application of 5-aminolevulinic acid:
an alternative modality for solar keratosis, superficial squamous
cell carcinomas, and basal cell carcinoma? J Am Acad Dermatol.
1993;23:17–21.
7 Kennedy JC, Pottier RH. Prossdc. Photodynamic therapy with
endogenous protoporphyrin IX: basic principles and present clini-
cal experience. J Photochem Photobiol B. 1990;6:143–148.
8 Jeffes EW, McCullough JL, Weinstein GD, et al. Photodynamic
therapy of actinic keratoses with topical aminolevulinic acid
hydrochloride and fluorescent blue light. J Am Acad Dermatol.
2001;45:96–104.
9 Touma D, Yaar M, Whitehead S, et al. A trial of short incubation,
broad-area photodynamic therapy for facial actinic keratoses and
diffuse photodamage. Arch Dermatol. 2004;140:33–40.
10 Christiansen K, Bjerring P, Troilius A. ALA for photodynamic
photorejuvenation – optimization of treatment regime based on
normal-skin
fluorescence
measurements.
Lasers
Surg
Med.
2007;39:302–310.
11 Fritsch C, Homey B, Stahl W, et al. Preferential relative por-
phyrin enrichment in solar keratoses upon topical application of
delta-aminolevulinic
acid
methylester.
Photochem
Photobiol.
1998;68:218–221.
12 Kuijpers DI, Thissen MR, Thissen CA, et al. Similar effectiveness
of methyl aminolevulinate and 5-aminolevulinate in topical
photodynamic therapy for nodular basal cell carcinoma. J Drugs
Dermatol. 2006;5:642–645.
13 Ceburkov O, Gollnick H. Photodynamic therapy in dermatology.
Eur J Dermatol. 2000;10:568–575.
14 Fritsch C, Goerz G, Ruzicka T. Photodynamic therapy in derma-
tology. Arch Dermatol. 1998;134:207–214.
15 Metcalf S, Crowson AN, Naylor M, et al. Imiquimod as an anti-
aging agent. J Am Acad Dermatol. 2007;56:422–425.
16 Goldman MP, Atkin D, Kincaid S. PDT/ALA in the treatment
of actinic damage. Real world experience. Lasers Surg Med.
2002;14S:79.
17 Alster TS, Tanzi EL, Welsh EC. Photorejuvenation of facial skin
with topical 20% 5-aminolevulinic acid and intense pulsed light
treatment: a split-face comparison study. J Drugs Dermatol.
2005;4:35–38.
18 Dover JS, Bhatia AC, Stewart B, et al. Topical 5-aminolevulinic
acid combined with intense pulsed light in the treatment of
photoaging. Arch Dermatol. 2005;141:1247–1252.
19 Gold MH, Bradshaw VL, Boring MM, et al. A: Split-face compar-
ison of photodynamic therapy with 5-aminolevulinic acid and
intense pulsed light versus intense pulsed light alone for photo-
damage. Dermatol Surg. 2006;32:795–801.
20 Ruiz-Rodriguez R, Lo´pez L, Candelas D, Zelickson B. Enhanced
efficacy of photodynamic therapy after fractional resurfacing:
fractional
photodynamic
rejuvenation.
J
Drugs
Dermatol.
2007;6:818–820.
21 Nootheti PK, Goldman MP. Aminolevulinic acid-photodynamic
therapy for photorejuvenation. Dermatol Clin. 2007;25:35–45.
65
Photodynamic Treatment

Skin-Tightening Devices
Included on DVD
Radiofrequency and infrared technologies
Alessandra Haddad, Marian Cantisano-Zilkha
BASIC CONCEPTS
Improvement in skin laxity following laser treat-
ments was first observed in the early 1990s during
ablative resurfacing treatments with a CO2 laser.1,2
While it was initially assumed that the benefits of
these treatments were due to the removal (ablation)
of tissue, cosmetic improvements were often more
significant than could be explained by ablation of
tissue alone.3 Ablation typically removed 20 mm of
tissue, but a residual thermal zone of 60–120 mm
depth was also created.3 The temperature rise and
duration of this heating were sufficient to denature
collagen, leading to a visible contraction of the skin
during treatment. This led to a tighter, fresher look
as a component of the ablative laser treatment.
Results seen after a long-term follow-up showed
histologically that resurfacing techniques are an
effective alternative to deep phenol peels. On the
negative side, prolonged recovery time, long training
and learning curves for the practitioner, added to
the high incidence of complications (scarring, dis-
chromias, infections and pain), caused the decline
of resurfacing procedures.
That has led to a question: Is it possible to get the
benefits of tissue tightening non-ablatively?
The answer is yes, and non-ablative tissue tight-
ening is one of the newest and most exciting proce-
dures in the aesthetic marketplace today (Table 7.1).
Grekin and colleagues published the first large
prospective study evaluating a radiofrequency (RF)
resurfacing system (Visage®) for treating wrinkles.4
The results of this study, involving 95 individuals
with mild to severe photodamage in the periorbital
or perioral regions, showed positive improvement
in the Fitzpatrick Wrinkle Score. The degree of
improvement was linked with the severity of wrin-
kles at baseline. Primary adverse effects were
transient postinflammatory hyperpigmentation (26%)
and hypertrophic scarring (4%). They concluded that
the efficacy of RF resurfacing may be comparable with
that of laser resurfacing. In addition, RF resurfacing
may provide more rapid healing and less pain and
erythema than CO2 lasers. Similar results are possible
with non-ablative skin-tightening devices.4,6
The goal of this chapter is to provide an under-
standing of non-ablative skin tightening. We will
examine what is required for tissue tightening, as
well as the different approaches available today.
As it is common, there are many conflicting and
confusing claims made by manufacturers, and hope-
fully this chapter will allow readers to make an
7

informed analysis in their decision to use non-
ablative technologies.
DEFINITIONS AND TERMINOLOGY
Collagen
Before going further, it is worthwhile to give some
definitions. Collagen is a family of structural proteins,
providing strength and resilience to the skin and other
tissues.5 Collagen is produced by fibroblasts in an
early-stage form called procollagen. It is composed
of a triple helix of protein chains, with interchain
bonds creating a crystalline structure for the collagen.
Type I collagen is the most common form of col-
lagen found in the dermis and provides the tensile
strength of the skin. This form of collagen is also
believed to be a key component in skin aging, since
the quantity has been shown to be lower in photo-
damaged skin and to increase after some skin reju-
venation treatments.3,4 Type III collagen is the
second most common form of collagen found in
the skin and forms thinner diameter fibers than
type I collagen. Both procollagen and type III colla-
gen are formed initially in the wound-healing pro-
cess, with type I collagen being produced later.6
Skin Laxity
As part of the aging process, the skin reduces its
production of elastin and collagen, the main struc-
tural proteins in the dermis. With less support
structure in the skin, areas can sag due to gravity.
Common areas for this to occur are the neck, jowls,
underarms, and the abdomen, particularly postpar-
tum (Fig. 7.1).
As part of the treatment of skin laxity, it is
important to differentiate skin that is sagging due
to laxity from skin that is sagging due to excess
fat. As a general rule, thin skin without underlying
excess fat can be treated most effectively.
Collagen Contraction
The goal in treating skin laxity is to create a bulk
change in the support structure of the skin to coun-
teract the skin laxity caused by aging. If sufficient
heat is delivered to the collagen, the structure of
the collagen will change, causing the fibers to con-
tract and thicken. An extreme example of collagen
denaturation is cooking: we have all seen how a slice
of bacon shrinks as it is heated.
Table 7.1
Ablative rejuvenation.
• CO2 and erbium YAG devices
• YSGL device (Pearl)
Semi-ablative rejuvenation
• Fractional CO2 or erbium
Non-ablative
• Radiofrequency
• Infrared
A
B
Fig. 7.1 These photographs show examples of skin laxity due to aging. Common areas in which skin laxity occurs are the
lower half of the face, underarms and abdomen. (Photographs courtesy of Alessandra Haddad, MD).
68
Aesthetic Oculofacial Rejuvenation

While most of the laboratory studies on collagen
shrinkage or denaturation have been performed
ex vivo, these studies have shown that heated colla-
gen transforms from the crystalline triple-helical
structure to an amorphous, random-coil structure
through breakage of the hydrogen bonds linking
the protein strands of the triple helix.7 This creates
a thickening and shortening of the collagen fibers as
the chains fold and assume a more stable configura-
tion, as shown schematically in Figure 7.2. This
immediate collagen contraction can be used for cos-
metic treatments to treat skin laxity or other signs
of aging on the face or body.
It should be noted that this immediate tissue
tightening is different from the long-term collagen
stimulation caused by a thermally induced wound
response. These immediate changes can be observed
both during treatment and through electron micro-
graph studies.
Sustained Volumetric Heating
As noted, temperature is a key component in colla-
gen contraction or denaturation but it is not the only
factor. While some people refer to a ‘magic temper-
ature’ for collagen contraction, this is actually a mis-
leading statement. Knowing only the temperature
achieved in the dermis is not sufficient to under-
stand if collagen denaturation will occur. Collagen
contraction will occur only through a combination
of time and temperature – or sustained volumetric
heating. The collagen must be heated to a tempera-
ture and kept there for a sufficient length of time.
This combination varies; similar collagen contrac-
tion can be achieved at a lower temperature if the
duration of the heating is increased, but the heat
must be delivered uniformly over the treatment
area.
Studies have shown that, for a 5
C decrease in
temperature, the duration of the heating must be
increased by an order of magnitude (10 times) to
achieve a similar degree of collagen contraction.3
So while millisecond pulses are sufficient for colla-
gen contraction at the temperatures achieved during
CO2 treatments, significantly longer pulse times
are required for the treatment temperatures used
in non-ablative treatments. All the protocols for
the proven non-ablative treatments of skin laxity
include multisecond treatment times.
The target depth for skin laxity treatments is the
dermis. This will require a balance: providing the
heat at a superficial level will not create the volume
changes that are desired, while heating too deeply
might affect the subcutaneous fat. To achieve this
balance, the heat should be targeted at a depth of
a couple of millimeters (Table 7.2).8
Cooling
While the temperature required in the dermis for
collagen contraction with multisecond exposure
times is above 55–60
C, a blister will form if the
epidermal temperature is above 50
C. It is obvious
A
C
B
Collagen fiber strand
before treatment.
Contraction caused
by applied heat.
Contraction caused
by applied heat.
Fig. 7.2 Collagen response to uniform controlled heat. A, Schematic diagram demonstrating structured triple helix
molecule of collagen. B, Initial response of collagen from a structured triple helix to a random coil structure.
C, Long-term collagen rebuilding continues for 3–12 weeks after treatment.
Table 7.2
Requirements for a skin laxity device
• Sustained volumetric heating
• Heat at the appropriate depth
• Uniform heating to obtain the maximum contraction
• Cooling system to protect epidermis
• Histological and scientific evidence of the results
• Cost per procedure reasonable (no or few
consumables)
69
Skin-Tightening Devices

that cooling will play a major role in any non-
ablative approach to the treatment of skin laxity.
In fact, with the heat that is deposited to contract
the collagen, aggressive cooling before, during and
even after the heating pulse is required. Postcooling
helps protect the epidermis, as the intense heat
from the dermis diffuses to the surrounding tissue.
Forms
of
cooling
can
include
parallel
cooling
through a sapphire window or cryogen cooling.
Neocollagenesis
It is important to differentiate between immediate
collagen contraction and longer-term collagen pro-
duction. Neocollagenesis is simply the formation of
new collagen, for example as occurs during a wound
response. This longer-term production of new collagen
was the goal of the early laser-based non-ablative skin
rejuvenation treatments. In this process, laser treat-
ments trigger a thermally induced wound response.
This response can be triggered at a temperature much
lower than is required for immediate collagen contrac-
tion. Also, most of the demonstrated procedures for
new collagen production require multiple treatments
to obtain the desired results. In addition to evidence
from before and after photographs, these results can
be observed histologically by examining the collagen
fibers prior to and a few months after the treatment.
APPROACHES TO THE TREATMENT
OF SKIN LAXITY
To the best of the authors’ knowledge at the time of
publication, only a few approaches to the treatment
of skin laxity have published histological evidence
of immediate collagen contraction. Some of these
approaches are the Titan™by Cutera, the Therma-
Cool® device by Thermage®,9,10 Visage™by Arthro-
care Corp (Sunnyvale, CA), and Accent XL® by
Alma Lasers (Caesarea, Israel). While this does not
mean that other devices may not effectively treat
skin laxity, the reader should look for scientific evi-
dence and medical papers before making a decision.
Various lasers, such as the Nd:YAG 1450 nm and
Nd:YAG 1540 nm, emitting in the mid-infrared,
have been used for the treatment of fine wrinkles
and acne scars. However, these lasers need multiple
treatments with a delayed and relatively minimal
clinical softening of the wrinkles. They do not pro-
duce deep dermal tightening or lifting since they
affect only the superficial parts of the dermis.
New devices have emerged to treat skin laxity and
wrinkles in a non-ablative way, regardless of skin type
and color. These devices are of three types:
1. devices using only RF11,12
2. devices using RF combined with infrared energy
3. devices using near- and mid-infrared pulsed light,
the so-called infrared skin-tightening devices.
All these devices use different frequencies. The
choice of energy and appropriate frequency that
will be selectively concentrated in the dermis is of
cardinal importance.
Optical energy (intense pulsed light and lasers) is
absorbed by melanin chromophores in the epider-
mis and hair shafts, and hemoglobin in vessels. This
kind of energy cannot treat wrinkles because colla-
gen fibers, which are involved in the pathophysio-
logy of wrinkling, do not contain chromophores.
To satisfy the need for energy, which acts on the
dermis without affecting the epidermis, RF and infra-
red radiation were found to be the most appropriate
tools. The main difference between lasers and RF
is that lasers affect collagen in the upper dermis,
improving fine lines, wrinkles and skin texture, while
RF energy is able to penetrate deeper into the skin and
affect the deeper dermis and subcutaneous layers,
causing tightening and improvement to the underlying
tissue structure, but with little change in skin texture.
RF is considered more selective to the depth
of the dermis targeted than infrared frequencies. In
the past, it has been used mainly in surgery, but
now it is also considered to be the newest alternative
in skin-tightening procedures and will be further
discussed later in this chapter.
Infrared Technology
The general goal of tissue tightening is to provide
enough heat to the dermis while protecting the epi-
dermis. We will describe the Titan™in more detail,
since one of the authors (AH) has achieved very
consistent results over the last 2 years.
In the Titan™(Cutera, Inc., CA), water is the
target chromophore and a wavelength is selected
based on the absorption characteristics of water.
Figure 7.3 shows the water absorption curve. Based
on this curve, wavelengths in the range of 1100–1800
nm are used to achieve heating at a depth of 1–2 mm.
This depth is chosen to heat the dermis, but without
any risk of heating the subcutaneous fat. There is a
strong water absorption peak in the 1400–1500 nm
range, and this wavelength is filtered from the Titan™
output to further optimize the treatment.
70
Aesthetic Oculofacial Rejuvenation

Each Titan™treatment pulse consists of a multi-
second exposure. The temperature profile in the
dermis can be measured through animal studies.
Figure 7.4 shows a cross-section with a maximum
temperature rise of approximately 25
C. This maxi-
mum temperature occurs at a depth of approximately
1–2 mm, whereas the epidermis is protected through
contact cooling with a sapphire window.
The heating provided by the Titan™has been
shown histologically to provide immediate changes
to the collagen.9–12 The denaturing of the collagen
fiber can be seen in Figure 7.5.
This immediate collagen contraction can also be
seen clinically. Many physicians will treat one side
of the face before moving to the other side. In
the middle of the procedure, the physician lets the
patients sit up and confirm that they can see the
difference in the treated and untreated sides. This
is not simply edema since, in most of the area
treated, edema would create a swelling that would
make the area look worse, not tighter.
To demonstrate that these results can be consis-
tently reproduced, a retrospective study of over 1000
patients was performed. In this study, covering results
from four different practices, physicians reported a
satisfaction level above 80% with the Titan™.13,14
The safety of the Titan™device was also examined
as part of this retrospective study. Only two side
effects were reported in over 1000 treatments. Both
of these side effects healed without complication.
Since the Titan™uses an infrared light source
(lamp), each handpiece has a finite lifetime, either
10 000 or 15 000 pulses. Based on the replacement
cost and the number of pulses per treatment, the
cost per procedure is roughly $90. With typical pro-
cedure fees in the range of $800–2500 per procedure
based on a survey of Titan™users across the USA
and Brazil, this per procedure cost is acceptable.
PREPARATION AND INFRARED
SKIN-TIGHTENING TECHNIQUE
Preoperative Considerations
v Conduct a patient consultation complete with
medical history prior to treatment.
v Clean the skin, including removal of all make-up
and other skincare products. Any creams or
products left on the skin can interact with the light
and increase the risk of unwanted side effects.
v Shave any hair in the area to be treated. Hair in
the treatment area may not allow full contact of
the handpiece with the skin.
v Preoperative photographs should be taken with
consistent technique (patient positioning, camera
settings and room lighting).
v These treatments can be tolerated without
anesthesia. The use of sedation, nerve blocks or
local injectable anesthetics is not recommended
for these treatments as patient feedback is very
important and, with the proper technique, is not
required. Topical anesthesia can be used if
desired. It must be completely removed prior to
treatment.
Optimizing Outcomes
v When treating near the mouth, rolled-up gauze
can be placed between the lips and teeth to
protect the teeth from discomfort.
v Some physicians make this treatment part of an
overall skincare regimen along with topical
retinoids, topical vitamin C, sun protection
and/or microdermabrasion.
v Do not treat over areas with tattoos.
Surface of tissue
Fig. 7.4 Thermal camera measurement of a cross-section
of animal tissue following a Titan™pulse. The maximum
heating is shown in red and occurs approximately 1–2 mm
below the surface.
10
1
0
1000
Titan
100
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
Wavelength (nm)
Absorption coefficient (cm–1)
Fig. 7.3 Absorption curve of water. The range 1100–1800 nm
provides the moderate absorption needed for heating at a
depth of 1–2 mm.
71
Skin-Tightening Devices

v Extreme caution should be used when treating
near the eye, taking care to avoid ocular
damage from the light. Patient eye protection
appropriate for the given treatment should be
used. The light should always be pointed away
from the eye and only applied to the skin outside
of the orbital rim. Skin at the edge of the orbital
rim can be treated by pulling it away from the eye
while simultaneously holding the goggles in place,
so treatment is kept outside of the orbital rim.
Titan™Treatment Parameters
v Fluency should be adjusted as low as 28 J/cm2
and raised to as high as 46 J/cm2 based on patient
tolerance and the area being treated (Table 7.3).
v Sensitive areas and bony areas may require lower
fluences for some patients.
v It is common to feel a sensation at the end of
the heat cycle, depending on the area that is
treated. This should resolve as the handpiece is
moved to the next treatment spot. If the patient
still feels this sensation, or heat, stop the treatment
and cool the area with the handpiece and/or ice
pack.
A
B
C
D
Fig. 7.5 Transmission electron microscopy of collagen fibers at the 0 to 1 mm depth. A, Control showing typical
cross sectioned collagen fibers. B, Collagen fibers after four passes at 30 J/cm2. The left-hand side shows normal
morphology while the right demonstrates a transition to contracted collagen. C, Collagen fibers after four passes at
45 J/cm2. The entire field shows contracted collagen. D, Collagen fibers after four passes at 65 J/cm2. Many fibers are
contracted to several times their normal size. Original magnification  4320. (Brian Zelickson, M.D.)
Table 7.3
Typical starting fluence in a
treatment area
Skin type
Fluence (face,
neck, and chest)
Fluence
(body)
I–VI (including
tanned skin)
34–38 J/cm2
36–46 J/cm2
72
Aesthetic Oculofacial Rejuvenation

Recommended Technique
v When the face is being treated, it is typically
divided into three regions (forehead and both
cheeks), as shown in Figure 7.3. Similar-size areas
can be treated when treating the neck, generally
divided into two or three regions. One section at
a time is treated, completing all passes in that
area before moving to the next.
v Apply a layer of clear gel (such as ultrasound gel),
approximately 3 mm thick, to the treatment
area. For patient comfort, reapplication of cooled
gel as the treatment progresses may be helpful.
v Hold the handpiece to ensure complete contact
of the window with the surface of the skin to be
treated. Activate the exposure with the foot
pedal. Do not lift the handpiece until the audible
tone and the blue light have ended: losing contact
with the skin during a pulse can result in
blistering and increased risk of side effects.
v Instruct the patient to alert you if the discomfort
level becomes intolerable.
v Place the next pulse adjacent to the previous one
without overlapping.
v Always observe the epidermis during the
treatment, watching for signs of damage
(epidermal separation or gray coloration). If
damage is seen, stop the treatment, cool the skin
and reduce the fluence before continuing.
v Apply all passes (usually three to four) in one
area before beginning treatment in the next area.
This allows for sustained heating. As the skin
temperature increases with each pass, it may be
necessary to lower the fluence by a small amount
on the latter passes for patient comfort.
v Extreme caution should be used when treating
near the eye, taking care to avoid ocular
damage from the light. Patient eye protection
appropriate for the given treatment should be
used. The light should always be pointed away
from the eye and only applied to the skin outside
of the orbital rim. Skin at the edge of the orbital
rim can be treated by pulling it away from the eye
while simultaneously holding the goggles in place,
so treatment is kept outside of the orbital rim.
v Erythema is a common immediate reaction seen
from this treatment. This typically resolves
within 2 hours but can last longer.
Postoperative Care
v Localized erythema may also be present and
typically resolves within 24–48 hours. If
prolonged erythema occurs, future treatments
should be performed at a lower fluence.
v If a wound develops, an antibiotic ointment may
be recommended.
v Treatment intervals of 4 weeks are commonly
used, with an average of two to four treatments.
See Figures 7.6 and 7.7.
CONCLUSION
Therearemultiple criteria as you evaluate the different
approaches to skin tightening. Collagen contraction can
only be obtained through sustained volumetric heating,
often requiring multisecond pulses for the non-ablative
approaches discussed in this book. With the significant
heat that is delivered during treatment, cooling will be
a critical element for safety. Any manufacturer should
also be able to support their marketing claims with
both histological and clinical evidence. A good skin lax-
ity device should also offer consistent results, leading
to a high level of patient satisfaction. Finally, the
operating cost of the device should be reasonable
to allow you to offer a fair procedure cost while
obtaining a good return on your investment. Only
when all these criteria are met should you consider
purchasing and working with a skin laxity device.
Fig. 7.6 Example segmentation of the face/neck for Titan™
procedure.
73
Skin-Tightening Devices

REFERENCES
1 Kirsch KM, Zelickson BD, Zachary CB, et al. Ultrastructure of
collagen thermally denatured by microsecond domain pulsed CO2
laser. Paper presented at the 17th Annual Meeting of the American
Society of Lasers in Medicine and Surgery, Phoenix; April 1997.
2 Fitzpatrick RE, Rostan EF, Marchell N. Collagen tighetening
induced by carbon dioxide laser versus erbium:YAG laser. Lasers
Surg Med. 2000;27(5):395–403.
3 Ross VE, McKinlay JR, Anderson RR. Why does carbon dioxide
resurfacing work? A review, Arch Dermatol. 1999;135(4):444–454.
4 American Society for Aesthetic Plastic Surgery. Cosmetic Plastic
Surgery National Data Bank Statistics.
download/2005stats.pdf.
5 Grekin RC, Tope WD, Yarborough Jr JM, et al. Electrosurgical
facial resurfacing: a prospective multicenter study of efficacy
and safety. Arch Dermatol. 2000;136(11):1309–1316.
6 Schmults CD, Phelps R, Goldberg DJ. Nonablative facial remo-
deling. Arch Dermatol. 2004;140:1373–1376.
7 Lennox
FG.
Shrinkage
of collagen.
Biochim
Biophys Acta.
1949;3:170–187.
8 Narins RS, Tope WD, Pope K, Ross EV. Effects associated with a
radiofrequency tissue tightening device: rare, preventable, and
correctable with subcision and autologous fat transfer. Dermatol
Surg. 2006;32:115–124.
9 Zelickson
B,
Ross
V,
Kist
D,
Counters
J,
Davenport
S,
Spooner G. Ultrastructural effect of an infrared handpiece on
forehead and abdominal skin. Dermatol Surg. 2006;32:897–901.
10 Zelickson BD, Kist D, Bernstein E, et al. Histological and ultrastruc-
tural evaluation of the effects of a radiofrequency-based nonablative
dermal remodeling device. Arch Dermatol. 2004;140:204–209.
11 Ruiz-Esparza J. Noninvasive skin tightening induced by radiofre-
quency and infrared light devices. In: Goldman MP, ed. Cutane-
ous and Cosmetic Laser Surgery. Elsevier; 2006.
12 Dierickx C. The role of deep heating for noninvasive skin rejuve-
nation. Lasers Surg Med. 2006;38:799–807.
13 Taub AF, Battle Jr EF, Nikolaidis G. Multicenter clinical perspec-
tives on a broadband infrared light device for skin tightening.
J Drugs Dermatol. 2006;5:771–778.
14 Battle Jr EF, Fincher EF, Moy RL, Nikolaidis G, Taub AF. Multi-
center clinical perspectives on Titan. Journal of Drus Dermato-
logy. 2006;5:771–778.
Radiofrequency technology
Reynaldo M Javate, Nikolaos Trakos, Raul T Cruz Jr
INTRODUCTION
Redundant facial, neck or body laxity is a major fea-
ture of aging. Just a few years ago, the only choice for
the treatment of skin laxity was surgery or ablative
lasers. As previously discussed in this chapter, tech-
nology continues to evolve, and procedures that once
required major surgical intervention are gradually
being replaced by minimally invasive treatments.
Recently, monopolar radiofrequency (MRF), bipolar
A
B
Fig. 7.7 Pre- and post- two
treatments of Titan™– 38-41J:
200 shots each session.
74
Aesthetic Oculofacial Rejuvenation

radiofrequency (BRF) and infrared light sources have
been introduced for non-ablative tissue tightening by
volumetric heating of the deep dermis.
RF energy is different from optical energy because
it depends on the electrical properties of the skin,
rather than on the levels of pigmentation, for the
selective thermal destruction of targeted areas,
which is known as electrothermolysis. Systems using
RF current alone have achieved good results for skin
resurfacing, with comparable efficacy to laser resur-
facing and potentially more rapid healing.
Two typical configurations of electrodes are used in
RF devices: the unipolar and the bipolar. In a unipolar
system, electric energy is emitted through the metal-
lic tip of the electrode and transmitted to the target
tissue in a depth, which can be estimated as half
the electrode size (Fig. 7.8). In the face, therefore, a
5 or 10 mm tip can be used with a penetration depth
of 2.5 mm. In a bipolar system, the penetration depth
is estimated as half the distance between electrodes
(Fig. 7.9). Although they differ in the way the RF cur-
rent is controlled and directed at the target tissue,
there is no difference in the final tissue effect at the
same RF. The bipolar handpiece creates local, super-
ficial dermal heating on delicate areas, such as the
face. The unipolar and larger handpieces provide deep
dermal and subdermal heating of larger areas.
MONOPOLAR SYSTEMS
Monopolar systems deliver energy through one elec-
trode. A relatively small contact point is applied to
the treatment area, while a larger ground electrode
is placed on the body in a location far from the
active electrode. A cylindrical electrode is applied
to the skin surface, concentrating the electrical
energy near the tip of the electrode, decreasing
rapidly with distance. The depth of penetration is
approximately half the electrode size. For example,
the penetration depth of a 10 mm electrode is
about 5 mm, which is deep enough to reach mus-
cles. Monopolar systems are popular in electrosur-
gery where a small electrode is used because it is
able to create a high power density on the surface
of the electrode. The primary disadvantage of a
monopolar system is that its behavior as the current
passes through the body to the grounding electrode
is unpredictable. Monopolar systems commonly
used in aesthetic medicine include Visage®, Ther-
macool®
(Thermage),
Radiage®
(now
renamed
Pelleve`™) (Ellman Int. Inc.) (Table 7.4), and others
previously described.
Radiofrequency serves as the primary principle
employed in the Ellman Dual RF Surgitron Unit1 and
Ellman Surgitron Dual RF S5 device (Fig. 7.10) (Ell-
man International Inc, New York), used in the proce-
dure Radiage (now renamed Pelleve`™) which has
been utilized in oculofacial plastic surgery to date.2
One of the authors (RMJ), had conducted studies on
Radiage which was one of the studies submitted to
the Food and Drug Administration (FDA) and had
given lectures worldwide on the topic Nonablative
4 MHz Dual Radiofrequency Treatment for Periorbi-
tal Rhytides and Midface Laxity. Last May 18, 2009,
the FDA had granted clearance to Pelleve`™, for the
non-ablative treatment of mild to moderate facial
wrinkles and rhytides for skin phototypes I–IV.
The latest monopolar application, currently in the
final 544 Investigational Protocol of the US Food
and Drug Administration (FDA) process, is able to
penetrate to a depth of 100 mm. This device, the
Fig. 7.8 Schematic representation of a unipolar system.
Fig. 7.9 Schematic representation of a bipolar system.
75
Skin-Tightening Devices

Lipotron® (RevecoMED International, Anaheim, CA),
unlike its predecessors, will be used not only for wrinkle
reduction, rejuvenation of the face, and cellulite
smoothing, but also for body contouring. The most sig-
nificant feature of the Lipotron® (Fig. 7.11), with its
depth of heat penetration, is that it affects the visceral
fat as well as the subcutaneous fat. It operates at
0.5 MHz and feels like a warm massage to the patient.
BIPOLAR SYSTEMS
Bipolar systems pass an electrical current between two
electrodes separated by a fixed distance. Both
electrodes are applied to the treated area, and electri-
cal current flows only in the area between the electro-
des. The penetration depth of the electric current is
approximately half the distance between the electro-
des. The primary advantage of bipolar systems is the
controlled distribution of RF current inside the tissue,
which is limited by the area between the electrodes.
Although bipolar systems are not as suitable for elec-
trosurgery, they are appropriate for hemostasis and
controlled vessel contraction using an intravascular
catheter. There are certain bipolar devices used in aes-
thetic medicine that combine the action of infrared
diode laser and RFs (Polaris™) and the action of
Table 7.4
A brief comparison between two non-ablative RF technologies
Thermage system
Ellman (Pelleve`™) system
1. Very high 6 MHz RF with high leakage
current
2. External cryo cooling of skin surface
3. Capacitive coupling of RF to skin
4. Non-standard special electrode with
essentially flat broad area contact surface
5. Deeply penetrating RF heating
6. High-power RF for deep penetration
7. Minimizes skin burning by cryocooling
8. Copper/steel electrodes
1. Optimum 4 MHz RF with low leakage current
2. Monoclysmic thermal gels for external cooling
3. Patented capacitive coupling for RF energy device
4. Ball or spherical proprietary composition alloy electrode to provide
a uniform electric field and optimum transfer of non-ablative
energy
5. Primarily surface RF heating and energy transfer to optimally
re-orient charged particles
6. Low power RF is sufficient
7. Minimizes skin burning by low power, constant electrode
movement and efficient energy transfer
8. Highly conductive proprietary composition alloy electrodes for
inherent electrode cooling effect
A
B
Fig. 7.10 A, Ellman Surgitron Dual RF S5 device, Wrinkle Treatment Handpiece and RF Cool Gel. B, A 10 mm Wrinkle
Treatment Handpiece is moved in a circular motion on top of the hand of the patient.
76
Aesthetic Oculofacial Rejuvenation

pulsed light and RFs (Aurora™). Both (Syneron
Medical Ltd, Yokneam, Israel) use the BRF system.
Polaris™combines RF with infrared energy of
900 nm diode laser and Aurora™combines RF with
pulsed light in order to have a synergistic effect,
although it has not yet been confirmed. Both of them
can treat wrinkles and vascular lesions. Neither of
these devices should be used on the eyelids within
the orbital rim in contrast to RF devices, which can
be used.
Aluma™(Lumenis Inc., Santa Clara, CA) com-
bines
RF
and
vacuum
suction.
Another
FDA-
approved RF device for treating wrinkles and rhytids
is the Accent XL® (Alma Lasers, Caesarea, Israel). It
combines two RF modes into a single device. Each
proprietary mode – bipolar and unipolar – is deliv-
ered by a discrete handpiece to distribute therapeu-
tic heat at different tissue depths within the body.
Refirme™will be further discussed later in this
chapter as one example of a bipolar system.
The result of the RF procedure is eyebrow lift,
reduction in static wrinkles of the periorbital area
and face, softening of nasolabial folds, improvement
of jowls and neck skin laxity, and face contour
renewal.
MECHANISM OF ACTION
Incision, excision, ablation or coagulation of the tar-
geted tissue is achieved by RF surgery, which tradi-
tionally utilizes a wave of electrons to cause heating
of tissues. In particular, in aesthetic rejuvenation,
RF creates an electrical field, which is alternated
rapidly from positive to negative, causing molecules
that are charged to move within this field. Resis-
tance to this movement or rotation creates heat.
Heat is described by Joule’s law:
H ¼ j2=s
where j is the density of electrical current and s is
the electrical conductivity. The value opposite to
conductivity is named resistance or impedance.
Bone has higher impedance and, therefore, elec-
trical current does not penetrate bone. Dry skin
and subcutaneous fat tissue have high impedance,
and for this reason dry skin must be hydrated to
allow passage of electrical current into the underly-
ing tissues.
The thermal effect is determined by the formula:
ðJÞ ¼ I2  R  T
where I is the current, R is the impedance of tissue
and T is the time of application. Immediate heat-
induced changes in collagen structure and long-term
dermal collagen remodeling are believed to induce
tissue tightening.
Specifically, a certain threshold of heating creates
a breakage of intramolecular bonds in the collagen
fibrils. In this way, collagen fibrils change shape from
a crystalline triple helical structure to a coil struc-
ture, becoming shorter,3 as explained in the infrared
section.
The amount of collagen contraction is determined
by time and temperature. Low temperatures are
desired to avoid pain and burns, but enough heat is
required to achieve this controlled collagen denatu-
ration. No single shrinkage temperature exists.
According to histopathologic findings, the heating
of the dermis at a level of 2–3 mm beneath the
surface results in a tissue temperature of 55–70
C.
The shrinkage temperature of collagen is believed
to be 57–61
C.4 At these temperatures controlled
Fig. 7.11 Lipotronic device.
77
Skin-Tightening Devices

denaturation of a small amount of collagen can be
achieved, resulting in modification of dermal colla-
gen and shortening of the fibrous septae extending
from the dermis into subcutaneous tissue (Fig. 7.12).5
This tightening is more efficient if the energy is
delivered to special anchoring points, which vary from
patient to patient. Their selection is based on the fact
that there are vectors pulling the tissues of the face up
according to the collagen’s contraction. These vectors
are based on the insertion points of the superficial
musculoaponeurotic system (SMAS).6 For example,
the anchoring point for smoothing nasolabial folds is
in the preauricular area.
According to studies, it seems that this heat acts
only in collagen in dermis and does not destabilize
hyaluronic acid in the matrix and probably does
not alter enzymes at the neuromuscular synapses,
which are under the subcutaneous tissue; therefore
RF can be used in patients who have had hyaluronic
acid fillers and botulinum toxin treatment.7,8
Initial protocols using single-pass high-energy set-
tings were associated with higher incidences of side
effects such as erythema, edema, blistering and sub-
cutaneous fat necrosis. Now the concept is that we
use pain as an indicator, marking the highest amount
of energy that should be avoided in all cases. Multi-
ple treatments also tend to give better results than
a single treatment.6,9
Multiple passes with low-energy settings are pre-
ferred, which is probably safer, more tolerable and
efficacious than a single pass with high-energy set-
tings. Zelickson et al. observed that a greater number
of low-energy pulses produced acute morphologic
changes similar to those produced by a single higher-
energy pulse.9 The usual energy levels range from
79 to 100 J/cm2 in ThermaCool® and from power
setting 12–40, Cut mode, in Radiage® (now renamed
Pelleve`™), depending on the area of the face and tol-
erance of the patient. Finally, another level of action
of RF is fat lysis. In particular, by concentrating the
heat in deeper level with stacking pulses, unwanted
fat in the submental area can be reduced, which can
paradoxically work in an opposite direction if you
remove fat from wrong places.10
INDICATIONS AND CONTRAINDICATIONS
The best candidates for skin tightening treatment are
patients aged 35–60 years, having mild-to-moderate
skin laxity.
Ideally, non-smokers should have relatively good
skin tone, modest photodamage and average amounts
of subcutaneous fat present. Previous use of fillers is
not a contraindication.
Good candidates are those with fine lines or
wrinkles on the face who desire a subtle and natural
improvement in their appearance and skin tone,
with minimal down time and minimal risk.
On the other hand, patients who have orbital fat
prolapse and generalized excessive skin laxity and
those having unrealistic expectations or seeking
impressive results are not considered good candidates.
Absolute contraindications for this procedure are
pacemakers and defibrillating devices in the patient.
It is not wise to treat patients with a tendency to
hypertrophy scarring or koebnerizing dermatoses,
A
Epidermis
RF
cooling gel
RF dome
Contracted
collagen
Subcutaneous
tissue
Deep dermis
Cooled dermis
B
Fig. 7.12 A, Schematic diagram demonstrating the heat shrinkage of collagen from a structured triple helix to a
random-coil structure. B, Schematic diagram demonstrating the heat shrinkage of collagen from a structured triple helix
to a random-coil structure during RF application.
78
Aesthetic Oculofacial Rejuvenation

or while on Isotretinoin (Accutane) treatment, or
within a year of such treatment.
PREPARATION AND RF SKIN-TIGHTENING
TECHNIQUE
Photographs and baseline wrinkle evaluation using
the
Fitzpatrick
Wrinkle
Classification
System
(FWCS) (Table 7.5) should be obtained. Patients
should
have
realistic
expectations
because
the
results tend to be subtle and gradual and may not
even be noticed by the patients themselves. Dra-
matic improvement is rare but can be seen even
after one treatment session. Immediate results can
be seen, depending on technique and perhaps many
other, as yet unidentified, factors. If patients have
realistic expectations and adequate photographs
are secured, the index of patient satisfaction is
much better. The degree of clinical improvement
on treatment efficacy of treated areas such as gla-
bellar, forehead and lower eyelid wrinkles, crow’s
feet, nasolabial folds, and midface laxity can be
assessed using the FWCS on pre- and postapplica-
tion photographs.
Remove any cosmetic agents or other facial emul-
sions on the skin. Make-up or oily material changes
the impedance of the skin surface.
The first step in using the Ellman Surgitron Dual
RF S5 device is to place the return electrode/antenna
plate on the back of the patient’s head. Later the skin
should be covered with Ellman RF cool gel.11 This
lowers the skin temperature by 7–8
C. The purpose
is to protect and prevent overheating of the epider-
mis and at the same time deliver the RF energy to
the warmer deep dermis to allow thermal changes.
For practicing the control of the foot pedal, we
should use a 10 mm Wrinkle Treatment Handpiece
connected to an Ellman Surgitron Dual RF S5 device
with the power level set at 2 (Cut mode). The depth
of the heating is dependent on the treatment set-
tings. The settings for energy delivery, the treatment
dome tip size and the impedance of the skin tissue all
impact the treated area. Neither topical anesthesia
nor sedative are given pretreatment.
Before delivering an Ellman RF skin-tightening
treatment, a test touching of the RF is done on
the back of the patient’s hand. This is done to
determine the average power setting for commenc-
ing the RF treatment and is based on the patient’s
impedance and resistance. Every patient’s threshold
is different, and this is a very good method to deter-
mine the base power setting. Move the energized
dome tip in an oval motion over the top of the hand,
applying slight pressure on the tip.
The intensity of the treatment is controlled by
the patient; it should be of bearable warmth, and
there should be no uncomfortable hot feeling. The
sensation should be what the patient can tolerate
comfortably. Settings may vary due to the skin
location and the skin thickness. Patients should be
informed that for maximum benefit the sensation
should feel as though the skin were heating to the
brink of pain, but be tolerable, and then subside.
Areas of thin skin against bone such as the temple,
malar, mastoid and mandibular areas are more sensi-
tive and require less energy.
When using the machine on a patient’s face the
authors recommend starting with the cheek area.
The device is set at a range of power setting of
12–40 (Cut mode) and adjusted to the maximum
level of tolerance.
When treating the eyelid and forehead areas, the
authors turn the power down to a lower setting and
use fast, quick movements, as this area is less fleshy
and the skin heats up more quickly.
Table 7.5
The Fitzpatrick wrinkle classification system
Class
Wrinkling
Score
Degrees of elastosis
I
Fine wrinkles
1–3
Mild (fine textural changes with subtly accentuated skin
lines)
II
Fine to moderate depth
wrinkles
4–6
Moderate (distinct popular elastosis [individual papules with
yellow translucency under direct lighting] and dyschromia)
III
Fine to deep wrinkles with or
without redundant skin folds
7–9
Severe (multipapular and confluent elastosis [thickened
yellow and pallid] approaching or consistent with cutis
rhomboidalis)
79
Skin-Tightening Devices

Cheek andneck flaccidity, whenimproved, givesthe
general aspect of rejuvenation (Figs 7.13 and 7.14).
Treatment of the cheek starts at the preauricular area,
crossing below the malar eminence and stopping at
the nasolabial folds. The jawline includes the areas
stretching from the posterior angle of the mandible
along the jowls to the lateral chin.
The upper neck treatment includes the area from
the inferior border of the mandible down to the
level of the thyroid cartilage. The midline submen-
tal soft-tissue region is also included (Fig. 7.15).
The most important thing to remember is not to
take the electrode off the skin when your foot is
activating the pedal, as it causes a shock to the
patient.
After the RF tightening treatment, a cold pack or
an ice roller can be used over the treated skin area
to lock the unraveled collagen into position.
OPTIMIZING OUTCOMES
v Areas of thin skin against bone such as temples,
malar, mastoid and mandibular areas are more
sensitive and require us to use less energy.
v After the procedure, the physician must ask if
there are areas of lingering burning sensation.
v The patient is asked to apply ice cubes wrapped
in gauze directly against the area that burns until
the burning sensation has disappeared. This may
avoid a real burn.
A
B
Fig. 7.13 A, Pretreatment. Cheek laxity. B, After two treatment sessions showing nasolabial fold diminished in depth
and improvements in oral commissures and marionette lines.
A
B
Fig. 7.14 A, Pretreatment frontal view of the patient. B, 6 months post-treatment of the patient showing tissue tightening
of the cheeks, with improvement in the nasolabial fold, cheek contour, marionette lines and the jaw line.
80
Aesthetic Oculofacial Rejuvenation

v The skin should be inspected for areas of redness,
dusky gray color, pale wheal-like papules or red
squares.
v Areas of dusky gray color almost always progress
inexorably to a second-degree superficial burn.
They are uncommon.
v Contraction of elastin will occur after 7–10 days,
and newly produced collagen resumes in a steady
way. New application can be made after 1 week.
COMPLICATIONS AND SIDE EFFECTS
The most commonly noted adverse reactions were
transient erythema lasting for a few hours to a day,
tolerable pain during the procedure described as a
warm sensation and mild edema lasting for 1–2 days.
Lower settings and multiple passes are advised to
reduce the risk of adverse events such as severe
pain, blistering, burns, bruising and scarring, and
late side effects such as cutaneous depressions,
which can occur weeks or months post RF applica-
tion as a result of overheating of adipose tissue and
fibrous septae. Mild depressions resolved spontane-
ously; however, severe contour irregularities and
scarring may be improved with subcision, autolo-
gous fat transfer or cosmetic fillers.12 Fortunately,
there were no scarring, burns, bruising or dysesthe-
sia noted in any of our patients.
POSTOPERATIVE CARE
Apply a bland moisturizer, and no other postopera-
tive care is required.
REFERENCES
1 Garito J. Inventor; Dual RF Radiowave Device. Assigned to Ellman
International Inc; 2008 US Patent 5,954,686, 21 September 1999.
2 Bosniak SL, Javate RM, Aquino MS, et al. Radiosurgery: a new
approach to eyelid, orbital, and lacrimal surgery. Int J Aesthetic
Restorative Surg. 1995;3:9–15.
3 Ross VE, McKinlay JR, Anderson RR. Why does carbon dioxide
resurfacing
work?
A
review.
Arch
Dermatol.
1999;135(4):
444–454.
4 Zelickson BD, Kist D, Bernstein E, et al. Histological and ultra-
structural evaluation of the effects of a radiofrequency-based non-
ablative dermal remodeling device: a pilot study. Arch Dermatol.
2004;140(2):204–209.
5 Biesman BS, Baker SS, Carruthers J, Silva HL, Holloman EL.
Monopolar radiofrequency treatment of human eyelids: a pro-
spective, multicenter, efficacy trial. Lasers Surg Med. 2006;38
(10):890–898.
6 Alam M, Levy R, Pajvani U, et al. Safety of radiofrequency treat-
ment over human skin previously injected with medium-term
injectable soft-tissue augmentation materials: a controlled pilot
trial. Lasers Surg Med. 2006;38(3):205–210.
7 Semchyshyn NL, Kilmer SL. Does laser inactivate botulinum
toxin? Dermatol Surg. 2005;31(4):399–404.
8 Fritz M, Counters JT, Zelickson BD. Radiofrequency treatment
for middle and lower face laxity. Arch Facial Plastic Surg.
2004;6:370–373.
9 Finzi E, Spangler A. Multipass vector (mpave) technique with
nonablative radiofrequency to treat facial and neck laxity. Derma-
tol Surg. 2005;31:916–922.
10 Dawson E, Willey A, Lee M. Adverse events associated with non-
ablative cutaneous laser, radiofrequency, and light-based devices.
Semin Cutan Med Surg. 2007;26:15–21.
11 Garito J. Inventor; Non-Ablative Skin Tightening RF Electrode
And Procedure. Assigned to Ellman International; 2008 US Patent
11/709,692, 23 February 2007.
12 Narins RS, Tope WD, Pope K, et al. Overtreatment effects
associated with a radiofrequency tissue-tightening DEVICE:
Rare, preventable, and correctable with subcision and autologous
fat transfer. Dermatol Surg. 2006;32:115–124.
A
B
Fig. 7.15 A, Pretreatment. B, After three treatment sessions of the neck to the submental area showing decrease in
submental fullness.
81
Skin-Tightening Devices

Bipolar radiofrequency
Neil S Sadick
The ReFirme™ST Applicator (Syneron Medical
Ltd., Yokneam, Israel) is a combination of broad-
band IR (700–2000 nm) and bipolar RF energies.
The author uses the ReFirme to non-ablatively
improve both skin laxity and rhytids. The RF energy
provides deep tissue heating, whereas IR energy
heats the dermal ground substance because it is
absorbed by water and possibly by collagen as well.
This combination of optical and RF energy is an
example of electro-optical synergy (ELOS), which
is believed to permit the use of lower levels of both
types of energy, thus lowering the risk of adverse
effects.1,2 To optimize outcomes, patients usually
require three to five treatment sessions 4–6 weeks
apart. Erythema and edema during and after the
treatment are transitory and usually do not require
treatment. Slight lifting of the lax areas should be
evident at the final treatment.
PRETREATMENT CARE
v Avoid skin irritation and intentional tanning.
v Use sunscreen when exposed to the sun.
v Discontinue irritant topical agents for 2–3 days
(before treatment visit).
v Arrive at the physician’s office with cleaned skin.
v Remove all lotion, make-up, perfume, powder
and bath/shower oil from areas to be treated.
v Avoid topical anesthetics unless directed by a
physician.
v Inform the treating clinician of dental crowns,
caps, braces or other metal implants.
TREATMENT PROCEDURE
The recommended treatment parameters are shown
in Table 7.6. Settings are guidelines and should be
adjusted according to individual responses to test
spots. Topical anesthesia is not required.
1. Obtain a photograph of each side of the face
before treatment.
2. Ask the patient to sit up for treatment.
3. Apply conductive gel to the treatment area.
4. Place applicator perpendicular to the skin using
full contact and slight pressure.
5. Treat one side of the face (or any area of loose
skin) to use as a reference endpoint during
subsequent passes.
6. For the first pass, cover the complete area
with 30–50% overlap. Do not use the autorepeat
mode on bony, thin or delicate areas of skin.
7. Make consecutive passes with 30–50% overlap
on vector zones of 20–30 pulses each. One side
of the face typically requires approximately
400 pulses. Make passes until you see sustained
tightening and edema. Erythema is often
present at this endpoint as well.
8. If patient voices discomfort or the skin
responds excessively to treatment, reduce the
energy level and, if necessary, change the
cooling level to the strong setting. Use patient
tolerance as a guide.
9. Do not stack pulses, lest a blister develop.
10. Treat the other side of the face with 400 pulses.
The total number of pulses for the entire face
should be approximately 800.
POSTREATMENT CARE
After treatment with the ReFirme, patients should:
v apply sun block (SPF 30 or higher) to the treated
area and avoid intentional suntanning for several
days
v apply cold compresses to the treated area to
reduce swelling and redness, and apply
hydrocortisone or antibiotic ointment if
prescribed by the physician
v wash the treated area gently for 3 days without
harsh or abrasive products
v avoid hot baths, saunas or exposure of treated
area to excess heat for 3 days
v cleanse and pat dry areas with superficial crusts
or scabs; do not rub, scratch or remove scabs
v call the physician at the first sign of a blister;
apply antibiotic ointment if prescribed.
82
Aesthetic Oculofacial Rejuvenation

CONCLUSION
The combination of broadband IR (700–2000 nm)
and bipolar RF energies has been shown in the
author’s practice to be a safe and effective modality
for the treatment of skin laxity.
REFERENCES
1
Yu CS, Yeung CK, Shek SY, Tse RK, Kono T, Chan HH. Com-
bined infrared light and bipolar radiofrequency for skin tightening
in Asians. Lasers Surg Med. Jul 2007;39(6):471–475.
2
Gold MH, Goldman MP, Rao J, Carcamo AS, Ehrlich M. Treat-
ment of wrinkles and elastosis using vacuum-assisted bipolar
radiofrequency heating of the dermis. Dermatol Surg. 2007;33
(3):300–309.
Table 7.6
Radiofrequency treatment parameters for ReFirme applicator
Skin type
Tx area
RF energy (J/cm3)
Cooling
Number of passes/Tx area
I–VI
Lower face, under chin
100–120
Normal*
4–7
I–VI
Forehead, bony areas
90–120
Normal*/strong{
2–5
*Equivalent to 10
C.
{Equivalent to 5
C.
RF, radiofrequency; Tx, treatment.
83
Skin-Tightening Devices

Botulinum Toxin for Oculofacial
Aesthetic Rejuvenation
Doris M Hexsel, Luitgard Wiest, Mariana Soirefmann
Included on DVD
SUMMARY
Botulinum toxin (BTx) is one of the most revolution-
ary treatments in facial aesthetics and rejuvenation.
The cosmetic use of BTx in the upper third of the face
began in the late 1980s and gradually advanced to
applications in the mid and lower face, neck and other
areas of the body. Its use has permitted a better
understanding of the physiopathological process of
aging, specifically the role of the muscles. Nowadays,
more accurate techniques and the adjunctive use of
BTx allow physicians to make more precise applica-
tions and achieve better, natural-looking results.
Every year, new perspectives on the clinical and cos-
metic uses of BTx show the utility and versatility of
this therapeutic modality in dermatology and other
specialized areas of medicine.
INTRODUCTION
Nowadays, the value of image plays an important role
in our society. Since the development of numerous
minimally invasive procedures for facial beauty and
rejuvenation, it has become easy and safe for patients
to improve their appearance. New and less invasive
techniques for facial rejuvenation give quick results,
with a low incidence of side effects and minimal
downtime, as patients can return immediately to their
normal daily activities.
Facial wrinkles are caused by several factors,
including aging (intrinsic and photoaging), gravity,
positional pressure (sleep lines) and facial expres-
sions.1,2 Repeated muscular contractions involved in
facial expression are one of the most important etio-
logic factors causing facial lines and rhytides, particu-
larly in the upper third of the face. Glabellar, frontal
and periorbital are the main areas involved in facial
expression. Moreover, these muscular contractions
may also contribute to the development of redundan-
cies of the skin over these hyperkinetic muscles and
lines. Some dynamic wrinkles that are initially caused
by muscular movements become static with the
addition of other factors such as chronic solar expo-
sure and the development of cutaneous flaccidity.3
Glabellar folds are usually interpreted as suggesting
negative feelings, such as sadness, anger4 and frustra-
tion.5 Although small-to-moderate furrows may be
interpreted positively for men, as indicating the abil-
ity to concentrate, leadership and even sensitivity,
large furrows are more often perceived negatively.6
In an attempt to diminish the undesirable expres-
sive rhytides of the face, BTx has been widely used
to produce precise and reversible weakness of the
hyperfunctional mimetic muscles of facial expres-
sion.7 It is therefore currently considered the best
alternative for the treatment of dynamic wrinkles,8
alone or in combination with other minimally inva-
sive or invasive techniques.9–11
BTx injections are of special benefit for patients
between 30 and 50 years of age, since the etiology
of facial lines in this group is more related to the
underlying muscles than to other factors.1 The
treatment of facial expression lines not only repre-
sents a matter of aesthetics and vanity, but also
leads to improvement of self-esteem.12
The medical literature of the cosmetic use of BTx
is currently dominated by open-label reports, uncon-
trolled studies and personal experience reviews. A
few double-blind, placebo-controlled studies have
been published, some of them in the glabellar
area.5,13–16 In the lateral periorbital area, BTx injec-
tions can be safely performed when strict attention
is given to the reconstituted BTx pharmacology and
to the anatomy of the periorbital muscles, although
it is considered an off-label procedure.17
HISTORY OF THE COSMETIC USE
OF BOTULINUM TOXINS
BTx is known as the substance with the highest spe-
cific potency of all natural or synthesized compounds.
It is produced by an anaerobic, Gram-positive,
rod-shaped organism, Clostridium botulinum.
8

BTx became famous as the cause of botulism and
as a biological weapon. Botulism is well known in
historical accounts, and has probably been known
since the beginning of the human race. In medieval
times, it was known in Europe that production of
sausages bore a high risk of food poisoning from
BTx, so strict guild regulations were imposed on
sausage production.
In 1822, Justinus Kerner, a physician in the state of
Wu¨rttemberg in South Germany, provided one of the
earliest detailed descriptions of the clinical picture of
botulism. He was also the first to speculate on a pos-
sible therapeutic use of BTx in conditions like Hun-
tington’s chorea.18 In 1895, Emile Pierre Marie van
Emergen identified botulinum neurotoxin as the
cause of a botulism outbreak amongst musicians in
the Belgian village of Ellezelles. In 1919, the isolation
of different BTx types, known as A (BTx-A) and B
(BTx-B) was achieved. In 1920, Hermann Sommer
of the Hooper Foundation at the University of
California concentrated BTx into a relatively pure
form. Research and study into the activity of botuli-
num neurotoxins was stimulated by the events of
World War II. Edward Shantz, Carl Lamanna and
their colleagues at Fort Detrick successfully isolated
BTx-A for the US Army in 1946, and in 1949 Burgen
discovered BTx’s mechanism of action.
Medical use of BTx began in the 1950s with the
work of Vernon Brooks. By the late 1960s, the inhib-
itory effects of BTx-A on acetylcholine release at the
neuromuscular junction were shown in experimental
animals. These studies were significantly advanced
by
ophthalmologist
Alan
Scott
of
the
Smith-
Kettlewell Institute of Visual Sciences in San
Francisco in the 1970s. He used BTx-A for treat-
ment of strabismus and blepharospasm. In 1977,
the first treatment was attempted in humans.19
The batch of BTx-A developed by Schantz under
the name of Oculinum in 1979 was approved for
human use in 1989, and later acquired by Allergan
Inc. Under the name of Botox® it has been used
as the primary treatment for focal dystonias since
the late 1980s.
In 1987, while treating patients for essential bleph-
arospasm, Jean Carruthers, an ophthalmologist, noted
that these patients had significant improvement
of dynamic rhytids in the glabella region. Alastair
Carruthers, a dermatologist, together with his wife,
started systematic studies of BTx for cosmetic use,
which were published in 1992, demonstrating the
safe and effective use of BTx-A in the treatment of
dynamic rhytids in the glabella20 and bringing in the
era of cosmetic use of BTx.
In 1993, Blitzer et al. described the use of BTx
for wrinkles of the forehead.21 Later researchers,
such as Arnold Klein, Nicholas Lowe, Patricia
Wexler, Richard Glogau and Steven Fagien, contri-
buted publications of their experiences to the
widespread use of BTx-A. Subsequently, new indi-
cations for cosmetic use such as crow’s feet, and
new areas as the perioral region and platysma were
discovered.22 Botox® Cosmetic (in other countries
Vistabel® or Vistabex®) was approved by the FDA
in 2002. Other BTx-A products have been launched
into the market in other countries. The most impor-
tant are Dysport® by Ipsen, Prosigne® by Lanzhou
and Xeomin® by Merz.
At first, BTx-A used the principle of identical
doses and injection sites for all patients, but in
recent years cosmetic treatment with BTx has
become much more differentiated and today a more
individualized approach prevails, aiming at a global
rejuvenation: the BTx ‘face lift’. Frequent reports
of potential novel uses of BTx-A in facial muscula-
ture indicate that we stand at the beginning of its
use in aesthetic medicine.
CURRENTLY AVAILABLE
BOTULINUM TOXINS
The toxin produced by Clostridium botulinum is
isolated, purified and stabilized before it can be
used as a drug. There are seven different types of
BTx, which are known and designated by the letters
A, B, C, D, E, F and G. The different BTx types
differ slightly in the amino acid sequences of their
neurotoxin and in their associated non-toxic pro-
teins. All seven BTx-types share a similar molecular
structure and have the same basic mechanism of
action: they bind to the same glycoprotein struc-
tures and they all block the cholinergic synapse,
preventing the release of acetylcholine at the neuro-
muscular junction of striated muscle fibers, creating
a flaccid paralysis of the muscle. Differences in the
intracellular protein target or target site cleaved by
the light chain of each serotype lead to variations in
duration of action and possibly other defects. Only
the A and B toxins are available as drugs (Table 8.1).
BTx-B (Myobloc®, Solstice Neuroscience) is less
potent than BTx-A in humans and requires approx-
imately 50–150 times the dose of BTx-A to achieve
similar results in dynamic rhytides. It appears to
have a shorter duration of action than type A, as
well as more autonomic side effects. Myobloc®
comes in the form of a solution.
86
Aesthetic Oculofacial Rejuvenation

Table 8.1
Comparison of different BTx-A
XEOMIN®
Botox®
Vistabel®
Dysport®/
Reloxin®
Dysport®
Cosmetics®
Prosigne®
Neurobloc®/
Myobloc®
Company
Merz
Pharmaceuticals
Allergan
Allergan
Ipsen/Medicis
Ipsen/
Medicis
Lanzhou Institute of
Biological Products
Solstice
Neuroscience
Type
Type A
Type A
Type A
Type A
Type A
Type A
Type B
Approvals
Europe Union,
Mexico,
Argentina, Brazil
In over 75
countries all
over the world
In 16
countries,
including
the USA,
Canada,
Italy and
France
Dysport: In over
65 countries
Germany,
some other
European
countries and
the USA
China, North Korea,
Morocco, the
Philippines,
Indonesian, Brazil,
Peru, Ecuador, Chile,
Paraguay, Uruguay,
Venezuela, Thailand
and some others
Europe and
the USA
Active
substance
Botulinum
neurotoxin type
A (150 kD)
Botulinum toxin
type A complex
(900 kD)
Botulinum
toxin type
A complex
(900 kD)
Botulinum toxin
type A complex
(900 kD)
Botulinum
toxin type A
complex
(900 kD)
Botulinum toxin type
A complex (150 kD)
Botulinum
toxin type B
complex
Comparison of
strength of
action
1
1:1
1:1
Approx. 1:2.5 to
1:3
Approx. 1:2.5
to 1:3
1:1
1:1000
Indications
Blepharospasm
Cervical
dystonia
Many
indications,
including
blepharospasm
and cervical
dystonia
Glabellar
lines
Many
indications,
including
blepharospasm
and cervical
dystonia
Glabellar
lines
Blepharospasm,
strabismus,
hemifacial spasm
and other dystonias
Cervical
dystonia only
Mode of action
SNAP 25
SNAP 25
SNAP 25
SNAP 25
SNAP 25
SNAP 25
VAMP
Pharmaceutical
form
Powder for
solution for
injection
Powder for
solution for
injection
Powder for
solution for
injection
Powder for
solution for
injection
Powder for
solution for
injection
Powder for solution
for injection
Solution
Units/vial
100
100
50
500
500
100
2500/5000/
10 000
Volume
max. 8 ml
max. 10 ml
1.25 ml
max. 2.5 ml
max. 5 ml
max. 8 ml
0.5 ml/1 ml/
2 ml, max.
3.5 ml
Continued
87
Botulinum Toxin for Oculofacial Aesthetic Rejuvenation

Table 8.1
Comparison of different BTx-A—cont’d
XEOMIN®
Botox®
Vistabel®
Dysport®/
Reloxin®
Dysport®
Cosmetics®
Prosigne®
Neurobloc®/
Myobloc®
Reconstitution
0.9% NaCl
solution
0.9% NaCl
solution
0.9% NaCl
solution
0.9% NaCl
solution
0.9% NaCl
solution
0.9% NaCl solution
Prepared
solution,
dilutable
Storage
25
C
2–8
C or freezer
5
C
2–8
C
<5
C
2–8
C
2–8
C
2–8
C
2–8
C, do not
freeze
Shelf-life
(unopened)
36 months
36 months
36 months
24 months
24 months
36 months
24 months
Shelf-life
reconstituted
24 hours
24 hours
24 hours
24 hours
24 hours
4 hours
24 months
(closed)
Auxilliary
substances
Albumin 1 mg,
sucrose 4.7 mg
Albumin
0.5 mg, NaCl
0.9 mg
Albumin
0.5 mg,
NaCl
0.9 mg
Albumin
0.125 mg,
lactose 2.5 mg
Albumin
0.125 mg,
lactose
2.5 mg
Gelatin 5 mg, dextran
25 mg and sacarosis
25 mg
Albumin, NaCl,
succinat,
octanolat,
tryptophan
pH-Wert
5–7
5–7
5–7
5–7
5–7
5–7
5.6
Foreign protein
load in dose-
equivalence
range
0.6 ng/100 U
5 ng/100 U
2.5 ng/
50 U
5 ng/500 U
5 ng/500 U
4–5 ng/100 U
100 ng/
10 000 U
Specific activity
(MU per ng
protein)
166 MU/ng
20 MU/ng
20 MU/ng
100 MU/ng
100 MU/ng
20–25 MU/ng
100 MU/ng
88
Aesthetic Oculofacial Rejuvenation

In aesthetic medicine, BTx-A has been used the
most so far, although some trials have been under-
taken utilizing BTx-B.23
MECHANISM OF ACTION
The activity of the different types of BTx is exerted
through a multistep process which includes binding
to nerve terminals, internalization and inhibition of
neurotransmitter release.
The biologically active component is BTx neuro-
toxin, which consists of two polypeptide chains
with molecular masses of 50 kDalton (kD) and
100 kD. These two polypeptide chains are linked
together by a single disulfide bond. Thus, BTx neu-
rotoxin is a complex and highly fragile macromole-
cule. Changes in pH or exposure to light or heat
induce changes and finally destruction of the macro-
molecule, with loss of its biological activity. BTx
neurotoxin is associated with various non-toxic pro-
teins, some with hemagglutinating and some with
non-hemagglutinating properties.
Clinically, BTx induces a blockade of the choliner-
gic innervation of the target tissue. When BTx is
injected into muscle tissue, muscular paralysis results
within 24–72 hours, reaching its maximum effect
after 1–2 weeks. The degree of muscular paralysis
can be controlled by the amount of BTx administered.
The mode of action of BTx is illustrated in
Figure 8.1. BTx neurotoxin with its heavy chain
binds to BTx acceptors on the presynaptic nerve
membrane. This binding is rapid and irreversible.
Subsequently, the light chain is transported into
the nerve cytoplasm. The synaptic fusion complex
is made up of a group of proteins known as the
SNARE proteins (soluble N-ethylmaleimide-sensi-
tive factor attachment protein receptors) that allow
the preformed acetylcholine vesicles to dock and
fuse to the membrane. This SNARE complex is
the location of action for BTx. Inside the nerve end-
ing, the light chains of BTx-A, C and E catalyze the
cleavage of SNAP-25 (synaptosomal-associated pro-
tein), a 25 kDa protein of the SNARE complex.
The different subtypes of BTx have unique areas
on the nerve membrane to which they bind and
Exposure to
botulinum toxin
Botulinum
toxin endocytosed
Light chain
cleaves specific
SNARE proteins
Light chain
Heavy chain
Botulinum toxin
Muscle cell
Types B, D, F, G
Types A, C, E
Type C
Neurotransmitter
not released
SNARE complex
does not form
Membranes
do not fuse
Muscle fiber
paralyzed
Fig 8.1 Mechanism of action of botulinum neurotoxins. Reproduced with permission from J Am Med Assoc 2001;285(8):
1059–70. All rights reserved.
89
Botulinum Toxin for Oculofacial Aesthetic Rejuvenation

have different proteins within the presynaptic nerve
terminal that they cleave. They all have the same
mechanism of action: to act as a zinc-dependent
endoproteinase and inhibit the release of acetylcho-
line at the peripheral neuromuscular junction.24
The action of BTx within the target tissue
decreases over time as the affected axons start to
sprout new nerve terminals within 28 days, which
continually restore the impaired transmission. Dur-
ing this time the damaged synapse itself will regen-
erate its function.25 After 3 months, reinnervation
occurs normally and muscles return to their normal
function 2–5 months after injection.
The dose of BTx is measured in units of biological
activity in a standardized mouse model. One unit
(U) of biologic activity is the amount required to kill
50% (lethal dose or LD50) of 18–20 g female Swiss-
Webster mice when injected interperitoneally. The
dosage units of the different products do not relate
to each other. Apart from one clinical trial with
methodological shortcomings26 there are no compar-
ative clinical studies for aesthetic indications. On the
other hand, comparison of efficient doses of Botox®4
and Dysport®16 for cosmetic applications in the gla-
bella in two controlled studies shows strong evidence
of an equivalence of 2.5:1 U between the two pro-
ducts (Dysport® and Botox®). Comparing the stud-
ies cited above, the effects obtained with 20 U of
Botox® in the treatment of the glabellar area4 were
similar to those obtained with 50 U of Dysport® in
the treatment of the same area.16 These support
the clinical evidence that 1 U of Botox® is equivalent
to 2.5 U of Dysport® for glabellar lines, giving similar
results for efficacy, intensity and duration of paraly-
sis. The manufacturers of Botox®, Dysport® and
Xeomin® recommend the reconstitution of their
products with 0.9% sterile preservative-free saline.
Since BTx-B is marketed as a solution, it does not
have to be reconstituted.
INDICATIONS FOR OCULOFACIAL
COSMETIC USE OF BTX-A
The major cosmetic indications for BTx-A use are
located in the upper face. This chapter is focused
on oculofacial cosmetic uses.
Glabellar Frown Lines
The use of BTx in the glabella can improve brow
reposition and delay physiological ptosis of the
eyelids and eyebrows, leading to a more jovial
appearance and attractive look, retarding the indica-
tion of a blepharoplasty.6,27,28 Glabellar lines, also
called ‘frown lines’, occur as a result of the pull
on the skin of the underlying facial musculature,
predominantly the procerus and the corrugator
supercilli muscles (Fig. 8.2). Glabella is the main
indication for BTx treatment.7,29
Muscles produce the vertical lines of glabella
including corrugator supercilli and the medial orbital
portion of the orbicularis oculi, both of which move
the brow medially, and the depressor supercilli
muscle, which pulls the brow inferiorly.30,31 The
procerus muscle pulls the brow inferiorly and pro-
duces the horizontal lines of the glabella.30,31 The
sole brow elevator is the frontalis. Injection of BTx
into glabellar muscles diminishes the appearance of
frown lines, suppresses their mobility and also
reduces the expressiveness of eyebrows.32 Moreover,
BTx treatment in the glabellar area is able to produce
brow lift5 (Figs 8.3 and 8.4), change the eyebrow
shape33 and correct eyebrow asymmetries.34
Deep glabellar lines can be treated with BTx-A
alone or in combination with fillers and/or Subci-
sion® for better results.
Periorbicular Area
Crow’s feet result largely from hyperkinetic muscle
function of the orbicularis oculi, and experience has
shown that chemodenervation of the lateral aspect
of this muscle can greatly attenuate the appearance
of lateral orbital rhytids, also called ‘crows feet
wrinkles’, without impairing the ability to squint
and protect the eyes from foreign bodies or bright
Fig. 8.2 Glabellar lines due to frowning of procerus and
corrugator muscles.
90
Aesthetic Oculofacial Rejuvenation

light. The dynamic component of these wrinkles
may also be treated with BTx (Figs 8.5 and 8.6).3
PREOPERATIVE CONSIDERATIONS
The following are important preoperative consider-
ations:
v the patient understands the procedure and its
limitations
v obtain informed consent and good preoperative
photographs (at rest and in movement) have
been obtained
v if possible, to discontinue the use of medication/
supplementation that might enhance bleeding
(anticoagulants, gingko biloba, vitamin E, aspirin)
7–10 days prior to injections
v to discontinue the use of medication that can
interfere with BTx-A action (aminoglicosides)
v the individual facial balance, looking at the
patient at rest and in movement
v the cosmetic use of BTx-A in patients with pre-
existing neuromuscular disorders that alter the
neuromuscular junction, such as the Eaton–
Lambert syndrome (myasthenic syndrome) and
major myasthenia, should be avoided.7
Fig. 8.4 Same patient as Figure 8.3, showing the
browlift after BTx injections.
Fig. 8.3 Upper face at rest before injections, showing
the original position of eyebrows.
Fig. 8.5 Crow’s feet wrinkles, radiating from the lateral
canthus, before treatment.
Fig. 8.6 Same patient as Figure 8.4, after treatment
with BTx.
91
Botulinum Toxin for Oculofacial Aesthetic Rejuvenation

TECHNIQUES AND DOSES
Treatment is delivered in an outpatient setting. The
patient sits upright on a chair, with the upper part
of the body elevated and topical anesthetic is
applied. Antisepsis with 70% alcohol or iodinated
alcohol is performed before the injections. A marking
pen can be used to indicate specific injection points.
Small syringes are preferable for the application
of BTx-A. The needle should be oriented in the
opposite direction of the ocular globe. Local, light
manual compression6 or the application of cold
compresses6 help to control the size of bruises if
they appear during the procedure. Another consid-
eration in this area is to avoid the use of medicines
that interfere with blood coagulation.
For glabellar application, BTx-A is slowly injected
into the belly of the corrugator muscle, taking care
to maintain the needle tip approximately 1 cm supe-
rior to the orbital rim. The needle should be posi-
tioned perpendicularly and advanced slightly in a
vertical direction toward the hairline within the
muscle fibers.6
One or two injection sites may be used on the
belly of the procerus to treat the horizontal lines
that appear at the root of the nose. The injection
point is in the midline at a point below a line joining
the brows and above the crossing point of the ‘X’
formed by joining the medial eyebrow to the
contralateral inner canthus (Fig. 8.7).6,35,36
Five-point injections have been described as the
standard technique to weaken the entire glabella in
women with highly arched brows,10 as they have
less mass in the muscles that produce frowning.2
If they have more horizontal brows or deep folds
they will require a greater quantity of BTx-A, which
may be a higher dose or an extra point above each
midpupillary line.10 In men, although the muscles
that cause frowning are of greater mass, the accen-
tuated high arching of the eyebrows is unacceptable,
as this characterizes a female pattern. To avoid this,
an additional dose of BTx-A is injected at the mid-
point of each side of the eyebrow, at least 1 cm
above the supraorbital prominence.5
Several studies have demonstrated the efficacy
and safety of the use of BTx-A in the gla-
bella.10,16,37–39 The first multicenter, double-blind,
randomized, placebo-controlled study proving the
efficacy and safety of BTx-A injection for the treat-
ment of glabellar lines was published in 2002.39
This study described good results with the use of
the five-point technique, injecting 4 U of BTx-A
(Botox®/Vistabel®) into the midline point of the
procerus muscle and two points on either side of
the corrugator supercilii, using a total dose of 20 U
of Botox®/Vistabel®.39 A multicenter, double-blind
study conducted by Ascher showed that 50 U of
Dysport® is an efficacious dose to treat glabellar
lines.16 A study from Monheit and colleagues also
concludes that the same dose of 50 U Dysport®
gives the most cost-effective results.
Doses and techniques for the application of BTx-
A in the glabellar area vary greatly, as treatments
must be customized. A randomized study has inves-
tigated the efficacy and safety of two injection site
patterns of BTx-A (Dysport®) in the treatment of
glabellar and central forehead wrinkles. Patients
received three injections of BTx-A or placebo in
the procerus and corrugator muscles or five injec-
tions of BTx-A or placebo in the procerus and cor-
rugator and the two additional sites approximately
1 cm cranial from the corrugator sites.40 The
authors concluded that three central injection sites
are essential for the treatment of glabellar wrinkles.
The two additional injection sites in the forehead
region
targeting
the
frontalis
muscle
did
not
improve the efficacy significantly.40
For the treatment of periorbital wrinkles, the pri-
mary muscle is the orbicularis oculi. This sphinc-
teric muscle sits circumferentially around the eye
and has the important function of providing deliber-
ate closure of the eyelids to protect the globe. BTx
applications for lateral periorbital wrinkles should
be made in the area of the wrinkles, at least 1 cm
lateral to the lateral orbital rim in the subcutaneous
area (Fig. 8.8).2,41
Fig. 8.7 The injection point in the procerus muscle.
92
Aesthetic Oculofacial Rejuvenation

Doses for the application of BTx-A in the peri-
orbicular area may also vary. The literature describes
doses of Botox® for periorbital wrinkles ranging
from 4–5 U/site42 to 5– 15 U/site,43,44 distributed
over two or three, but sometimes four to five,
injection sites. A bilateral, double-blind, randomized
study tested placebo against 6, 12 and 18 U of
Botox® injected into the periorbital or crow’s feet
area. All doses were significantly superior to placebo
with no clear dose–response relationship.13 In the
periorbital wrinkles, doses of Dysport® may vary
from 835,45 to 60 U35,46 and can be distributed over
up to five application points.
Intradermic injections of BTx into the pre-septal
portion of the lower eyelid reduce some fine
wrinkles in this region and augment eyelid opening,
especially when combined with BTx treatment of
lateral periorbital wrinkles.47,48 Patients should be
carefully selected for this treatment, as it may aggra-
vate laxity of the lower eyelids.49
In order to slightly weaken and not to cause com-
plete paralysis of the orbicularis oculi, some authors
suggest small doses of BTx-A be injected subcutane-
ously, and not intramuscularly.50,51 On the other
hand, the results from intramuscular or subcutaneous
injections of BTx-A of the same doses are similar,
due to the diffusion of the product.
POST-PROCEDURE CARE
To minimize the risks of side effects and complica-
tions, the treated areas should not be manipulated
for 3–4 hours after the injections. It is also recom-
mended that the patient remain in an upright
position for this time.52 The patient should avoid
strenuous physical activities for the rest of the
day.53,54 Some authors also recommend that patients
contract the treated muscles repeatedly in the first
few hours after the injections.55
COMPLICATIONS AND SIDE EFFECTS
Complications related to the injection itself include:
v mild stinging, burning or pain
v edema and erythema around injection site
v mild headache.
There are a number of immediate hypersensiti-
vity reactions that are not technique dependent:
v urticaria
v dyspnea
v anaphylaxis.
Particular techniques may cause other reactions,
and these are described below.
Ecchymoses and Bruising
Ecchymoses and bruising are caused by deep injec-
tions into the crow’s feet or into the lower eyelid
and may last from 7 to 15 days. For this reason
BTx should be injected subdermally and using low
dose volumes.
Ptosis of the Upper Eyelid
Ptosis of the upper eyelid is the most significant
complication of BTx injections and may be caused
by migration of injected BTx through the orbital
septum, weakening the elevator palpebrae superioris
(Fig. 8.9). If BTx is injected close to the bony supra-
orbital margin at the midpupillary line where some
of the muscle fibres of the elevator palpebrae super-
ioris insert inferiorly to the bony attachment of the
Fig. 8.8 The injection points for lateral periorbital wrinkles.
They should be made at least 1 cm lateral to the lateral
orbital rim.
Fig. 8.9 Ptosis of the upper left lid, 8 days after treatment
of the glabella with BTx-A.
93
Botulinum Toxin for Oculofacial Aesthetic Rejuvenation

orbital septum, diffusion into the upper eyelid leva-
tor may cause ptosis of the upper eyelid. This may
last 2–4 weeks or longer.22 Instillation of alpha-
adrenergic
Apraclonidine
0.5%
eyedrops,
three
times a day will stimulate Mueller’s muscle to con-
tract, raising the upper eyelid about 1–3 mm.
Brow Ptosis
Older patients frequently compensate for a heavy
brow, using the lower fibers of their frontalis to lift
the soft tissue of the brow. Brow ptosis is caused
by the diffusion of BTx into the low fibers of the
frontalis when BTx is injected too rapidly or with
too high volumes. A latent eyebrow ptosis can then
no longer be compensated by frontalis muscle
action.
Lip Ptosis and Possible Oral Incompetence
The zygomaticus major and minor originate at or
near the lateral aspect of the superior margin of
the zygomatic arch. Injecting the lateral canthus
may affect the muscle fibres of some of the levators
of the lateral upper lip and the corners of the mouth
which may result in lateral upper lip ptosis and
possible oral incompetence, causing an asymmetric
smile, possible drooling and incontinence. If BTx is
injected or diffuses more medially and inferiorly to
the superior margin of the zygomatic arch, the cen-
tral deep levators can be affected, causing possible
interference with upper lip competence, including
eating and speaking. Injections in this area should
be intradermal and of low volume.
Ectropion, Keratitis
In elderly patients with attenuated orbital septa,
diffusion of BTx into the superior and inferior pal-
pebral portion of the orbicularis occuli may weaken
the lateral tendon, producing lower eyelid ectro-
pion. Prolonged corneal exposure can lead to dry
eye and corneal damage. To avoid this, injections
should be at least 1.0–1.5 cm lateral to the lateral
canthus.
Injecting BTx medial to the midpupillary line of
the lower eyelid or involuntary diffusion of BTx in
the palpebral portion may weaken the sphincteric
function of the palpebral orbicularis occuli, which
may impair forced eyelid closure. Weakening the
blink reflex may diminish the action of the lacrimal
pump and may cause epiphora.56 A snap test is
often recommended prior to injections.
Diplopia
Anatomical considerations mean that it is possible for
there to be accidental migration of BTx to the lateral
and inferior rectus, and to the inferior oblique. Con-
sultation with an ophthalmologist is mandatory.
Complications that Occur Injecting
the Lower Eyelid
In patients who have festooning, pseudoherniation of
the infraorbital fat pad can be worsened by injecting
BTx into the inferior palpebral orbicularis oculi. This
is a particular concern with older patients. This
effect may be due to muscular weakness or lym-
phatic drainage impairment. Flynn et al.57 found no
substantial adverse effects in patients treated with
2 U of Botox® injected pretarsally in the lower eye-
lid, whereas of those patients who had 4 U injected
pretarsally in two divided doses of 2 U each, less than
half suffered from ‘dry eyes’. With 8 U injected pre-
tarsally into the lower eyelid in two divided doses of
4 U, persistent lower lid edema droopy eyebags and
photophobia with difficulty in squinting resulted.
CONCLUSION
Treatment of the facial wrinkles through the use of
BTx-A has revolutionized the treatment of facial
aging since its first application for cosmetic use by
Carruthers and Carruthers in 1992. It represents
one of the most important advances in minimally
invasive techniques for skin rejuvenation, producing
a high degree of patient satisfaction. Moreover, it is
a rapid, non-surgical rejuvenation treatment with
minimal recovery time.
After 20 years of cosmetic use of BTx and with a
large number of published studies suggesting its
efficacy and safety, this treatment has become pop-
ular
and
well-established
around
the
world,
approved by relevant regulatory agencies, such as
the FDA and its counterparts.
Knowledge of muscular anatomy, the physiology
of treatment targets, awareness of potential compli-
cations and appropriate injection technique are keys
to the successful use of BTx.
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central forehead region. Arch Dermatol. 2006;142(3):320–326.
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Aesthetic Oculofacial Rejuvenation

Facial Fillers and Volumizers
Marian Cantisano-Zilkha, Alessandra Haddad
Included on DVD
INTRODUCTION
The aging process is a very complex phenomenon,
engendered by genetically determined intrinsic and
extrinsic factors. Sun exposure with its cumulative
ultraviolet effects, even not related to intrinsic
aging, represents the most important leading cause
of aging of the skin and its undesirable aesthetic
effects. Ultraviolet exposure is aggravated by life-
style and habits, such as cigarette smoking, poor
nutritional practices and chemical exposure to
different pollutants and irritants, which lead to
biological and immunological changes. As a conse-
quence, we see visible and histological signs of skin
aging, such as decreased thickness of the epidermis,
dermis and subcutaneous tissue, which are clinically
manifested by smile lines, crow’s feet and facial
creases. Over the last few decades, soft tissue aug-
mentation using injectable fillers, combined with
other modalities, has become the standard clinical
approach for correcting these age-related defects
(Fig. 9.1).1 Soft tissue fillers can temporarily restore
a smoother, younger-looking skin by helping to fill
in these lines and creases, to recreate symmetry,
volume and a smooth skin surface. The ease of per-
formance, lack of down time and infrequency of
complications have increased the popularity and
patient acceptance of injectable fillers.2
Ideal fillers (SCALES 1953):
v are not modified by liquids or organic tissues
v are chemically inert
v do not cause inflammatory reactions
v are non-carcinogenic or mutagenic
v are capable of resisting to mechanical tensions
v do not produce allergic reactions
v are capable of resisting to mechanical strains
v can be manufactured in different formats
v can be sterilized.
After the decision has been made to perform soft
tissue augmentation, selecting the filling substance
and proper technique are of utmost importance.
However, with so many new products of different
nature and longevity, and so many others waiting
for approval for use in a particular market, it
becomes increasingly important to know the proper-
ties, composition and mechanism of action of each
particular filler, as well as their interactions and tis-
sue responses. None of the currently available fillers
meets all the desired criteria, but, while we still
search for the ideal fillers, hyaluronic acid (HA)
fillers have become the new gold standard in soft
tissue augmentation, fulfilling many of our desired
criteria. Although they are very well tolerated, the
durability of the HA fillers and, to a lesser degree,
collagen fillers varies from several months up to
1–2 years, depending on stabilization
methods,
molecular size and injection site. In contrast, silicone
oil lasts for life and some other synthetic fillers stay
for decades.
Whether they are permanent or temporary, all
fillers have similar application techniques and are
part of the treatment planning for use either alone
or in combination with other modalities. In this
chapter, we will discuss the current and most recent
fillers, FDA and non-FDA approved, their charac-
teristics and skin interactions, different formula-
tions and presentation, best indications (Fig. 9.2),
techniques and complications.
EVOLUTION
The implantation of gold plates to correct cranial
facial defects was first described by Fallopius in
the 16th century.3 The search for the ideal material
for correcting facial skin irregularities has continued
for over 500 years. Many injectable or implantable
substances that are not compatible with the human
skin, or that have been adulterated in their formula-
tion, have been proposed for cosmetically improving
soft tissue defects. Over 100 years ago, autologous
fat was one of the earliest agents used for soft
tissue augmentation.4 Interest in autologous fat has
9

continued, with the development of new and
improved application techniques of structured fat
grafting and microinjections (see Chapter 10).
The original concept of tissue augmentation in
the modern era involved injecting collagen into the
skin. It was believed that the collagen, which has
been used for more than 30 years, would incorpo-
rate into the skin’s own collagen. However, it
turned out that collagen only occupies space. That
concept continued and was recently altered to
include fillers derived from HA, which was also
believed to be a passive filler. As it turned out,
HA does promote a certain degree of fibroblastic
activity.5 During the last decade, the technology of
fillers and volumizers has begun evolving toward
using fillers that would induce hyperplasia and
make filling more efficient and long lasting.
Silicone is the oldest filling material to be used in
the USA. It was first used in 1930. Since1965, both
Orenttreich and associates and Barnett have used it
for nasolabial augmentation, with good cosmetic
results. The FDA has never approved silicone for
cosmetic use.
In the 1950s, Gottlieb developed another dermal
filler (Fibrel®), a gelatin matrix implant that is now
only of historical interest. The principle was to use
a fraction of plasma containing fibrinogen and pro-
thrombin to fill up scars and wrinkles. The mecha-
nism of action was based on the normal coagulation
and wound healing process, resulting in new collagen
formation. Fibrel is no longer available. In 1981, for
the first time, a form of xenogenic agent, bovine
collagen, received FDA approval.6 Although those
bovine collagen-derived fillers had great potential
for hypersensitivity reactions, they had a good safety
record and, therefore, have been the most widely
used agents for the last 30 years. However, their
short duration is a big disadvantage. The HA and
hylan fillers represent a big breakthrough for aug-
mentation technology, and they are among the most
popularly used dermal fillers. Restylane® (Q-Med,
Upsala, Sweden) was the first HA to be approved
in the USA in 2003.7
CLASSIFICATION
There are many different ways to classify fillers and
volumizers, which leads to some degree of confusion.
Traditional fillers have been biodegradable, meaning
that they are absorbed and eliminated from the
body. We will describe the most popular fillers in
detail, according to their properties, tissue interac-
tion, source and longevity, application techniques,
side effects and complications. Since this is a market
that is developing rapidly, there are many fillers wait-
ing for FDA approval and the CE mark in Europe,
which is much less rigorous than in the USA. We
will discuss the most used fillers with biodegradable
and non-biodegradable properties (Table 9.1).
BIODEGRADABLE FILLERS
Collagen Products
For more than 30 years, collagen products have been
the most readily available and widely used injectable
soft fillers for facial rejuvenation. The main idea was
Fig. 9.2 Areas for facial contouring: perioribital
augmentation, glabellar, nasolabial and melomental folds,
chin and jaw line enhancement, nasal defects, malar
enhancement and cheek augmentation.
Younger
Older
Fig. 9.1 The aging face.
98
Aesthetic Oculofacial Rejuvenation

that once injected into the skin the product would be
incorporated into new collagen, producing long-last-
ing correction. This concept was abandoned when it
became apparent that injectable collagen was just a
passive space occupier. Collagen products today
include human combination collagen, cultured colla-
gen, bovine and porcine, and collagen combined with
synthetic and natural substances. Some of them
require skin
pretesting
for
hypersensitivity
and
others do not.
Animal Collagen (Bovine and Porcine) –
Xenogenic
Bovine collagen is made from extracted cow skin
that is highly purified, sterilized and processed into
a liquid form before being used for cosmetic pur-
poses. Because collagen is a protein that is eventu-
ally metabolized by the body, bovine collagen
injections are not permanent. Three variations of
bovine collagen are currently available: Zyderm I,
Table 9.1
Biodegradable and non-biodegradable fillers
Biodegradable
Non-biodegradable
Slowly
biodegradable
Biodegradable with fibroplastic
properties
AcHyal
Aquamid
Radiesse
Radiesse
Alloderm
Artefill (Artesense)
New Fill/Sculptra
Hyaluronic Acid/Hylan fillers
Autologen
Bioplastique
New Fill/Sculptra
Cymetra
Evolution
Bioinblue
Gore-Tex
Dermal grafting
Meta-Crill
Dermaplant
Silicone oil (Adatosil,
Silikon 1000)
Elevess
Softform
Endoplast 50
Fascian
Fat
Human placental
collagen
Hyal system
Isologen
Evolence
Juvederm
NewFill/Sculptra
Belotero
Perlane
Restylane (family)
Reviderm
Surgilift
Teosyal
Cosmoderm/
Cosmoplast
Zyderm/Zyplast
99
Facial Fillers and Volumizers

Zyderm II and Zyplast® (Allergan, Irvine, CA).
They are 95–98% type I collagen, and the remainder
is type III.
Zyderm I, the least concentrated, is available in a
concentration of 35 mg/mL, dispersed in phos-
phate-buffered physiological saline. It is indicated
for superficial rhytids or for layering on top of a
deeper filling agent. It should be placed in the
superficial papillary dermis. As much of Zyderm I
is saline, the treatment area should be overcor-
rected 150–200%.
Zyderm II is more viscous, with a concentration
of 65 mg/mL dispersed in phosphate-buffered
physiological saline. It is recommended for the
treatment of deeper lines and wrinkles with a
deeper placement into the papillary dermis and a
recommended overcorrection of 100–150%. It has
twice the viscosity of Zyderm I. Both contain
0.3% lidocaine (3 mg/mL) to provide local anesthe-
sia at the time of the injection. They are provided in
sterile disposable syringes ready for use and should
be kept refrigerated until usage. Each syringe should
only be used once. Since they are produced from
animal sources, a skin sensitivity test should be per-
formed, at 8 and 4 weeks prior to treatment.
Zyderm I and II last for an average of 3 months,
but some have been reported to last longer.8–10
Zyplast® contains purified bovine dermal glutar-
aldehyde cross-linked collagen in a concentration
of 35 mg/mL because the cross-linkage with glutar-
aldehyde
makes
the
collagen
fibers
stronger.
Zyplast® is indicated for correction of deeper skin
wrinkles and deformities. Since the agent does not
decompose at the same rate as non-cross-linked
collagen, it lasts longer (more than 3 months).
Zyplast® should be injected without overcorrection.
Bovine collagens may be easier to inject in facial
areas, such as lip borders, because they are liquid
and not thick. They may also be less painful for
patients because they are mixed with anesthetics.
Evolence® is a porcine collagen gel implant comp-
osed of 35 mg/mL homogenous Type I collagen that
received FDA approval in June 2008. It is extracted
and purified from porcine tendons, suspended in
phosphate-buffered saline (PBS) and cross-linked
with a technology that uses sugar (ribose) instead of
chemicals – ‘Glymatrix’ technology. This porcine col-
lagen-derived dermal filler is supposed to be less
immunogenic, since the allergenic telopeptides are
removed, making it more compatible with human col-
lagen. No pretesting is necessary.
Evolence® is supplied as single-use 1 cm3 pre-
filled sterile syringe. It is indicated for dermis
correction of moderate-to-deep facial wrinkles and
folds, such as nasolabial folds, and meets the criteria
for correction lasting from 9 to 12 months.11 As
there has been some postinjection granuloma forma-
tion, some doctors do not recommend using it for
lips.12 Patients with a history of dietary porcine
allergy should not use Evolence®. Based on preclin-
ical studies, the use of Evolence® in individual
patients should be limited to 10 mL over a 1-year
period. The safety of injecting greater amounts has
not been established.13
Other Non-FDA-Approved
Xenogenic Collagen
Permacol® (Tissue Science Laboratories, Aldershot,
UK), a porcine dermal–collagen matrix graft, is a
micronized and cross-linked injectable form of the
sheet material used to reconstruct dermal tissue
defects. It is produced in a saline vehicle and is
available in Europe in 2.5 cm3 syringes. It is an
off-label use because it is approved in Europe for
urinary incontinence.
Atelocollagen® (Koken Co. Ltd, Tokyo, Japan) is
a collagen-derived filler from breeds of very young
Australian calves to decrease the risk of transmis-
sion of bovine spongiform encephalitis. It is sup-
plied with 1 cm3/mg cartridges and is injected
with dental syringes. We have not found too much
information on Atelocollagen® in the literature.14
Allogenic Collagen (Synthetic or Cadaveric)
Human synthetic collagen products are derived
from a single human fibroblastic cell culture from
a source other than the recipient. They are purified
and prepared in the form of a buffered saline sus-
pension, with lidocaine being added to reduce the
pain associated with injection. Human synthetic
injectable collagen is similar to bovine collagen in
its properties and durability, and it is used in much
the same way; allergy testing is not required prior
to use. There are currently three FDA-approved
injectable synthetic human collagen products avail-
able in the USA: CosmoDerm1®, CosmoDerm 2®
and Cosmoplast™(Allergan, Irvine,
CA), and
unlike Dermalogen™and Cymetra®, which are
described below, they are not cadaveric.
CosmoDerm 1® and CosmoDerm 2® have the
same indications as the bovine collagens, Zyderm I
and Zyderm II, and similar longevity. CosmoDerm
1® has a concentration of 35 mg/mL and Cosmo-
Derm 2® has a concentration of 65 /mL; they are
100
Aesthetic Oculofacial Rejuvenation

not recommended for individuals who have severe
allergies that include a history of anaphylaxis to
bovine or other collagen products.
Cosmoplast™is a concentration of 35 mg/mL of
human-derived collagen, which is cross-linked with
glutaraldehyde and recommended for correcting
deeper wrinkles – the FDA approved both Cosmo-
Derm® and Cosmoplast™on March 11, 2003.
They do not require a pretreatment skin test.
Because of the flow characteristics and lidocaine
content of the cell culture collagen products, there
may be some practical advantages to combining
these products with HA injections. For instance,
using Cosmoplast™to first outline upper lip bor-
ders may facilitate augmentation of the body of
the lip with Restylane®.
Cadaveric collagen products are allograft materials
that are derived from tissue banks and subject to
FDA screening for transmissible diseases. Cadaveric
collagen products are tightly regulated by the FDA,
as is other donated tissue. They are intact human col-
lagen fibers or acellular dermal matrix from cadavers
for human implants. There are three products: Allo-
derm®, Cymetra® and Dermalogen™.
Alloderm® and Cymetra® (LifeCell Corporation,
Branchburg, NJ) are approved by the FDA for
cosmetic corrective use. They are harvested from
donated and acellular human donor tissue, freeze
dried and processed to eliminate infections, and
available from most tissue banks. Alloderm is indi-
cated for transplantation to repair dermal tissue
and is widely used to treat full-thickness burns as
well as soft tissue augmentation. It requires surgical
implantation. Cymetra® is a micronized form of
Alloderm® that is more suitable for injection. Both
Alloderm® and Cymetra® are rehydrated with
saline solution or lidocaine in the physician’s office
1 hour prior to injection. Cymetra® is injected deep
into the dermis for lip augmentation and to treat
rhytids and scars. Since the material is still viscous
and generally requires a 23–26-gauge needle for
injection, regional blocks are recommended. The
manufacturer does not require pretesting for aller-
gies, but 2.1% of patients develop temporary local
reactions.15 Host tissue incorporation, with fibro-
blast in-growth, and collagen deposition are seen 1
month after implantation.16 Cymetra® has been
contraindicated in patients with history of auto-
immune connective disorder.
Dermalogen™(Collagenesis, Beverly, MA) is
another injectable human dermal implant material
made from a suspension of pooled human cadaver
collagen.17 It is the allogenic version of Autologen
(discussed below). Apparently, development of
new collagen and neovascularization is possible, but
it is a long process requiring many sessions and is
very expensive. Although they are, theoretically,
non-immunogenic and incapable of potential allergic
reactions, these cadaveric agents have lost their ini-
tial appeal, and the two injectable forms (Cymetra®
and Dermalogen™) are no longer available.
Autologous Collagen
Although autologous human collagen is derived
from the patient’s own collagen, this is still techni-
cally difficult to produce with consistency and with
adequate volume. These products are ideal because
there is no immunological response and less chance
of infectious complications.
Autologen™(Collagenesis Inc., Beverly, MA) is
collagen
harvested
and
reformulated
from
the
patient’s own skin so allergic reactions are considered
impossible. Theoretically, it should last longer than
other biological fillers. The patient’s own skin is har-
vested during a previous procedure – such as blepha-
roplasty, facelift or another operation in which skin
is removed – and sent to a commercial laboratory
where the collagen is extracted, sterilized and
prepared for reinjection. The amount of collagen
available for injection is limited by the amount of
skin removed and the quality of the skin. A total
of two to four injections of Autologen may be per-
formed at 1–3-month intervals. If not needed, the
remaining processed liquid collagen can be stored
for 5 years. Autologen™injections seem to last
longer than bovine collagen injections, but longevity
varies. Unfortunately, the company manufacturing
Autologen™is no longer in business.
Isolagen® (Isolagen Inc., Houston, TX) is another
autologous collagen that has been temporarily taken
off the market pending FDA approval. It is com-
posed of injectable autologous fibroblasts cultured
for 4–6 weeks from a 3 mm punch biopsy taken
from postauricular skin. Like Autologen™, the
patient’s own collagen is harvested, purified and
packaged in a suspension for injection into the skin.
A minimum of three injections, given at 2-week
intervals, is recommended. A 70% improvement
can be expected following the third injection and,
because live cells are used, improvement may con-
tinue for several months after the last injection.
Because the material is from the patient’s body, little
risk of allergic response exists. Phase III clinical
trials are taking place, for FDA approval. Research
has shown it to be effective, and it can last for up
101
Facial Fillers and Volumizers

to 4 years.18 Several other autologous and allogenic
collagen products have been intermittently avail-
able. They initially require multiple injection ses-
sions
to
attain
an
acceptable
result
and
the
residence time is limited.
Recombinant Collagen
Recombinant collagen is still in initial FDA trial
phases, for non-cosmetic applications.
Collagen combined with different materials is
discussed under non-biodegradable fillers (Artefill®,
FDA approved since 2005, and its precursor Arte-
coll®) (Table 9.2).
HYALURONIC ACID AND HYALURONANS
HA is a naturally occurring substance found in the
skin and connective tissues of all mammals that plays
an important role in keeping tissue lubricated.
Because it is a uniform, unbranched linear polysaccha-
ride with a simple chemical structure that is identical
in all species and tissues, it can be considered an ideal
biomaterial.19 HA supports collagen and elastin fibers
and helps retain moisture to give skin its characteristic
texture. To produce a gel suitable for use as an inject-
able filler, HA is chemically modified by cross-linking
the molecules. It can be used to fill out facial lines and
remove wrinkles, and for soft tissue augmentation,
such as lip plumping (Fig. 9.3). Injectable HA fillers
remove wrinkles immediately, and the results last
longer than other biodegradable fillers. Because HA is
a natural substance, hyaluronic fillers are associated
with fewer hypersensitivity reactions than other colla-
gen products.20 Although they can be either animal
based or non-animal based, no pretreatment skin test-
ing is required. Most of the HA preparations are
synthesized by bacteria, purified and cross-linked to
provide a variety of viscosities for injection. The
FDA has approved Restylane®, Perlane®, Captique®,
Juve´derm™, Hylaform®, Hylaform Plus® and Ele-
vess® HA gels for use in the USA. With the exception
of Hylaform® and Hylaform Plus®, which are derived
from the rooster combs, they are all non-animal
stabilized HA (NASHA™) fillers.
Recent studies have shown that HAs also induce a
certain degree of fibroplasias.5 To minimize the prob-
ability of protein impurities bound to the entangled
HA, they are biosynthesized from a non-animal
source and stabilized with relatively few cross-links
in a continuous three-dimensional molecular network
to create a gel that can take any form or shape.21
The longevity of the HA products depends on the
size of the gel particle, the concentration, the area to
Table 9.2
US FDA approved collagens
Type
Collagen
concentration
Indication
Volume
(cc)
Placement
Overcorrection
Year
approval
Zyderm I
35 mg/mL
bovine
Fine superficial
lines
0.5,
1.0,1.5
Superficial
papillary
dermis
150–200

1981
Zyderm II
65 mg/mL
bovine
Mild/moderate
rhytids, scars
0.5, 1.0
Mid dermis
100
150

1983
Zyplast
35 mg/mL
bovine (cross-
linked
glutaraldehyde)
Deep lines and
folds
1.0, 2.0,
2.5
Deep
dermis
None
1985
CosmoDerm1
35 mg/mL
human derived
Fine/superficial
rhytids
1.0
Superficial
papillary
dermis
150–200

2003
CosmoDerm2
65 mg/mL
human derived
Mild/moderate
rhytids, scars
0.5, 1.0
Mid-dermis
100–150
2005
CosmoPlast
35 mg/mL
human derived
Deeper rhytids
and folds
1.0
Deep
dermis
None
2003
Evolence
30 mg/mL
porcine derived
Fine to mild
wrinkles
1.0
Mid dermis
None
2008
Cosmoderm, Cosmoplast and Evolence: no pretesting necessary
102
Aesthetic Oculofacial Rejuvenation

be injected and the presence of inflammation in the
area. In healthy tissue, the extracellular capacity to
degrade HA (into carbon dioxide and water) is
extremely low. Because the molecule is extremely
hydrophilic and the amount of HA in the gel bead
is about five times larger than needed to maintain
its volume, NASHA™gels will remain approxi-
mately the same size and shape despite continuous
degradation. The excess material allows the gel bead
to last longer, a process called isovolemic degrada-
tion. The limited cross-linking allows for significant
ability to absorb water and maintain volume.21 HAs
are hyaluronans, whether or not they are derived
from bacterial fermentation or an animal.
Restylane® (Q-Med, Upsala, Sweden or, in the
USA, Medicis, Scottsdale, AZ) was the first HA
to receive USA FDA approval, in December 2002.
For many, it is considered the ‘ideal filler.’ It has
20 mg/mL of HA with a gel bead size of 250 mm
and 100 000 units per mL. Restylane® is indicated
for fine and moderate lines and wrinkles, and for
lip augmentation and tear trough defect repair.22
The authors have used HA to reshape nasal defor-
mities while a patient was contemplating corrective
rhinoplasty (Fig. 9.4). All the Restylane® products
have a concentration of 20 mg/cm3, but the particle
size varies. It is dispensed in a 1.0 cm3 and 0.5 cm3
prepacked syringe, with a 30-gauge
1.5-inch-long
needle. Restylane Fine Lines® has 20 mg/mL of HA
with a gel bead size of 100 mm and 200 000 units
per mL. It is good for very fine perioral lines and
temporary correction of double Asian eyelid creases
(Fig. 9.5), with great patient satisfaction level and
instant gratification. Restylane Lipp® was designed
for the vermilion border of the lip or to create more
volume. Restylane SubQ® is the thickest version of
the Restylane® family with cosmetic indication. It is
a volumizer, with 1000 gel particles per milliliter.
Perlane® (Q-Med, Upsala, Sweden), which gained
USA FDA approval in 2006, has 20 mg/mL of HA
A
B
Fig. 9.3 A, Before Restylane® injection for lip augmentation on the vermilion border and on the ‘body’ of the lip. B, After
Restylane® injection for lip augmentation on the vermilion border and on the ‘body’ of the lip.
A
B
Fig. 9.4 A, Double eyelid crease on Asian eyelid. B, Immediately after Restylane® injection there is bilateral eyelid
symmetry.
103
Facial Fillers and Volumizers

with a gel bead size of 1000 mm and 10 000 units per
milliliter. It is dispensed in a 1.0 cm3 and 0.5 cm3
prepacked syringe, with a 27-gauge
1.5-inch long
needle. It is indicated for deeper defects and for
broader areas such as nasolabial folds, malar enhance-
ment and other facial irregularities.
Captique® (Genzyme and Allergan, Irvine, CA)
received FDA approval for cosmetic use in August
2004. It is a product derived from bacterial fermen-
tation (non-animal) HA. Captique® is plant based.
No pretest is needed. Captique® is a clear gel that
is indicated for injection into the mid-to-deep der-
mis for correction of moderate-to-severe wrinkles.
Juve´derm™(Genzyme, Framingham, MA, and
distributed by Allergan, Irvine, CA) was approved
by the FDA in June 2006 for treating facial wrinkles
and folds.23 It is developed by bacterial fermenta-
tion and differs from the other HA products
because it is a homogeneous gel, with the highest
concentration of cross-linked HA (above 90%) of
any dermal filler currently available. According to
the manufacturer, because of its soft consistency,
Juve´derm creates a smooth, natural look and a feel
that lasts longer, and requires fewer touchups fol-
lowing the initial treatment. In Europe, Juve´derm™
is available in five formulations: Juve´derm™18, 24,
24 HV, 30 and 30 HV. HV indicates a higher
viscosity and a greater degree of cross-linking for that
product. They all have a concentration of 24 mg/mL
of HA and are differentiated by the degree of
cross-linking. The FDA approved three formulations
for Juve´derm™, offering physicians the flexibility
to tailor treatments to the particular needs of each
patient. They are Juve´dermUltra™24 HV, recom-
mended
for
contouring
and
volumizing
facial
wrinkles and folds; Juve´dermUltra Plus™30 HV,
recommended for deeper folds and wrinkles; and
Juve´derm 30™, for subtle correction of facial wrin-
kles and for lip augmentation (Fig. 9.6) and folds.
Elvess® (Anika Therapeutics Inc., Woburn, MA)
was approved by the FDA in December 2006. It is a
sterile, non-pyrogenic gel implant, composed of hya-
luronan produced by Streptococcus equi (bacterial fer-
mentation), which is cross-linked and suspended in a
buffer solution at a concentration of 28 mg/mL, with
0.3% lidocaine HCl, and contains sodium metabisul-
fite as an antioxidant. It is indicated for injection
into the mid-to-deep dermis for the correction of
moderate-to-severe facial wrinkles and folds (such as
nasolabial folds). It is contraindicated for patients
with a history of allergies to sulfites (although rare)
or for patients with severe allergies manifested by a
history of anaphylaxis. It is the only HA filler to have
local anesthetic in its formulation.24
Hylaform®
and
Hylaform
Plus®
(Allergan,
Irvine, CA) are sterile, non-pyrogenic, viscoelastic,
A
B
Fig. 9.6 A, Before Juvederm™injection on vermilion border and ‘body’ of upper lip. Courtesy Dr Yoannis Glavas.
B, Immediately after Juvederm™injection.
Fig. 9.5 Technique of injection very superficially on the
double crease with the purpose of camouflaging the
crease and giving instant gratification to a very common
Asian eyelid problem.
104
Aesthetic Oculofacial Rejuvenation

transparent gel implants composed of cross-linked
molecules
of
hyaluronan.
(These
products
are
derived from minced rooster combs, which consist
predominantly of HA, and may contain avian pro-
tein.) In theory, this extraction technique could
subject them to a higher level of impurities or con-
taminants. Although no allergy tests are needed
before treatment with these products, individuals
with avian allergies may not be good candidates.
In their composition, they have 5.5 mg/mL of
HA and 20% cross-linking. Hylaform Plus®, which
is used much like Perlane®, has a larger gel particle
and is more viscous than Hylaform®, which is used
much like Restylane®. No long-term studies have
been conducted to determine the longevity of these
products, but it appears to be less than that of
Restylane® and Perlane®.21
Hylaform® was approved in April 2004 to cor-
rect superficial defects and fine wrinkles, and lasts
for 6–8 months. Hylaform Plus® was approved in
October 2004 to correct moderate-to-severe irregu-
larities and folds and has an average duration of 8–9
months.
HA, derived from rooster combs (Biomatrix,
Inc., Ridgefield, NJ), has been used for almost three
decades by ophthalmic surgeons during intraocular
procedures. One of the authors (MCZ) participated
in its early development with Dr Stephen Bosniak
(NY, NY) in the reconstruction of sockets of owl
monkeys that had become disfigured in fights while
in captivity. It was used to enhance and replace
volume in the reconstructive and cosmetic areas
during unpublished Hylan B gel monkey studies,
conducted from 1990 to 1995 (Figs 9.7 and 9.8).
It is contraindicated for both monkeys and humans
with a history of hypersensitivity to avian protein.
There are many more fillers approved in Europe
and South America than there are in the USA.
Following are a few HA products that are not
approved for use in the USA.
Belotero® or Esthelis® (Anteis, Switzerland) is a
monophasic, non-cross-linked HA that is marketed
in some countries in Europe. Designed by HA
biofermentation, it is completely biodegradable
and biocompatible. It is created using Cohesive
Polydensified Matrix®, a technology that gives this
product great elasticity and easy flow through the
needle. It is available in two forms. Belotero Basic®
is meant for treating deeper furrows, lip augmenta-
tion, facial outlines, nasolabial folds, glabellar lines
and facial depressions. Belotero Soft® is designed
to treat perioral lines, lip commissures and forehead
wrinkles.
Fig. 9.7 Owl monkey.
A
Fig. 9.8 Macroscopic and microscopic specimen of
superior sulcus of owl monkeys. The superior orbital sulcus
had been injected and reconstructed with cross-linked HA
while in captivity in 1990–1995, Biomatrix, Ridgefield, NJ,
in preliminary studies of Hyalan B gel as an injectable for
socket reconstruction and wrinkle softening. Material still
present after 1 year of injection, no inflammatory reaction.
It camouflages the crease and gives instant gratification
to a very common Asian eyelid problem. Courtesy of
Dr Stephen Bosniak and Dr Marian Zilkha.
105
Facial Fillers and Volumizers